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HAZZARD’S
GERIATRIC MEDICINE
AND GERONTOLOGY
Notice
Medicine is an ever-changing science. As new research and clinical experience broaden our knowledge, changes in
treatment and drug therapy are required. The authors and the publisher of this work have checked with sources believed
to be reliable in their efforts to provide information that is complete and generally in accord with the standards accepted
at the time of publication. However, in view of the possibility of human error and changes in medical sciences, neither
the editors nor the publisher nor any other party who has been involved in the preparation or publication of this
work warrants that the information contained herein is in every respect accurate or complete, and they disclaim all
responsibility for any errors or omissions or for the results obtained from use of the information contained in this
work. Readers are encouraged to confirm the information contained herein with other sources. For example and in
particular, readers are advised to check the product information sheet included in the package of each drug they plan
to administer to be certain that the information contained in this work is accurate and that changes have not been
made in the recommended dose or in the contraindications for administration. This recommendation is of particular
importance in connection with new or infrequently used drugs.
HAZZARD’S GERIATRIC MEDICINE
AND GERONTOLOGY
Sixth Edition
EDITORS
JEFFREY B. HALTER, MD
Professor of Internal Medicine
Chief, Division of Geriatric Medicine
Director, Geriatrics Center and Institute of Gerontology
University of Michigan
Ann Arbor, Michigan
JOSEPH G. OUSLANDER, MD
Professor and Associate Dean for Geriatric Programs
Charles E. Schmidt College of Biomedical Science
Professor (Courtesy), Christine E. Lynn College of Nursing
Florida Atlantic University
Professor of Medicine (Voluntary)
Division of Gerontology and Geriatric Medicine
University of Miami Miller School of Medicine
Boca Raton, Florida
MARY E. TINETTI, MD
Gladys Phillips Crofoot Professor of Medicine, Epidemiology, and Public Health
Director, Program on Aging
Yale University School of Medicine
New Haven, Connecticut
STEPHANIE STUDENSKI, MD, MPH

Professor, Department of Medicine (Geriatrics)
University of Pittsburgh
Staff Physician, VA Pittsburgh GRECC
Pittsburgh, Pennsylvania
KEVIN P. HIGH, MD, MS

Professor of Medicine, Sections on Infectious Diseases,
Hematology/Oncology and Molecular Medicine
Chief, Section on Infectious Diseases
Wake Forest University Health Sciences
Winston-Salem, North Carolina
SANJAY ASTHANA, MD
Duncan G. and Lottie H. Ballantine Chair in Geriatrics
Professor and Head, Section of Geriatrics & Gerontology
University of Wisconsin School of Medicine and Public Health
Director, Geriatric Research, Education and Clinical Center (GRECC)
William S. Middleton Memorial Veterans Hospital
Associate Director, Wisconsin Alzheimer’s Institute
Madison, Wisconsin
EDITOR EMERITUS AND SENIOR ADVISOR

WILLIAM R. HAZZARD, MD
Professor of Medicine
University of Washington
Director, Geriatrics and Extended Care
VA Puget Sound Health Care System
Seattle, Washington
SENIOR EDITORIAL ASSISTANT

NANCY F. WOOLARD
Winston-Salem, North Carolina
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Contents
Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix
Part II
Foreword . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xxv
PRINCIPLES OF GERIATRICS
Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xxvii
10. Evaluation, Management, and Decision Making
Part I with the Older Patient . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
PRINCIPLES OF GERONTOLOGY Sharon E. Strauss and Mary E. Tinetti
1. Biology of Aging and Longevity . . . . . . . . . . . . . . . . . . . . . 3 SECTION A Assessment

Richard A. Miller
11. Principles of Geriatric Assessment . . . . . . . . . . . . . . . . . . 141
2. Genetics of Age-Dependent Human Disease . . . . . . . . . 15
David B. Reuben and Sonja Rosen
Thomas B. L. Kirkwood
12. Mental Status and Neurological Examination in
3. Immunology and Aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Older Adults . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153
Birgit Weinberger, Daniela Weiskopf,
James E. Galvin
and Beatrix Grubeck-Loebenstein
13. Assessment of Decisional Capacity and
4. Inflammation and Aging . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
Jeremy D. Walston Competencies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171
Margaret A. Drickamer and James M. Lai
5. Demography and Epidemiology . . . . . . . . . . . . . . . . . . . . 45
Jack M. Guralnik and Luigi Ferrucci 14. Principles of Screening in Older Adults . . . . . . . . . . . . . 177
Louise C. Walter
6. International Gerontology . . . . . . . . . . . . . . . . . . . . . . . . . 69
Roberto Bernabei, Len Gray, John Hirdes, Xiaomei Pei,
Jean Claude Henrard, Palmi V. Jonsson, Graziano Onder, SECTION B Organization of Care
Giovanni Gambassi, Naoki Ikegami, Annette Hylen Ranhoff, 15. Health Care System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185
Iain G. Carpenter, Rowan H. Harwood, Brant E. Fries, Chad Boult
John N. Morris, and Knight Steel 16. Transitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197
7. Psychosocial Aspects of Aging . . . . . . . . . . . . . . . . . . . . . . 97 William L. Lyons and Eric A. Coleman
Richard Schulz and Steven M. Albert 17. Acute Hospital Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209
8. General Principles of Pharmacology . . . . . . . . . . . . . . . 103 Scott A. Flanders, Paula M. Podrazik, Chad Whelan,
Sarah N. Hilmer and Gary A. Ford and Caroline Blaum
9. Preventive Gerontology: Strategies for Optimizing 18. Emergency Department Care . . . . . . . . . . . . . . . . . . . . . . . 221
Health Across the Life Span . . . . . . . . . . . . . . . . . . . . . . . 123 Scott T. Wilber and Lowell W. Gerson
Elizabeth A. Phelan, Miguel A. Paniagua, and 19. Critical Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229
William R. Hazzard Eric B. Milbrandt and Derek C. Angus
v
vi Contents
20. Subacute Care. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .237 41. Disorders of Swallowing . . . . . . . . . . . . . . . . . . . . . . . . . . . 483

Edward R. Marcantonio and Mark Yurkofsky JoAnne Robbins, Jacqueline Hind, and Steven Barczi
21. Nursing Facility Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251 42. Oral Cavity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 501
Mary Pat Rapp and Keith L. Rapp Jonathan A. Ship
22. Community-Based Long-Term Care and
Home Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275
Jennifer Hayashi and Bruce Leff SECTION F Sensory Function
23. Rural Aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .283 43. Assessment and Rehabilitation of Older Adults
Kenneth Brummel-Smith with Low Vision . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 511
Gale R. Watson
44. Age-Related Changes in the Auditory System . . . . . . . . 525
SECTION C Special Management Issues
Su-Hua Sha, Andra E. Talaska, and Jochen Schacht
24. Appropriate Approach to Prescribing . . . . . . . . . . . . . . . 289
Paula A. Rochon, Jennifer Tjia, Sudeep S. Gill, and
Jerry H. Gurwitz
SECTION G Gender and Sexuality
25. Complementary and Alternative Medicine . . . . . . . . . . . 303
45. Sex and Gender Across the Human Life Span . . . . . . . . 535
Joseph T. Hanlon, Marc R. Blackman, and Ronald M. Glick
William R. Hazzard
26. Team Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309
46. Menopause and Midlife Health Changes . . . . . . . . . . . . 557
Ellen Flaherty, Kathryn Hyer and Terry Fulmer
MaryFran R. Sowers
27. Social Work . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .317
47. Sexuality, Sexual Function, and the Aging Woman . . . 567
Ruth E. Dunkle and Mary Catherine Dennis
Stacy Tessler Lindau
28. Self-Management of Health Behavior in Geriatric
48. Gynecologic Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 583
Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325
Karen L. Miller and Tomas L. Griebling
W. Jack Rejeski, Lawrence R. Brawley, and Mary E. Jung
49. Sexuality, Sexual Function, Androgen Therapy,
29. Rehabilitation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343
and the Aging Male . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 595
Cynthia J. Brown and Claire Peel
J. Lisa Tenover
30. Pain Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 359
50. Benign Prostate Disorders . . . . . . . . . . . . . . . . . . . . . . . . . 607
Bruce A. Ferrell and Susan L. Charette
Catherine E. DuBeau
31. Palliative Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 373
Audrey Chun and R. Sean Morrison
32. Legal Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 385
Marshall B. Kapp Part III
33. Spirituality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393 GERIATRIC SYNDROMES
Timothy P. Daaleman
34. Ethical Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 399 51. Aging and Homeostatic Regulation . . . . . . . . . . . . . . . . . 621
Jason H. T. Karlawish and Bryan D. James George A. Kuchel
52. Frailty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 631
Linda P. Fried, Jeremy D. Walston, and Luigi Ferrucci
SECTION D Surgical Management 53. Delirium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 647
35. Perioperative Evaluation and Management . . . . . . . . . . 407 Sharon K. Inouye, Michael A. Fearing, and
Preeti N. Malani, Peter V. Vaitkevicius, and Edward R. Marcantonio
Mark B. Orringer 54. Falls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 659
36. Anesthesia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 417 Mary B. King
Jeffrey H. Silverstein and G. Alec Rooke 55. Sleep Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 671
37. Surgical Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 431 Mairav Cohen-Zion and Sonia Ancoli-Israel
Emily Finlayson and John D. Birkmeyer 56. Dizziness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 683
Aman Nanda and Richard W. Besdine
57. Syncope . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 693
SECTION E Nutrition Rose Anne Kenny
38. Nutrition and Aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 439 58. Pressure Ulcers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 703
Dennis H. Sullivan and Larry E. Johnson Barbara M. Bates-Jensen
39. Weight and Age: Paradoxes and Conundrums. . . . . . . .459 59. Incontinence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 717
Tamara B. Harris Theodore M. Johnson II and Joseph G. Ouslander
40. Malnutrition and Enteral/Parenteral Alimentation . . . 469 60. Elder Mistreatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 731
Jeffrey I. Wallace Mark S.Lachs
Contents vii
81. Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 975

Part IV
Mark A. Supiano
ORGAN SYSTEMS AND DISEASES
SECTION A Human Brain

SECTION C Respiratory System
61. Cellular and Neurochemical Aspects of the
82. Aging of the Respiratory System . . . . . . . . . . . . . . . . . . . . 983
Aging Human Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 739
Paul L. Enright
Mark P. Mattson
83. Chronic Obstructive Pulmonary Disease . . . . . . . . . . . . 987
62. Cognitive Changes Associated with Normal and
Sachin Yende, Anne B. Newman, and Don Sin
Pathological Aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 751
84. Diffuse Parenchymal Lung Disease . . . . . . . . . . . . . . . . 1003
Suzanne Craft, Brenna Cholerton, and Mark Reger
Victor J. Thannickal and Galen B. Toews
63. Psychoactive Drug Therapy . . . . . . . . . . . . . . . . . . . . . . . . 767
Bruce G. Pollock, Todd P. Semla,
and Christina E. Forsyth
SECTION D Nephrology
64. Cerebrovascular Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . 779
85. Changes in Kidney Function . . . . . . . . . . . . . . . . . . . . . . 1009
Eric Edward Smith, Ferdinand Buonanno, Aneesh Bhim
Jocelyn Wiggins and Sanjeevkumar R. Patel
Singhal, and J. Philip Kistler
86. Renal Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1017
65. Dementia Including Alzheimer’s Disease . . . . . . . . . . . . 797
Lynn Schlanger, Jeff M. Sands, and James L. Bailey
Cynthia M. Carlsson, Carey E. Gleason, Luigi Puglielli,
and Sanjay Asthana 87. End-Stage Renal Disease . . . . . . . . . . . . . . . . . . . . . . . . . . 1035
Mark L. Unruh
66. Parkinson’s Disease and Related Disorders . . . . . . . . . . . 813
Stanley Fahn 88. Disorders of Fluid Balance . . . . . . . . . . . . . . . . . . . . . . . . 1047
Myron Miller
67. Other Neurodegenerative Disorders . . . . . . . . . . . . . . . . . 823
Victor Valcour and Bruce Miller
68. Traumatic Brain Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . 833
SECTION E Gastroenterology
Sterling C. Johnson
89. Effect of Aging on Gastrointestinal Function . . . . . . . 1059
69. Epilepsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 841
Karen E. Hall
Ilo E. Leppik
90. Hepatic, Biliary, and Pancreatic Disease . . . . . . . . . . . . 1065
70. Late-Life Mood Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . 849
Justin C. Rice, Courtney Barancin, Mark Benson, and
Dan G. Blazer
Michael Lucey
71. Schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 859
91. Upper Gastrointestinal Disorders . . . . . . . . . . . . . . . . . . 1075
Danielle L. Anderson and Peter V. Rabins
Alberto Pilotto and Marilisa Franceschi
72. General Topics in Geriatric Psychiatry . . . . . . . . . . . . . . 865
92. Common Large Intestinal Disorders . . . . . . . . . . . . . . . 1091
Mustafa M. Husain, Shawn M. McClintock, Kip E.
Leon S. Maratchi and David A. Greenwald
Queenan, Aaron Van Wright, and Rajbir Bakshi
93. Constipation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1103
73. Management of Agitation in Dementia . . . . . . . . . . . . . . 873
Danielle Harari
Marcella Pascualy, Eric Petrie, Lucy Y. Wang,
Suzanne B. Murray, and Elaine Peskind
SECTION F Oncology
SECTION B Cardiology
94. Oncology and Aging: General Principles . . . . . . . . . . . 1123
74. Effects of Aging on Cardiovascular Structure Arati V. Rao and Harvey Jay Cohen
and Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 883 95. Breast Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1137
Dalane W. Kitzman and George Taffet Gretchen G. Kimmick and Hyman B. Muss
75. Aging and Atherosclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . 897 96. Prostate Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1149
Susan Cheng, Susan M. Bell, and Susan J. Zieman Kenneth J. Pienta
76. Coronary Heart Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . 909 97. Lung Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1159
Eric D. Peterson and Shahyar M. Gharacholou Daniel Morgensztern, Ramaswamy Govindan, and
77. Valvular Heart Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 921 Michael C. Perry
Nikhila Deo and Niloo M. Edwards 98. Gastrointestinal Malignancies . . . . . . . . . . . . . . . . . . . . . 1167
78. Heart Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 931 Nadine A. Jackson and Peter C. Enzinger
Michael W. Rich 99. Intracranial Neoplasms . . . . . . . . . . . . . . . . . . . . . . . . . . . 1177
79. Cardiac Arrhythmias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 951 Noelle K. LoConte, Julie E. Chang, and H. Ian Robins
Xiao-Ke Liu, Arshad Jahangir, and Win-Kuang Shen 100. Skin Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1183
80. Peripheral Vascular Disease . . . . . . . . . . . . . . . . . . . . . . . . 967 Mathew W. Ludgate, Timothy M. Johnson, and
Andrew W. Gardner, John D. Sorkin, and Azhar Afaq Timothy S. Wang
viii Contents
SECTION G Hematology 116. Osteoarthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1411

101. Aging of the Hematopoietic System . . . . . . . . . . . . . . . . 1193 Shari M. Ling and Yvette L. Ju
Gurkamal S. Chatta and David A. Lipschitz 117. Osteoporosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1421
102. Anemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1201 Gustavo Duque and Bruce R. Troen
Paulo H. M. Chaves 118. Hip Fractures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1435
103. White Cell Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1215 Ram R. Miller, Colleen Christmas,
Heidi D. Klepin and Bayard L. Powell and Jay Magaziner
104. Non-Hodgkin’s and Hodgkin’s Lymphomas and 119. Myopathy, Polymyalgia Rheumatica, and
Myeloma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1229 Temporal Arteritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1445
William B. Ershler and Dan L. Longo Yuri R. Nakasato and Bruce A. Carnes
105. Thrombosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1243 120. Rheumatoid Arthritis and Other Autoimmune
Martin O’Donnell, Jeffrey S. Ginsberg, and Clive Kearon Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1453
106. Hemorrhagic Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . 1253 Raymond Yung
Julia A. M. Anderson and Agnes Y. Y. Lee 121. Back Pain and Spinal Stenosis . . . . . . . . . . . . . . . . . . . . . 1471
Leo M. Cooney, Jr.
122. Primary Considerations in Managing the Older
SECTION H Endocrinology and Metabolism Patient with Foot Problems . . . . . . . . . . . . . . . . . . . . . . . 1479
107. Aging of the Endocrine System and Selected Arthur E. Helfand
Endocrine Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1267 123. Fibromyalgia and Myofascial Pain Syndromes . . . . . . 1491
David A. Gruenewald and Alvin M. Matsumoto Cheryl D. Bernstein and Debra K. Weiner
108. Thyroid Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1287
Jerome M. Hershman, Sima Hassani, and Mary H. Samuels
SECTION J Infectious Diseases and
109. Diabetes Mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1305
Immunology
Annette M. Chang and Jeffrey B. Halter
124. Infection in the Elderly . . . . . . . . . . . . . . . . . . . . . . . . . . . 1507
110. Dyslipoproteinemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1325
Kevin P. High
Leslie I. Katzel, Jacob Blumenthal, John D. Sorkin, and
Andrew P. Goldberg 125. General Principles of Antimicrobial Selection . . . . . . 1517
Maureen Bolon and Stephen G. Weber
111. Hyperparathyroidism and Paget’s Disease of Bone . . 1343
Kenneth W. Lyles 126. Pneumonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1531
Thomas J. Marrie
127. Urinary Tract Infections . . . . . . . . . . . . . . . . . . . . . . . . . . 1547
SECTION I Mobility and Musculoskeletal Lindsay E. Nicolle
System 128. Human Immunodeficiency Virus Infection . . . . . . . . . 1561
112. Aging of the Muscles and Joints . . . . . . . . . . . . . . . . . . . 1355 Amy C. Justice
Richard F. Loeser, Jr. and Osvaldo Delbono 129. Herpes Zoster . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1567
113. Biomechanics of Mobility . . . . . . . . . . . . . . . . . . . . . . . . . 1369 Jack I. Twersky and Kenneth Schmader
James A. Ashton-Miller and Neil B. Alexander 130. Influenza and Respiratory Syncytial Virus . . . . . . . . . . 1577
114. Exercise: Physiologic and Functional Effects . . . . . . . . 1381 Mark B. Loeb
Robert S. Schwartz and Wendy M. Kohrt
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1583
115. Mobility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1397
Jennifer Brach, Caterina Rosano, and Stephanie Studenski Color Plate appears between pages 772 and 773.
Contributors
INTERNATIONAL ADVISORY BOARD
Australia Professor Leonard C. Gray, MD, PhD, Ireland Rose Anne Kenny, MD, FRCPI, FRCP
FRACP Professor, Geriatric Medicine/Consultant
Professor in Geriatric Medicine Medical Gerontology
Department of Medicine Trinity Centre, St. James Hospital
University of Queensland Trinity College Dublin, College Green
Princess Alexandra Hospital Dublin, Ireland
Woolloongabba, Australia
Brazil Renato Maia Guiaraes, MD, MSc Israel A. Mark Clarfield, MD, CCFP, FRCPC
President, International Association of Sidonie Hecht Professor of Gerontology
Gerontology and Geriatrics Faculty of Health Sciences
Director, Geriatric Medical Centre Ben Gurion University
Hospital Universitario de Brasilia Department of Geriatrics
Brasilia, Brazil Soroka Hospital
Beersheva, Israel
China Wu Wei-kang, MD
Professor and Director
Institute of Integrated Traditional Chinese
Italy Roberto Bernabei, MD
and Western Medicine
Sun Yat-sen University
Dipartimento di Scienze Gerontologiche-
Guangzho, China
Geriatriche e Fisiatriche
Universita Cattolica del Sacro Cuore
France Bruno Vellas, MD
Roma, Italy
President Elect, International Association
of Gerontology and Geriatrics
Chief, Department of Internal Medicine Japan Naoki Ikegami, MD, PhD
and Geriatrics Professor and Chair of Health Policy and
Chief, Alzheimer’s Disease Clinical Management
Research Centre Keio School of Medicine
Toulouse University Hospital Keio, Japan
Toulouse, France
Iceland Palmi V. Jonsson, MD, FACP Netherlands Professor Doctor Rudi G. J. Westendorp
Professor and Chief of Geriatrics Department of Gerontology and Geriatrics
Landspitali University Hospital Department of Clinical Epidemiology
University of Iceland School of Medicine Leiden University Medical Center
Reykjavik, Iceland Leiden, The Netherlands
ix
x Contributors
Spain Dr. Francisco Javier Ortiz Alonso Switzerland Dr. Jean-Pierre Michel
Associate Professor in Health Sciences Professor of Medicine
Departamento de Medicina Chair of Rehabilitation and Geriatrics
Universidad Complutense de Madrid University of Geneva Medical School
Chief Geriatric Section Geneva University Hospitals - Geriatric
Hospital General Universitario Gregorio Department
Maranon Geneva, Switzerland
Madrid, Spain
Sweden Professor Bengt Winblad, MD, PhD United Kingdom Professor Gary Ford
Professor of Geriatric Medicine and Chief Professor of Pharmacology of Old Age
Physician Director Clinical Research Centre
Karolinska Institute University of Newcastle upon Tyne
Neurotec Newcastle upon Tyne, United Kingdom
Karolinska University Hospital
Stockholm, Sweden
CHAPTER AUTHORS
Numbers in brackets refer to the chapters written or co-written by the contributor

Azhar Afaq, MD Derek C. Angus, MD, MPH
Fellow, Department of Endocrinology Professor and Chair, Department of Critical Care Medicine
University of Oklahoma Health Sciences Center University of Pittsburgh School of Medicine
Oklahoma City, Oklahoma [80] Pittsburgh, Pennsylvania
Steven M. Albert, PhD, MSPH

James A. Ashton-Miller, PhD
Professor of Behavioral & Community Health Sciences
Albert Schultz Collegiate Research Professor of
Graduate School of Public Health
Mechanical Engineering
University of Pittsburgh
College of Engineering,
Pittsburgh, Pennsylvania [7]
Research Professor, Institute of Gerontology
Neil B. Alexander, MD
Ann Arbor, Michigan [113]
Division of Geriatric Medicine
Director, Mobility Research Center Sanjay Asthana, MD, FRCP(C)
Research Professor, Institute of Gerontology Duncan G. and Lottie H. Ballantine Chair in Geriatrics
University of Michigan Professor and Head, Section of Geriatrics & Gerontology
Director, VA Ann Arbor Health Care System GRECC University of Wisconsin School of Medicine and Public Health
Ann Arbor, Michigan [113] Director, GRECC
Sonia Ancoli-Israel, PhD Associate Director, Wisconsin Alzheimer’s Institute
Professor of Psychiatry Madison, Wisconsin [65]
University of California, San Diego
Director, Sleep Disorders Clinic James L. Bailey, MD
VA San Diego Health System Professor of Medicine, Renal Division
San Diego, California [55] Emory University School of Medicine
Atlanta, Georgia [86]
Danielle L. Anderson, MD
Postdoctoral Fellow, Section of Geriatric Psychiatry and
Neuropsychiatry Rajbir Bakshi, MD
Johns Hopkins University Assistant Professor of Psychiatry
Baltimore, Maryland [71] University of Texas Southwestern Medical Center
Dallas, Texas [72]
Julia A.M. Anderson, MBChB, BSc, MD, FRCP(Edin),
FRCPath Courtney Barancin, MD
Associate Professor, Consultant Hematologist Instructor in Medicine
Department of Clinical and Laboratory Hematology Division of Gastroenterology and Hepatology
Royal Infirmary of Edinburgh University of Wisconsin
Edinburgh, United Kingdom [106] Madison, Wisconsin [90]
Contributors xi
Steven Barczi, MD Daniel G. Blazer, MD, PhD

Associate Professor of Medicine Professor of Psychiatry
Director, Geriatric Medicine Fellowship Duke University Medical Center
University of Wisconsin Medical School Durham, North Carolina [70]
Associate Director—Clinical
William S. Middleton Memorial Veterans Hospital GRECC Jacob B. Blumenthal, MD
Madison, Wisconsin [41] Assistant Professor of Medicine
Barbara Bates-Jensen, RN, PhD University of Maryland School of Medicine
Associate Adjunct Professor of Medicine Veteran Affairs Maryland Health Care System
Division of Geriatrics Baltimore, Maryland [110]
Anna & Harry Borun Center for Gerontological Research
David Geffen School of Medicine at UCLA Maureen Bolon, MD, MS
Reseda, California [58] Assistant Professor of Medicine
Division of Infectious Diseases
Susan M. Bell, MBBS, BSc Northwestern University Feinberg School of Medicine
Clinical Fellow, Division of Cardiovascular Medicine Chicago, Illinois [125]
Vanderbilt University Medical Center
Nashville, Tennessee [75] Chad E. Boult, MD, MPH, MBA
Professor of Health Policy and Management
Mark Benson, MD Director, Lipitz Center for Integrated Health Care
Fellow, Division of Gastroenterology and Heptology Johns Hopkins School of Public Health
Department of Medicine Baltimore, Maryland [15]
University of Wisconsin
Madison, Wisconsin [90] Jennifer S. Brach, PhD, PT, GCS
Assistant Professor of Physical Therapy
Roberto Bernabei, MD University of Pittsburgh
Professor of Internal Medicine Pittsburgh, Pennsylvania [115]
Universita Cattolica del Sacro Cuore
Dipartimento di Scienze Gerontologiche-Geriatriche e Fisiatriche Lawrence R. Brawley, PhD
Roma, Italy [6] Canada Research Chair in Physical Activity in Health
Promotion and Disease Prevention
Cheryl D. Bernstein, MD University of Saskatchewan
Assistant Professor of Anesthesiology Saskatoon, Saskatchewan, Canada [28]
UPMC Pain Medicine
University of Pittsburgh Cynthia J. Brown, MD, MSPH
Pittsburgh, Pennsylvania [123] Assistant Professor of Medicine
Richard W. Besdine, MD, FACP, AGSF University of Alabama-Birmingham
Professor of Medicine Birmingham, Alabama [29]
Center for Gerontology and Health Care Research Kenneth Brummel-Smith, MD
Brown Medical School Charlotte Edwards Maguire Professor and Chair
Providence, Rhode Island [56] Department of Geriatrics
Florida State University
John D. Birkmeyer, MD College of Medicine
George D. Zuidema Professor of Surgery Tallahassee, Florida [23]
Chair, Surgical Outcomes Research
University of Michigan Ferdinand Buonanno, MD
Ann Arbor, Michigan [37] Assistant Professor of Neurology
Harvard Medical School
Marc R. Blackman, MD Massachusetts General Hospital
Veteran’s Affairs Medical Center Stroke Service
Washington, DC [25] Boston, Massachusetts [64]
Caroline Blaum, MD Cynthia M. Carlsson, MD, MS

Associate Professor of Internal Medicine Assistant Professor of Medicine
Division of Geriatric Medicine Section on Geriatrics and Gerontology
University of Michigan University of Wisconsin School of Medicine and Public Health
Research Scientist, VA Ann Arbor Healthcare System GRECC William S. Middleton Memorial Veterans Hospital GRECC
Ann Arbor, Michigan [17] Madison, Wisconsin [65]
xii Contributors
Bruce A. Carnes, PhD Colleen Christmas, MD

Professor, Donald W. Reynolds Department of Geriatric Medicine Assistant Professor of Medicine
University of Oklahoma Health Sciences Center Division of Geriatric Medicine
Oklahoma City, Oklahoma [119] Johns Hopkins University School of Medicine
Baltimore, Maryland [118]
Iain G. Carpenter, MD
Professor, Centre for Health Services Studies
Audrey Chun, MD
University of Kent
Assistant Professor, Brookdale Department of
Canterbury, Kent, United Kingdom [6]
Geriatrics and Adult Development
Director, Martha Stewart Center for Living
Annette M. Chang, MD
Mt. Sinai School of Medicine
Assistant Professor of Internal Medicine
New York, New York [31]
Division of Metabolism, Endocrinology & Diabetes
University of Michigan Health System
VA Ann Arbor Healthcare System Harvey Jay Cohen, MD
Ann Arbor, Michigan [109] Walter Kempner Professor and Chair, Department of Medicine
Director, Center for the Study of Aging and Human
Julie E. Chang, MD Development
Assistant Professor of Medicine Duke University Medical Center
Section on Hematology/Oncology Durham, North Carolina [94]
University of Wisconsin School of Medicine and Public Health
Madison, Wisconsin [99] Mairav Cohen-Zion, PhD
Assistant Research Scientist, Department of Psychiatry
Susan L. Charette, MD University of California, San Diego
Geriatric Medicine San Diego, California [55]
University of California, Los Angeles Health System
Los Angeles, California [30] Eric A. Coleman, MD, MPH
Gurkamal S. Chatta, MD Division of Health Care Policy and Research
Associate Professor of Medicine University of Colorado Health Sciences Center
Division of Hematology-Oncology Aurora, Colorado [16]
UPMC Cancer Institute
University of Pittsburgh Medical Center
Leo M. Cooney, Jr. MD
Chief, Hematology-Oncology
Humana Foundation Professor of Medicine
VA Pittsburgh Health Care System
Chief, Section of Geriatric Medicine
Yale–New Haven Hospital
Paulo H.M. Chaves, MD, PhD New Haven, Connecticut [121]
Assistant Professor of Medicine
Division of General Internal Medicine
Core Faculty, Center on Aging and Health Suzanne Craft, PhD
Johns Hopkins University Professor of Psychiatry and Behavioral Sciences
Baltimore, Maryland [102] University of Washington School of Medicine
VA Puget Sound Health Care System
Susan Cheng, MD Seattle, Washington [62]
Fellow, Cardiovascular Medicine, Brigham and Women’s
Hospital Timothy J. Daaleman, DO, MPH
Department of Medicine Associate Professor of Family Medicine
Divisions of Gerontology and Geriatric Medicine and Research Fellow, Program on Aging, Disability &
Cardiovascular Medicine Long-Term Care
Harvard Medical School Cecil G. Sheps Center for Health Services Research
Boston, Massachusetts [75] University of North Carolina at Chapel Hill
Chapel Hill, North Carolina [33]
Brenna Cholerton, MD
Clinical Assistant Professor of Psychiatry and Behavioral Osvaldo DelBono, MD, PhD
Sciences Professor of Internal Medicine
University of Washington School of Medicine Section on Gerontology and Geriatric Medicine
VA Puget Sound Health Care System GRECC Wake Forest University School of Medicine
Seattle, Washington [62] Winston-Salem, North Carolina [112]
Contributors xiii
Mary Catherine Dennis, MSW Stanley Fahn, MD

Doctoral Candidate, Joint Program in Social Work Professor of Neurology
and Social Science Neurological Institute
School of Social Work Columbia University Medical Center
University of Michigan New York, New York [66]
Michael A. Fearing, PhD
Nikhila Deo, BS, MEng Research Fellow, Aging Brain Center
University of Wisconsin School of Medicine and Public Health Institute for Aging Research
Madison, Wisconsin [77] Harvard Medical School
Boston, Massachusetts [53]
Margaret A. Drickamer, MD Bruce A. Ferrell, MD
Associate Professor of Medicine Professor of Clinical Medicine
Section of Geriatric Medicine Division of Geriatrics
Yale University School of Medicine UCLA David Geffen School of Medicine
New Haven, Connecticut [13] Los Angeles, California [30]
Catherine E. DuBeau, MD Luigi Ferrucci, MD, PhD

Professor of Medicine Director, Baltimore Longitudinal Study of Aging
Section of Geriatrics National Institute on Aging
Director, Geriatric Continence Clinic Baltimore, Maryland [5] [52]
University of Chicago
Chicago, Illinois [50] Emily Finlayson, MD, MS
Assistant Professor of Surgery
Ruth E. Dunkle, PhD Division of Colon & Rectal Surgery
Wilbur J. Cohen Collegiate Professor of Social Work University of Michigan
School of Social Work Ann Arbor, Michigan [37]
Ellen Flaherty, PhD, APRN, BC
Vice President for Quality Improvement
Village Care of New York
Gustavo Duque, MD, MPH New York, New York [26]
Associate Professor of Medicine
Head of the Discipline of Geriatric Medicine Scott A. Flanders, MD
Director of the Aging Bone Research Program at Nepean Associate Professor of Medicine
Clinical School University of Michigan
University of Sidney Ann Arbor, Michigan [17]
Sidney, Australia [117]
Gary A. Ford, MB, BCh
Niloo M. Edwards, MD Professor of Pharmacology of Old Age
Professor and Chairman, Division of Cardiothoracic Surgery Director, Clinical Research Centre
University of Wisconsin School of Medicine and Public Health School of Clinical & Laboratory Sciences
Madison, Wisconsin [77] University of Newcastle upon Tyne
Newcastle upon Tyne, United Kingdom [8]
Paul L. Enright, MD
Professor of Medicine Christina E. Forsyth, HSc
College of Public Health Rotman Research Institute at Baycrest
University of Arizona Toronto, Ontario, Canada [63]
Tucson, Arizona [82] Marilisa Franceschi, MD
Research Fellow Istitudo di Ricovero e Cura a
Peter C. Enzinger, MD Carattere Scientifico (IRCCS)
Instructor in Medicine Casa Sollievo della Sofferenza Hospital
Harvard Medical School San Giovanni Rotondo, Italy [91]
Linda P. Fried, MD, MPH
William B. Ershler, MD Dean and DeLamar Professor of Public Health
Deputy Clinical Director Professor of Epidemiology and Medicine
National Institute on Aging Senior Vice President, Columbia University Medical Center
Baltimore, Maryland [104] New York, New York [52]
xiv Contributors
Brant E. Fries, PhD Ronald M. Glick, MD

Professor of Health Management and Policy Assistant Professor of Psychiatry and Physical Medicine and
School of Public Health Rehabilitation
Research Professor, Institute of Gerontology Medical Director, Center for Integrative Medicine
University of Michigan University of Pittsburgh Medical Center
Chief, Health System Research Pittsburgh, Pennsylvania [25]
VA Ann Arbor Healthcare System GRECC
Ann Arbor, Michigan [6] Andrew P. Goldberg, MD
Professor of Medicine, Division of Gerontology
Terry Fulmer, PhD, RN, FAAN
University of Maryland School of Medicine
Dean of the College of Nursing and the Erline
Director, GRECC, Baltimore VA Maryland Health Care System
Perkins McGriff Professor
New York University
Ramaswamy Govidan, MD
James Galvin, MD, MPH Associate Professor of Medicine, Division of Oncology
Associate Professor of Neurology, Psychiatry and Neurobiology Washington University School of Medicine
Director, Memory Diagnostic Center St. Louis, Missouri [97]
Hope Center for Neurological Disorders
Washington University School of Medicine Len Gray, MB, BS, MMed, PhD, FRACP
St. Louis, Missouri [12] Professor of Geriatric Medicine
Department of Medicine
Giovanni Gambassi, MD University of Queensland
Associate Professor, Centro Medicina dell’Invecchiamento Princess Alexandra Hospital
Universita Cattolica del Sacro Cuore Woolloongabba, Australia [6]
Rome, Italy [6]
Andrew W. Gardner, PhD David A. Greenwald, MD
CMRI Hobbs-Rechnagel Professor Associate Professor of Clinical Medicine
General Clinical Research Center Division of Gastroenterology
University of Oklahoma Health Sciences Center Montefiore Medical Center
Oklahoma City, Oklahoma [80] Bronx, New York
Lowell W. Gerson, PhD Tomas Griebling, MD

Professor Emeritus of Epidemiology Associate Professor and Vice Chair of Urology
Department of Community Health Sciences Assistant Scientist, Center on Aging
Northeastern Ohio Universities College of Medicine University of Kansas School of Medicine
Senior Scientist, Emergency Medicine Research Center Kansas City, Kansas [48]
Bonita Springs, Florida [18]
Shahyar M. Gharacholou, MD Professor Beatrix Grubeck-Loebenstein
Fellow, Divisions of Geriatrics and Cardiology Director, Institute for Biomedical Aging Research
Duke University Medical Center Austrian Academy of Sciences, Immunology Division
Durham, North Carolina [76] Innsbruck, Austria [3]
Sudeep S. Gill, MD, MSc, FRCPC David A. Gruenewald, MD

Assistant Professor of Medicine Associate Professor of Medicine
Queens University, St. Mary’s of the Lake Hospital University of Washington School of Medicine
Kingston, Ontario, Canada [24] VA Puget Sound Health Care System
Seattle, Washington [107]
Jeffrey Ginsberg, MD
Division of Hematology and Thromboembolism Jack M. Guralnik, MD, PhD
McMaster University Senior Investigator
Hamilton, Ontario, Canada [105] Chief, Epidemiology and Demography Section
National Institute on Aging
Cary E. Gleason, PhD Bethesda, Maryland [5]
Senior Scientist, Department of Medicine
Section of Geriatrics and Gerontology Jerry H. Gurwitz, MD
University of Wisconsin School of Medicine and Public Health Executive Director, Myers Primary Care Institute
William S. Middleton Memorial Veterans Hospital GRECC University of Massachusetts
Madison, Wisconsin [65] Worcester, Massachusetts [24]
Contributors xv
Karen E. Hall, MD, PhD Arthur E. Helfand, DPM

Associate Professor of Internal Medicine Professor Emeritus and Retired Chair
Division of Geriatric Medicine Department of Community Health, Aging & Health Policy
University of Michigan Health System Temple University School of Podiatric Medicine
Research Scientist, GRECC Narbeth, Pennsylvania [122]
Ann Arbor VAMC
Ann Arbor, Michigan [89] Jean Claude Henrard, MD
Professor, Centre de Gerontologie
Jeffrey B. Halter, MD Hospital Sainte Perine
Professor of Internal Medicine Paris, France [6]
Chief, Division of Geriatric Medicine
Director, Geriatrics Center and Institute of Gerontology Jerome M. Hershman, MD, MACP
University of Michigan Distinguished Professor of Medicine
Ann Arbor, Michigan [109] David Geffen School of Medicine at UCLA
VA Greater Los Angeles Healthcare System
Joseph T. Hanlon, PharmD, MS Los Angeles, California [108]
Professor of Medicine, Division of Geriatrics
Research Health Scientist Kevin P. High, MD, MS, FACP
University of Pittsburgh Professor of Medicine, Sections on Infectious Diseases,
Pittsburgh, Pennsylvania [25] Hematology/Oncology and Molecular Medicine
Chief, Section on Infectious Diseases
Danielle Harari, MB, BS Wake Forest University Health Sciences
Consultant Physician & Clinical Lead in Elderly Medicine Winston-Salem, North Carolina [124]
Honorary Senior Lectuere (KCL)
Department of Ageing and Health Sarah N. Hilmer, PhD, FRACP
St. Thomas’ Hospital Senior Lecturer in Medicine
London, England [93] Department of Clinical Pharmacology and Aged Care
University of Sydney, Royal North Shore Hospital
Tamara B. Harris, MD, MS St. Leonards, New South Wales, Australia [8]
Senior Investigator and Chief, Geriatrics Epidemiology Section
Laboratory of Epidemiology, Demography, and Biometry Jacqueline Hind, MS, CCC-LP, BRS-S
Intramural Research Program Outreach Program Manager
National Institute on Aging University of Wisconsin School of Medicine and Public Health
Bethesda, Maryland [39] William S. Middleton Memorial VA Hospital
Madison, Wisconsin [41]
Rowan H. Robins Harwood, MSc, MD
Professor, Community Health Sciences John Hirdes, PhD
Nottingham City Hospital Professor of Health Studies and Gerontology
Nottingham, United Kingdom [6] University of Waterloo
Waterloo, Ontario, Canada [6]
Sima R. Hassani, DO
Clinical Instructor in Medicine Mustafa M. Husain, MD
David Geffen School of Medicine at UCLA Professor of Psychiatry and Internal Medicine
Kaiser Permanente Medical Center Chief, Division of Geriatric Psychiatry
Woodland Hills, California [108] University of Texas Southwestern Medical Center
Dallas, Texas [72]
Jennifer Hayashi, MD
Assistant Professor of Medicine Kathryn Hyer, PhD, MPP
Johns Hopkins University School of Medicine Associate Professor, School of Aging Studies
Baltimore, Maryland [22] Florida Policy Exchange Center on Aging
University of South Florida
William R. Hazzard, MD Tampa, Florida [26]
University of Washington Naoki Ikegami, MD
Director, Geriatrics and Extended Care Professor and Chair of Health Policy and Management
VA Puget Sound Health Care System Keio University School of Medicine
Seattle, Washington [9][45] Shinjuku-ku, Tokyo, Japan [6]
xvi Contributors
Sharon K. Inouye, MD, MPH Mary E. Jung, MSc

Professor of Medicine University of Saskatchewan
Harvard Medical School Saskatoon, Saskatchewan, Canada [28]
Beth Israel Deaconess Medical Center
Institute for Aging Research Amy C. Justice, MD, PhD
Roslindale, Massachusetts [53] Associate Professor of Medicine
Nadine A. Jackson, MD, MPH Chief, Section of General Medicine
Clinical Fellow, Medical Oncology West Haven VA Healthcare System
Dana-Farber Cancer Institute West Haven, Connecticut [128]
Marshall B. Kapp, JD, MPH, FCLM
Arshad Jahangir, MD
Garwin Distinguished Professor of Law & Medicine
Co-Director, Center for Health Law & Policy
Mayo Clinic
Southern Illinois University School of Law
Scottsdale, Arizona [79]
Carbondale, Illinois [32]
Brian D. James, M Bioethics
Center on Aging and Health Jason H.T. Karlawish, MD
Johns Hopkins Bloomberg School of Public Health Professor of Medicine
Baltimore, Maryland [34] Ralston-Penn Center
University of Pennsylvania
Larry E. Johnson, MD, PhD Philadelphia, Pennsylvania [34]
Associate Professor of Geriatrics & Family and Preventive
Medicine Leslie I. Katzel, MD, PhD
University of Arkansas for Medical Sciences Associate Professor of Medicine
Central Arkansas Veteran’s Healthcare System Division of Gerontology and Geriatric Medicine
North Little Rock VA Hospital University of Maryland School of Medicine
North Little Rock, Arkansas [38] Associate Director, Clinical
Veteran Affairs Maryland Health Care System GRECC
Sterling C. Johnson, PhD Baltimore, Maryland [110]
University of Wisconsin School of Medicine and Public Health Clive Kearon, MB, MRCP (I), FRCP (C), PhD
William S. Middleton Memorial Veterans Hospital Professor of Medicine
Madison, Wisconsin [68] McMaster University
Head, Clinical Thrombosis Service
Theodore M. Johnson, II, MD, MPH Henderson General Hospital
Associate Professor of Medicine Hamilton, Ontario, Canada [105]
Emory University
Manager, Geriatrics and Extended Care Service Line
Atlanta VA Medical Center Rose Anne Kenny, MD, FRCPI, FRCP
Decatur, Georgia [59] Professor, Geriatric Medicine/Consultant
Medical Gerontology
Trinity Centre, St. James Hospital
Timothy M. Johnson, MD
Trinity College Dublin, College Green
Lewis and Lillian Becker Professor of Dermatology
Dublin, Ireland [57]
Gretchen G. Kimmick, MD, MS
Palmi V. Jonsson, MD, FACP Associate Professor of Medicine
Professor and Chief of Geriatrics Division of Medical Oncology
Landspitali University Hospital Duke University Medical Center
University of Iceland School of Medicine Durham, North Carolina [95]
Reykjavik, Iceland [6]
Mary B. King, MD
Yvette L. Ju, DO Assistant Professor of Clinical Medicine
Intramural Research Program University of Connecticut School of Medicine
National Institute on Aging Hartford Hospital Geriatric Program
Bethesda, Maryland [116] Hartford, Connecticut [54]
Contributors xvii
Thomas B.L. Kirkwood, PhD Ilo E. Leppik, MD

Professor of Medicine and Institute Director Professor of Neurology
Institute for Aging and Health University of Minnesota School of Medicine
Newcastle University MINCEP Epilepsy Care
Newcastle upon Tyne, United Kingdom [2] Minneapolis, Minnesota [69]
J. Philip Kistler, MD Stacy Tessler Lindau, MD, MAPP

Professor of Neurology Assistant Professor
Harvard Medical School Departments of Obstetrics and Gynecology and
Director, Stroke Service Medicine-Geriatrics
Massachusetts General Hospital Chicago Core on Biomeasures in Population Based
Boston, Massachusetts [64] Health and Aging Research
University of Chicago
Dalane W. Kitzman, MD Chicago, Illinois [47]
Sections on Cardiology and Gerontology and Geriatric Medicine
Shari M. Ling, MD
Staff Clinician, Clinical Research Branch
Winston-Salem, North Carolina [74]
Translational Research and Medical Services Section
National Institute on Aging
Heidi D. Klepin, MD
Section on Hematology and Oncology
Wake Forest University Health Sciences David A. Lipschitz, MD, PhD
Winston-Salem, North Carolina [103] Longevity Center-St Vincent Senior Health
Little Rock, Arkansas [101]
Wendy M. Kohrt, PhD
Professor of Medicine, Division of Geriatrics XiaoKe Liu, MD
University of Colorado Denver Heart Center for Excellence
Aurora, Colorado [114] Kalamazoo, Michigan [79]
George A. Kuchel, MD, FRCP Noelle K. LoConte, MD

Professor of Medicine Assistant Professor of Medicine
Travelers Chair in Geriatrics and Gerontology Section of Hematology/Oncology
Director, UConn Center on Aging University of Wisconsin School of Medicine and Public Health
Chief, Division of Geriatric Medicine Madison, Wisconsin [99]
University of Connecticut Health Center
Farmington, Connecticut [51] Mark B. Loeb, MD
Professor of Pathology and Molecular Medicine and of Clinical
Mark S. Lachs, MD, MPH Epidemiology and Biostatistics
Professor of Medicine McMaster University
Co-Director, Division of Geriatric Medicine and Gerontology Hamilton, Ontario, Canada [130]
Weill Medical College of Cornell University
Richard F. Loeser, Jr., MD
The Dorothy Rhyne Kimbrell and Willard Duke Kimbrell
James M. Lai, MD
Professor of Arthritis and Rheumatology
Postdoctoral Fellow, Section of Geriatrics
Chief, Section on Molecular Medicine
New Haven, Connecticut [13]
Winston-Salem, North Carolina [112]
Agnes Y.Y. Lee, MD, MSc, FRCPC
Associate Professor of Medicine Dan L. Longo, MD
Division of Hematology and Thromboembolism Scientific Director
Medical Director, Thrombosis Program National Institute on Aging
McMaster University Baltimore, Maryland [104]
Hamilton, Ontario, Canada [106]
Michael Lucey, MD
Bruce Leff, MD Professor of Medicine
Associate Professor of Medicine Head, Section of Gastroenterology and Hepatology
Johns Hopkins University School of Medicine University of Wisconsin School of Medicine and Public Health
Baltimore, Maryland [22] Madison, Wisconsin [90]
xviii Contributors
Mathew W. Ludgate, MB, ChB Shawn M. McClintock, PhD

Lecturer, Department of Dermatology Postdoctoral Fellow, Department of Psychiatry
University of Michigan University of Texas Southwestern Medical Center
Ann Arbor, Michigan [100] Dallas, Texas [72]
Kenneth W. Lyles, MD Eric B. Milbrandt, MD, MPH, FCCP

Professor of Medicine Assistant Professor, CRISMA Laboratory
Vice-Chair for Clinical Research Department of Critical Care Medicine
Duke University Medical Center University of Pittsburgh School of Medicine
VA Medical Center Pittsburgh, Pennsylvania [19]
Durham, North Carolina [111]
Myron Miller, MD
William L. Lyons, MD Professor of Medicine
Assistant Professor of Internal Medicine Johns Hopkins University School of Medicine
Section of Geriatrics and Gerontology Baltimore, Maryland [88]
University of Nebraska Medical Center
Omaha, Nebraska [16] Bruce Miller, MD
Professor of Neurology
Jay Magaziner, PhD, MSHyg Director, UCSF Alzheimer’s Disease Research Center
Professor and Director, Division of Gerontology University of California, San Francisco
Department of Epidemiology and Preventive Medicine San Francisco, California [67]
Baltimore, Maryland [118] Karen L. Miller, MD
Associate Professor of Obstetrics and Gynecology
Preeti N. Malani, MD University of Utah
Assistant Professor of Internal Medicine Salt Lake City, Utah [48]
Divisions of Geriatric Medicine and Infectious Diseases
University of Michigan Health System Ram R. Miller, MD, CM
Veterans Affairs Ann Arbor Healthcare System Assistant Professor
Ann Arbor, Michigan [35] Epidemiology and Preventive Medicine
Leon S. Maratchi, MD Baltimore, Maryland [118]
Gastroenterology Consultants, P.A. – Hollywood
Hollywood, Florida Richard A. Miller, PhD
Professor of Pathology
Edward R. Marcantonio, MD, SM Associate Director, Geriatric Center
Associate Professor of Medicine University of Michigan
Harvard Medical School Investigator, VA Ann Arbor, GRECC
Director of Research, Division of General Medicine and Ann Arbor, Michigan [1]
Primary Care
Beth Israel Deaconess Medical Center Daniel Morgensztern, MD
Brookline, Massachusetts [20][53] Assistant Professor of Medicine
Section on Medical Oncology
Thomas J. Marrie, MD Washington University School of Medicine
Professor of Medicine St. Louis, Missouri [97]
Dean, Faculty of Medicine and Dentistry
University of Alberta John N. Morris, PhD
Edmonton, Alberta, Canada [126] Co-Director, Hebrew Senior Life Institute for Aging Research
The Alfred A. and Gilda Slifka Chair in Social Gerontological
Alvin M. Matsumoto, MD Research
Professor of Medicine Harvard Medical School
University of Washington School of Medicine Boston, Massachusetts [6]
Associate Director, GRECC
VA Puget Sound Health Care System R. Sean Morrison, MD
Seattle, Washington [107] Director, National Palliative Care Research Center
Hermann Merkin Professor of Palliative Care
Mark P. Mattson, PhD Professor of Geriatrics and Medicine
Gerontology Research Center Brookdale Department of Geriatrics and Adult Development
National Institute on Aging Mt. Sinai School of Medicine
Baltimore, Maryland [61] New York, New York [31]
Contributors xix
Suzanne B. Murray, MD Miguel A. Paniagua, MD

Assistant Professor of Psychiatry and Behavioral Sciences Assistant Professor of Clinical Medicine
University of Washington School of Medicine Division of Gerontology and Geriatric Medicine
Seattle, Washington [73] University of Miami Miller School of Medicine
Miami VA Medical Center
Hyman B. Muss, MD Miami, Florida [9]
University of Vermont and Vermont Cancer Center
Burlington, Vermont [95] Marcella Pascualy, MD
Associate Professor of Psychiatry
Yuri R. Nakasato, MD, MBA Director, Geriatric Psychiatry Fellowship
Assistant Professor of Rheumatology and Geriatrics University of Washington
Department of Rheumatology VA Puget Sound Health Care System
University of North Dakota Seattle, Washington [73]
MeritCare Health Systems
Fargo, North Dakota [119] Sanjeevkumar R. Patel, MD, MS
Aman Nanda, MD University of Michigan
Assistant Professor of Medicine Ann Arbor, Michigan [85]
Division of Geriatrics
Rhode Island Hospital
Brown Medical School Claire Peel, PhD, PT, FAPTA
Providence, Rhode Island [56] Associate Provost for Faculty Development/Affairs
University of Alabama-Birmingham
Anne B. Newman, MD, MPH Birmingham, Alabama [29]
Professor of Epidemiology and Medicine
Director, Center for Aging and Population Health Xiaomei Pei, PhD
University of Pittsburgh Professor, Department of Sociology
Pittsburgh, Pennsylvania [83] Tsinghua University
Beijing, China [6]
Lindsay E. Nicolle, MD
Professor of Medicine and Medical Microbiology
University of Manitoba Michael C. Perry, MD, MS, FACP
Winnipeg, Manitoba, Canada [127] Professor and Director
Division of Hematology and Medical Oncology
Martin O’Donnell, MB, PhD, MRCPI University of Missouri/Ellis Fischel Cancer Center
Associate Professor of Medicine Columbia, Missouri [97]
McMaster University
Hamilton General Hospital
Elaine Peskind, MD
Hamilton, Ontario, Canada [105]
Professor of Psychiatry
Graziano Onder, MD, PhD University of Washington School of Medicine
Assistant Professor, Centro Mefdicina dell’Invecchiamento VA Puget Sound Health Care System
Universita Cattolica del Sacro Cuore Seattle, Washington [73]
Rome, Italy [6]
Eric Petrie, MD
Mark B. Orringer, MD Associate Professor of Psychiatry
John Alexander Distinguished Professor of Thoracic Surgery Division of Psychiatric Neurosciences
Head, Department of Thoracic Surgery University of Washington School of Medicine
University of Michigan VA Puget Sound Health Care System
Ann Arbor, Michigan [35] Seattle, Washington [73]
Joseph G. Ouslander, MD
Professor and Associate Dean for Geriatric Programs Eric D. Peterson, MD, MPH
Charles E. Schmidt College of Biomedical Science Professor of Medicine
Professor (Courtesy), Christine E. Lynn College of Nursing Division of Cardiology
Florida Atlantic University Associate Vice Chair for Quality
Professor of Medicine (Voluntary) Director of CV Research
Division of Gerontology and Geriatric Medicine Associate Director, Duke Clinical Research Institute
University of Miami Miller School of Medicine Duke University Medical Center
Boca Raton, Florida [59] Durham, North Carolina [76]
xx Contributors
Elizabeth A. Phelan, MD Annette Hylen Ranhoff, MD, PhD

Assistant Professor of Medicine Professor, Ullevaal University Hospital
Division of Geriatrics and Gerontology Diakonhjemmet Hospital
Harborview Medical Center Medical Department
University of Washington School of Medicine Oslo, Norway [6]
Seattle, Washington [9]
Arati V. Rao, MD
Kenneth J. Pienta, MD Assistant Professor of Medicine
Professor of Internal Medicine and Urology Divisions of Medical Oncology and Geriatrics
University of Michigan Duke University Medical Center
Ann Arbor, Michigan [96] Durham VA Medical Center
Durham, North Carolina [94]
Alberto Pilotto, MD
Director, Department of Medical Sciences
Head, Geriatrics Unit & Gerontology-Geriatric Laboratory Keith L. Rapp, MD, CMD
Research CEO, Geriatric Associates of America, PA
Istitudo di Ricovero e Cura a Webster, Texas [21]
Carattere Scientifico (IRCCS)
Casa Sollievo della Sofferenza Hospital Mary Pat Rapp, PhD, RN, GNP-BC
San Giovanni Rotondo, Italy [91] Assistant Professor of Nursing
University of Texas School of Nursing
Paula M. Podrazik, MD Houston, Texas [21]
Section of Geriatrics Mark Reger, PhD
University of Chicago Research Neuropsychologist
Chicago, Illinois [17] Department of Psychology
Madigan Army Medical Center
Bruce G. Pollock, MD, PhD Tacoma, Washington [62]
Professor of Psychiatry
The Rotman Research Institute
Baycrest Center for Geriatric Care W. Jack Rejeski, PhD
Toronto, Ontario, Canada [63] Professor of Health and Exercise Science
Wake Forest University
Bayard L. Powell, MD Winston-Salem, North Carolina [28]
Chief, Section on Hematology and Oncology David B. Reuben, MD
Wake Forest University Health Sciences Professor of Medicine
Winston-Salem, North Carolina [103] Chief, Geriatric Medicine & Gerontology
David Geffen School of Medicine at UCLA
Luigi Puglielli, MD, PhD Los Angeles, California [11]
Assistant Professor of Medicine
Section of Geriatrics and Gerontology Justin C. Rice, MD
University of Wisconsin School of Medicine and Public Iowa Clinic
Health West Des Moines, Iowa [90]
GRECC
Madison, Wisconsin [65] Michael W. Rich, MD
Kip E. Queenan, MD Washington University School of Medicine
Assistant Professor of Psychiatry Director, Cardiac Rapid Evaluation Unit
University of Texas Southwestern Medical Center Barnes-Jewish Hospital
Dallas, Texas [72] St. Louis, Missouri [78]
Peter V. Rabins, MD Ian H. Robbins, MD, PhD

Professor of Psychiatry Professor of Medicine and Neurology
Division of Geriatric Psychiatry and Neuropsychiatry Medical Oncology Section
Johns Hopkins University University of Wisconsin School of Medicine and Public Health
Baltimore, Maryland [71] Madison, Wisconsin [99]
Contributors xxi
JoAnne Robbins, PhD Kenneth E. Schmader, MD

Professor of Medicine, Radiology, Nutritional Professor of Medicine
Sciences, and Biomedical Engineering Chief, Division of Geriatrics
University of Wisconsin School of Medicine and Public Health Duke University Medical Center
Associate Director of Research/GRECC Director, Durham VA Medical Center GRECC
William S. Middleton Memorial VA Hospital Durham, North Carolina [129]
Madison, Wisconsin [41]
Richard Schulz, PhD
Paula Rochon, MD, MPH Professor of Psychiatry, Epidemiology, Sociology, Psychology,
Professor, Department of Medicine Community Health, and Health and Rehabilitation Sciences
Senior Scientist, Institute for Clinical Evaluative Sciences Director, University Center for Social and Urban Research
Assistant Director, Kunin-Lunenfeld Applied Research Associate Director, Institute on Aging
Unit – Baycrest Centre University of Pittsburgh
University of Toronto Pittsburgh, Pennsylvania [7]
Toronto, Ontario, Canada [24]
Robert S. Schwartz, MD
G. Alec Rooke, MD, PhD
Goodstein Professor of Medicine
Professor of Anesthesiology
Division Head, Geriatric Medicine
Visiting Professor of Anesthesia, Critical Care and Pain Medicine
University of Colorado Health Sciences Center
Beth Israel Deaconess Medical Center
Aurora, Colorado [114]
Caterina Rosano, MD, MPH Todd P. Semla, MS, PharmD

Assistant Professor of Epidemiology VA Pharmacy Benefits Management Service
Graduate School of Public Health Hines, Illinois [63]
Center for Aging and Population Health
University of Pittsburgh Su-Hua Sha, MD
Pittsburgh, Pennsylvania [115] Research Investigator
Kresge Hearing Research Institute
Sonja Rosen, MD Director, Molecular Otology and Signal Transduction Laboratory
Assistant Clinical Professor of Medicine University of Michigan
Division of Geriatric Medicine Ann Arbor, Michigan [44]
UCLA School of Medicine
Santa Monica, California [11] Win-Kuang Shen, MD
Mary H. Samuels, MD Mayo Clinic
Professor of Medicine Rochester, Minnesota [79]
Division of Endocrinology, Diabetes and Clinical Nutrition
Program Director, Clinical and Translational Research Center Jonathan A. Ship, DMD∗
Oregon Health & Science University Professor, Department of Oral Medicine
Portland, Oregon [108] New York University College of Dentistry
Director, Bluestone Center for Clinical Research
Jeff M. Sands, MD
Juha P. Kokko Professor of Medicine and Physiology
Director, Renal Division
Jeffrey H. Silverstein, MD
Associate Dean for Clinical and Translational Research
Professor of Anesthesiology
Emory University
Associate Dean for Research
Atlanta, Georgia[86]
Mt. Sinai School of Medicine
Jochen Schacht, MD New York, New York [36]
Professor of Biological Chemistry
Director, Kresge Hearing Research Institute Don D. Sin, MD, MPH
Department of Otorhinolaryngology Canadian Research Chair in Chronic Obstructive Lung Disease
University of Michigan Associate Professor of Medicine
Ann Arbor, Michigan [44] University of British Columbia
James Hogg iCAPTURE Centre for Cardiovascular and
Lynn E. Schlanger, MD Pulmonary Research, St. Paul’s Hospital
Assistant Professor of Medicine Vancouver, British Columbia, Canada [83]
Renal Division
Emory University School of Medicine
∗
Atlanta, Georgia[86] deceased
xxii Contributors
Aneesh Bhim Singhal, MD George E. Taffet, MD

Assistant Professor of Neurology Associate Professor of Medicine
Harvard Medical School Chief, Section on Geriatrics
Assistant Neurologist Section on Cardiovascular Sciences
J. Philip Kistler MGH Stroke Research Center Baylor College of Medicine
Massachusetts General Hospital Houston, Texas [74]
Andra E. Talaska, BS
Eric Edward Smith, MD, MPH Research Associate
Assistant Professor of Neurology Department of Biological Chemistry
Harvard Medical School University of Michigan
Assistant Neurologist Ann Arbor, Michigan [44]
J. Philip Kistler MGH Stroke Research Center
Massachusetts General Hospital
Boston, Massachusetts [64] Joyce Lisa Tenover, MD, PhD
John D. Sorkin, MD, PhD Division of Geriatrics Medicine and Gerontology
Associate Professor of Medicine, Gerontology Wesley Woods Center of Emory University
Chief, Biostatistics and Informatics Emory University School of Medicine
University of Maryland School of Medicine Atlanta, Georgia [49]
Baltimore VA Medical Center
Baltimore, Maryland [80][110] Victor J. Thannickal, MD
MaryFran R. Sowers, MS, PhD Division of Pulmonary and Critical Care Medicine
Professor of Epidemiology University of Michigan Health System
John G. Searle Professor of Public Health Ann Arbor, Michigan [84]
Director, Center for Integrated Approaches to Complex Diseases
Mary E. Tinetti, MD
Gladys Phillips Crofoot Professor of Medicine,
Epidemiology, and Public Health
Knight Steel, MD
Director, Program on Aging
Professor, Hackensack University Medical Center
Hackensack, New Jersey [6]
New Haven, Connecticut [10]
Sharon E. Strauss, MD
Associate Professor of Medicine Jennifer Tjia, MD, MSCE
University of Calgary and University of Toronto Assistant Professor of Medicine
Foothills Medical Centre Division of Geriatric Medicine
Calgary, Alberta, Canada [10] University of Massachusetts Medical School
Worcester, Massachusetts [24]
Stephanie Studenski, MD, MPH
Professor, Department of Medicine (Geriatrics) Galen B. Toews, M.D.
University of Pittsburgh Professor of Internal Medicine
Staff Physician, VA Pittsburgh GRECC Chief, Division of Pulmonary and Critical Care Medicine
Pittsburgh, Pennsylvania [115] University of Michigan Health System
Dennis H. Sullivan, MD
Professor of Medicine and Geriatrics
Vice Chairman, Donald W. Reynolds Department of Geriatrics Bruce R. Troen, MD
University of Arkansas for Medical Sciences Associate Professor of Medicine
Director, VA Little Rock GRECC University of Miami Leonard M. Miller School of Medicine
Little Rock, Arkansas [38] Miami VA Medical Center
Miami, Florida [117]
Mark A. Supiano, MD
Professor and Chief, Division of Geriatrics Jack I. Twersky, MD
University of Utah School of Medicine Associate Clinical Professor of Medicine
University of Utah Center on Aging Duke University Medical School
Director, VA Salt Lake City GRECC Durham VA Medical Center
Salt Lake City, Utah [81] Durham, North Carolina [129]
Contributors xxiii
Mark L. Unruh, MD, MS Birgit Weinberger

Assistant Professor of Medicine Institute for Biomedical Aging Research
Renal-Electrolyte Division Immunology Division
University of Pittsburgh School of Medicine Austrian Academy of Sciences
Pittsburgh, Pennsylvania [87] Innsbruck, Austria [3]
Peter V. Vaitkevicius, MD Debra K. Weiner, MD

Associate Professor of Medicine Associate Professor of Medicine, Psychiatry and
Chief, Department of Cardiology Anesthesiology (Geriatrics)
Wayne State University School of Medicine University of Pittsburgh Medical Center Pain Medicine
John D. Dingell VA Medical Center Program
Detroit, Michigan [35] University of Pittsburgh
Victor Valcour, MD
Adjunct Clinical Assistant Professor of Geriatrics in Neurology
Memory and Aging Center Daniela Weiskopf
University of California, San Francisco Institute for Biomedical Aging Research
San Francisco, California [67] Immunology Division
Austrian Academy of Sciences
Jeffrey I. Wallace, MD, MPH Innsbruck, Austria [3]
Division of Gerontology and Geriatric Medicine Chad Whelan, MD
University of Colorado Health Sciences Center Associate Professor of Medicine
Aurora, Colorado [40] University of Chicago
Chicago, Illinois [17]
Jeremy D. Walston, MD
Jocelyn Wiggins, BM, BCh, MRCP
Division of Geriatric Medicine and Gerontology
Johns Hopkins University
Baltimore, Maryland [4][52]
Louise C. Walter, MD
University of California, San Francisco Scott T. Wilber, MD, FACEP
Staff Physician, San Francisco VA Medical Center Associate Professor of Emergency Medicine
San Francisco, California [14] Northeastern Ohio Universities College of Medicine
Director, Emergency Medicine Research Center
Lucy Y. Wang, MD Summa Health System
Senior Fellow, Department of Psychiatry and Behavioral Akron, Ohio [18]
Sciences
University of Washington School of Medicine Aaron Van Wright III, MD
VA Puget Sound Health Care System Associate Clinical Professor
Seattle, Washington [10] Department of Psychiatry
University of Texas Southwestern Medical Center
Timothy S. Wang, MD Dallas, Texas [72]
Associate Professor of Dermatology
Ann Arbor, Michigan [73][100] Sachin Yende, MD, MS
Assistant Professor of Critical Care Medicine
Gale R. Watson, MEd, CLVT University of Pittsburgh School of Medicine
National Director, Blind Rehabilitation Service Pittsburgh, Pennsylvania [83]
RS-OPS, Veterans Health Central Office
Washington, DC [43] Raymond Yung, MB, ChB
Associate Professor of Internal Medicine
Stephen G. Weber, MD, MS Divisions of Geriatric Medicine and Rheumatology
Assistant Professor of Medicine University of Michigan
Section of Infectious Diseases Associate Director, Research
University of Chicago VA Ann Arbor GRECC
Chicago, Illinois [125] Ann Arbor, Michigan [120]
xxiv Contributors
Mark Yurkofsky, MD, CMD Susan J. Zieman, MD, PhD

Chief of Extended Care, Palliative Medicine and Intensive Assistant Professor of Medicine
Home-based Programs Divisions of Cardiology and Geriatric Medicine
Harvard Vanguard Medical Associates Medical Director John Hopkins University School of Medicine
The Boston Center for Rehabilitative and Subacute Care Baltimore, Maryland [75]
Instructor of Medicine
Harvard Medical School
Foreword
Publication of the 6th edition marks an important milestone in the Encouraged by this promising beginning, the accelerating pace
evolution of this work-in-progress—passing the baton from the last of progress in aging research, and the recognition of Geriatrics as a
of the original editors to a new (albeit thoroughly seasoned) group legitimate, scientifically-based medical discipline (and by the thou-
from the next generation of geriatricians and gerontologists, ex- sands of practitioners and fellows who were certified through the
panded now to 6 under the senior leadership of Jeffrey Halter, who first examination developed as a joint effort by the American Board
bring the latest and the best in this growing field to students and of Internal Medicine and the American Board of Family Practice in
practitioners of our discipline on behalf of the aging patients we 1988), we proceeded to assemble the 2nd edition as an expanded vol-
serve. ume, notably through the contributions of a of fourth editor for the
This orderly succession gives me an enormous sense of pride and neural sciences (John Blass), and a section devoted to the Geriatric
confidence that the progressive maturation of this textbook over Syndromes, which was published in 1990. With its solid reputation
the first 5 editions will continue unabated for the foreseeable fu- established, the 3rd edition (with Nancy Woolard as editorial assis-
ture. From the outset this has been buttressed by the unflagging tant) followed in 1994, with additional editors in Jeffrey Halter (an-
commitment to our field demonstrated by McGraw-Hill since this other endocrinologist turned geriatrician) and Walter H. Ettinger,
project was but a gleam in the eye of Derek Jeffers, senior pub- Jr. (a rheumatologist but also the first fellowship-trained geriatrician
lisher’s editor for Harrison’s Principles of Internal Medicine. In the on the panel), and the first turnover on the editorial board in the
late 1970s he conceived it as an important and timely initiative retirement of Andres from the panel. The 4th edition was published
on behalf of our new field to bring students and practitioners up in 1999 with Joseph Ouslander, another trained geriatrician, suc-
to modern standards in caring for the already burgeoning num- ceeding Ed Bierman following his death in 1995. Subsequently, as
bers of elderly patients. He first enlisted the collaboration of Edwin Ettinger left the board, he was succeeded by Mary Tinetti, another
L. Bierman, who had recently added Gerontology to his title as card-carrying geriatrician, and the 5th edition was published in 2003.
head of the Division of Metabolism in the Department of Medicine A token of appreciation given to all contributors to the 5th edition vi-
at the University of Washington, to develop a new textbook for sually summarized this history of the Principles of Geriatric Medicine
our field to serve as a companion to Harrison’s and the first such and Gerontology : a photograph on a mouse pad of the first five vol-
American contribution in this discipline. Ed, mentor from umes standing between the book-ends that exemplify the enduring
metabolism fellowship days at the University of Washington, turned philosophy of editions of this textbook: our enduring commitment
in rapid order first to his long-time friend and colleague, Reubin An- to aging, both “successful” and “usual”(Figure 1), portraying a striv-
dres, clinical director of the Gerontology Research Center (GRC) ing runner on one end symbolizing the price and rewards of a robust
of the National Institute on Aging in Baltimore, to serve as senior old age while on the other end the discouraged, frail old person to
editor and soon thereafter to me, as a junior member of his division, whom much of our professional effort is devoted with heart, mind,
to join in a tripartite effort to launch the first edition of the Prin- and soul.
ciples of Geriatric Medicine and Gerontology. This came to fruition Now with the publication of the 6th edition in 2009 the ed-
over the next 5 years, during which I moved to Baltimore to join the itorial succession is complete as the last members of the early
Department of Medicine at Johns Hopkins as vice-chairman and to boards leave with the retirement of John Blass and my “promo-
develop a new Geriatric program based principally at the East Balti- tion” to emeritus status, Jeffrey Halter assumes the reins of leader-
more (now Hopkins Bayview) campus that was the site of the GRC. ship, and three vigorous new members join to expand and broaden
And with the steady support of Jeffers and the editorial assistance the effort: Sanjay Asthana, a geriatrician with primary professional
of Ellen Hazzard, in 1985 the first edition was published, receiving expertise in the neural sciences (notably Alzheimer’s Disease and
favorable reviews and an enthusiastic reception from members of related disorders); Kevin High, an infectious disease subspecialist
our still fledgling field. with broad interests and ties in subspecialty internal medicine and
xxv
xxvi Foreword
FIGURE 1.
t
geriatrics; and Stephanie Studenski, a geriatrician and rheumatolo- To focus our information and our chapters upon the learning
gist/rehabilitation specialist. needs of those who will lead our field as it continues to evolve and
I am proud to remain associated with this tradition of excellence its scientific underpinnings become evermore secure and compre-
and I am entirely confident that the solid principles upon which this hensive: most clearly the fellows in training who will become the
textbook were founded will assuredly remain undiminished with the future practitioners, researchers, and educators in this rapidly
strong support of James Shanahan at McGraw-Hill and the leader- advancing field and whose contributions will be leveraged maxi-
ship of the board of editors of the 6th edition: mally among the broad array of students and practitioners whom
t
To publish a timely, comprehensive, state-of-the-art textbook as they instruct and with whom they collaborate.
t
an icon and practical, day-to-day tool of our discipline that is To hold our aging and elderly patients squarely in the center of
anchored in science, evidence-based medicine, and the balanced, our vision for the future of our field, for they are and always will
patient-centered practice of our specialty. be the raison d’etre of our discipline.
William R. Hazzard
2009
Preface
On behalf of the Editors, it is an honor and privilege to provide this multiple health professions and disciplines are represented among
Preface to Hazzard’s Geriatric Medicine and Gerontology, 6th Edi- the authors. Two of the textbook’s editors are women, and nearly
tion. In an accompanying Foreword for the 6th edition, Bill Hazzard 30% of the lead authors of chapters, as well as many other co-authors,
provides a brief history of this textbook, which has become a main- are women.
stay of the rapidly developing field of geriatric medicine. Adding A major step forward is the online version of the 6th edition. One
to the already rich history of this book, first published in 1985, of the original goals of working with McGraw-Hill as the publisher
the 6th edition emerges renewed and vibrant. It is particularly spe- of this textbook, as described in Bill Hazzard’s Foreword, was to
cial that it is the first edition of this textbook to carry the name provide a link with Harrison’s Principles of Internal Medicine. While
of its founding editor Bill Hazzard in its title. What we and our there have been a number of parallels with Harrison’s over previ-
publisher McGraw-Hill have done is to simply formalize the re- ous editions, the link becomes substantial with the online version
ality of the imprint that Bill Hazzard has made, as the textbook of Hazzard’s Geriatric Medicine and Gerontology, 6th Edition. Both
has been known informally as Hazzard’s Textbook already for many Harrison’s Online and Hazzard’s are part of McGraw-Hill’s Access
years. Medicine, a comprehensive online resource for medical students,
The 6th edition is substantially different from its predecessors, residents, clinicians, and researchers. In addition to Harrison’s On-
reflecting the substantial growth and increasing sophistication of line and Hazzard’s, Access Medicine includes the ability to quickly
geriatrics as a defined medical discipline. The main sections of this search across more than 50 titles from McGraw-Hill’s Clinical and
edition have been reorganized to make the sections more function- Lange Libraries. There are a number of important implications of
ally aligned. Vitality and continued rejuvenation has been enhanced our textbook becoming a part of McGraw-Hill’s Access Medicine.
through the addition of 9 new chapters: Inflammation and Aging, First, it adds a living presence to the textbook as additional material
International Gerontology, General Principles of Pharmacology, can be added as needed as online updates. We anticipate that such
Transitions (of care), Emergency Room Care, Rural Aging, Social updates will be available for many chapters of the textbook on a
Work, Psychoactive Drug Therapy, and Appropriate Antibiotic Use. regular basis. We are especially pleased that students of the health
Furthermore, we have recruited new authors for over 40% of the professions, both undergraduate and postgraduate, will have full ac-
chapters. As Bill Hazzard has outlined in his Foreword, three new cess to our textbook through the online version if they are at an
editors have played a critical role in the renewal of this textbook: institution that subscribes to Access Medicine. Finally, our authors
Sanjay Asthana. Kevin High and Stephanie Studenski. They have are no longer encumbered by page limits for the published text.
joined me (my 4th edition), Joe Ouslander (his 3rd edition) and Additional complementary material and illustrations, as well as ed-
Mary Tinetti (her 2nd edition) to make a vital new editorial team. ucational materials, can now be made available through the online
Fortunately for all of us, Bill Hazzard has stayed actively involved as edition.
Editor Emeritus and Senior Advisor. Thus just as our population is inexorably aging, and medicine is
The 6th edition acknowledges and recognizes the worldwide faced with an ever growing number of older patients with multiple
growth of the field of geriatric medicine in several ways. A distin- and complex problems, we have been able to bring together the best
guished International Advisory Board has been created; the previ- minds and leaders in the field to provide authoritative guidance,
ously mentioned, new chapter on International Gerontology sum- including a highly diverse and breadth of thinking that has not
marizes a number of important issues around the world; and we are previously existed in our textbook of geriatric medicine. We hope to
very pleased that 11 of the chapters in the 6th edition have been reach a broader audience through the availability of the electronic
written by authors who are in countries outside of the United States. version of the textbook and to keep it a living and growing document
Overall, our authors are a large and diverse group including many that encompasses the rapid stream of new information which is
geriatricians but also a substantial number of other specialists, who helping us to provide an evidence base for more effective care for
come from a range of medical and surgical disciplines. In addition our elderly population.
xxvii
xxviii Preface
Putting together a textbook of this magnitude requires enormous is made possible by the outstanding efforts of James Shanahan and
effort by many people. Again on behalf of the editors, I wish to colleagues who have ensured the progress of the publication and the
particularly thank the many chapter authors who have contributed important next steps in the textbook’s evolution. We especially ap-
to the book. Their dedication and commitment is exemplified by preciate the efforts of Nancy Woolard from Wake Forest University
Jonathan Ship, whose untimely death in 2008 is a major loss to the School of Medicine, who has served as a senior editorial assistant
field of geriatric dentistry. Jonathan wrote the Oral Cavity chapter for four previous additions. Her role has been critical to provide a
for the last three editions. Because it has become a classic, I asked strong link to our past history and as the final common pathway for
Jonathan if he would be willing to revise and update the chapter assembly of the 6th edition. We also wish to acknowledge the staff
for the 6th edition. We both knew that he had a terminal diagnosis that provided support for editorial efforts from our academic offices.
and would not likely live to see the final publication. However, I was These include Jane Harlow and Beverly Williams at the University
not surprised when Jonathan immediately accepted the invitation to of Michigan, Jane Mallory at Yale University, Lori Hasse at the Uni-
revise his chapter, which he did with his usual vigorous and thorough versity of Wisconsin, Sheila Rutledge at Wake Forest University, and
effort. A little bit of Jonathan thus lives on in the 6th edition. Susan Ratliff at Emory University.
The editors also greatly appreciate the strong and effective work-
ing relationship that we have with McGraw-Hill. This relationship
I
PART
PRINCIPLES OF
GERONTOLOGY
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1
CHAPTER
Biology of Aging and Longevity

Richard A. Miller
Aging is the process that converts young adults, most of them healthy test molecular ideas about the basis for the retardation of the aging
and in no need of assistance from physicians, into older adults whose process.
deteriorating physiological fitness leads to progressively increasing
risks of illness and death. The effects of aging are so familiar to health
professionals and aging adults that it is viewed by both parties as
WHAT IS AGING?
something immutable, taken for granted, an arena in which diseases
and their treatments take place, but not itself subject to intervention This question—what is aging?—is posed not as an invitation to se-
or modulation. The major discovery in biogerontology, gradually mantic quibbling, but to initiate reexamination of facts so familiar
emerging from decades of work in animal model systems, is that this that they are seldom examined. A case history of an individual who
old-fashioned viewpoint is wrong, and that the aging process can has mild arthritis, some loss of hearing acuity, some evidence of
be delayed or decelerated in mammals, built very much like human incipient cataract, loss of muscle mass and strength, a progressive
beings, by simple manipulations of nutritional signals and genetic decline in capacity for aerobic exercise, troubles with learning and
circuits similar to those already well-documented in people. It is now remembering, and an increased vulnerability to infectious illness
absolutely routine to extend lifespan, in rats and mice, by about 40%, would lead any physician to assume that the individual described
i.e., about 10 times the increase in active life expectancy that would is a man or woman of 60 or more years of age. But the list of signs
ensue from a complete elimination of all neoplastic illnesses, or all and symptoms refers with equal accuracy to a 20-year-old horse,
heart attacks, in a human population. It thus seems plausible that or a 10-year-old dog, or a 2-year-old mouse. The specific list of
a more detailed understanding of the factors that determine aging deficits and impairments shifts a bit from person to person, and
and the processes by which aging increases the risk of such a wide from species to species, but it is extremely rare to find an 80-year-
range of lethal and nonlethal illnesses and disabilities could, in the old person, or 3-year-old mouse, or 14-year-old dog that has avoided
foreseeable future, have a profound impact on preventive medicine. all of these age-associated problems. The aging process is synchro-
Aging is a mystery, in the same sense that infectious disease was nized, in that it is common to see all of these difficulties in older
once a mystery, and consciousness still is: an area of investigation people, horses, dogs, and mice, but rare to encounter any of them
in which well-informed researchers cannot really be confident that in young adults just past puberty. This synchrony, though entirely
they have selected a line of investigation bound to be productive. familiar to schoolchildren, physicians, and scientists alike, is the cen-
Until recently, most published papers in biogerontology journals tral challenge in biological gerontology: how is it that such a process
consisted of descriptions of the ways in which young mice, rats, or affects so many cells, tissues, organs and systems at a rate that varies,
people differed from older ones, originally in terms of anatomy and even among mammals, over a 100-fold range from the shortest lived
physiology, as indicated by levels of enzymes or hormones, and more shrews to the longest lived whales? Structural features of shrews,
recently by exhaustive catalogs of protein and mRNA levels. This mice, dogs, and people are remarkably similar at scales from the ar-
descriptive era is gradually being superseded by one focused on spe- rangement of DNA and histones in the nucleus, to the architecture
cific molecular hypotheses about the key factors that regulate aging. of the kidney, heart, and thymus, to the role of the central nervous
The foundation of this modern approach to the biology of aging was system (CNS) and endocrine systems in regulating responses to heat
the development of genetic models and nutritional manipulations and cold, hunger and thirst, infection, and predators. Why, then, in
which could delay aging, and the exploitation of this leverage to molecular terms, will the eye, kidney, immune system, brain, and
4 PART I / Principles of Gerontology
joints of a mouse last only 2 to 3 years under optimal conditions, aging, it has seemed implausible to regard aging as less complex than
while the same cells and organs and systems persevere for 50 or more its (apparent) constituents. Considering aging as a process, rather
years in people, and longer still in some species of whales? than a collection of complex processes, has thus seemed to be an
The definition proposed at the beginning of this chapter—aging oversimplification.
as a process for turning young adults into distinctly less healthy old However, two lines of evidence support the merits of the view of
ones—is straightforward enough to appear simple-minded, but in aging as a unitary process, with its own (still ill-defined) physiological
practice draws some prominent distinctions. In this view, aging is not and molecular basis, which underlies and tends to synchronize the
a disease: Diseases are certainly among the most salient consequences multiple changes seen in older individuals. The first of these discov-
of aging, but aging produces many changes not classified as diseases, eries was caloric restriction: The observation that rodents allowed to
and many diseases also affect young people. Similarly, lifespan and eat only 60% of the amount of food they would voluntarily consume
mortality risks are influenced by many factors besides aging. Thus, would live 40% longer than controls permitted free access to food.
evidence that a gene or diet or public health measure has altered This observation, first made by McCay in the 1930s, has now been
life expectancy, upwards or downwards, does not imply that the repeated in more than a dozen species in scores of laboratories, and
effects have been achieved by an effect on aging. In the context of ongoing studies in rhesus monkeys have now produced preliminary,
the whole organism definition of aging used in this chapter, it is but highly suggestive, evidence that similar benefits may accrue in
hard to interpret the meaning of changes that occur as individual our own order of mammals. The key point is not merely that lifes-
cells “age” in tissue culture. While cell culture studies can provide pan is extended, but that nearly all of the consequences of aging are
valuable information of great relevance to ideas about aging, the two coordinately delayed. Caloric restriction delays changes in cells that
processes are likely to be fundamentally different. proliferate continuously (such as gut epithelial cells), cells that can
From a biological standpoint, a critical distinction is the differ- be triggered to proliferate when called upon (such as lymphocytes),
ence between aging and development. Development creates a healthy and those that never proliferate (such as most neurons), as well as
young adult from a fertilized egg, and is strongly molded by natural on tissues that are extracellular or acellular (such as lens tissue and
selection. Genetic mutations that impair development, creating a extracellular collagen fibrils). It delays aspects of aging characterized
slower falcon, a near-sighted chipmunk, or a chimpanzee uninter- by excess proliferation, such as neoplasias, and those characterized by
ested in social cues, are rapidly weeded from the gene pool. But the failure to proliferate (such as immune senescence). It delays or decel-
force of natural selection diminishes dramatically at ages that are erates age change at the tissue level (such as degradation of articular
seldom reached. Mice, for example, typically live only 6 months or cartilage) and those involving complex interplay among multiple
so in the wild, before they succumb to predation, starvation, or other cells and tissues (such as loss of cognitive function and endocrine
natural hazard. There is strong selective pressure against mutations control circuits). Because caloric restriction alters, in parallel, so vast
that cause cataracts in the first few months of mouse life, but little or an array of age-associated changes, it seems inescapable that these
no pressure against genotypes that postpone cataract formation for many changes, distinct as they are, must be in some measure timed,
2 years. Mice protected, in a laboratory setting, against predation, i.e., synchronized by a mechanism altered by caloric intake.
starvation, and other risks typically do develop cataracts in their A second, more recent, set of experiments leads to the same in-
second or third year. In wolves, however, a genotype that delayed ference. In 1996, Bartke and his colleagues showed that Ames dwarf
cataracts for only 2 years would be a disaster; natural selection favors mice, in which a developmental defect in the pituitary impairs pro-
wolf genes that preserve lens transparency for a decade or more. A duction of growth hormone (GH), thyrotropin, and prolactin, had
similar process, working on our ancestors in environments where an increase of more than 40% in both mean and maximal lifes-
survival to 15 was common, but survival to 55 distinctly uncom- pan compared to littermates with the normal allele at the same lo-
mon, has filled our own genome with alleles that postpone cancer, cus. Since then studies of this mutant, and the closely similar Snell
osteoarthritis, coronary disease, Alzheimer’s, presbycusis, cataracts, dwarf, have documented delay in kidney pathology, arthritis, cancer,
sarcopenia, immune senescence, and many other familiar maladies, immune senescence, collagen cross-linking, cataracts, and cognitive
for about 50 to 60 years. Thus, although aging and development decline, making a strong case that these genetic changes in endocrine
seem, superficially, to be similar processes in that both lead to changes levels do indeed modulate the aging process as a whole, with con-
in form and function, they are different in a fundamental and critical sequent delay in a very wide range of age-synchronized pathology.
way: Development is molded directly by the forces of Darwinian se- Since 1996, mouse researchers have documented increased lifespan
lection and the changes of aging are the consequence of the failure of in at least nine other mutations, of which five others, like the Ames
these selective processes to preserve function at ages seldom reached and Snell mutations, lead to lower levels of or responses to GH
by individuals in any given species. and/or its mediator insulin-like growth factor I (IGF-I).
These observations, on calorically restricted (CR) rodents and
now also in mutant mice, justify a sea change in thinking about
Aging as a Coordinated, Malleable Process
aging and its relationship to disease. The new framework includes
The definition of aging as a process that turns young adults into old two key tenets: (1) the aging process, despite the complexity of its
ones conflicts with a view of aging as instead a collection of pro- many effects, can usefully be considered as a single, coordinating
cesses, some that lead to arterial disease, some that affect endocrine mechanism and (2) the rate at which aging progresses can be decel-
function, some that impair cognition or cause neoplastic transfor- erated in mammals as well as in other taxa. From this perspective,
mation, etc. Because each of these ailments is itself the outcome of a fundamental challenge to biogerontologists is to develop and test
a complex interaction among many factors, including genes, diet, models of how age-dependent changes are themselves coregulated,
accidents, viruses, toxins, antibiotics, and physicians, and because during middle age, to produce old people or old mice or old worms.
each of these diseases, and many others, seems an inextricable part of Studies of the aged, as opposed to studies of aging, are relevant to this
CHAPTER 1 / Biology of Aging and Longevity 5
challenge only insofar as they are exploited to generate or test ideas has already been implicated in control of cell death in human and
about coregulation and synchrony, rather than ideas about disease- rodent cells, and studies of the role of FoxO family members in aging
specific pathogenesis. The key resource for meeting the challenge is are under way. A second family of proteins, the sirtuins, was initially
not comparisons between young and old donors, but rather com- implicated in lifespan regulation in studies of the budding yeast
parisons between young or middle-aged adults who are known to be Saccharomyces cerevisiae, but then shown also to be able to increase
aging at different rates. Fortunately, the same experiments that have lifespan in nematode worms. There is some evidence that members
documented the malleability of aging rate have done so by producing of the sirtuin family may contribute to the improved health and
sets of animals that do indeed age at normal or slower-than-normal longevity of mice on a calorie-restricted diet, and interest in these
paces. With luck, future studies may produce at least tentative an- proteins has been spurred by observations that median lifespan of
swers to the two key questions in biogerontology: How does aging mice on a diet high in saturated fat can be increased significantly
produce the signs and symptoms of aging and what controls the rate by resveratrol, whose many biochemical effects include stimulation
of this process in mammals? of sirtuin activity. Work with invertebrates has also brought new
attention to the possible role of TOR, the “target of rapamycin,”
in control of lifespan and responses to dietary interventions. TOR
Key Themes from Studies of Invertebrate Models
plays a major role, conserved throughout the evolutionary tree, in
Four main ideas have emerged, in the period 1990–2008, from regulating protein translation rates in response to both external cel-
studies of genetically convenient invertebrate models, the nema- lular stress and the available supply of amino acids. TOR inhibition
tode worm Caenorhabditis elegans and the fruit fly Drosophila by rapamycin is a mainstay of clinical immunosuppressive therapy
melanogaster. (1) Single gene mutations—lots of them—can extend after organ transplantation, and TOR inhibitors also show promise
lifespan in worms and flies (and mice). Most mutations discovered so as antineoplastic agents. Other molecular circuits, including those
far are “loss of function,” in which eliminating or crippling the gene triggered by the p66 (shc) protein, the tumor-suppressor p53, and
product leads to slower aging and lifespan extension. (2) The genes the stress-responsive kinase JNK, were initially discovered through
whose elimination slows aging are typically those used by the normal work with rodents and now are also being examined in the context
animal to notice and respond to environmental poverty; they are se- of invertebrate models for aging. Each of these biochemical path-
lected, by evolution, to permit the animal to take on alternate forms ways has powerful and still only partially defined links to hormonal
or functions to deal with the relative absence of nutritional con- signals, neoplastic transformation, stem cell homeostasis, and the
ditions optimal for rapid growth and reproduction. Many of these balance between cell growth and cell death, so their elucidation is
genes are familiar to physicians and biological scientists: they encode likely to provide both rationale and direction for translational work
insulin, insulin-like growth factors, possibly thyroid hormones, and aimed at slowing the aging process and retarding age-related disease
other regulators of fuel usage and metabolic fluxes, as well as the and dysfunction.
intracellular proteins that change cell properties in response to these
hormones. (3) The mutations that extend lifespan in worms and
Delayed Aging in Mice and Rats
flies (and perhaps in mice) render the animals more resistant to
lethal injury, such as that resulting from heavy metals, ultraviolet ir-
Caloric Restriction
radiation, heat, oxidizing agents, and chemicals that damage DNA.
It thus seems plausible that augmentations of stress resistance are Mice or rats fed approximately 30% or 40% less food than they
the mechanism by which these mutant genes slow aging. (4) This would ordinarily consume typically live up to 40% longer than freely
three-way association, connecting aging to stress to signals about fed animals. These CR animals stay healthy and active, with good
nutrition, has very deep evolutionary roots and can be noted (albeit physical, sensory, and cognitive function, at ages at which most of
with species-specific nuances) in yeast, flies, worms, and mice. The the controls have already died. The intervention extends lifespan if
suggestion here is that the pathways tying nutrition to stress to aging initiated at very young ages (e.g., at weaning), or when started early
rate evolved extremely early in the eukaryotic lineage, in an ancestor in adulthood (e.g., at 6 months, in a species where puberty occurs
predating the branch points between yeast, flies, worms, and verte- at 2 months and median survival is about 28 months). Whether CR
brates. The key implication is that investigations into the cell biology diets extend lifespan when initiated in animals already older than
of these linked processes in conveniently short-lived organisms may half the median lifespan is controversial, with some early studies
provide valuable insights into aging and disease in humans. suggesting little or no response, and some more recent experiments
leading to a positive result. Lifespan can be extended using CR di-
ets of widely varying composition, and there is strong evidence that
Molecular Leads for Further Study
total caloric intake, rather than proportions of specific fuel sources
Studies of the invertebrate model systems have also called attention (carbohydrates, fats, proteins), is responsible for the beneficial ef-
to a range of intracellular pathways that influence longevity, per- fects. CR diets do not, except in the first few months after their
haps through regulation of resistance to a variety of forms of lethal imposition, alter metabolic rate or oxygen consumption per gram of
and metabolic stress. Components of these pathways are now under lean body mass because CR rodents lose weight, or if adolescent fail
scrutiny to see if they also affect aging and disease in rodents. Many to gain weight, so that lean body mass matches calorie supply once
of the antiaging mutations in worms, for example, act by increasing equilibrium is established. Although CR rodents are less obese than
the actions of a DNA-binding factor called Daf-16, whose targets control animals, it seems unlikely that the effect of CR diets on aging
include genes that modulate resistance to oxidative damage, DNA is caused entirely by avoidance of obesity, in part because CR diets
repair, and other modes of cellular defense. The mammalian equiva- extend lifespan in mice genetically engineered to lack leptin (ob/ob
lent to Daf-16, a member of the FoxO group of transcription factors, mice). When placed on a CR diet, ob/ob mice are both longer lived
and more obese than normal mice with normal caloric intake. There of hormones in the insulin/IGF family, i.e., the same family of signals
is some evidence that CR diets can delay at least some aspects of implicated in lifespan extension in worms and (later) flies, provided a
aging, for example, changes in immune function, in nonobese rhe- key foundation for exploiting comparative cell biology in biogeron-
sus monkeys, but definitive evidence, based on lifespan data, is not tology research. Subsequent work then showed that similar degrees
yet available. of lifespan extension could be seen in Snell dwarf mice, whose en-
Mice and rats on CR diets show delay or deceleration in a very docrine defects are very similar to those of Ames dwarfs, and also
wide range of age-dependent processes, including neoplastic and in mice that lack the GH receptor (GHR-KO mice) (Figure 1-1).
nonneoplastic diseases, changes in structure and function of nearly This last observation, together with documented lifespan extension
all tissues and organs evaluated, endocrine and neural control cir- in mice lacking GH-releasing hormone receptor (GHRHR) and in
cuits, and ability to adapt to metabolic, infectious, and cardiovascular mice with diminished expression of the IGF-I receptor (IGF1R het-
challenges. Mouse stocks that have been engineered for vulnerability erozygotes), suggested strongly that a common factor, i.e., low pro-
to specific lethal diseases, such as models of lupus or early neopla- duction of or response to IGF-I, is a major cause of lifespan extension
sia, also tend to live longer when placed on a CR diet. Intensive in all five models, although it is certainly possible that other factors,
study of CR rodents in the past 20 years has suggested many ideas such as altered insulin sensitivity, thyroid tonicity, adipokine levels,
about the mechanism of its effects, including ideas about altered etc., may contribute to antiaging effects in some of these mouse
levels and responses to glucocorticoids and/or insulin, increases in models. Male and female mice are affected by each of these muta-
stress-resistance pathways including resistance to oxidative injury, ditions except that the effect of the IGF1R mutation seems stronger
minished inflammatory responses, changes in stem cell self-renewal, in females than in males. Mice in which tissue levels of IGF-I are
and many others, each plausible, none of them at this point more reduced by genetic manipulation of a protease that controls local
than plausible. Further work on the early and midterm effects of concentrations of IGF-I binding proteins are also long-lived, again
CR diets is among the most attractive avenues for testing basic ideas consistent with models in which abnormally low IGF-I levels cause
about aging in mammals. lifespan extension in mice. Studies of Snell and Ames dwarf mice
have shown that the exceptional longevity of these mice is accom-
panied by a delay or deceleration of age-dependent changes in T
Methionine-Restricted Diets
lymphocytes, skin collagen, renal pathology, lens opacity, cognitive
Rats fed a diet containing much reduced levels of the essential amino function, and neoplastic progression; taken with the lifespan data,
acid methionine were shown, in 1993, to live 40% longer than rats, these observations suggest strongly that these mutations, like the CR
on a standard diet, and more recent work has shown a similar, though diet, act to slow the aging process itself.
smaller, effect on mice. These animals are not calorically restricted— In addition to the six mutations that lead to lower levels of IGF-I
they eat more calories, per gram of lean body mass, than control rats, signals, there are now five other mutations that have been shown,
and rats pair-fed normal food at levels that match the total caloric in each case in a single unreplicated report, to extend lifespan in
intake of a methionine-restricted (MR) rat show a much smaller de- mice. Table 1-1 presents a summary of these 11 published mutations
gree of lifespan extension. MR diets could, in principle, affect aging that extend maximal lifespan in mice. Transgenic overexpression of
by causing changes in protein translation or rate of protein turnover, urokinase-type plasminogen activator in the brain has been reported
by changes in DNA methylation (which depends upon metabolites to produce a significant extension of lifespan, perhaps by suppression
of methionine), by alterations in levels or distribution of the an- of appetite with consequent mimicry of a CR diet. Mice in which
tioxidant glutathione (also a metabolite of methionine), by changes the insulin receptor has been inactivated specifically in adipose tissue
in hormone levels (MR mice show low levels of insulin, glucose, show an 18% lifespan increase, consistent with the idea that altered
and insulin-like growth factor 1, IGF-I), or by induction, through insulin sensitivity or adipokine levels might play a role in aging rate
hormesis, of augmented stress response pathways at the cellular level. in this species. Transgenic mice overexpressing the klotho protein,
Some of these ideas could be tested using diets that restrict levels of a cofactor for fibroblast growth factor (FGF) signals whose absence
other amino acids, and there is older, fragmentary evidence that such leads to early death by elevation of vitamin D levels, have been re-
diets, too, may induce lifespan extension in rodents. MR is thus the ported to live 19% to 31% longer than controls, perhaps reflecting
second confirmed method for extending lifespan in mammals and the ability of klotho to block insulin or IGF-I signals. A mutation
comparisons of similarities and differences between CR and MR that inactivates the 66 kDa splice variant of the Shc protein, in-
rodents are likely to prove highly informative. volved in the pathway to programmed cell death after exposure to
hydrogen peroxide or ultraviolet light, also extends longevity (by
about 28%), as does transgenic overexpression, in mitochondria, of
Single-Gene Mutations That Extend Mouse Lifespan
catalase, an enzyme involved in detoxification of hydrogen perox-
The initial reports in the 1980s and 1990s that mutations of single ide (a 20% lifespan increase). These last two reports, if confirmed
genes in worms, and then in flies, could produce dramatic increases in other laboratories, may give new insights into the connections
in lifespan were the strongest support, along with the CR data, for linking aging and late-life diseases to agents that damage DNA or
viewing aging as a unitary process that could be decelerated. The induce oxidative injury at intracellular sites.
report in 1996 by Bartke and his colleagues that the lifespan of mice More work is needed to determine to what extent these mutations
could be extended more than 40% by mutation of a gene required influence common pathways, to see whether they do or do not influ-
for pituitary development opened the door to new genetic models ence aging through the same mechanism. It is possible, for example,
for study of aging in mammals. This Ames dwarf gene (Prop1) leads that some of these mutations diminish risk of cancer, a common
to an endocrine syndrome featuring low levels of growth hormone cause of death in many inbred mouse strains, without effect on any
(GH), IGF-I, thyrotropins and the thyroxines, and prolactin. The other age-dependent trait, while others may modulate the effects
observation that longevity in mice could be improved by reduction of aging on multiple organ systems, thus diminishing mortality risk
A B
C D
FIGURE 1-1. (A) A young adult Snell dwarf mouse, with a littermate control (on the vehicle). (B) Survival curves for Snell dwarf (dw/dw) mice and littermate
controls. (C) Glomerular basement pathology scores, at terminal necropsy, for Snell dwarf (N = 40) and control (N = 46) mice. Higher scores indicate a
greater degree of kidney pathology. Despite living 40% longer, a higher percent of Snell dwarfs had 0 scores at necropsy and a smaller percent had scores
of 2 or 3. (D) Cataract scores determined by slit lamp examination in Snell dwarf and littermate control mice at 18 and 24 months of age. p < 0.001
for the difference between dwarfs and controls at each age. (B) Data from Flurkey K, Papaconstantinou J, Miller RA, Harrison DE. Lifespan extension and
delayed immune and collagen aging in mutant mice with defects in growth hormone production. Proc Natl Acad Sci U S A. 2001;98(12):6736–6741. (C
and D) Data from Vergara M, Smith-Wheelock M, Harper JM, Sigler R, Miller RA. Hormone-treated Snell dwarf mice regain fertility but remain long-lived
and disease resistant. J Gerontol Biol Sci. 2004;59:1244–1250.
from both neoplastic and nonneoplastic diseases. There are hints, for that the effects are at least partly additive. The survival curves in Fig-
example, that CR diets and the Ames dwarf gene may affect longevity ure 1-2 also suggest that the Ames dwarf mutation may be affecting
by different mechanisms. As shown in Figure 1-2, caloric restriction the age at which deaths begin to occur (“delay” of aging), and that
extends lifespan in normal as well as in dwarf mice, and the Ames the CR diet may affect, instead, the rate at which deaths occur once
mutation extends lifespan on both CR and control diets, showing mortality risks become detectable (“deceleration” of aging). Dwarf
TABLE 1-1
Mouse Mutants That Improve Longevity
MUTATION EFFECT ON LIFESPAN (%) COMMENT
Ames dwarf (df), Prop1 50 Low GH, IGF-I, thyrotropin, thyroxine, prolactin
Snell dwarf (dw), Pit 42 Low GH, IGF-I, thyrotropin, thyroxine, prolactin
GHRHR (lit, little) 23 Low GH, IGF-I
Survival increase on low-fat diet only
GHR-KO 42 Low IGF-I
IGF-I receptor 26 Heterozygous mice; significant only in females only
Pregnancy-associated plasma protein A, PAPP-A 38 Protease for IGF-I binding proteins
Klotho transgenic 19–31 Impairs insulin and IGF-I signals
Insulin receptor; FIRKO 18 Receptor diminished in adipose cells only
Shc-66 28 Lower apoptosis after UV, H2 O2
Urokinase-type plasminogen activator, uPA 18 Transgenic, expressed in brain; may suppress appetite.
Catalase transgenic, MCAT 19 Overexpression in mitochondria only
FIRKO, fat-specific insulin receptor knockout; GH, growth hormone; GHRHR, growth hormone–releasing hormone receptor; GHR-KO, growth hormone receptor knockout; IGF-I, insulin-like growth factor I;
MCAT, mitochondria-specific catalase transgenic; PAPP-A, pregnancy-associated plasma protein A; UV = ultraviolet; Pit-1, POU domain, class 1, transcription factor 1; Prop-1, prophet of Pit-1; Shc-66, 66
kDa splicing isoform of Src homology 2 domain containing transforming protein 1.
mouse stocks bred by selection for slow early life growth trajectory
are found to be smaller than controls and also longer-lived. There
is also highly suggestive evidence for a similar relationship between
IGF-I, body size, and lifespan in dogs and horses. For dogs, several
studies have shown greater longevity in small-size breeds than in
large breeds, and a strong relationship between body size and life
expectancy among mixed-breed (mongrel) dogs as well (Figure 1-3).
Anecdotal and limited published data suggest that pony breeds of
horses are also substantially longer lived than horses of full-sized
breeds. The relationship between body size and life expectancy in
humans is complicated by the strong effects of socioeconomic sta-
tus on both endpoints: wealthier people tend to be both taller and
longer-lived than poor people. On the whole, tall stature is associated
with lower mortality risks from cardiovascular diseases, which are a
FIGURE 1-2. Survival curves for genetically normal (wild-type [WT]) or major cause of mortality in developed countries. In contrast, a re-
Ames dwarf (df) mice on caloric-restricted diet (CR) or on unrestricted ad libi- markably consistent set of studies (Table 1-2) show that tall stature
tum (AL) food intake. Each symbol represents a mouse dying at the indicated
age. The dwarf mice live longer than the WT mice on either diet, and the CR
is associated with significantly higher mortality risk from a wide
diet extends the life span of mice of either genotype. Reproduced with per- range of neoplastic diseases. There is also limited data that cente-
mission from Bartke A, Wright JC, Mattison JA, Ingram DK, Miller RA, Roth, narians, on average, were shorter as mature adults than those who
GS. Extending the lifespan of long-lived mice. Nature. 2001;414:412. do not attain centenarian status. Testing the idea that short midlife
stature is associated with delayed or decelerated aging in humans
will depend on measuring a wide range of age-dependent traits,
and CR mice also differ dramatically in adiposity (CR mice are ex- rather than merely lifespan, on large populations of middle-aged
tremely lean; dwarf mice have average or above-average proportions people.
of fat), and in resistance to liver toxicity induced by acetaminophen
poisoning. Analysis of the mechanisms by which each of the muta-
Stress Resistance and Aging
tions shown in Table 1-1 affects lifespan and age-dependent traits
will help to sort out questions about whether initial mortality rate Mutations that extend lifespan in invertebrates typically render the
and mortality rate doubling time are under separate physiological animals resistant to multiple forms of lethal injury, whether the
control. threat comes from oxidative agents, heat, heavy metals, or irra-
As Table 1-1 suggests, the evidence from mice indicates that diation. Indeed, this stress resistance seems likely to represent the
diminution of IGF-I levels, either in early life, adult life, or per- mechanism by which these mutations delay the aging process. Thus
haps both, can create mice that are long-lived compared to controls. presumably much of the cellular and extracellular pathology that
The association has also been noted using experimental designs in produces dysfunction and increases mortality risk in older animals
which individual mice are tested for IGF-I levels as young adults: is held in abeyance by the same, poorly defined, defenses that permit
those mice with the lowest IGF-I levels were found to live signifi- nematodes and flies to survive when exposed to external stress in an
cantly longer than those with higher IGF-I concentrations. Similarly, experimental setting. Genetic dissection of the relevant pathways has
A B
FIGURE 1-3. Longevity, size, and insulin-like growth factor I (IGF-I) levels among breeds of purebred dogs. Left panel shows mean breed lifespan as a
function of mean breed weight for each of 16 breeds of dogs; three breeds are indicated by arrows. Data from Li Y, Deeb B, Pendergrass W, Wolf N.
Cellular proliferative capacity and life span in small and large dogs. J Gerontol A Biol Sci Med Sci. 1996;51(6):B403–B408. Right panel shows mean
plasma IGF-I levels as a function of body mass in eight breeds of purebred dogs. For details and citations see Miller and Austad. Growth and aging: why
do big dogs die young? In: Masoro EJ, Austad, SN, eds. Handbook of the Biology of Aging. 6th ed., New York, New York: Academic Press; 2006.
TABLE 1-2
Population-Based Association Between Short-Stature and Lower Mortality Risk for Multiple Neoplastic Diseases
TEST POPULATION TALL PEOPLE DO BETTER SHORT PEOPLE DO BETTER
15 000 Scots All-cause stroke Colorectal, prostate, hematopoietic cancers

Coronary disease
12 000 NHANES (United States); men Cancers; 40–60% effect; adjusted for race, smoking, income
NHANES women Breast and colorectal cancer
22 000 U.S. male physicians Cancer; adjusted for age, BMI, exercise, smoking
570 000 Norwegian women Breast cancer
400 000 American women Breast cancer, postmenopause
1.1 million Norwegians Esophageal cancer
England and Wales (by county) All-cause mortality Breast, prostate, ovarian cancer
Ischemic heart disease
NHANES, National Health and Examination Survey.

For reference citations, see Miller RA, Austad, SN. Growth and aging: why do big dogs die young? In: Masoro EJ, Austad SN, eds. Handbook of the Biology of Aging. 6th
ed. New York, New York: Academic Press; 2006:512–533.
shown, surprisingly, that in normal, nonmutant worms, the levels of by cadmium, peroxide, heat, a DNA alkylating agent (MMS), ul-
stress resistance, and thus resistance to aging, are actively diminished traviolet light, and paraquat (which induces mitochondrial damage
by specific DNA-binding transcription factors. These factors, whose by free radical generation). Mice prepared by CR or MR diets are
human homologs are members of the FoxO family, are retained by resistant to liver damage induced by the oxidative hepatotoxin ac-
evolutionary pressures because they provide reproductive advantages etaminophen, and long-lived mutant mice are somewhat more re-
in the natural environment, in which animals must be able to quickly sistant to death induced by paraquat injection. Stress resistance also
take advantage of transient access to nutrients. Genetic inactivation seems to play a role in evolution of long-lived species in that cells
of these FoxO pathways in the laboratory produces mutant animals from long-lived rodents and other mammals are resistant in culture
that are not ideally suited for natural conditions, but which are resis- to several forms of oxidative and nonoxidative damage. This work
tant to many kinds of stress and which age more slowly than normal. provides initial support for models that attribute variations in aging
Studies of gene expression patterns in the long-lived mutant worms rate to differences in stress resistance pathways, but many questions
have shown that the FoxO proteins can trigger transcription of over remain unanswered at this early stage. Figure 1-4 shows representa-
100 genes that together protect against many different forms of cel- tive results for resistance to stress in long-lived mutant worms and
lular damage. The list includes enzymes that destroy free radicals, cells from long-lived mutant mice, as well as data on resistance of
heat shock proteins, and other chaperones that guard against mis- CR and MR mice to an oxidative hepatotoxin. Figure 1-5 presents
folded proteins, proteins that protect against infection, and chelating data from two studies showing stress resistance in culture of cells
agents that bind toxic metal ions, among others. from longer-lived mammalian species.
The connection between induction of these stress-resistance path-
ways and late-life diseases has been shown by two sets of informative
Genetic Approaches to Analysis of Aging in Humans
experiments. In the first, genetically identical worms were exposed
to a brief, nonlethal heat stress, and physically separated into those Attempts to find genetic variations that influence aging in humans
that showed a strong response of chaperone proteins and those that have been plagued with practical and conceptual problems in ad-
did not. Worms with the most robust response to transient stress dition to the obvious difficulty that selection of mating partners is
were found to be longer lived than those with lower stress responses. not amenable to experimental control. For one thing, heritability
A second approach involved worms bearing genetic variants that calculations show that only about 15% to 20% of the variation in
cause aggregation of proteins and neurodegeneration (Huntington’s lifespan among humans can be attributed to genetic factors. Fur-
disease) in people; neurological dysfunction in these worms can thermore, an unknown but potentially large fraction of this genetic
be delayed, and in some cases prevented entirely, by augmenta- variation probably reflects genetic variants that influence susceptibil-
tion of the FoxO-dependent stress-resistance pathways. Similarly, ity to diseases of childhood, infectious agents, and specific common
age-dependent increases in susceptibility to stress-induced cardiac illnesses of old age. For example, genetic variants that cause Hunt-
arrhythmias in Drosophila can be significantly postponed by activa- ington’s disease or type 1 diabetes or which triple the normal risk of
tion of FoxO-dependent protective pathways. myocardial infarction by the age of 50 years would all contribute to
Studies of the relationship of stress resistance to aging in mam- the measured heritability of lifespan, but do so by altering mortality
mals are underway, but suggestive data have begun to emerge. Both risks from a specific form of illness rather than by alteration of aging
CR diets and at least some of the long-lived endocrine mutant stocks with its effects on multiple late-life traits. Thus genetic variants that
show elevated levels of enzymes with antioxidant action, heavy metal mold lifespan by effects on aging per se, if they exist at all, are likely
chelators, and intracellular chaperone proteins, as well as have lower to influence only a small fraction of variation (perhaps 5%) in how
levels of oxidative damage to DNA, proteins, and lipids. Cells grown, long people live.
in tissue culture, from long-lived Snell and Ames dwarf mutant mice, Formal analyses of the genetics of human aging have so far re-
or from mice lacking GH receptor, are resistant to lethal injury caused lied mostly on candidate gene approaches, in which the investigator
Maximum Lifespan (percent of N2)

300 e1391
250 e979 e1369
200 m212 m579

m596
e1368
m120
150 sa193
m577 e1371 e1370
100 N 2 m 41 e1365
100 120 140 160 180 200

Thermotolerance (percent of N2 controls)
A B
C D
FIGURE 1-4. Association of stress resistance to longevity. (A) Resistance to heat shock (thermotolerance) is higher in mutant worms that have extended
longevity. Each point is the mean for one mutant strain. (B) Resistance of skin-derived fibroblasts to lethal hydrogen peroxide concentrations is higher in cells
from Ames dwarf (df/df) mice compared to controls. Each symbol shows an individual mouse. (C) Hydrogen peroxide (H2 O2 ) resistance of skin-derived
fibroblasts from long-lived growth hormone receptor knock out (GHRKO) mice. LD50 is the amount of peroxide that kills 50% of the cells. (D) Resistance of
calorie-restricted (Cal-R) mice to liver injury induced by injection of acetaminophen (APAP); serum LDH levels indicate the level of damage to hepatocytes at
varying intervals after a single injection (unpublished data of Chang and Miller). (A) Reproduced with permission from Gems D, Sutton AJ, Sundermeyer
ML, et al. Two pleiotropic classes of daf-2 mutation affect larval arrest, adult behavior, reproduction and longevity in Caenorhabditis elegans. Genetics.
1998;150:129–155. (B and C) Reproduced with permission from Salmon AB, Murakami S, Bartke A, Kopchick J, Yasumura K, Miller RA. Fibroblast cell
lines from young adult mice of long-lived mutant strains are resistant to multiple forms of stress. Am J Physiol Endocrinol Metab. 2005;289(1):E23–E29.
A B
FIGURE 1-5. Stress resistance in fibroblasts from animals of long-lived species. Left panel: Resistance of cultured skin fibroblasts to hydrogen peroxide
as a function of species maximum lifespan in years. Species, from left to right, are hamster, rat, rabbit, sheep, pig, cow, and human. Reproduced with
permission from Kapahi P, Boulton ME, Kirkwood TB. Positive correlation between mammalian life span and cellular resistance to stress. Free Radic Biol
Med. 1999;26(5–6):495–500. Right panel: Resistance of cultured skin fibroblasts to cadmium as a function of species maximum lifespan in years. Species,
left to right, are laboratory mouse, wild-caught mouse, rat, red squirrel, white-footed mouse, deer mouse, fox squirrel, porcupine, beaver, and little brown
bat. LD50 is the amount of hydrogen peroxide or cadmium that kills 50% of the cells. Reproduced with permission from Harper JM, Salmon AB, Leiser SF,
Galecki AT, Miller RA. Skin-derived fibroblasts from long-lived species are resistant to some, but not all, lethal stresses and to the mitochondrial inhibitor
rotenone. Aging Cell. 2007;6:1–13.
evaluates long-lived and control populations for variations at one elderly people in some ways: they frequently suffer from cataracts and
or a small number of genetic loci, selected on theoretical grounds premature graying of the hair, and by their early thirties often develop
as most likely to be involved in aging or disease processes. The osteoporosis, diabetes, and atherosclerosis. On the other hand, many
alternate approach, whole genome screening of large populations for features of normal aging are not seen in Werner’s patients and many
association of longevity to hundreds of thousands of genetic variants, features of Werner’s syndrome are not seen in normal old individu-
is also beginning to produce initial results at an accelerating pace. als. Werner’s syndrome patients, for example, do not show signs of
Although most of the published studies, and those in progress, focus Alzheimer’s disease or other amyloidoses, hypertension, or immune
on nuclear genes, there are tantalizing suggestions from studies of failure. Mesenchymal tumors, which are rare in normal people, are
large families that a surprisingly high proportion of inherited effects about 100-fold more frequent in Werner’s patients, but the epithelial
on lifespan may come through the maternal line alone, suggesting and hematopoietic tumors characteristic of normal aging are not seen
that variations in mitochondrial gene sequences (which are inherited in Werner’s syndrome patients. Furthermore, Werner’s patients ex-
almost entirely from mothers to both sons and daughters) may also hibit many features that are not seen in normal aging, including sub-
influence life expectancy in humans. cutaneous calcifications, altered fat distribution, vocal changes, flat
A major problem with all these approaches, from the perspective feet, malleolar ulcerations, high levels of urinary hyaluronic acid, and
of biological gerontology, is the lack of a defensible phenotype: a a number of other idiosyncrasies not seen commonly in elderly indi-
measure of aging better than lifespan. There are now several dozen viduals. Mice with mutations in the WRN gene live a normal lifespan
reports of candidate loci at which particular alleles are overrepre- and do not show signs of premature senescence. It seems possible that
sented among centenarians or near-centenarians, and advocates of investigation of the pathogenesis of Werner’s syndrome may provide
this strategy hope that among this collection are some loci that con- key clues to the mechanisms of age-related diseases. But it seems
trol aging rate. But skeptics note that alleles that increase risk of at least equally plausible that the WRN mutation, perhaps through
cardiac disease, or Alzheimer’s disease, or stroke, or various common alteration of cells responsible for connective tissue maintenance, in-
forms of cancer, or severe osteoporosis are likely to have contributed duces multiorgan failure through processes quite distinct from the
to disease and death before the age of 90 or 100 years, and thus to changes that impair some of the same organs in normal aging.
have been eliminated or greatly reduced among the very old. Thus
it should be assumed that a collection of genetic loci whose fre-
quency discriminates very old people from others of the same birth
AGING, CELLULAR SENESCENCE, TELOMERES,
cohort will include many genes with influence over common forms
AND CANCER
of lethal illnesses rather than genes that modulate aging per se. This
problem is not one that can be solved by technological innovation The famous observation of Hayflick that human diploid fibrob-
or larger numbers of tested subjects; it requires development of a lasts cease to grow in culture after a limited number of population
phenotype that provides more information about health in old age doublings sparked a line of experimentation that continues to yield
than merely a record of the age at death. For example, a genetic allele important insights into the molecular control of cell growth, differ-
that identified, among 70-year-old people, those most likely to have entiation, and neoplastic transformation. Human fibroblasts placed
excellent eyesight and hearing, no history of cancer, angina, diabetes, in tissue culture will continue to divide until approximately 50 cell
or arthritis, above-average responses to vaccination, and retention of doublings have occurred, after which the remaining cells can sur-
baseline levels of cognition and muscle strength would be a much vive indefinitely in a healthy but nondividing state. In the 1970s
stronger candidate for an authentic “antiaging” gene than one that and 1980s, this “clonal senescence” model seemed to be an attrac-
predicted survival to the age of 100 years. tive approach to study the genetics and cell biology of aging. It is
now clear that growth cessation of continuously passaged human
fibroblasts is caused principally by the progressive loss of telomeric
Models of Accelerated Aging
DNA at the ends of each chromosome at each mitosis. The chem-
There are a small number of rare, inherited, diseases, of which istry of DNA replication requires that duplication of the end of
Werner’s syndrome and Hutchinson-Gilford syndrome are the most each DNA molecule be conducted by a specialized enzyme com-
celebrated, that have been mooted as possible examples of “acceler- plex called telomerase, and telomeres will therefore become shorter
ated” aging. Some of the physical features and symptoms of these at each cell division except in cells, like most tumor cells, that ex-
diseases do resemble, at least superficially, some of the changes that press telomerase. The very short telomeres that eventually develop
typically affect older people, including in particular changes in skin in proliferating cells then trigger, through steps not yet fully defined,
and connective tissues. Hutchinson-Gilford syndrome, sometimes expression of new genes that block further mitotic cycles but do not
called “progeria,” is now known to be caused by mutations in the lead to cell death.
gene for Lamin A, a component of the nuclear membrane. Werner’s The challenge of showing that this in vitro system can deliver
syndrome patients usually have mutations in an enzyme (“WRN”) important clues about the biology of aging, that is, about the process
that has activity as a DNA helicase (unwinding coiled DNA) and as that converts healthy young adults into old people, has remained
an endonuclease. Patients with Hutchinson-Gilford syndrome typ- a serious hurdle. The most obvious possibility is that some of the
ically survive to their early teens, and Werner’s syndrome patients diseases and disabilities of the elderly population might represent a
frequently survive to their mid-forties, about 10 years after the age loss, with age, in proliferative capacities of one or more cell types. But
of typical diagnosis. there are many reasons to be skeptical of analogies between growth
However, it is highly debatable whether either of these diseases cessation of cells in continuous culture and the complex network of
provides strong clues about the molecular or cellular basis for age- reinforcing failures that lead to aging of intact organisms. For one
related changes in normal individuals. Werner’s patients do resemble thing, aging clearly leads to dysfunction of many cell types that do
not divide at all, like neurons and skeletal muscle myocytes, and tic transformation should require development of strong antitumor
to dysfunction of extracellular structures like teeth, cartilage, and defenses not needed in smaller creatures. The average human has
lens, and it is difficult to see how clonal senescence can affect these approximately 3000 times as many cells as a mouse; if each had the
processes. Telomere erosion has been postulated to contribute to dys- same annual likelihood of neoplastic transformation as a mouse cell,
function of memory T cells in elderly subjects; but it is hard on this the annual cancer incidence in humans would be 3000 times higher
ground to explain the equally poor function, in the same subjects, of than in mice. In fact, however, humans usually avoid neoplasia over
naı̈ve memory T cells, whose telomeres are similar in old age to those a lifetime that is 30 times longer than the mouse’s lifespan; evo-
of memory cells found in young adults. In addition, there are many lution has developed strategies that reduce per cell transformation
cell types, such as intestinal crypt stem cells and hematopoietic rate by a factor of about 90 000 in evolving humans from shorter-
progenitor cells, that can divide many thousands of times over lived, smaller progenitor species. These defenses may well include
the course of a lifespan, but which nonetheless show age-related telomere-based clonal senescence responses, as well as improvements
functional decline. In addition, telomere-dependent replicative in repair of somatic mutations and reduction of intracellular levels
failure cannot be responsible for the effects of aging in mice or rats, of DNA-modifying agents. There is no reason to believe, however,
or indeed in the many other species known to have longer telomeres that evolved defenses against cancer in humans could not be further
and shorter lives than humans. If 70 years of human lifespan are just improved: similar considerations show that whale cells, for example,
sufficient to produce perceptible shortening of the 6 to 10 kilobases are about 10 000-fold more resistant than human cells to neoplastic
of human telomeres, it is hard to see how the 2 to 3 years of rodent transformation.
lifespan could have much impact on the 20 to 100 kilobases of Recent work on stem cell biology has suggested a key role for
telomeric deoxyribonucleic acid (DNA) with which rats and mice a specific protein, p16/INK4a, as a mediator of the balance be-
are endowed. Furthermore, genetic manipulations have produced tween anticancer and antiaging mechanisms. INK4a is induced as
lines of mice whose telomeres are indeed at the same, short length part of the process by which cellular senescence halts cell prolif-
seen in proliferating cell types in elderly humans. While these mice eration. An increase in levels of INK4a in many tissues of aging
show specific abnormalities (skin ulceration, infertility, frequently mice, but particularly in stem cells, has suggested that senescent
lethal gastrointestinal lesions, and increased frequencies of certain stem cells may indeed accumulate as a consequence of normal aging
forms of neoplasia), they do not resemble normal aged mice in most and may represent an evolved mechanism to prevent early life neo-
respects. plasia. New evidence suggests that INK4a may lead, in parallel, to
The possibility that clonal senescence might contribute to some diminished stem cell function in the aging bone marrow, brain, and
of the signs of aging thus faces some serious obstacles, but perhaps pancreas. Mice engineered to have lower levels of INK4a have now
not insuperable ones. There is evidence that the cellular changes been shown to retain stem cell activities at ages at which these cells
(“cell senescence”) induced in human cells by overshort telomeres perform poorly in normal animals, even though the same mice are
might be triggered, in human and nonhuman cells, as a response somewhat more cancer-prone than normal controls. Interventions
to other forms of DNA damage, and it is thus possible that senes- that prevent age-related induction of INK4a might be an attractive
cent cells could accumulate, with advancing age, through different approach to diminishing many forms of late-life illness in parallel if
mechanisms in long-lived and short-lived species. Early work based the intervention did not simultaneously increase cancer risk.
on histological assays suggested that senescent cells were rare (less
than 0.1%), even in biopsies from very old donors, although new
methods for detecting other aspects of the senescent phenotype have
AGING RESEARCH AND PREVENTIVE MEDICINE
led to upward revisions of this estimate. It remains a challenge, how-
ever, to develop and test models to explain how properties of tis- The central rationale for biological gerontology is the hope that dis-
sues, organs, and multiorgan systems (like the brain and endocrine coveries in this field will lead to innovations in preventive medicine:
circuits) might be altered by the presence of a small admixture of an authentic antiaging drug that produced the same demographic
nondividing senescent cells. Senescent cells in vitro express a suite of changes seen in rodents on CR or MR diets would yield about 10-
secreted enzymes and cytokines that are not produced by dividing fold greater improvement in mean life expectancy than would the
fibroblasts and it is possible that these may contribute to aging at complete elimination of cancers or of myocardial infarctions (Figure
the tissue or organ level. 1-6). A detailed understanding of the molecular pathways that lead
Telomere-dependent clonal senescence does seem to play a critical to coordinated stress resistance in cells of dwarf mice, or of the ad-
role in the protection of humans from many forms of late-life cancer. justments that render CR rats resistant to autoimmune, neoplastic,
The key finding was the observation that telomerase is turned on, and and degenerative diseases, or of the evolutionary changes that per-
telomere diminution prevented or reversed, in approximately 90% mit large animals to survive cancer-free and cataract-free for many
of clinically significant human neoplasias. It thus seems likely that decades should in principle suggest avenues to preventive medical
short telomeres and stringently repressed telomerase gene expression care that could dramatically postpone disability and lethal illnesses.
evolved during the course of human evolution to protect us against Empirical testing of drugs that are thought likely to slow the ag-
fatal neoplasias that would otherwise arise early in life. Because most ing process in mice has already documented two compounds that
cancers are clonal, and each clinically significant tumor represents can extend median lifespan significantly, either in mice consuming
the outcome of several stages of selection for rare cellular variants a high-fat diet (resveratrol) or in mice consuming a normal diet
for independence from growth control, resistance to immune de- (nordihydroguiaretic acid); data on extension of maximum lifespan
fenses, and barriers to metastasis, evolution of large-bodied species, extension from these or other agents are likely to emerge in the next
with a much higher number of potential target cells for neoplas- few years.
cluding melatonin, dehydroepiandrosterone (DHEA), homeopathic

remedies, and many others, can retard, delay, or reverse aging in hu-
mans or animal models. However, it seems possible that agents that
did prove, in animal studies, to have the ability to delay or decelerate
aging might make their way into human use, or into clinical trials.
The high value placed by many dog and cat owners on the health of
their pets may lead to sponsorship of trials of antiaging medications
in these carnivores, whose lifespan is intermediate between rodents
and humans; such trials might lead to further evidence of health and
efficacy of the agents tested in a large mammal model. If a promising
agent can be shown through typical short-term clinical tests to be
Life Expectancy at Age 50 (yr) useful for the treatment or prevention of a specific disease, Food
and Drug Administration (FDA) approval for administration of the
FIGURE 1-6. Theoretical remaining life expectancy of a 50-yr-old white agent might then lead to further study of disease prevention and
woman in the United States under a variety of demographic assumptions.
The top bar shows remaining life expectancy with disease-specific mortality
enhanced survival.
rates that prevailed in 1985. The four middle bars show projected life ex-
pectancy under the assumption that mortality risks for the indicated diseases
were in fact zero. Data from Olshansky SJ et al. Science 1990;250:634.
The bottom line shows projected longevity if it were possible to retard hu- ANTIAGING RESEARCH: SOCIAL OBSTACLES AND
man aging to the same degree that is obtained in the typical study of caloric ETHICAL CONCERNS
restriction in rats or mice. Figure reprinted with permission from Miller RA.
Extending life: scientific prospects and political obstacles. Milbank Quart Serious research into the basic biology of aging, and proposed trans-
2002;80:155–174. lational research to turn gerontological discoveries into antiaging
medicines have long been hobbled by pessimism, specifically the
assumption that aging is immutable, and by stigma, arising from
But the pathway connecting discovery in this area of basic science claims made for allegedly effective antiaging potions promoted un-
to intervention is strewn with obstacles, some scientific, but others scrupulously for commercial gain. For these reasons, many political
political, economic, and legal. Even if research in mice or rats were and scientific leaders have been understandably shy of lending sup-
to demonstrate a dramatic effect of a specific agent on the aging pro- port for research efforts whose goal is to develop antiaging interven-
cess, producing (for example) a 40% increase in mean and maximal tions for human use. Journalists, who are often aware of promising
lifespan, showing that the agent was able to safely extend human discoveries in biological gerontology, are nonetheless often drawn
lifespan would require vast resources and treatment of young or ineluctably toward promotion of extreme claims, which, while en-
middle-aged adult subjects for many decades. Pharmaceutical firms tertaining, go well beyond scientific evidence and thus further impair
have little commercial incentive for embarking on expensive tests the credibility of the antiaging research enterprise. Although several
that might (or might not) demonstrate safety and efficacy of an decades of evidence has now clearly refuted the common assump-
agent many decades in the future, and governmental agencies, al- tion that the aging process is too complex or too stable to be altered,
ready strained by limited resources and competition among medical the attitudes and expectations of opinion leaders and the lay public
researchers with alternate priorities, are also unlikely to be able to greatly undermine and complicate efforts to attract support for this
support such an ambitious long-term undertaking. Indeed, the laws research agenda.
that govern testing of candidate drugs in the United States permit A related concern is often posed as a question of ethics: if the
investigative studies only of agents proposed to treat or prevent a goal of antiaging research is to help keep people alive and healthy
specific disease and explicitly exclude aging from consideration as a for several decades beyond their current “natural” lifespan, would
“disease” for the purposes of this classification. Nor are many scien- not realization of this goal greatly complicate efforts to solve the
tists eager to devote their careers to an experiment whose conclusions current set of Malthusian dilemmas? In a world where resource de-
are unlikely to emerge around the time of their own planned retire- pletion, food shortages, and environmental degradation already con-
ment. A hypothetical agent that is active in those already old could, sign billions to great suffering, would not methods that delay aging
in principle, be tested with a relative short follow-up, i.e., over a and death lead to unacceptable exacerbations of these and related
period of 5 to 10 years. However, there is at present no empirical problems? Arguments along these lines are often influenced by the
evidence, or theoretical basis, for assuming that interventions that unstated assumption that old people are typically ill, unhappy, and
retard the aging process could be effective in older subjects in which unproductive, and a desire to avoid creating a society in which an
this process has already led to major disruptions in cellular and tissue ever-increasing proportion of the population has the problems that
functions. can afflict people at the very end of life.
Introduction of authentic antiaging compounds into the practice This concern that development of antiaging medicines would be
of health care is thus likely to involve relatively unconventional path- unethical is widespread, but easy to refute. Most of modern medical
ways. The public has shown an unbridled appetite for consumption research is designed to help prevent or treat diseases with a high risk
of compounds and mixtures, labeled as “nutritional supplements,” of mortality and thus to increase the likelihood that patients will
which are exempt from laws that govern prescription and nonpre- enjoy additional years or decades of good health. Efforts to develop
scription drugs, and are purported to oppose the effects of aging. vaccines for influenza, or to eradicate residual tumor burden by ad-
Thus far, there is no evidence that any of the agents so touted, in- juvant chemotherapy, or to correct arrhythmias, or the symptoms
of diabetes or gall stones are all designed to allow patients to re-

main healthy and active as long as possible. These research ef- ACKNOWLEDGMENTS
forts are appropriately considered ethical and indeed heroic, even
Preparation of this chapter, and some of the unpublished data, was
though patients so treated are quite likely to encounter additional
supported by NIH grants AG024824 and AG023122. I appreciate
illnesses, often associated with suffering, at later ages. A similar moti-
the willingness of several colleagues, mentioned in the figure legends,
vation and justification underlies translational research in biological
to share with me some of their own data for inclusion in this chapter.
gerontology. Clearly, there is no pressing need for agents that merely
prolong life in people who are in the final stages of a dementing ill-
ness or nearing death in great pain, and developing drugs that extend FURTHER READING
lifespan without improvements in health would not be an attractive Austad SN. Why We Age: What Science Is Discovering About the Body’s Journey Through
goal. Fortunately, each of the dietary and genetic manipulations Life. Chichester: Wiley; 1999.
Bartke A, Wright JC, Mattison JA, Ingram DK, Miller RA, Roth GS. Extending the
shown in rodent models to extend longevity does so by an increase lifespan of long-lived mice. Nature. 2001;414:412.
in the length of healthy lifespan; postponement of death goes hand Chen D, Guarente L. SIR2: a potential target for calorie restriction mimetics. Trends
in hand (and is almost certainly caused by) postponement of a very Mol Med. 2007;13:64–71.
Flurkey K, Papaconstantinou J, Miller RA, Harrison DE. Lifespan extension and
wide range of diseases and forms of disabilities. A society in which delayed immune and collagen aging in mutant mice with defects in growth
many people remain active and productive at ages of 80–100 years hormone production. Proc Natl Acad Sci USA. 2001;98(12):6736–6741.
or so would indeed require economic adjustments and alterations Gems D, Sutton AJ, Sundermeyer ML, et al. Two pleiotropic classes of daf-2 mutation
affect larval arrest, adult behavior, reproduction and longevity in Caenorhabditis
of assumptions about retirement ages and family structure, just as elegans. Genetics. 1998;150:129–155.
adjustments of this kind have been required as societies have expe- Harper JM, Salmon AB, Leiser SF, Galecki AT, Miller RA. Skin-derived fibroblasts
rienced reductions in infant and childhood mortality that greatly from long-lived species are resistant to some, but not all, lethal stresses and to
the mitochondrial inhibitor rotenone. Aging Cell 2007;6:1–13.
increase the proportion of newborns that reach the ages of 20 to 50 InfoAging Web site. http://websites. afar.org [Accessed August 1, 2008]
years. Such adjustments are not trivial, but such fears have not raised Kapahi P, Boulton ME, Kirkwood TB. Positive correlation between mammalian life
concerns about the ethical merit of insulin therapy, vaccination pro- span and cellular resistance to stress. Free Radic Biol Med. 1999;26(5–6):495–500.
Kirkwood T. Time of Our Lives: The Science of Human Aging. Chichester: Oxford
grams, smoking cessation clinics, or adjuvant chemotherapy, and University Press; 2000.
from this perspective it is hard to understand why success in antiag- Li Y, Deeb B, Pendergrass W, Wolf N. Cellular proliferative capacity and life span in
ing research should be considered pernicious. small and large dogs. J Gerontol A Biol Sci Med Sci. 1996;51(6):B403–B408.
Miller RA. Extending life: scientific prospects and political obstacles. Milbank Quart.
There is, however, a serious ethical concern about antiaging in- 2002;80:155–174.
terventions that deserves more attention than it has received. There Miller RA. Kleemeier Award Lecture: are there genes for aging? J Gerontol Biol Sci.
is some basis for believing that agents that decelerate aging, either by 1999;54A:B297–B307.
Morimoto RI. Stress, aging, and neurodegenerative disease. N Engl J Med. 2006;355:
alteration of IGF-I signals or through the still undiscovered mecha- 2254–2255.
nisms used by CR and MR diets, might be more effective if imposed Olshansky SJ, Hayflick L, Perls TT. Anti-aging medicine: the hype and the reality.
early in life, perhaps as early as the childhood years. In such a case, J Gerontol Ser A Biol Sci Med Sci. 2004;59:B513–B514.
Olshansky SJ, Perry D, Miller RA, Butler RN. In pursuit of the longevity dividend:
decisions about use of such preventive treatments might have to be what should we be doing to prepare for the unprecedented aging of humanity?
made by parents on behalf of their young children. If such agents had Scientist. March 2006:28–36.
side effects, such as postponement of puberty, or permanent short Salmon AB, Murakami S, Bartke A, Kopchick J, Yasumura K, Miller RA. Fibroblast
cell lines from young adult mice of long-lived mutant strains are resistant to
stature, would parents be acting ethically to impose these side effects multiple forms of stress. Am J Physiol Endocrinol Metab 2005;289(1):E23–E29.
on their children in order to provide them with additional decades Science of Aging Knowledge Environment. http://sageke.sciencemag.org/ [Accessed
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Tatar M, Bartke A, Antebi A. The endocrine regulation of aging by insulin-like signals.
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Questions of this kind are harder to answer than concerns about Snell dwarf mice regain fertility but remain long-lived and disease resistant. J
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whether postponement of late-life illnesses is or is not desirable on Weindruch R, Sohal RS. 1997. Caloric intake and aging. N Engl J Med. 1997;337:
its own merits. 986–994.
2
CHAPTER
Genetics of Age-Dependent
Human Disease
Thomas B. L. Kirkwood
tions that affect duration of life. However, although genes influence

THE BIOLOGICAL NATURE OF INTRINSIC AGING longevity, genes appear to account for only about 25% of the variance
in human life span.
Understanding the biology of intrinsic aging is important for geria-
The nature of the genetic contribution to the aging process has
tricians because of the insights it provides into: (i) why and how the
received much attention, both from the perspective of evolution-
body becomes progressively more vulnerable to disability and dis-
ary theory and through experimentation. The evolutionary angle is
ease as we grow older; (ii) how we might intervene in the underlying
valuable because it can tell us a great deal about the kinds of genes
mechanisms; and (iii) what is the exact nature of the relationship
that are likely to underlie the aging process. A commonly held belief
between “normal” aging and age-related diseases. Although there is
is that aging evolved as an evolutionary necessity—for instance, to
significant variability in how aging affects individuals, certain un-
remove older individuals who might otherwise consume resources
derlying processes appear to follow a common course. Furthermore,
needed by the young. However, there is little support for the idea
humans share some features of aging with a wide range of other an-
that aging does actually fulfill such a role. In nature, the vast majority
imal species. Thus, even though much of the research on intrinsic
of animals die young, long before they could become obstructive to
aging is done using simple animal models such as the roundworm
the interests of the next generation. Out of a population of newborn
Caenorhabditis elegans or the fruitfly Drosophila melanogaster, it ap-
wild mice, for example, nine out of 10 of them will be dead before
pears that common regulatory pathways are at least partially con-
10 months even though half of the same animals reared in captivity
served across the spectrum that includes mammals, and in particu-
would still be alive at 2 years. Thus, aging in mice is seen only in
lar humans. This is especially the case for fundamental mechanisms
protected environments, and until relatively recently the same would
that protect cells against shared threats such as damage to DNA aris-
have been true for human populations. It is only in the last 200 years
ing from endogenous stressors like reactive oxygen species (ROS),
that human life expectancy, even in the most advantaged countries,
which are essential molecular by-products of the body’s dependence
exceeded 40 years.
on oxygen to provide energy.
Since it is rare that an animal survives long enough to show any
sign of aging, a genetically programmed means to limit population
size and avoid overcrowding, if it exists, is not often brought into
Why Aging Occurs
play. Furthermore, the idea that aging could be beneficial needs to
One of the central questions in the biology of aging is the nature of be set against the fact that even if an animal did reach older age,
the genetic contribution to longevity. How do genes act on the aging the adverse effects of intrinsic senescence on fertility and risk of
process, and how does an individual’s genetic endowment contribute dying are far from beneficial as far as the individual is concerned.
to their longevity? The idea of programmed aging rests on the notion that organisms
Aging and longevity are clearly influenced by genes. Firstly, the should weaken and die altruistically, for the “good of the species.”
life spans of human monozygotic twin pairs are more similar than life While there may be instances where natural selection has produced
spans of dizygotic twins. Secondly, there are differences in life span apparently altruistic outcomes, evolutionary biologists have carefully
between different genetically inbred strains of any given laboratory delineated the rather special circumstances required for this kind
animal, such as the mouse. Thirdly, studies of simple organisms like of selection force to work. Aging does not fit these requirements.
fruit flies, nematode worms, and yeast have identified gene muta- The argument against programmed aging can be summarized by
observing that if such a program did exist, what would prevent a by Williams, who suggested that genes with beneficial effects would
mutation occurring that abrogated the program and allowed the be favored by selection even if these genes had adverse effects at
mutant to survive indefinitely? The fact that such mutants are never later ages. This is known as the theory of “antagonistic pleiotropy,”
observed is empirical support that backs up the other objections. the term pleiotropy meaning that the same gene can have different
The evidence from nature is that instead of being programmed effects in different circumstances.
to die, organisms are genetically programmed to survive. However, The current synthesis of evolutionary ideas about why aging oc-
in spite of a formidable array of survival mechanisms, most species curs can thus be summarized in four points:
appear not to be programmed well enough to last indefinitely. A 1. There are no specific genes for aging.
key to understanding why this should be so, and what governs how
long a survival period there should be, comes from studying survival 2. Genes of particular importance for aging and longevity are those
patterns in wild populations. If 90% of wild mice are dead by the governing durability and maintenance of the soma.
10 months, any investment in programming for survival much be- 3. There may exist other genetically determined trade-offs between
yond this point can benefit at most 10% of the population. This benefits to young organisms and their viability at older ages.
immediately suggests that there will be little evolutionary advantage 4. There may exist a variety of gene mutations with late deleterious
in programming long-term survival capacity into a mouse. The ar- effects that contribute to the senescent phenotype.
gument is further strengthened by the observation that nearly all
Given these points, it is clear that multiple genes contribute to the
of the survival mechanisms required by the mouse to combat in-
aging phenotype. A cornerstone of the current research agenda is to
trinsic deterioration (DNA damage, protein oxidation, etc.) require
identify these genes and discover which are the most important.
metabolic resources. Metabolic resources are scarce, as is evidenced
by the fact that the major cause of mortality for wild mice is cold,
due to insufficient energy to maintain body temperature. From a Mechanisms of Aging
Darwinian point of view, the mouse will benefit more from invest-
Aging appears to be driven by the progressive accumulation through
ing any spare resource into thermogenesis or reproduction than into
life of a variety of random molecular defects that build up within
better DNA repair capacity than its need for longevity.
cells and tissues. These defects start to arise very early in life, probably
This concept, with its explicit focus on evolution of optimal
in utero, but in the early years, both the fraction of affected cells and
levels of cell maintenance, is termed the “disposable soma” theory.
the average burden of damage per affected cell are low. However, over
In essence, the investments in durability and maintenance of somatic
time the faults increase, resulting eventually in age-related functional
(nonreproductive) tissues are predicted to be sufficient to keep the
impairment of tissues and organs (Figure 2-1). This concept makes
body in good repair through the normal expectation of life in the
clear the life-course nature of the underlying mechanisms. Aging is a
wild environment, with some measure of reserve capacity. Thus, it
continuous process, starting early and developing gradually, instead
makes sense that mice (with 90% mortality by 10 months) have
of being a distinct phase that begins in middle to late life.
intrinsic life spans of around 3 years, while humans (who probably
Since there are multiple kinds of molecular and cellular dam-
experienced something like 90% mortality by the age of 50 years
age, and a corresponding variety of mechanisms to protect against
in our ancestral environment) have intrinsic life spans limited to
and repair them, aging is a highly complex process involving mul-
about 100 years. The distinction between somatic and reproductive
tiple mechanisms at different levels. This multiplicity of candidate
tissues is important because the reproductive cell lineage, or germ
mechanisms can easily become confusing, particularly since those
line, must be maintained at a level that preserves viability across the
researching a specific mechanism have a tendency to suggest that
generations, whereas the soma needs only to support the survival of
their preferred choice is the mechanism that drives aging. It will be
a single generation.
This concept helps to explain why species differ in their intrinsic
life spans. It is noteworthy, for example, that species of birds and
Delayed by good diet, lifestyle, and
Age-Related Frailty, Disability, and Disease
Accelerated by stress, poor diet,
bats tend to have greater longevity than flightless species. The reason
is thought to be that flight is a very successful way of reducing an
favorable environment
adverse environment
animal’s mortality risk, since it is possible to escape many predators

and to forage over a greater range, thereby lessening the risk of Accumulation of Cellular Defects
starvation caused by a local food shortage. If risk is reduced, the
statistical chance of living a bit longer is increased, and so it becomes
worthwhile to invest in a higher level of somatic maintenance and
repair. Studies comparing the biochemistry of cellular repair among Random Molecular Damage
long- and short-lived species bear this prediction out. Cells from
long-lived organisms exhibit greater capacity to repair molecular
damage and withstand biochemical stresses than cells from short-
lived species. FIGURE 2-1. The aging process is driven by a lifelong accumulation of
molecular damage, resulting in gradual increase in the fraction of cells
The disposable soma theory provides a bridge between under- carrying defects. After sufficient time has passed, the increasing levels of
standing not only why aging occurs but also how aging is caused these defects interfere with both the performance and functional reserves of
in molecular and cellular terms. It thus extends earlier considera- tissues and organs, resulting in age-related frailty, disability, and disease.
tions by Medawar, who suggested that because organisms die young Stress, adverse environment, and poor nutrition can increase the rate at
there is little force of selection to oppose the accumulation within which molecular damage arises. Intrinsic maintenance mechanisms, such
as DNA repair and antioxidants, can slow the rate of accumulation.
the genome of mutations with late-acting deleterious effects, and
CHAPTER 2 / Genetics of Age-Dependent Human Disease 17
apparent from the previous section that, in fact, it is highly unlikely in humans is normally expressed only in germ cells (in testis and
that any single mechanism can tell the whole story. We will consider ovary) and in certain adult stem cells. Some studies have suggested
the prominent hypothesized mechanisms below. For each mecha- that in dividing somatic cells, telomeres act as an intrinsic “division
nism, there is evidence supporting the hypothesis that it is indeed counter,” perhaps to protect us against runaway cell division as hap-
an agent of senescence. However, the extent of the contribution to pens in cancer but causing aging as the price for this protection.
senescence is generally too small for the mechanism to be a sufficient Erosion of telomere length below a critical length appears to trigger
explanation of age-related degeneration. The clear inference is that activation of cell cycle “checkpoints,” especially the p53/p21/pRb
aging is multicausal and that the various mechanisms all play their system, resulting in permanent arrest of the cell’s capacity for further
part and are likely to interact synergistically. For example, a build-up division.
of mitochondrial DNA mutations will lead to a decline in the cell’s The loss of telomeric DNA is often attributed mainly to the so-
energy production, and this will reduce the capacity to carry out called “end-replication” problem—the inability of the normal DNA
energy-dependent protein clearance. In recent years, novel methods copying machinery to copyright to the very end of the strand in the
based on computer modeling of interactions and synergism between absence of telomerase. However, biochemical stress has an even big-
different aging mechanisms have begun to build a better integrated ger effect on the rate of telomere loss. Telomere shortening is greatly
picture of how cells break down with age and there is growing ex- accelerated (or slowed) in cells with increased (or reduced) levels of
perimental evidence that interactions between multiple mechanisms stress. The clinical relevance of understanding telomere maintenance
are important. and its interaction with biochemical stress is considerable. A growing
body of evidence suggests that telomere length is linked with aging
and mortality. Not only do telomeres shorten with normal aging in
Oxidative Damage
several tissues (e.g., lymphocytes, vascular endothelial cells, kidney,
An important theme linking several different kinds of damage is the liver), but also their reduction is more marked in certain disease
action of ROS (also known as free radicals), which are produced states. For example, there appears to be a 100-fold higher incidence
as by-products of the body’s essential use of oxygen to produce of vascular dementia in people with prematurely short telomeres.
cellular energy. Of particular significance are the contributions of Furthermore, the psychological stress associated with provision of
ROS-induced damage to cellular DNA through (i) damage to the long-term care for those with chronic illness has also been associ-
chromosomal DNA of the cell nucleus, resulting in impaired gene ated with premature shortening of telomeres, presumably through
function, (ii) damage to telomeres—the protective DNA structures biochemical sequelae to the chronic activation of stress hormones.
that appear to “cap” the ends of chromosomes (analogous to the plas- Short telomeres may therefore serve as a general indicator of previous
tic tips of shoelaces), and (iii) damage to the DNA that exists within exposure to stress and as a prognostic indicator for disease conditions
the cell’s energy-generating organelles, the mitochondria, resulting in which stress plays a causative role.
in impaired energy production.
DNA Damage and Repair Mitochondria

Damage to DNA is particularly likely to play a role in the lifelong An important connection between oxidative stress and aging is sug-
accumulation of molecular damage within cells, since damage to gested by the accumulation of mitochondrial DNA (mtDNA) dele-
DNA can readily result in permanent alteration of the cell’s DNA tions and point mutations with age. Mitochondria are intracellular
sequence. Cells are subject to mutation all the time, both through organelles, each carrying its own small DNA genome, which are re-
errors that may become fixed when cells divide and as a result of ROS- sponsible for generating cellular energy. As a by-product of energy
induced damage, which can occur at any time. Numerous studies generation, mitochondria are also the major source of ROS within
have reported age-related increases in somatic mutation and other the cell, and they are therefore both responsible for, and a major
forms of DNA damage, suggesting that an important determinant target of, oxidative stress. Any age-related increase in the fraction of
of the rate of aging at the cell and molecular level is the capacity for damaged mitochondria is likely to contribute to a progressive decline
DNA repair. in the cell and tissue capacity for energy production. Age-related in-
A key player in the immediate cellular response to DNA damage creases in frequency of cytochrome c oxidase (COX)-deficient cells
is the enzyme poly(ADP-ribose) polymerase-1 (PARP-1). There is have been reported in human muscle and brain, associated with
a strong, positive correlation of PARP-1 activity with the life span increased frequency of mutated mtDNA.
of the species: cells from long-lived species having higher levels of Initial evidence for age-related accumulation of mtDNA mu-
PARP-1 activity than cells from short-lived species. Similarly, human tations came mainly from tissues such as brain and muscle where
centenarians, who have often maintained remarkably good general cell division in the adult, if it occurs at all, is rare. This led to the
health, appear to have a greater poly(ADP-ribosyl)ation capacity idea that accumulation of mtDNA mutation was driven mainly by
than the general population. the dynamics of mitochondrial multiplication and turnover within
nondividing cells. However, there is now strong evidence of age-
dependent accumulation of mtDNA mutations in human gut ep-
Telomeres
ithelium, which has the highest cell division rate of any tissue in the
In many human somatic tissues, a decline in cellular division capac- body. Thus, it appears that accumulation of defects in mitochon-
ity with age appears to be linked to the fact that the telomeres, which dria may be a widespread phenomenon. This is also supported by
protect the ends of chromosomes, get progressively shorter as cells the discovery that mitochondrial dysfunction may be an important
divide. This is due to the absence of the enzyme telomerase, which driver of the contribution to cellular senescence that is made by the
shortening of telomeres, confirming the synergism and interaction Multistage Progression of Age-Related Disease
between different molecular mechanisms of aging.
Disease B
Proteins
In addition to damage affecting cellular DNA, damage to protein
molecules occurs to a considerable extent, and accumulation of
faulty proteins contributes to important age-related disorders such as Disease A
cataract, Parkinson’s disease, and Alzheimer’s disease. In some ways,
the accumulation of defective proteins is harder to explain than the
accumulation of DNA damage, since individual protein molecules
are subject to a continual cycle of synthesis and breakdown. Thus, Disease C
damaged individual protein molecules should be cleared as soon as
that molecule is degraded. However, there is evidence that the protein
degradation mechanisms themselves deteriorate in function with ag-
ing. This is thought to occur because these mechanisms eventually
become overwhelmed by a build-up of defective protein molecules ‘Upstream’ ‘Downstream’
that are resistant to breakdown, for example, because they form ag- FIGURE 2-2. Multistage progression of age-dependent diseases. The in-
gregates large enough to withstand the normal removal systems. It trinsic aging process, as well as most age-dependent diseases, are driven
is the build-up of such aggregates that is commonly linked with cell by the gradual accumulation of molecular and cellular faults. Although in-
dividual age-dependent diseases may be defined by particular “end-stage”
and tissue pathology.
cellular pathology, common upstream processes, such as DNA damage or
oxidative damage to proteins, are shared between many age-related dis-
eases and intrinsic aging. Intervention in these upstream processes has the
potential, therefore, to be effective against multiple age-related diseases.
THE RELATIONSHIP BETWEEN NORMAL AGING
AND DISEASE
The relationship between normal aging and age-related disease has so-called hallmarks of classic Alzheimer’s disease) even though they
long been controversial. At stake is the question of whether the may show no evidence of major cognitive decline. In this instance,
term “normal aging” should be reserved for individuals in whom what determines whether or not the diagnosis of Alzheimer’s disease
identifiable pathology is absent, whereas specific age-related diseases, is called for may be not so much the presence of lesions as which
such as Alzheimer’s disease, are seen as distinct entities. However, this specific targets are affected.
concept gives rise to a conundrum. As a cohort ages, the fraction As the upstream mechanisms giving rise to age-related diseases
that can be said to be aging “normally” declines to a very low level. often involve the kind of damage that is thought to contribute to
Whether the word “normal” can usefully be applied to such an intrinsic aging, similar damaging processes may contribute to the
atypical subset is debatable. pathogenesis of multiple disorders, even though the final nature of
In a clinical context, it often makes sense to try and draw a the end-stage lesions may be different (Figure 2-2). For example,
distinction between normal aging and disease, since this may have oxidative stress may be a factor in protein aggregation in neurode-
implications for treatment. However, if the aim is to understand the generative diseases, in cell defects contributing to atherogenesis in
mechanisms responsible for age-related conditions, such a distinction cardiovascular diseases, and in impaired function of osteoblasts in
can obscure what is really going on, since the boundary between osteoporosis. If this concept is correct, future interventions that tar-
aging and disease pathogenesis may be somewhat arbitrary. For the get underlying processes of normal aging may postpone multiple
vast majority of chronic, degenerative conditions, such as dementia, age-related diseases.
osteoporosis, and osteoarthritis, age is the biggest single risk factor The role played by basic cell maintenance systems both in secur-
predisposing to the disease in question. What is it about aging that ing longevity and in protecting against a spectrum of age-associated
renders the older cell or tissue more vulnerable to pathology? conditions is nicely illustrated by the human CDKN2a locus, which
Aging involves the progressive accumulation of cellular and intriguingly codes for two different proteins via different open read-
molecular lesions, and the same is generally true of the age-associated ing frames. One of these proteins is p16INK4a , a cyclin-dependent
diseases. Thus, there is considerable potential for overlap between protein kinase inhibitor; the other is ARF, a potent regulator of
the causative pathways leading to normal aging and age-related dis- p53. The level of p16INK4a is associated with cellular aging in skin,
eases. In the case of osteoporosis, for example, progressive bone loss pancreatic islets, and hematopoietic and neuronal stem cells, and
from the late twenties onwards is the norm. Whether an individual p16INK4a , together with ARF, is involved in regulating cell senescence
reaches a critically low bone density, making him or her highly sus- and tumor suppression. At the population level, polymorphism at
ceptible to fracture, is governed by how much bone mass they had the CDKN2a locus is associated with risk for type 2 diabetes and
to start with and by their individual rate of bone loss. The process with the preservation of physical function at older age. It seems likely
that leads eventually to osteoporosis is thus entirely “normal.” but that further study of the gene and its protein products will reveal
what distinguishes whether or not this process results in an overtly important interconnections with aging and age-related diseases.
pathological outcome is a range of moderating factors. In the case Through increased understanding of how fundamental mainte-
of Alzheimer’s disease, most people above the age of 70 years have nance systems are involved in protection against both aging and
extensive cortical amyloid plaques and neurofibrillary tangles (the disease, it can be expected that future interventions will be found
that can target underlying processes of normal aging, with the benefit Environmental
of postponing multiple age-related diseases. modulation
GENETIC AND NONGENETIC EFFECTS ON AGING Antioxidant

The disposable soma theory predicts that at the heart of the evolu- defences
tionary explanation is the principle that organisms have been acted
upon by natural selection to optimize the utilization of metabolic
resources (energy) between competing physiological demands, such DNA repair
as growth, maintenance, and reproduction. Consistent with this pre-
diction, it is striking that insulin signaling pathways appear to have
effects on aging that may be strongly conserved across the species Protein
range. Insulin signaling regulates responses to varying nutrient lev- turnover
els. Allied to the role of insulin signaling pathways is the discovery
that a class of proteins called sirtuins appears to be centrally in- Period of longevity assured
volved in fine-tuning metabolic resources in response to variations FIGURE 2-3. Gene regulation of longevity is effected through the genetic
in food supply. As described in Chapter 1, restricted intake of calo- specification of many individual pathways for maintenance and repair of
ries in laboratory rodents simultaneously suppresses reproduction somatic cells and tissues. Among these pathways are those for antioxidant
defense, DNA repair, and protein turnover. Natural selection is thought
and upregulates a range of maintenance mechanisms, resulting in an
to have tuned these mechanisms to provide similar periods of “longevity
extension of life span and the simultaneous postponement of age- assured” before the lesions resulting from the imperfect nature of the main-
related diseases. Although dietary restriction may not have an effect tenance and repair processes give rise to age-dependent frailty, disability,
of similar magnitude in humans, it will be surprising if there are no and disease. In some organisms, there appears to have evolved a capacity
metabolic consequences of varying food supply. to respond to changes in the environment, e.g., the availability of food,
to fine-tune the overall settings of maintenance and repair processes so as
One of the clearest examples of how metabolic signaling affects ag-
to optimize the investments in maintenance and repair to suit different cir-
ing and longevity comes from a study on genes of the insulin/insulin- cumstances. One such example is the effect of dietary restriction in small
like growth factor 1 (IGF-1) signaling pathway in C. elegans. When animals, which results in suspension of reproduction and a coordinated in-
threatened with overcrowding, which the larval worm detects by the crease in maintenance and repair, which in turn postpones both intrinsic
increasing concentration of a pheromone, its development is diverted aging and age-dependent diseases. The extent to which such capacity for
environmental modulation exists in humans is as yet unclear, but it is likely
from the normal succession of larval molts into a long-lived, disper-
to be less than in small animals for which reproduction constitutes a much
sal form called the “dauer” larva. Dauers show increased resistance to greater fraction of the organism’s energy budget.
stress and can survive very much longer than the normal form, revert-
ing to complete their development should more favorable conditions
be detected. An insulin/IGF-1-receptor gene, daf-2, heads the gene
environment, e.g., the abundance of food, and adjust metabolism
regulatory pathway that controls the switch into the dauer form, and
accordingly. The discoveries that have been made during the current
mutations in daf-2 produce animals that develop into adults with
expansion of research on genetic and nongenetic factors affecting
substantially increased life spans. In common with other members of
aging in nonhuman animal models are now beginning to be extended
the evolutionarily conserved insulin/IGF-1 signaling pathway, daf-2
to human health and disease. Broad similarities are expected to exist,
also regulates lipid metabolism and reproduction. The daf-2 gene
although in view of the different ecological circumstances affecting
product exerts its effects by influencing “downstream” gene expres-
humans, as compared to a small animal like a nematode worm,
sion, in particular via the actions of another gene belonging to the
the existence and nature of the higher-level, environment-sensing
dauer-formation gene family, daf-16, which it inhibits.
genetic pathways cannot be assumed to be identical.
Gene expression profiling has identified more than 300 genes that
appear to have their expression levels altered by daf-16 regulation.
This large number suggests that, as predicted by the evolutionary
theory, many genes are involved in determining longevity. The genes
GENETICS OF HUMAN LONGEVITY AND THE
modulated by daf-16 can be grouped into several broad categories.
IMPLICATIONS FOR AGE-DEPENDENT DISEASE
The first category includes a variety of stress-response genes, in-
cluding genes for antioxidant enzymes. A second group of genes While genetics is unlikely to have played any important part in
encode antimicrobial proteins, which are important for survival in the near doubling of human life expectancy over the last two cen-
this organism because its death is commonly caused by prolifera- turies, the emergence of large numbers of people attaining great age
tion of bacteria in the gut. A miscellaneous third group included has revealed information about the genetic contribution to human
genes involved in protein turnover, which is an important cellular longevity that was unavailable previously. Population genetics ex-
maintenance system. plains how much of the variation in a trait—in this case, longevity—
The picture that emerges from both evolutionary theory and is due to innate differences in gene endowment and how much is due
the empirical evidence is that the genetic control of longevity is to the environment. When few individuals survived to the limit of
mediated through a large array of mechanisms specifying individual the biological potential, the genetic contribution was masked by the
maintenance and repair systems (Figure 2-3). Acting above these large contribution to variance that arose from the environment and
may exist a hierarchy of genes that serve to sense the quality of the also, of course, from luck. During the last two decades, the possibility
of applying genetic techniques to understanding the heritability of or another pathway that leads to permanent cell cycle arrest. Which
innate factors influencing longevity has seen the burgeoning of stud- of these routes is taken depends in large part on the risk, posed by
ies on the genetics of human longevity. Initially, these examined the damage, of potentially initiating a tumor. If the cell is a stem cell,
longevity records for monozygotic and dizygotic twins. From these it is more likely to undergo apoptosis. Teleologically this appears to
analyses emerged the finding that, in the population at large, gene make sense, since the cancer transformation risk of preserving a cell
differences account for 20% to 30% of the variation in human life that belongs to a highly proliferative tissue compartment is greater,
span. More recently, studies of families with extreme longevity, such and so it is logical for the cell to be deleted and replaced. On the
as centenarians, support the idea that there is an important genetic other hand, if the cell belongs to a more general category, such as
contribution to an individual’s chance of attaining great age. Siblings a fibroblast, it is less likely that apoptosis will be triggered and the
of centenarians are more likely to become centenarians themselves, cell instead is subjected to permanent arrest, or senescence. Various
and these effects extend also to other family members. A number of genes influence the likelihood of adopting one or another of these
candidate-gene studies have tested the hypothesis that specific alleles alternatives. Furthermore, experimental modulation of these genes
associated with reduced risk of disease, or with improved somatic or naturally occurring polymorphisms have been found to influence
maintenance, may be found to be more prevalent in centenarians the outcome. For example, if the function of the tumor suppressor
than in younger age groups. The positive results reported from such p53 is genetically enhanced, apoptosis is more likely, and this is found
studies support the notion that, out of an initially heterogeneous to be associated with a reduced lifetime risk of cancer. However,
cohort, those with a genetic endowment predisposing to somatic this protection comes at a cost, since in mouse models, at least,
durability and freedom from disease will become increasingly nu- the process of intrinsic aging, caused by age-dependent tissue loss
merous, as a fraction of the surviving members, while the cohort of cellularity, is accelerated by genetic enhancement of p53 activity.
grows ever older. Life span is reduced and various age-dependent pathological changes
The advent of rapid genome analysis techniques has made pos- occur earlier.
sible the scanning of the entire human genome for genetic markers In terms of the genetics of specific age-dependent diseases, there
that are associated with longevity in kin groups, without requir- is likely to be considerable overlap between the underlying pathways
ing any prior hypothesis as to the nature of the genes associated contributing to intrinsic aging generally and to the lesions associated
with these markers. Several current studies are exploiting these tech- with individual diseases. It is striking that even in the cases where
niques using, for example, DNA from surviving nonagenarian sib- gene polymorphisms have been linked to particular diseases, such
lings to search for markers that might confer familial predisposition as Alzheimer’s, the dominant risk factor in sporadic cases, i.e., those
for healthy aging. The rationale for these studies is that while, for not associated with strongly familial, early-onset presentation, is age
an individual, surviving to great age might be a matter of chance, rather than genotype. Thus, in pursuing the genetics of these kinds
the fact that two or more individuals from the same family have of age-dependent conditions, the research question is more likely to
done so makes it more likely that something in their shared genetic be answered if it is formulated in terms of addressing how specific
endowment is responsible. genes affect the underlying pathogenesis of intrinsic aging, rather
Early results from genetic studies on human longevity are now than driving a pathway that is mechanistically distinct.
emerging. In line with the evidence from nonhuman animal models,
there is some indication that long-lived humans have decreased levels
of IGF-1, consistent with the hypothesis that insulin/IGF-1 response
MALLEABILITY OF THE HUMAN AGING PROCESS
is associated with longevity. Further studies on gene polymorphisms
linked to the insulin/IGF-1-signaling pathways are likely to reveal One of the striking features of the increase in human life expectancy
this association in further detail. Similarly, there is growing interest in recent decades is that, contrary to demographic forecasts of the
in the possibility that polymorphisms in members of the sirtuin major national and international agencies, life span has continued to
gene family (proteins that influence the activity of essential factors increase steadily. This was initially surprising because it was thought
regulating the general patterns of gene expression), already shown to that there was a fixed ceiling on human life expectancy imposed
be important in connection with longevity-associated metabolism by the intrinsic, programmed nature of the aging process itself.
in yeast and animal models, may have connections with life span By this logic, once death rates in the early and middle years had
regulation in humans. been pushed down to the low levels seen in most developed coun-
Among the factors that directly affect cellular maintenance, pre- tries, there would be little opportunity for life expectancy to climb
dicted by evolutionary theory to be central to regulating aging and further.
longevity, there is growing evidence that genes regulating funda- The failure of the limited life span paradigm can, however, be
mental DNA repair processes are linked to life span. The human understood within the framework for the intrinsic biology of aging
progeroid condition Werner’s syndrome is caused by mutation in outlined previously. If there is no intrinsic genetic program for aging,
the WRN gene, which codes for an enzyme that has multiple roles in then the mechanisms that drive the aging process—accumulation
DNA maintenance and repair, while Hutchinson-Gilford syndrome of molecular and cellular damage—are amenable to environmental
(a more extreme form of progeria) is associated with mutation in the modulation. Aging is the result of a gradual but progressive accumu-
LMNA gene coding for a component of the external envelope of the lation of damage to cells, tissues, and organs. However, the process
cell nucleus. is not entirely passive, since the rate of accumulation is strongly
Other gene associations with aging are being discovered among resisted by maintenance and repair processes, which are controlled
genes that regulate the cellular response to damage. When a cell by genes. Furthermore, both the incidence of damage and the reg-
detects that it has suffered damage, particularly to its DNA, it may ulation of these genes may be influenced by extrinsic factors. This
activate a pathway that leads to programmed cell death (apoptosis) picture readily accommodates the roles of at least five major elements
contributing to the individuality of the human aging process: genes, Esiri MM, Matthews F, Brayne C, et al. Pathological correlates of late-onset dementia
nutrition, lifestyle (e.g., exercise), environment, and chance. in a multicentre, community-based population in England and Wales. Lancet.
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Wilhelmi Tellistä ja Sveitsinmaan
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Title: Kertomus Wilhelmi Tellistä ja Sveitsinmaan vapauttamisesta
Author: Alexandre Dumas
Translator: Antti Räty
Release date: July 5, 2024 [eBook #73969]
Language: Finnish
Original publication: Helsinki: SKS, 1849
Credits: Jari Koivisto and Tapio Riikonen
*** START OF THE PROJECT GUTENBERG EBOOK KERTOMUS

WILHELMI TELLISTÄ JA SVEITSINMAAN VAPAUTTAMISESTA ***
KERTOMUS WILHELMI TELLISTÄ JA SVEITSINMAAN VAPAUTTAMISESTA
Kirj.
Alexandre Dumas
Ruotsista suomentanut
A. Räty
Helsingissä, Suomalaisen Kirjallisuuden Seuran kirjapainossa,

1849.
Imprimatur: I. U. Wallenius.
Ensimäinen Luku.
Werner Stauffaherista ja Melhtalista.

Keisari Albrehti Itävallasta, Habspurin su’usta, astui keisarilliselle
istuimelle v. 1298. Tullessaan hallitsemaan ei ollut Sveitsissä
minkäänlaista liitto- eli yhteys-kuntaa, eikä silloin vielä herroin
päiviäkän pidetty. Mitä keisarin valtaan tässä maassa tulee, niin oli
hänellä siinä siellä ja täällä iso joukko kaupunkia, vahvoja linnoja
(varustuksia) ja maakuntia, joitten ylitse hän niinkuin päämies
reivillisestä Habspurin su'usta hallitsi. Muut reivilliset heimolaiset,
joitten omana muu maa oli, olivat reiviä Savoyista, Neufchatelista ja
Rapperschvylista.
Waikea ja vieläpä varsin mahdotoinki olisi kirjoittaa erityistä

historiaa tästä äveriäästä, rauhattomasta ja mielen huvituksiin
vajonneesta vapasukuisesta säädystä, joka alati oli kääreyttyneenä
tahi sotiin eli huvittelemisiin, eikä huolien alamaistensa veren
vuodattamisesta, tuhlasivat he heidän omaisuuksiansa ja
tavaroitansa säälimätä ja varustaen jokaisen vuoren nyppylän
linnoilla ja varustuksilla laskeutuivat he sieltä kuin raatelevaiset
kotkat pesistänsä, ryövätäkseen ympäristöltä, mitä mielensä halasi,
ja palasivat kotiinsa vieden saaliinsa säilyyn linnojensa muurin ta'a.
Eikä tässä ole luultava ainoasti maallisen Esivallan harjoitelleen tätä
ryöstöä; ei suinkaan, hengelliset herratki nimittäin Baseli'n,
Constanzia'n, Coire'n ja Lausanne'n piispat elivät samate, ja rikas
papisto S:t Gallenissa kuin myös erokkaat seurasivat näissä aikeissa
uutterasti korkeita esimiehiänsä, niinkuin ala-aateli muita
suurisukuisia valtoja.
Keskellä tätä orjilta ja pahantekiöiltä täytettyä maata oli kuitenni

kolme liitto-kuntaa (communer) päässyt vapaaksi; nimiltään Uri,
Sveitsi ja Unterwalden, jotka jo vuodesta 1291, edellänähden
surkeat onnettomuuden päivät ja vaarat lähestyviksi, antautuivat
toisinensa liittokuntaan, vahvasti luvaten puollustaa toistensa henkiä,
pereitä ja omaisuuksia ja tarvista myöten toisiansa myös neuvoilla ja
kehoituksilla auttaa. Tämä liittolaisuus antoi sille nimen vala-yhteys
(Eidsgenossen). Albrehti tullen jo levottomaksi tästä vihollisuuden
merkistä kohtaansa, koki luovuttaa heitä keisarin, heidän ainoan
päällikkönsä suojelluksesta ja saattaa Habspurin reivien vallan alle,
arvellen jos ei joku pojistansa tulisi valituksi jälkeiseksensä Ruomin
keisariksi, he kuitenkin mahtasivat olla valtivina tämän maan ylitse,
joka muutoin joutusi pois Itävallan herttuain käsistä.
Mutta Uri, Sveitsi ja Unterwalden olivat jo kylliksi vakuutetut niistä

ryöstöistä ja muista vallattomuuksista, joita heidän ympäristöllä
alituisesti tapahtui, eivät antaneet mokomalta ehdolta pettää
itseänsä. Sentähden kielsivätki suostumasta niihin aikeihin, joihin
Albrehtin lähettiläiset heitä v. 1305 myönnyttelivät, ja anoivat, että
he suotasiin olla hallitsevan keisarin suojelluksen alla rauhassa, tahi,
senaikusen puheen jälkeen, ettei heitä eroitettaisi Saksan
valtakunnasta.
Albrehti vastuutti heille aikovansa tehdä heitä ikään kuin lapsiksi

eli perillisiksi keisarillisesta su'ustansa, tarjoili maita ja tiluksia heidän
etuisimmille porvaleillensa ja lupasi tehdä kymmenen heistä ritaliksi
joka liittolais-kunnassa. Mutta nämät vanhat vuorilaiset vastasivat
ainoan pyyntönsä olevan, että heidän entiset sääntönsä ja
oikeutensa voimassa pidettäisiin, ja että he ei halanneet
minkäänlaisia uusia ja outoja etuja. Albrehti, havaittuaan ettei
maanittelemisensa mitään auttaneet, päätti kokea mitä julmuus
vaikuttaisi; sentähden laittoi hän heille kaksi voutia Itävaltakunnasta,
joitten kopia ja kiukkunen mielenlaatu oli hänelle jo entuudestaan
tuttu; nämät oli Herrman Gessler Brunekista ja ritari Beeringer
Landenbergista. Nämät uudet voudit asettuivatki suoraan vala-
liittolaisten maakuntaan asumaan, jota edellisensä ei mitenkään
uskaltaneet tehdä; Landenbergi pysähtyi keisarilliseen Sarnin linnaan
Unterwaldissa, ja Gessler, ei löytäen osakseen joutuneessa köyhässä
maakunnassa itselleen sopivaista asuntoa, rakennutti linnan, jonka
hän nimitti Joch Uri (Suomeksi Urin i'es.), ja tästä hetkestä alkoi hän
uutterasti täyttää Albrehtin käskyä, joka toivoi tämän julman
menetyksen kautta saavansa valtaliittolaiset itsestänsä eriämään
valtakunnasta ja antautumaan Itävallan hallinto-su'un suosioon;
arvattavasti korotettiin tullimaksot, vähimmätkin rikokset rankaistiin
suurilla sakoilla ja kansaa kohdeltiin pilkalla ja ylönkatseella.
Eräänä päivänä kuin Herrman Gessler ratsasti ympäri Sveitsin

yhteysmaita, seisahti hän erään rakennettavan talon eteen, joka oli
jo melkeen valmisna, ja jonka isäntää nimitettiin Werner Stauffacher
(Tämän talon jäännökset ovat vielä tänäpäivänä jäl'ellä ja osotetaan
matkustaville). — "Eikö ole synti ja häpiä", sanoi hän itseänsä
seuraavalle sotamiehelle, "nähdä orjain rakennuttavan tuommosia
taloja, kuin maankoppolit oikeestaan olisi heille ylen hyvät?" —
"Antakaapas heidän vaan saada sen valmiiksi, suurisukunen herra",
vastasi sotamies; "niin panetamme heti sen portille Habspurin valta-
merkin, ja me tahdomme nähdä, jos talon isäntä on kylliksi rohkea
sanomaan sitä omaksensa". — "Oikeen sanottu", virkki Gessler
ny'ästen hevoistansa kannuksillaan ja ajaen tiehensä. Wernerin
vaimo seisoi oven kynnyksellä; ja kuultuaan puheen käski hän
työmiesten heti pysähtymään työstänsä ja mennä tiehensä, jonka he
myös tekivät.
Kuin Werner tultuaan kotia näki rakennuksensa työmiehiltä

jätetyksi, kysyi hän hämmästyen vaimoltansa, miksi työväki oli
mennyt pois, ja ken heille siihen luvan antanut oli.
— Minä, vastasi vaimonsa.

— Mintähden, vaimo?
— Sentähden, että maankoppoli on hyvin sopiva
Werner huo'ahti ja astui huoneesensa. Hänellä oli nälkä ja jano, ja

arveli lounaan jo valmiina olevan. Sentähden istuin hän pöydän
ääreen, vaimonsa toi hänelle leipää ja vettä ja istuin hänen viereen.
— Eikös enään löydy viinaa kellarissa, ja vuohia vuorilla eli kaloja

järvessä, vaimo? kysäsi Werner.
— Täytyy tottua elämään säätynsä jälkeen; leipä ja vesi on orjain

ruoka.
Werner mulisti silmiään, söi leipää ja joi vettä.
Yön tultua, menivät he vuoteelle. Ennen kuin nukkuivat, tahtoi

Werner likistellä vaimoansa, mutta se työkkäsi hänen pois luotansa.
— Miksi sinä minua luotasi pois työkit, vaimo? kysyi Werner

(Elkäät lukiani oudoksuko jos asetan tämän Sveitsin tapauksen
täydellisessä luonnollisuudessaan; muutoin olisi se suureksi haitaksi
arvollensa ja tulisi olemaan puuttuvainen.)
— Ettei orjilla pidä intoa oleman siittämään lapsia, joitten täytyy

tulla orjiksi niinkuin heidän isänsäki.
Werner kapsahti heti ylös vuoteelta, veti, sanaakan hiiskumatta,

vaatteet yllensä, otti seinällä rippuvan ison miekan sivullensa ja meni
pois kotoansa.
Hän meni suruisilla ajatuksilla Brünniin. Sinne tultuaan soudatti

hän itsensä eräiltä kalamiehiltä toiselle puolelle järveä, ja ennättikin
jo kappaletta ennen päivän nousua Attinghausiin, ja kolkutti siellä
appensa Waltter Fürstin ovelle. Ukko tuli itse avaamaan ovea ja
vaikka oudostuen vävynsä öillistä tuloa, ei hän kuitenkaan kysynyt
häneltä syytä siihen, vaan käski palveliataan tuomaan vieraallensa
vohlan paistia ja pikarillisen viiniä.
— Ei, kiitoksia isä, sanoi Werner, minä olen erään lupauksen

tehnyt.
— Minkälaisen?
— Etten syödä muuta kuin leipää, enkä juoda muuta kuin vettä
siihen aikaan asti, joka kenties vielä sangen kaukana on.
— Mikäs aika se siis on?
— Kuin me tulemme vapaiksi.
Walter Fürsti istahti Wernerin vastapäätä ja sanoi: kyllähän toi

kuuluu kauniilta, mutta tohtisitkohan sanoa sitä muilleki eikä ainoasti
sille, jotas isäksesi kutsut.
— Minä olen valmis sanomaan samaa Jumalalle, joka on taivaassa

ja keisarille, joka on hänen siainen maan päällä.
— Oikeen sanottu poikani; minä olen jo kau'an sinulta tänlaista

tuloa ja vastausta odottanut. Wiimeiseltä arvelin, ettei molempiakaan
tule.
Uudestaan kuului kolkutos ovelle, ja Waltter Fürsti meni

avaamaan. Ulkona seisoi eräs nuori mies, kurikka ol'alla; ja samassa
valkaisi kuun valo hänen vaaleaa muotoansa.
— Melhtal! huusi äkkiä Waltter Fürst ja Stauffaher.
— Mikä sinulle tuli? kysäsi Waltter vieraalta, hämmästyen hänen

vaaleuttansa.
—Minä ha'en pakopaikkaa ja kostoa, vastasi Melhtal tummalla

äänellä.
— Saat molemmat, vastasi Waltter Fürst, jos kosto sekä

pakopaikka minun vallassani lienevät. Mutta mitäs sinulle tapahtunut
on, Melhtal?
— Minulle tapahtui, kuin kynsin peltoani ja atrani edessä oli pari

paraimpia härkiäni valjaissa, niin kulki eräs Landenbergarin
palvelioista ohitse, seisahti ja sanoi tullessaan minun luo: noi här'ät
ovat liian hyvät orjalle; sinun täytyy antaa ne pois.
— Nämät här'ät ovat minun omani, vastasin minä hänelle, ja että

minä heitä tarvitsen, sentähden en tahdo minä heitä myödä.
— Noh, kenpä niitä sinulta osteleekkan, sen tolvana?
Näitä sanoessaan veti hän vyöteiseltään veitsen ja leikkasi lenkut

poikki.
Mutta jos te minulta här'ät otatte, milläs minä sitten kynnän

peltoani? kysyin minä.
— Mokomat talonpojat, kuin sinä, taitavat hyvin kyllä itseki vetää

atraa, jos mielivät syödä sitä leipää, jota eivät ole ansainneet.
— Jättäkää här'ät, sanoin minä hänelle, vielä on aika. Jos menette

tiehenne, niin minä annan teille anteeksi.
— Missäpä sinulla on joutsi ja nuolet, ettäs niin tohdit puhua?
kysyi hän.
— Luonani seisoi eräs nuori mutta tukeva puu, jonka minä heti
taitoin. Min'en tarvitse sitä enkä tätä, sanoin minä; te nä'ette olevani
varustetun.
— Jos sinä liikahat askeleenkan verran tänne, sanoi hän minulle,

niin minä heti leikkaan mahasi puhki kuin vasikan.
Yhdellä hyppäyksellä seisoin minä hänen vieressään seiväs

pystyssä.
— Ja jos te vähääkän koskette minun atraani, niin minä paiskaan

teidät kuoliaaksi kuin si'an.
Hän ojensi kätensä ja kosketti atraani. Minä luulen, että hän liikutti
sitä hyppysillään.
Seipääni kaatui ja Landenbergarin palvelia sen myötä. Minä löin

häneltä käden poikki kuin risun.
— Siinä et sinä muuta tehnyt, kuin mikä oikeus oli, sanoivat

molemmat miehet.
— Sen tiedän minäkin, sanoi Melhtali, enkä sentähden kadukkaan

sitä, mutta kuitenkin täytyi minun pa'eta. Minä jätin sinne härkäni ja
piiloittelin koko päivän metsässä; mutta pimeän tultua muistin minä
teitä, joka niin hyvä ja ystävällinen olette; sentähden poikkesin minä
Sürchin vuoritielle, ja tulin näin tänne.
— Terve' tultua, Melhtali, sanoi Waltter Fürst, ojentain hänelle

kättänsä.
— Mutta siinä ei ole vielä kyllä, sanoi nuori mies; minä soisin myös
lähetettävän eräs ymmärtäväinen mies Sarniin, tiedustelemaan mitä
siellä sitten eilen tapahtunut on ja miten Landenbergari kokee kostaa
minulle.
Wielä tätä sanoessaan kuului joku tulevan ja heti kolkutti eräs

mies ovelle, sanoen: avaa, minä olen Rüder.
Melhtali kiiruhti avaamaan ovea, heittäytyäkseen isänsä uskollisen

palvelian syliin, mutta havaittuaan hänen olevan valjuna ja
suruisena, peräytyi hän paikalla takasi.
— Mitä kuuluu, Rüder? kysäsi Melhtali tärisemällä äänellä.
— Woih teitä poloista, te nuori isäntä! Woih sitä onnetointa maata,

joka hiljaan taitaa katsella senlaisia rikoksia! voih minua onnetointa,
jonka täytyy tuoda teille niin kauhistavia sanomia!
— Eihän toki lie jotain vanhalle isälleni tapahtunut? kysyi Melhtal;

ovathan he toki kunnioittaneet hänen korkea ikäänsä ja harmaata
päätänsä? Wanhuus on pyhä!
— Wielä vain he pitävät mitään arvossa? tahi on joku pyhä heille?
— Rüder!… huusi Melhtal väännellen käsiänsä.
— Ja, he ottivat hänen kiini, kertoi toinen, he vaativat häntä

sanomaan, kussa te olisitte, ja kuin ei hän ukko parka sitä tietänyt…
niin he puhkasivat häneltä silmät. Melhtal parkasi kauhialla äänellä.
Werner ja Waltter Fürst katselivat hämmästyen toisiansa silmiin.
— Sinä valehtelet, huusi Melhtali, kaapaten Rüderiä niskasta kiini;

sinä valehtelet: ei ole mahdollista, että niitä ihmisiä löytyy
maailmassa, jotka senlaisia rikoksia tehdä taitavat; oh, sinä
valehtelet; tunnusta vaan, ettäs valehtelet!
— Woih! oli Rüderin ainoa vastaus.
— He puhkasivat häneltä silmät, sanot sinä? Ja he tekivät sen

ainoasti siitä syystä, että minä pakenin kuin pelkuri! he puhkasivat
isältäni silmät sentähden, ettei hän tietänyt, kunne poikansa joutui!
he pistivät terävän raudan vanhan miehen silmiin ja he tekivät sen
päivän ja auringon valossa, Jumalan silmäin edessä! Ja vuoremme ei
ole langenneet heidän päällensä, järvemme eivät ole kohonneet
ääriensä yli ja hukuttaneet heitä; Ukkosen leimaus ei ole tullut
taivaasta alas ja musertanut heitä!. heillä ei ole kylliksi meidän
kyyneleistämme, vaan he tahtovat saattaa meitä itkemään verta! O
Sinä laupias Jumala, armahda meitä! näitä sanoessaan kaatui
Melhtal ikäänkuin juuriltaan nyväisty puu maahan, piehtaroi ja
heitteli itsiään kuin mato ja pureskenteli maata. Werner läheni häntä.
— Elä itke kuin lapsi, sanoi hän: eläkä piehtaroi maassa kuin
järjetöin luontokappale, vaan nouse ylös kuin mies: me tahdomme
kostaa isäsi edestä, Melhtali!
Nuorukainen kapsahti samassa seisalleen ikään kuin jänne olisi

hänen ylös heittänyt. — Kostaako, sanoitta te, Werner?
— Ja, totisesti me tahdomme kostaa sen, kertoi Waltter Fürst.
— Ah! huusi Melhtali kauhealla äänellä, ikään kuin mieli puoli.
Samassa kuului kaukaa ihana veisun hyminä, ja tien käännöksessä

näkyi, äsken nousseen auringon valossa, eräs mies tulevan tietä
myöten.
— Menkää, herra kulta, sisään, virkki Rüder Melhtalille.
— Jää paikallesi, sanoi Waltter Fürst; hän on ystävä.
— Ja joka kenties on meille hyödyksi, lisäsi Werner. Melhtali parka

vaipui eräälle pankolle.
Sill'aikaa tuli vieras yhäti lähemmäksi; hän oli noin 40:nen vuoden
paikoilla oleva mies, vaatehittu mustan puhakkaan kauhtanaan, joka
hänelle ainoasti polviin asti ylettyi ja näkyi olevan puoleksi
munkkipuoleksi tavallisen vaateparren kaltainen; kuitenkin havaittiin
hänen pitkästä tukastaan, viiksistään ja parrastaan, joka keritty
vapain maalaisten tavalla, jos hän olisiki luostari-väkeä, niin olisi se
sangen kaukaisesta maakunnasta. Päälliseksi näkyi hänen käyntinsä
enemmin sotijan kuin munkin kaltaiselta, ja olisi voitu arvella
sotamieheksi, jos hällä miekan siassa ei olisi ollut kirjoitus-aineet
sivullansa ja tyhjässä nuoli-torvessaan perkamenttikääry ja sulkia.
[Pergamentiksi mainitaan kuivattua ja ennen muinon Pergamos

nimisessä kaupungissa valmistettua eläimen luultavasti
vasikannahkaa, jolle muinoseen aikaan kirjoitettiin. Paperi sai taas
nimensä eräästä Papyrus nimisestä puusta, jonka isoja ja leveitä
lehtiä al'ettin sittemmin pergamentin puutteessa käyttämään
kirjoitus-levyksi. Wasta aikain oloon keksittiin tätä meidänki maassa
käytettävää paperia ruveta valmistamaan, jota eräät sanovat
tehtävänki vanhoista rievuista, rättilöistä, jauhetusta luusta j.n.e.,
joka kaikki ihan puuroksi vatkattua, lasketaan sitten kulkemaan
monen monituisen litistys koneiden läpitse, siksi kuin siitä viimein
syntyy paperi. Ja arvanneehan tuon jokainen, mistä kaikkia niitä
vasikoita otettaisiin, jos mekin aina vielä niitten nahalle vaan kaikki
asiamme kirjoittaisimme. Suom.]
Muutoin oli hänen yllänsä siniset pintaa myöten kiinitetyt housut,
ja jaloissaan puoli-saappaat päkiältä nahka nauhoilla kiini kurotut,
kädessään oli hänellä rauta-kärkinen sauva, jota paitsi ei vuorilainen
koskaan lähde liikkeelle loitommaksi.
Akättyään miehet Waltterin oven edessä herkesi hän laulamasta ja

läheni heitä ollen vakuutettu siinä tuttuja kohtaavansa. Tosin olikin
hän vielä hyvän matkan päässä, kuin jo Waltter Fürsti alkoi puhutella
häntä.
— Terve, terve, Wilhelmi! sanoi hän hänelle. Mihin sinä jo näin

varhain kul'et?
— Jumalan terve', Waltter! käynpähän ympäri maata, kokoillen

saatavia nais-luostarille Zürichissä, jonka toimitus-miehiä minä olen,
niinkuin te tiedätte.
— Etkö viipysi vähää aikaa luonamme?
— Mintähden?
— Kuullaksesi, mitä tällä nuorella miehellä olisi sanottavaa sinulle
— Wieras kääntyi Melhtalin puoleen ja nähden hänen itkevän, tuli

hän hänen luo ja ojensi hänelle kättänsä. Jumala kuivatkoon
kyyneleesi, veljeni! sanoi hän.
—Jumala kostakoon veren-vi'an! vastasi Melhtali… Ja nyt kertoi

hän, mitä hänelle äsköttäin tapahtunut oli.
— Wilhelmi kuunteli kertomisen suurella surkuttelemisella ja mieli-

pahalla.
— Noh mitäs te olette päättäneet tehdä? kysyi Wilhelmi,
kertomisen lopulla.
— Kostaa ja vapauttaa maamme! vastasivat kaikki kolme miestä.
— Jättäkäät veikkoset sekä kosto että Kansan vapauttaminen

Jumalan halttuun, sanoi Wilhelmi, se on Hänen työnsä.
— Mutta mitäs hän on jättänyt meidän tehtäväksi? Rukoilla ja

kärsiä, ne on aineet, jotka saattavat aikanansa koston pahalle.
— Ei hyvä Wille, ei se kelpaa, että sinä, joka niin tarkka ja uhkea

joutsi-mies olet, vastailet kuitenkin kuin munkki, koska sinua
puhutellaan niinkuin tavallista vapaata kansalaista.
— Jumala on luonut vuoret hirveä ja mäki-vuohta varten, ja mäki-

vuohen (filon) ja hirven ihmistä varten. Ja sentähden on Hän
antanut nopeuden eläimelle ja nerokkuuden ampujalle. Te petytte
siis, Waltter Fürst, kutsuissanne minua uhkeaksi joutsi-mieheksi, joka
en ole muu kuin kunnotoin ampuja parka.
— Noh hyvästi Wille, mene' rauhaan!…
— Jumala olkoon teidän kansanne, veljeni!
Wilhelm meni tiehensä. Miehet katsoivat vielä kau'an hänen

jälkeensä, siksi kuin hän ensimmäisessä tien käännöksessä katosi
heidän silmistänsä.
— Eipä nä'y olevan häneenkän luottamista, sanoi Werner

Stauffaher, ja kuitenkin olisi hänestä ollut hyvä apu. Jumala on
näköjään jättänyt maamme vapauttamisen yksinään meidän
haltuumme. Kiitos olkoon Herralle! Koskas me tartumme asiaan
käsiin? kysyi Melhtali. Minulla on kiiru… omat silmäni itkevät ja isäni
vuotavat verta…
— Me olemme jok' ainua eri kihlakunnasta; sinä Werner olet

Sveitsistä; toi Melhtali Unterwaldista ja minä Urista. Walitkaamme
kukin ystävistämme kymmenen uskottua miestä; ja kokoutukaamme
sitten Rütliin… Luojalla on voimaa tehdä, mitä tahtoo, ja
kolmekymmentäki, hänen teitänsä noudattamaa miestä, saavat kyllä
Hänen avulla niin paljon aikaan kuin koko sotajoukko…
— Koskas me kokoontumme? kysyi Melhtali.
— Ensi maanantakia vasten yöllä, vastasi Waltter Fürst.
— Me tulemme kaiken mokomin, vakuutti Werner ja Melhtali.

Tämän liiton tehtyä erosivat he, toisistansa.
Toinen Luku.
Konrad Baumgartenista.
Niiden kolmen miehen se'assa, jotka Unterwaldin kihlakunnasta

piti seuraaman Melhtalia Rütliin 17:ta Marraskuuta vasten yöllä, oli
eräs nuori mies nimeltään Konrad; hän oli äsköttäin nainut
kauneimman neidon Alzellissa, ja ainoasti halu vapauttaa maatansa
saattoi hänen yhdistymään liittolaisten kera, sillä hän oli muutoin
onnellinen.
Sentähden ei hän nuorelle vaimollensakaan virkkanut mitään

asiastansa, jonka tähden hänen täytyi kotoa lähteä. Hän teeskenteli
suuresti tarvitsevansa mennä Brünnin kylään ja vasta ehdolla 16 p.
mainittua Marraskuuta, ilmoitti hän vaimollensa, yöksi kotoa pois
lähtemänsä eikä ennen huomenta palautuvansa. Nuori puolisonsa
valkeni.
— Mikä sinulle tuli, Rosa? kysyi Konrad. Taitaako niin vähäpätöinen

asia niin kovin liikuttaa sinua!
— Kuules, Konrad, sanoi nuori vaimonsa, etkös voisi jättää lähtöäsi

toistaseksi?
— Se on mahdotoin.
— Noh etkös voisi ottaa minua kanssasi?
— Se on myös mahdotoin.
— Niin mene' sitten!
Konrad katsahti vaimoansa silmiin. Epäiletkös sinä jotakin

minusta? kysyi hän. Rosa nyhähti suruisesti. Ei, ei se ole mahdollista,
sanoi hän, Konrad, varmaanki on jotain tapahtunut, jotas salaat
minulta.
— Kenties ei ole minulla syytä pel'ätäkän, virkki Rosa huo'aten.
— Mitäs sulla olisi juuri pel'ättävääkän täällä kylässä, sukulaisten

ja ystävien keskellä?
— Tunnethan sinä, Konrad, meidän nuorta herraa?
— Tunnen kyllä, vastasi toinen mulistain filmiään; mitäs sitten? —

Hän näki minua Alzellissa, ennen kuin vaimoksesi tulin.
— Ja rakastui sinuun? kiljasi Konrad puristellen nyrkkiänsä ja
katsellen vaimoansa tuimilla silmin.
— Hän sanoi minulle sen.
— Jo ennen?
— Ja, mutta minä unhotin sen; vaan eilen kohtasin minä hänen
tiellä
Stantsiin, ja hän sanoi minulle sitä samaa.
— Hyvä, hyvä! sanoi Konrad itsekseen. Sen hävyttömiä herroja! te

etten tyydy rakkauteeni isänmaatani kohtaan, vaan te tahdotte että
minä sen ohessa alʼan vihaata teitä! mutta ko'olkaa vaan uusia vikoja
päällenne, sillä koston hetki on läsnä!
— Ketä sinä niin uhkailet? kysyi Rosa. Muista, Konrad, että hän on
meidän päällysmies!
— Hän on tosin herra ja päällysmies käskyläistensä, renkiensä ja

orjainsa ylitse, mutta minä, Rosa, minä näetsen olen vapa mies,
Stantsin kaupungin kansalainen, herra maani ja taloni ylitse, ja vaikk'
en minä ole mikään riitoin ratkaisia ja tuomari, niinkuin hän, on
minulla kuitenkin vapaus puolustaa itseäni ja hankkia oikeutta Lain ja
asetusten jälkeen.
— Nä'etsen nyt Konrad, olihan minulla syy pelätä?
— Ja.
— Ethän sinä siis jätä minua?
— Mitä minä kerran luvannut olen, sen tahdon minä täyttää.

— Noh otathan minut myötäsi?
— Johan minä sanoin sinulle kerran, että se on mahdotoin.
O hyvä Jumalani! huo'ahti Rosa.
— Kuuleppas nyt, sanoi Konrad lauhtuneempana; kenties me

syyttä pelkäämme; minä en ole kellenkään virkkanut lähteväni pois
kotoa; sitä lukua ei siis kukaan tiedä sitä. Minä en ole kau'emmin
pois kotoa kuin huomiseen puoleen päivään asti. Minut arvellaan siis
olevan luonasi, eikä sinulle mitään hätää tapahdu.
— Suokoon hyvä Isä, että niin olisi!
Konrad syleili Roosaa ja meni matkaansa.
Kohtaus-paikka oli, niinkuin jo sanoimme, Rütlissä; ei yhtään

kutsutuista puuttunut.
Tässä vähässä puilta ja pensailta piiritetyssä laaksossa, Seelis-

vuoren juurella, tapahtui yöllä, 17 p. Marras-kuuta v. 1307, se
kaikkein kummalisin kohtaus maan päällä, nimittäin niiltä kolmelta
mieheltä vahvistettu liittolaisuus, jotka valalla vannoivat panna
vaikka elämänsä altiksi, saadaksensa vapauden koko Kansakunnalle.
— Waltter Fürst, Werner Stauffaher ja Melhtali, nostivat kätensä
taivaaseen ja vannoivat sen Kaikkivaltiaan Jumalan edessä, jonka
kädessä Kuninkaat ja Kansakunnat ovat, että elää ja kuolla veljeinsä
edestä, yhteisesti kärsiä ja kantaa kaikki vaivat ja vastukset, kuin
heitä tässä aiheessaan kohtaajaisi, mutta ettei tehdä pienintäkään
vääryyttä kellenkään, arvossa pitää ja puollustaa Habspurin reivin
oikeuksia ja omaisuuksia, ei tehdä keisarin voudeillekan mitään
pahaa, vaan ainoasti tehdä loppu heidän julmuudellensa; sitten
rukoilivat he Jumalata, jos muka tämä vala olisi Hänelle otollinen,
Hän mahtasi sen jonkun ihmetyön kautta heille ilmoittaa. Samassa
sanotaan kolme lähte-suonta ruvenneen ruiskuamaan näitten
kolmen pää-liittolaisten jalkain juuressa.
[Nämät kolme lähdettä juoksevat vielä tänä päivänä niinkuin 500

vuotta takasin, ja matkalaiset käyvät niitä katsomassa; niiden
sanotaan, vanhan ennustuksen jälkeen, vasta sillon kuivauvan, kuin
Sveitsinmaa kadottaa vapautensa. Ensimmäinen vasemmalla kädellä
on Waltter Fürstin, toinen Werner Stauffaherin ja kolmas Melhtalin.
Silloin huusi koko seura: Kunnia olkoon Herralle! ja taas nostaen
kätensä ylös, vannoivat he uudestaan vapauttaa maatansa. Tämän
aiheen täyttäminen päätettiin tehtäväksi Uutta Joulua vasten v.
1308; päivän val'etessa erkanivat he toisistansa ja kukin heistä läksi
kotiansa.]
Waikka Konrad kyllä kiiruhti, oli kuitenkin päivä puolessa, ennen

kuin hän päästyään Dallenvylistä, näki kaukaa Wolffenschiessin kylän
ja kylän tällä puolella olevan talonsa, jossa Rosa häntä odotti; kaikki
tuntui olevan hiljaan. Tämän nähdessä heikkeni pelkonsa;
sydämmensä ei enää niin kovin tykyttänyt ja hän seisahtiin vähän
levätäksensä. Äkkiä tuntui hänestä, kuin olisi tuuli hymissyt hänelle
nimeänsä korviin. Hän vavahti ja alkoi taas kiiruhtaa edespäin.
Wähän ajan perästä kuuli hän toistasesti äänen huutavan hänen

nimeänsä. Hän kauhistui, sillä ääni oli valittavainen ja hän arveli siinä
tuntevansa Roosan äänen. Tämä kuului maantieltä, ja hän alkoi siis
juosten kiiruhtaa kylään.
Tuskin harppasi hän parikymmentä askelta, kuin hän äkkäsi erään

vaimon hajalla hapenin juoksevan vastaansa, ja joka nähtyään
Konraadin huusi häntä nimeltänsä, viimen voimien rau'ettua lankesi
se maahan keskelle maantietä. Yhdessä hyppäyksessä oli Konrad
hänen luonansa. Hän tunsi Rosan.
— Miten kanssasi on laita, kultani? kysyi hän.
— Pa'etkaamme, pa'etkaamme! sihisi Rosa henkästyneenä, kokein

nousta seisalleen.
— Miksi meidän siis täytyy pa'eta?
— Siksi että hän tuli, sinun poisollessasi…
— Hän tuli!…
— Ja… sinun poisollessasi tuli hän, ollessani yksin kotona…
— Mitä vielä, puhu Luojan tähden pikemmin! Hän käski minua

valmistamaan itsellensä saunaa…
— Sen hävytöin!… ja sinä tottelit?…
— Mitäs minä, kultaseni, taisin muuta tehdä… sitten alkoi hän

minulle puhella rakkaudestansa ja tahtoi kaapata minua… ja silloin
pakenin minä, huutaen sinua avukseni… minä olen juossut kuin
mielipuoli ja nähtyäni sinun, raukenivat voimani niin että minä
kaaduin kumoon, ikään kuin maa olisi letkahtanut altani.
— Missäs hän on?
— Hän on kotonamme… saunassa…
— Se hävitöin! kyllä minä hänelle näytän! kiljasi Konrad alkaen

rientää kotiinsa.
— Mitä ai'ot tehdä, onnetoin?
— Odotahan tässä vähän aikaa, Rosa, minä tulen paikalla takasi!
— Rosa lankesi polvillensa ojentain kätensä sinnepäin, johon

Konrad juoksi. Tässä tilassa oli hän noin neljännen-osan tuntia,
liikkumatoinna ja äänettömänä kuin kivi; sitten kapsahti hän äkkiä
ylös ja parkasi kauhistavalla äänellä. Sillä Konrad palautui valjuna
kasvoiltaan ja pidellen kädessään verellä tahrattua kirvestä.
— Pa'ettaamme Rosa, sanoi hän nyt vuorostaan; pa'etkaamme,

sillä emme voi olla rauhassa ennen kuin toisella puolella järveä. —
Pa'etkaamme tietämättömiä polkuja myöten… kau'as maantieltä ja
kylien tienoilta pa'etkaamme, jos et tahtone minun kuolla pel'osta, ei
omani vaan sinun elämäsi edestä!… Näitä sanoessaan sieppasi hän
vaimonsa myötänsä niitulle aidan yli.
— Rosa ei ollut joku niistä heikoista ja ar'oista kukista, joita

meidän maissa kasvaa, vaan hän oli vahva ja raitis vuorilais-vaimo,
rohkea ja pelkäämätöin vaarassa, luotu työtä ja helleyttä varten.
Konrad ja hän joutuivat siis pi'an vuoren toiselle puolelle. Tässä
tahtoi Konrad että levähtäsivät vähän, mutta Rosa osotti sormellaan
verta, jolla kirveen terä oli tahrattu.
— Kenen verta se on? kysyi hän.
— Hänen!.. vastasi Konrad.
— Pa'etkaamme! parkasi Rosa. Ja alkoi taas rientää tietä myöten.
Sitten peittyivät he metsän sakeuteen ja kapuilivat kalttoja mäkiä

ja vuoren rinteitä myöten, senlaisia polkuja, jotka ainoastansa
metsästäjille olivat tiettyjä. Jo monasti tahtoi Konrad seisahtua
levähtämään, mutta Rosa rohvaisi yhdäti toveriansa, vakuuttaen ei
olevansa väsyksissä. Wihdoin, melkeen jo syvän yöllä tulivat he
erään sangen korkian vuoren nyppylälle; sieltä kuului selkeästi
karjain äänteleminen, joita ajettiin Seidorffiin Bauin kyliin, ja näitten
kylien takaa äkkäsivät he laakson pohjalla Wahlstädtin järven,
tyyneenä ja kirkkaana kuin peili. Tämän nähdessä aikoi Rosa vielä
matkata eteenpäin, mutta eipä enää jaksanut, jo ensi askeleita
ottaessaan alkoi hän horjua. Silloin kehoitti Konrad häntä kaiken
mokomin vähän levähtämään, tehden puolisollensa pehmeän
vuoteen puitten lehdistä ja sammaleista, jolle Rosa käytyään levolle
samassa nukkui, mutta Konrad jäi valveille vartioimaan häntä.
Wähitellen kuuli Konrad kaikki äänet laaksossa vaikenevan ja näki

val'ot siellä, jotta vuorelta näkyivät kuin maalle pudonneet tähti-
sikerit, yhden toisensa perään sammuvan. Ihmellisten äänien ja
liikuntoin perästä seurasi luonnon omituinen hyminä; kuolevaisten
käsillä tehtyin val'oin siaan, aukeni taivaan avaruudelle Luojalta
luodut kirkkaat tähdet; maalla ja merellä ja koko luonnolla on omat
monet monituiset ääntelemisensä, jotka äkkiä keskellä yötä nousevat
sekä järvien pinnoilta että synkkäin metsäin sisältä. Wälistä kuulet
kosken kohinan, välistä tuulen kohinan, kaikki nämät luonnon äänet
puhutteleevat vuorilaista omituisella kielellä, jonka hän hyvin kyllä,
totutusta tavastaan, käsittää ja jolle hän vastailee tahi kovalla
huutoäänellä tahi iloisella kiitollisuuden veisuilla, sillä nämät äänet
ennustavat hänelle tahi elämän myrskyä eli levon ja rauhan
suloisuutta.
Samoin seurasi Konradikin sumua, joka alkoi järven pinnalta

nousta, hämärtäen sen välkkyyttä, ja joka vähitellen kokouten
laaksoon, vihdoin keräyty Axemin lumivuoren nyppylän ympärille.
Monasti vilkkui hän pel'olla sille puolelle taivasta, josta kuun piti
nouseman ja joka viimein näyttäytykin, mutta tummana ja ympäröity
sumun kiehkuralta, joka värjäsi sen vaaleeta val'oa; vähitellen
alkoivat myös pienoset tuulen-puuskatkin liikkua, tuoden mu'assaan
kastean maan löyhkää; Konrad kääntyi etelään päin, henkäsi sitä
metsä-koiran tavoin ja virkkoi itsekseen: jaa, kyllä minä tunnen
teidät, myrskyn ennustajat, ja minä kiitän teitä siitä; sanomanne
eivät ole turhaan annetut. Wihdoin lennätti viimeinen tuulen-puuska
mu'assaan ensi sumut Neufchatelin järvestä ja Moratin suon mutaa.
Silloin hoksasi Konrad olevan ajan lähteä liikkeelle ja kuuristui
herättämään Roosaa.
— Rakas puolisoni, sopotti hän hänelle korvaan, elä säikähdä;

minä olen, joka nostatan sinua…
— Rosa aukasi silmänsä ja heitti molemmat kätensä Konradin

kaulan ympäri.
— Kussa olemma me? kysäsi Rosa. Minua viluttaa…
— Meidän täytyy lähteä matkalle; taivas uhkaa kauhiaa myrskyä,

ja meillä on tuskin aikaa ker'etä Nischenbachin luolaan, jossa
taidamme olla suojassa; sen ohitse mentyä laskeumme me Baviin,
jossa me kyllä jonkun saattajan tapaamme, joka meidät Brünniin eli
Sissigiin viepi.
— Mutta emmekös me sillä tavoin kadota aikaa, Konrad tulta? Ja

eikös meidän olisi parempi mennä suoraan alas järven rannikoille?
Mitäs jos meitä takaa ajettaisiin…
— Samoin olisi huokea löytää mäki-vuohen ja kotkan jälkiä, jos

joku nyt meidät tapaasi, vastaisi Konrad. Ole vaan siitä rauhassa,
armaani, mutta katso! myrsky nousee, lähdetään matkalle.
Tosin kuuluikin jo kaukana ukon-jylină, joka kiersi laakson ympäri
ja vaipui Arembergin vuoren seuduilla.
— Oikeen sinä sanoit; meillä on tukala ajasta, sanoi Rosa;

kiiruhtakaamme, Konrad!
Näitä sanoessa ottivat he toisiaan kädestä ja riensivät niin kiiruusti

kuin mahdollista oli Rischenbachin luolaa kohti.
Sill'aikaa alkoi myrsky pauhata kauhiasti, sikäli kuin aamu valkeni.

Idästä vähän ajan takaa leimahteli taivas helkka-punasena ukon-
tulelta ja jyrinältä, pakolaisten päällitse, niin ettei he välistä
hoksanneet laksoakaan edessään; kiiruusti rientäen vuoren sivua
alas tulivat he melkeen läpimär'äksi hallasta, joka lievitti heitä varin
pakosta. Äkkiä, ukon-ilman vähän tau'ottua, jona koko luonto tuntui
kuin varustauvan vieläki kauheampaan liikuntoon, kuului kaukana
koiran haukunta.
— Se on Merkin ääni, sanoi Konrad, seisattuen äkisti paikalleen.

Hän on varmaanki päässyt kahleistaan irti, virkkoi Rosa, ja on
jahdilla vuoristossa.
Konrad käski hänen olla hiljaan ja kuulusteli ikään kuin nerokas

jahtaaja eli vuorilainen muinonkin, joka pienimmästä hiiskusta
hoksaa heti vaaran eli avun saapumilla olevan. Haukunta kuului
uudestaan; Konrad vapisi.
— Ja, ja, kyllä hän on jahtaamassa, sanoi hän hiljaan; mutta

tiedätkö minkälaista metsänotusta hän tavoittaa?
— Mitäs se meihin tulee?

— Mitäs on elämä sille, joka pakenee sitä suojellaksensa? Meitä
ajetaan takaa, Rosa; saatana on riivatuille pistänyt sen mielen
päähän, laskemaan Merkkiä irti ja seuraamaan hänen haistin johtaa,
kuin eivät tienneet minua muutoin kiini saavansa.
— Miten sinä sitä luulla taidat?…
— Kuunteleppas tarkemmin, miten Merkin haukunta lähenee

meitä; he pitävät häntä vitjassa kiini etteivät meidän pol'ulta eksyisi;
muuton olisi Merkki jo nyt meidän luonamme, sen siaan kuin kulun
vielä hyvä tunti aikaa, ennen kuin hän meidät ennättää.
Merkki haukkui taas, mutta tuntuvasti lähenemättä; ja vieläpä olisi

voitu luulla hänen olevan loitompana entistä.
— Hän eksyy jäliltämme, virkki Rosa ilolla; ääni kuuluu loitompaa.
— Ei, ei, sanoi Konrad. Merkki ei ole tuhma koira poikkenemaan

harha jäl'ille; se on ainoasti tuulen vika; kuule, kuule! Mutta
hirvittävä ukon-jyräys esti haukkua kuulemasta, joka toen kuuluiki
lähempää; tuskin heikkeni ukon-jyrinä, kuin se taas kuului.
— Pa'etkaamme, sanoi Rosa hätäytyneenä; pa'etkaamme luolaan!
— Ei se meitä nyt hyödytä, jos emme kahden tunnin kuluttua liene

toisella puolella järveä, niin olemme hukassa.
Näitä sanoessaan kaappasi hän häntä kädestä ja veti kanssansa.
— Kunne sinä kul'et? kysäsi Rosa; ethän sinä ensinkään järvelle

päin mene.
— Tule, tule; meidän täytyy kavaluudella taistella näitten
ihmisjahtaajain kera; tästä on vielä pari virstaa järvelle, ja jos
menisimme suoraa tästä sinne, niin sinä et vähän ajan perästä
jaksasi paikaltasi liikahtaa; tule, minä sanon.
— Rosa yhdisti hiiskumatta voimansa ja vähän aikaa kiiruusti

käytyä joutuivat he äkkiä erään jyrkän kallio-loman reunalle;
luultavasti jo iki-vanhoina aikona maanjärinältä lohkaistuna. Wuoren
aukeama oli sangen syvä ja leviä. Tähän tultua parkasi Konrad
kauhealla äänellä, sillä lauta joka siihen yli-käytäväksi oli laitettu, oli
muserrettuna eräältä isolta kallio-lomalta, joka oli vierynyt aina
Rostakki-vuoren harjalta asti. Rosa älysi, mitä Konradin parkaus
tarkoitti, hän laskeutu polvillensa uskoen olevansa kokonaan
hukassa.
— Ei, ei tässä nyt ole vielä aika rukoilla, kiljasi Konrad ilosta
välkkyvin silmin. Ole huoletta Rosa! ei Jumala meitä jätä.
Näitä sanoessaan hyppäsi hän erään vanhan juuriltaan nyväistyn

kuusen luo, joka oli kallistuneena avoimen reunalla, ja hakkasi sitä
kirveellään, saadakseen siitä välikappaletta päästäkseen toiselle
puolelle; puun, joutuen voimakkaamman vihollisen kynsiin kuin
tuuliaisen, kaatui heti maahan; tosi on, ettei yksikään puun hakkaaja
ole koskaan nopeemmin ja kovemmin puuta hakannut.
Rosa toki kaiketi rohkeuttaa puolisotaan, sikäli kuin kuuli Merkin

haukuntoa, joka kaikkein näiden vastusten ja esteiden alla kuului
yhdäti lähemmältä. — Elä pelkää, armaani, sanoi hän; rohkia! katso
miten puu heiluu! ah, miten vahva ja uhkea sinä olet; hakkaa päälle,
Konrad, katso puu letkuu, se kaatuu paikalla! Ja, totisesti jo
kaatuukin! ah, hyvä Jumala, minä kiitän sinua; me olemme
pelastetut!
Samassa räpäyksessä kaatuikin kuusi kumoon, ja kaikeksi onneksi
sille puolelle kunne Konrad tarkoittikin, nimittäin suoraan vuori-
aukeaman yli, jolla tavoin se tosin tuli olemaan siltana pakolaisille,
mutta jonka päällitse ei suinkaan pelkuri ja kokematoin olisi
vuovannut.
— Elä pelkää, sanoi Rosa, hypäten esinnä sitä myöten; elä pelkää,
Konrad, vaan seuraa minua!
Mutta seuraamisen siaan, heittäyty Konrad maahan painamaan

rinnallaan hirttä, minkä jaksoi, että se olisi muka sitä tukevampana
pysynyt armaansa jalka-portaana, myös hän ei vuovannut katsella
tätä vaarallista kulkua; sillä välillä kuului Merkin haukunto tuskin
parin virstan päästä; äkkiä tunsi Konrad puun heilunnan Rosan
käynnistä la'anneen ja hän uskalsi katsahtaa puolisotansa, joka
seisoen toisella reunalla ojensi käsiänsä hänen puoleensa ja kehoitti
tulemaan perästän ylitse.
Konrad tapsahti paikalla seisaalleen ja lähättiin tälle samalallee

portaalle, hän astui sitä niin tarkoilla askeleilla kuin kivisiltaa myöten,
ja tultua onnellisesti vaimonsa luo, käänsiin hän ja potkasi hirren
syvyyteen. Rosa katsoi sen perään, ja nähtyään sen musertuneena
keikkuvan yhdeltä kalliolta toiselle, käänsi hän silmänsä pois ja
valkeni. Konrad nosti sitävastaan ilo-huudon, niinkuin kotka eli
jalopeura voiton perästä; sitten kulkivat molemmat käsityste
senlaisia polkuja myöten, joita ainoasti metsäläiset heitä ennen oli
käyneet. Wiisi minuuttia heidän jälkeen, tulivat takaa-ajajat Merkiltä
johdatettuina vuori-syvyyden kohalle!…
Sillä välillä eneni rajuilma hirviästi; tulen leimaukset välähtelivät

ilmassa ehtimiseen, ja ukon-jyrinä ei räpäyksenkän ajaksi her'ennyt;
ranka sade valui kuin koski taivaasta; jahtaajain huuto, Merkin

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Classic Papers in Geriatric Medicine with Current

STEPHANIE STUDENSKI, MD, MPH

KEVIN P. HIGH, MD, MS

EDITOR EMERITUS AND SENIOR ADVISOR

SENIOR EDITORIAL ASSISTANT

1. Biology of Aging and Longevity . . . . . . . . . . . . . . . . . . . . . 3 SECTION A Assessment

20. Subacute Care. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .237 41. Disorders of Swallowing . . . . . . . . . . . . . . . . . . . . . . . . . . . 483

81. Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 975

SECTION A Human Brain

SECTION G Hematology 116. Osteoarthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1411

INTERNATIONAL ADVISORY BOARD

Numbers in brackets refer to the chapters written or co-written by the contributor

Steven M. Albert, PhD, MSPH

Steven Barczi, MD Daniel G. Blazer, MD, PhD

Caroline Blaum, MD Cynthia M. Carlsson, MD, MS

Bruce A. Carnes, PhD Colleen Christmas, MD

Mary Catherine Dennis, MSW Stanley Fahn, MD

Catherine E. DuBeau, MD Luigi Ferrucci, MD, PhD

Brant E. Fries, PhD Ronald M. Glick, MD

Lowell W. Gerson, PhD Tomas Griebling, MD

Sudeep S. Gill, MD, MSc, FRCPC David A. Gruenewald, MD

Karen E. Hall, MD, PhD Arthur E. Helfand, DPM

Sharon K. Inouye, MD, MPH Mary E. Jung, MSc

Thomas B.L. Kirkwood, PhD Ilo E. Leppik, MD

J. Philip Kistler, MD Stacy Tessler Lindau, MD, MAPP

George A. Kuchel, MD, FRCP Noelle K. LoConte, MD

Mathew W. Ludgate, MB, ChB Shawn M. McClintock, PhD

Kenneth W. Lyles, MD Eric B. Milbrandt, MD, MPH, FCCP

Suzanne B. Murray, MD Miguel A. Paniagua, MD

Elizabeth A. Phelan, MD Annette Hylen Ranhoff, MD, PhD

Peter V. Rabins, MD Ian H. Robbins, MD, PhD

JoAnne Robbins, PhD Kenneth E. Schmader, MD

Caterina Rosano, MD, MPH Todd P. Semla, MS, PharmD

Aneesh Bhim Singhal, MD George E. Taffet, MD

Mark L. Unruh, MD, MS Birgit Weinberger

Peter V. Vaitkevicius, MD Debra K. Weiner, MD

Mark Yurkofsky, MD, CMD Susan J. Zieman, MD, PhD

Biology of Aging and Longevity

MUTATION EFFECT ON LIFESPAN (%) COMMENT

TEST POPULATION TALL PEOPLE DO BETTER SHORT PEOPLE DO BETTER

15 000 Scots All-cause stroke Colorectal, prostate, hematopoietic cancers

NHANES, National Health and Examination Survey.

Maximum Lifespan (percent of N2)

250 e979 e1369

200 m212 m579

100 120 140 160 180 200

cluding melatonin, dehydroepiandrosterone (DHEA), homeopathic

of diabetes or gall stones are all designed to allow patients to re-

tions that affect duration of life. However, although genes inﬂuence