Systems Biology of Human Aging - Network Model 2019

Revised 4 December 2019

© 2000 - 2019 John D. Furber Arrangement, text, & art by John D. Furber
Legendary Pharmaceuticals
PO Box 14200
Gainesville FL 32604-2200 USA
Maintained updated online.
Download the PDF to print. www.LegendaryPharma.com/chartbg.html
All rights reserved. [email protected]

Enhance
Cytosolic Compartment Extracellular Spaces:
200
Mitochondrial
Fission
701 Lysosome - Hydrolysis of the Cell
Macroautophagy Mitochondria Shape Key
for recycling. Accumulation in nonmitotic cells. 417
014 ECM, Blood Plasma, Lymph, CSF
Giant
mitochondria in nonmitotic cell 750 Elamipretide
Causal Sequence of Events
001
001 accumulate when protects cardiolipin
Vitamin C, Spermidine, Fasting or Enhancement
Lysosomes enhance rate of autophagy. damage impairs mito from ROS damage
033 418
015 ROS
digest Junk, until fission. They canʼt be
Lamp2a 005 autophagized, & they generated Glucose Concentration
they become by mitochondrial in Bloodstream.
filled with LF imports tagged 011 produce more ROS. Very Important Pathway
LF - filled Lysosoms have soluble cytoplasmic metabolism (Moderate in healthy people;
reduced capacity & reduced 004 proteins to digest. Autophagosomes higher in Diabetes) 202
rate of digesting Junk. They detect damaged Lysosomes,
demand more lytic enzymes engulf them, transport to new
002 ROS oxidize Free Fe, 003 from Golgi, so less enzymes 404 Glycation: 203 Movement, Transport,
Lysosome for digestion.
released by digestion, go to functional Lysosomes. 421 mt ROS Mitochondrial sugars bond or Flow of things
Lysosomal proteins & lipids Cardiolipin bends attack IMM, 422
020
or trapped in LF, Apgy becomes inhibited when 012 423
021 mtDNA Antioxidants Glycated 204 to extracellular
Enzyme 702 LF - filled Lysosomes 007 IMM, enhancing cardiolipin, Damaged quench Level of IL-15
reacts with H2O 2 Lysms cannot accept more junk. replication extracellular proteins Glucose-
Augmentation with damage membranes Autophagosomes ETC function mt proteins, mtDNA or mistakes generate some ROS 419 & IL-15Rα proteins form Lowering
to make HO*. spill lytic enzymes & engulf junk, old mitos, organelles, replication
Therapy & mtDNA insertions, deletions in serum 201 AGEs and
006 reactive LF into cytoplasm proteasomes, ribosomes, damaged machinery 715 Drugs
006 Damaged 420 crosslinks
membranes & nuclear scaffolding. mitos produce
Oxidized lipids,
LF-formation proteins, & Fe Transport to Lysosome for digestion. less ATP & more 425 Lon
Inhibitor ROS; have lower Protease Igs crosslink to 205
crosslink to form ROS in Lysosomes 009 kidney glomerular Things:
Drugs 703 Lipofuscin Lipofuscin memb pot. Most digests 428 Quantities or Pools
008 cause damage to in cytoplasm are autophagized damaged 426 Basement Membrane,
Lysosomal membranes or causing 716 of Molecules, Cells,
Lipofuscin can trigger to Lysosome. mt proteins mutant
membrane scaffolding 424 O2* - Lon Protease Glycation
accumulates Apoptosis 014 Levels decline
mtDNA complement-mediated Subtances, etc.
LF-Removing which controls converted damage -Inhibitor
in Lysosomes of with age. Glycated 206
Drugs vesicle fusions to H2O 2 mt GPx Drugs
704 Post-Mitotic cells Arginine
015
029 by SOD degrades 432
416 H2O 2 can convert
Induce Exocytosis H2O 2 in H2O 2 429 Clonal to Ornithine
of LF - filled Lysosomes . 739 010
011 H2O 2 cytoplasm diffuses Enhance
amplification
diffuses out of mito of mutant mtDNA Detection &
into Lysm causes PM cell Turnover of
Process,
Oral 705 or skeletal muscle Reductive Hotspot: 207 ECM protein 717 mutant Action,
fiber segment to Altered Arg & residues can mtDNA
Spermidine 431 Anaerobic cells & Change,
become anaerobic Asp residues deamidate or
or Agmatine 430 muscle fiber segments isomerize, or Reaction
013 427 Rate of mito export electrons through disrupt RGD 208
Functionality biogenesis cell attachment which might
plasma membrane, Extracellular

Cell Nucleus - Genetics Spermidine Fe-S Cluster of collective 077 change folding
063 generating ROS 209
is anti-ox, anti-inflamm, assy depends on mt population 718
extracellular ROS
753 Sprouty-1 373 enhances autophagy, Catalase & mt memb potential
expn reduced improves anti-cancer cytosolic GPx Smoke, etc.
Reverse Transcriptase creates
by DNA methyln immunity, & decreases degrade H2O2.
Inhibitors inhibit RTases ROS
histone H3 acetylation
Organelle or
compartment
Sirtuin 706 Dietary
Activators Sirtuins deacetylate histones, or injected
& enhance DNA repair 372 335 Antioxidants
PGC-1α 336 719
333 Lon Protease 078
058 Peroxidized Lipids &
PGC-1β

CD38 751 016

Epigenetic
Methylation
Acetylation
of Histones 334 Methylation
of Histones 367 Activated NF-kB 368
mRNA
Endoplasmic oxidized cholesterol in LDL
are imported by other cells, & Fasting,
CR, or
Reticulum
inhibitors of DNA incorporated into membranes, ROS & sugars 720 Exercise
CD38 activates CD38 damaging membranes & peroxidize lipids Gradual
degrades mitos via lipid chain-reactions. reduce LDL
Retro- & glycate 210 levels Accumulation or
752 NAD+ 067 Damaged
N A D + 369 370
Transposable Reverse 371 proteins in Increase in
Niacin, NMN, or needed for PARP Transcriptases 066 proteasome circulating LDL Aβ oxidizes Quantity or Mass
NR supplements Elements (LINE-1) 098
055
& sirtuin activity mobilize RTEs Glycation: subunits turn- Normal Aβ 079 cholesterol with Aging
increase NAD+ insert, mutate, break DNA 065 Damaged over by CMA Misfolded & fatty acids;
sugars, AGEs, 097 in membrane
Junk to be proteins 056 generates
& ALEs bond reacts with Cu,
repaired or accumulate Oxidized H2O 2 & OH*
producing
Epigenetic 707 337
064
338 341
066 disassembled
to intracellular membrane lipids & H2O2 & ROS radicals 211
Reprograming Chromatin proteins proteins release 212
339 Nuclear 20S
(Yamanaka factors) conformation Telomeres proteasome 342 excess Ca2+ Antioxidants
Chromatin remodeling is altered oxidized, p53 340 in EC fluids Racemization of
rises removes Genome integrity Gradual
drugs.eg. HdAcs & damaged, or DNA repair damaged proteins contain Redox Potential quench ROS L- to D-Asp with
HdAc inhibitors 364 made too PARP-1 poise in cytoplasm aging of long-lived Loss or Decrease
proteins Fe-S Clusters. 082 in Quantity or
short activated increased by 064 060 protein cause Aβ & 242
363 Long oxidation. 081 RAGE & Mass with Aging
355 Oxidized α-synuclein fibrils
Telomeres This changes 068 Endogenous Scavenger Chronic
Telomerase nuclear pore Junk
required for intracellular signaling Antioxidant Receptors Periodontitis.
maintains proteins allow other molecules
Stem Cell & gene expression Production Gingivitis bacteria
Tmere Length 347
068 proteins in & out aggregate
function increase prodn
Genome integrity & crosslink 070
if not quickly of Aβ External
708 346 proteins & DNA 069 Proteasomes 749 Intervention, or
disassembled
Telomerase 343 nDNA Repair Enzymes digest damaged Environmental
345 (damaged by ROS) Hyperphosphorylated 741
& TERT Therapy adducts, cytoplasmic 085
061 Fe Factors
Position Effect Short Tmeres Tau forms PHF, which 080
& Activators Developmental breakage, proteins exported from Gamma sound
of genes near => end-joining bind Cu, produce H2O 2 Transferrin 243
Differentiation short Telomeres damage,& Cytoplasmic neuron to vibration
chromosomes carries Iron in 214
reduces mutation antioxidants EC transferrin metal ionophores
alters expression => nondysjunction blood plasma
Telomerase Cytoplasmic ROS quench ROS disaggregate toxic Αβ oligos; 740 40 Hz
expression 344 349
075 attack intracellular & pick up Cu, Zn; Physiological
flashingLight
ROS in membrane proteins and release Αβ monomer. Condition
nucleus Aβ (Senescence)
X-Rays & & lipids. Enzymes
ionizing & proteasomes 071 084 monomers
709 Intraneuronal aggregate with Sleep
radiation get inactivated. Interstitial spaces in brain
Short ROS activate NF-kB, 073 Fe generates Zn, Cu, to form
create ROS 366 which enters nucleus, 083 increase during sleep. 732
048 telomeres ROS 215 toxic Aβ oligos
Reactive Cu, Zn & Gamma brainwave
353 activating genes & plaques
Levels cause splicing 351 078 354 034 Aggregates, Intracellular EC Zn Αβ monomer 213 entrainment activates PBT2,
of miRNA errors 352 Glycation: giant mitochondria, & 074 Ca2+ levels rise, ZnT3 216 released into microglia, enhancing BBB-permeant
HMGB2 Tau hyperphosphorylation Aggs
in brain HMGB2 sugars bond Cytoplasmic tubulin LF-filled Lysosomes clog & inhibit generate ROS pumps Zn & Cu glutamatergic clearance of Αβ. 238 metal ionophores Enhancement Enhancement
mRNA accumulates in nucleus destabilizes microtubules, into neurons 095
change protein to nDNA & accumulate in cytoplasm, Proteasomes synapses during of Pathway of Rising Quantity
Signals 356
& damages chromatin blocks axon transport. 721
proteins 072 generate ROS, & neurotransmission Accelerates the
Αβ monomer 218 244 or Process
Reprogramming, to nucleus impair cell functioning Rate of Increase
slowly cleared by
Genetic Engineering, 710 glymphatic transport Bone deposition in Surgical shunt with Aging
Gene Editing: to lymph & urine cribiform plate restricts in cribiform plate
Increase expn of beneficial genes: 350 clearance of CSF & Αβ
eg TFAM, Lamp2a, hTERT, Metal 217 745
Lon Protease, Proteasome. Gene expression 358 Z n 088 Zn/Cu 220 Ionophores
Make super-fibroblasts. is altered 302 ZnT3 supply in activate take Cu, Zn
neurons
MMP2 & 3 219
Re-differentiate certain cells pre-Lamin-A mRNA MMP2&3 into neuron 737
Nrf2 Nano-
for improved performance. activates 357 accumulates R E S T 017 GnRH 163 slowly digest scavenger Enhancement Enhancement
protein levels secretion from Αβ monomer therapy cleans of Pathway of Decreasing
antiox genes Progerin 365
332 in neurons. Hypothalamus plasma or Process Quantity Slows
GnRH shortens 361 Low Zn
R- α− Lipoic 362 301 Rate of Decline OR
Acid reverses gene expn in Telomeres 360 Damaged 075
047 makes α2A Actually Increases
Spliceosome ZMPSTE24 087 092 cAMP
Nrf2 loss errors mis-splice hypothalamus Progerin nuclear Loss of converts 018 Oxidized neurons 090
052 receptors in 096 Infuse
711 proteins pigment enzymes 076 Excito- sick level in cytoplasm
Lamin-A and splice-variant nuclear 048 086 MAPK PFCN membranes 230 Young plasma
accumulate pre-Lamin-A Sprouty-1 toxicity of PFC neurons
of Lamin-A proteins in hair follicles Oxidized pERK or remove old
Splice cytoskeleton 359 to Lamin-A needed for kills EGF, 222
accumulates turn hair white membrane lipids & signaling
Enhancement mRNAs
satellite prolif neurons FGF Ca++ & Lipids GnRH 236 736 plasma
proteins degrade
Therapy Glycated LDL bound to elastin in Hypothalamus
712 transporters of Ca2+, cAMP opens maintains youth Inhibition Process
239 and RBCs
Na+, Glu, & glucose; Notch
091
K+ channels, FGF2 & GnRH of Pathway that is
231 229 crosslink to Injection
promote depolarization receptor Delta stops PFCNs VEGF secreted or Process inhibited
β2-microglobulin, endothelial 221
& Ca2+ influx Ligand from firing 093 TGFβ levels in by astrocytes, Oxidation 732
089 & Chemokines, arterial collagen
satellite cell niche, microglia, NSCs, & cleavage
incl CCL11, in & NPCs.
B marrow, & blood of ECM 223 TTR
plasma & CSF
proteins solubilizing
Drugs
722
Macrophages digest MMPs 232
Prostagladin PGE2 Inhibition Inhibition
LF - filled Exosomes . 748 secreted by
injection IM stimulates 754 143 arrested cells of Pathway of Rising Quantity
Crosslink- Slows Rate of
skeletal muscle stem cells Breaker or Process
Satellite Increase OR
cell proliferation Drugs
Damaged, 723 Actually Decreases
regenerates Hypochlorous acid 228 227 crosslinked, glycated,
Selective T-Cell skeletal muscle secreted by inflam 226
149 Good Cerebral 225 oxidized ECM proteins Wnt
Deletion Therapy Sick Cells: macrophages 234 amyloid angiopathy TTR-amyloid
Articlular Hormone accumulate & change signaling
Accumulated cytoplasmic Apop decreases in muscle & Elastic Osteocalcin
713 damage causes some of articlular 127 cartilage 235 Levels
elsewhere fibers 224 EC environment in blood proteins in
137 endothelial health 240
150 cells to function poorly chondrocytes deteriorates 241 serum
Anergic or self-destruct Inhibition Inhibition
Arrested Cell Division: 151 of Decreasing
Senolytic Drugs Short telomeres, 131
T-cell clones AGE signaling of Pathway
kill arrested cells to prevent accumulate & changes MSC Healthy or Process Quantity
altered nDNA, or
spread of damage damaged Lamins cause
suppress Differentiation endocrine Accelerates the
735 135 naive T-cells cells 167 Rate of Decline
some cells to stop dividing. Cell Death: 148
Cell-to-cell 141 Apoptosis with Aging
Naive Hypothalamic
Signaling T-cell population & necrosis kill cells

Whole
pathways important cells in 159 162
Trans-differentiation: shrinks, reducing
Arrested Senescent cells 168 ability to respond to slowly renewing Macrophages Cell 161 Endothelium
Altered gene expression secrete hormones, detachment Stimulate 000 Unique Reference Number
Brain infectious microbes. tissues. bind to extravasates small
patterns change some inflammatory cytokines, & 132 AGE-collagen promotes clots & debris in or engineer
cells to inappropriate Hyperactivity
toxins, which harm other cells metastasis capillaries super-Fibroblasts
139

Cells or
phenotypes 128 & MSCs to repair
Stem cells 155 ECM
replace some Fibroblasts 724
lost cells & MSCs
repair ECM

Tissues 166
129
Fibroblast
Inflammatory 133
cytokines (IL-6)
induce expression
IL-6 causes
neuronal
precursors 136
to become Neurotoxins
Macrophages
ingest peroxidized
Lipids, LDL, &

NF-kB
production
of elastin
of endothelial
adhesion
glial cells,
not neurons.
destroy
neurites, 156 RBCs to become
Foam Cells 160
Color Key
activity in 152 synapses,
Block NF-kB molecules Toxic
microglia & neurons
production neocortex Heavy Metals,
733 Pb, Hg,
neurons &
Motor 147 synapses 157 725 Pesticides
Stem Cell neurons Genetics,
Neurogenesis Cytoplasmic
Therapy or Trophic by Adult Neural 742 J147 increases ATP. Nucleus,
Factors NF-kB Endoplasmic molecules
714 TNFa 165 signaling by Stem Cells J147 induces NGF & BDNF,
secretion by hypothalamic activates AMPK, inhibits mTOR, Reticulum
Lung 138 142
microglia neurons 164 134 basal cells 140 protects neurons from toxicity of
Engineer cells Thymus 145 glutamate & Αβ
Arrested 144
to make anti-cancer MSCs & size Skeletal 153
Stem cells Cardiac NGF & Extracellular
immune cells functional (involution) muscle
738 stop dividing myocytes Commanding BDNF preserve Substances
fibroblasts fibers 158 Mitochondria
neuroendocrine neurons & & Structures.
Immune System 146
Targeted cells in neurons improve synapses
& Apoptosis Osteoblasts
Apoptotic kill some 130 hypothalamus in SN 154
Agents cancer cells Exercise
747 726 or
Hormone
Controlled Beneficial
Therapy
Degradation process or
& Turnover intervention

Inflammation of 727
900 Hypothalamus Persistent, 904 Pulmonary
asymptomatic Working 923 Fasting or CR,
& skin Emphysema, Erectile

Tissue, Organ,
935 Infections, eg. Sarcopenia 941 GnRH or food & Drugs Damaging
memory & Signaling
Cancer CMV, occupy
COPD Osteo- Parkinsonʼs
Dysfunction improves 936 that mimic fasting Substance
928 executive VCAM-1 Lung Pathway
immune system 933 porosis 926 Disease 919 Cognition, or Process
function in plasma Alveoli
901 muscle strength,
925 degraded skin, bone,
neurogenesis,

& Whole Body

Osteo- 922
Arthritis Reduced memory
Body Plan capacity of 744
903 urinary
Dysregulation Meno-
Weakness,
Alzheimerʼs
Bladder MK-0677 Senescence
pause & other Physiology
938 Frailty

Physiology 927 dementias Stiff skin, 918

931 tendons
924
921

Thin Skin; 728

& Pathology Thin Hair; Beneficial Harmful

Meditation
White Hair. Neuroendocrine Inhibition Process
Failure to Prostate & immune of Pathway that is
Regenerate Hyperplasia 905
functions 929 914 Cardiac 937 or Process inhibited
939 940 Macular Hypertrophy,
Impaired Impaired Hemorrhagic Stiff Heart. 746
Degeneration Small clots
wound healing & Stroke
906 907 917 kidney in neural 916 Lanosterol
tissue repair function. capillaries
Blindness Pathogenic Infections cause Cataracts
932
kill cells & micro-strokes 920
930 Harmful Beneficial
743 generate inflammation
SM04554 Inhibition Process
stimulates hair growth in of Pathway that is
androgenic alopecia Retinopathy or Process inhibited
Stiff arteries
908 & capillaries,
Pathogenic systolic 730
Infectious Agents, 909
hypertension, Anti-Inflammatory
viruses, bacteria, 999 cardiovascular
microbes Foods & Drugs Revised 4 December 2019
729 Heart disease including turmeric,
Revised 4 December 2019 Many other Heart
Failure 910
Ischemic Montelukast © 2000 - 2019 John D. Furber
All rights reserved.
© 2000 - 2019 John D. Furber
All rights reserved.
downstream Attack 912 911
Stroke
Atherosclerotic
Chronic
Psychological effects of 913 plaque buildup
stress 731 AGING Inflammation,
tissue remodeling,
Inflammatory proteins
secreted by Liver: Rheumatoid
C-RP, IL-6. Arthritis 934
915