Eric Topol, in his new book Super Agers and his Ground Truths newsletter, has extensively

highlighted that exercise is arguably the single most potent medical intervention known
for promoting healthy aging and improving human health across numerous organ systems. He
posits that if a drug could replicate the diverse, powerful benefits of regular exercise, it would
be considered a miraculous breakthrough.

Here's a detailed look at how exercise impacts human health, as discussed in Topol's sources:

Ubiquitous Benefits Across Organ Systems

Regular physical activity leads to favorable adaptations throughout the body:

 Cardiovascular Health: Exercise enhances cardiovascular function and protects

against atherosclerosis. It does this through multiple pathways, including reducing
blood lipids, increasing lipid oxidation by skeletal muscle, and lessening body-wide
inflammation by reducing white blood cell output from bone marrow. A study cited
by Topol in Super Agers showed that an increase in coffee intake, which can be linked
to higher physical activity, was consistently associated with less heart failure in large
cardiovascular cohort studies. Epidemiological evidence suggests a significantly
reduced cardiovascular mortality rate among physically active individuals compared
to sedentary ones.
 Brain and Cognitive Health: Exercise reduces brain inflammation. A significant
finding noted by Topol is that for older adults, even a mere 10% increase in ultra-
processed food (UPF) intake is associated with a 16% increased risk of cognitive
impairment, implying that diets that are not counteracted by sufficient exercise can
have severe cognitive impacts. Conversely, exercise can help lower p-Tau217 levels,
a crucial biomarker for Alzheimer's disease, suggesting its potential to delay or
prevent cognitive decline and dementia. Studies also indicate that physical activity,
particularly moderate-to-vigorous exercise, is linked to preserving cognitive
function in older adults and reducing the risk of dementia. The benefits are tied to
increased brain neurogenesis and plasticity, exercise's anti-inflammatory effect, and
improved cardiovascular health.
 Metabolic Health and Disease Prevention: Exercise improves insulin sensitivity
through its impact on the pancreatic, skeletal muscle, and adipose tissues. It is
associated with a reduced risk of Type 2 diabetes and obesity. Furthermore, Topol
notes that chronic exposure to fine particulate matter air pollution is estimated to
cause 20% of Type 2 diabetes cases, indirectly highlighting how exercise, which can
improve overall resilience, might mitigate some environmental stressors. Replacing
processed red meat with healthier protein sources, which is often part of an active
lifestyle, has been shown to reduce the risk of Type 2 diabetes.
 Immune System Function: Regular exercise enhances our immune system
responsiveness. Euan Ashley, a leader of the NIH MoTrPAC initiative, discussed with
Eric Topol how the immune system was commonly upregulated across multiple
tissues in exercising rats, even in surprising places like the small intestine. Topol has
also noted that an improved immune response is seen with calorie restriction and
potential antitumor effects in experimental models.
 Gastrointestinal Health and Gut Microbiome: Exercise leads to favorable
adaptations in the gastrointestinal tract, including enhanced production of short-
chain fatty acids (SCFAs). The MoTrPAC study found significant immune gene
changes in the small intestine, indicating a widespread systemic effect. Topol also
 highlights that plant-based diets, often associated with a healthy lifestyle including
exercise, promote a healthy gut lining and reduce inflammation via SCFA production,
with the gut microbiome being a key determinant of an individual's response to food.
 Musculoskeletal System: Exercise is crucial for preserving muscle mass and
strength, which decline significantly with age. It helps maintain core strength for good
posture, prevents back pain and joint inflammation, and promotes mobility and
balance. Resistance training, even for 60 minutes per week, is associated with a
25% reduction in all-cause mortality and benefits beyond strength, including less
visceral fat, better sleep, more bone density, and improved mental well-being. Grip
strength, a prognostic metric, linearly correlates with reduced all-cause mortality, with
every 5 kilograms making a difference.
 Mental Health: Exercise has dramatic benefits for mental health, including
reducing depression, anxiety, and stress. Topol references a study showing that
dancing, walking, and jogging outperformed mental health drugs like SSRIs in
treating depression. Euan Ashley noted that many people experience a "runner's high"
or "exercise high," which relates to changes in brain chemistry, including the release
of opioids.
 Sleep Quality: Physical activity is linked to improved sleep. A systematic review of
over four thousand participants studied for ten years found a significant improvement
in sleep with increased physical activity. Maintaining a regular pattern of exercise is
listed as a behavioral factor to promote healthy sleep.
 Cancer Prevention and Outcome: Regular exercise is associated with a 50%
reduction in the risk of many cancers. Topol notes a significant dose-response
curve where more exercise leads to less risk across seven cancer types (colon, breast,
kidney, liver, myeloma, non-Hodgkin lymphoma, and endometrial). Vigorous
exercise is further associated with reduced head and neck, lung, bladder, and
pancreatic cancers.
 Overall Mortality and Longevity: Regular exercise is unmatched in promoting
longevity. Euan Ashley told Eric Topol that "one minute of exercise bought you five
minutes of extra life," and for high-intensity exercise, "one minute would give you
seven or eight minutes of extra life," citing large studies. Briskly walking 450 minutes
per week was associated with living 4.5 years longer in a cohort of over 650,000
individuals. A systematic review of 196 studies with over thirty million participants
reported a 31% reduction in all-cause mortality with increased physical activity.
Topol also highlights a study of US veterans showing that physical activity, among
other lifestyle factors, was associated with significant years of added life expectancy.

Mechanisms of Action (Insights from MoTrPAC)

The Molecular Transducers of Physical Activity Consortium (MoTrPAC), a major NIH

initiative, has provided multiomic data to validate exercise's protective effects. Topol's
discussions with Euan Ashley shed light on these mechanisms:

 Systemic Molecular Changes: Exercise dramatically changes literally every tissue in

the body, as observed in rat studies, leading to significant molecular adaptations. It
triggers a multi-system, multi-tissue, multi-dimensional response that cannot be
mimicked by a single pill.
 Hormesis/Stress Conditioning: Exercise acts as a recurrent stressor, and the body
learns to deal with this stress. This is reflected by the prominence of the heat shock
 response across multiple tissues, involving molecular chaperones that prevent protein
aggregation and facilitate the degradation of damaged proteins.
 Mitochondrial Enhancement: Exercise induces big changes across mitochondrial
function, the "workhorses" and energy source of individual cells. This training
upregulates networks that are exactly the opposite of those involved in diseases like
liver disease and Type 2 diabetes.
 Immune System Modulation: The immune system is a common upregulated system
with exercise, with significant changes observed even in unexpected tissues like the
small intestine. This strengthening of the immune system may contribute to reduced
cancer risk.
 Organ-Specific Changes and Communication: MoTrPAC has identified that organs
like the adrenal gland undergo dramatic changes with exercise, beyond just the
muscles, heart, and lungs traditionally associated with physical activity. Exercise
appears to alter both brown and white adipose tissue in a positive health way,
affecting their makeup and reducing the amount of white adipose tissue. Topol and
Ashley discussed "exerkines" – molecules secreted into circulation or locally by
exercising muscles – as potential mediators of these widespread benefits.

Types and Intensity of Exercise

Topol emphasizes that exercise means more than just aerobic fitness; it includes:

 Aerobic Exercise: Examples include brisk walking, bicycling, dancing, gardening,

jogging, swimming laps, and competitive sports.
 Strength and Resistance Training: This dimension is critical, especially with age-
related muscle loss. It includes activities like push-ups, pull-ups, sit-ups, squats,
lunges, and using weights, bands, or machines, targeting all muscle groups. Isometric
exercises, such as wall squats, have been shown to lower blood pressure as effectively
as aerobic exercise.
 Balance and Flexibility: These are often neglected but are crucial, particularly for
older adults and those who sit for prolonged periods. Practicing one-leg stands or
heel-toe walking improves balance, while stretching, Pilates, or yoga enhance
flexibility.

Regarding intensity, Topol and Ashley note that while "one minute of exercise bought you
five minutes of extra life," if you did high-intensity exercise, it could give you even more,
potentially "seven or eight minutes of extra life". However, the primary message is to get
moving regularly, even if it's moderate activity, before pushing for higher intensity. Topol
recommends a combination of both aerobic and strength exercise, typically suggesting a 2-to-
1 ratio favoring aerobic, but stressing that both are important. He advocates for exercising
five or six days a week to build a habit.

Challenges and Nuances

 Sex-Specific Differences: Euan Ashley highlighted that exercise's effects can be sex-
specific, with profound differences observed in adipose tissue responses between
males and females at rest and amplified by exercise. Topol notes that women
generally benefit more than men from physical activity with respect to all-cause and
heart-related mortality.
  Long COVID: The issue of exercise intolerance and fatigue in Long COVID patients
creates a "vicious cycle." While exercise could help, the inability to perform it due to
fatigue is a significant challenge. Topol and Ashley agree on the need for very gradual
exercise to help break this cycle, as even a little movement can provide benefits.
 Over-Exercising: While generally positive, extreme exercise in ultra-endurance
athletes has been linked to atrial fibrillation, though this is considered the only
significant downside with good data. Topol mentions that high-level exercisers might
also have more coronary artery calcium, but their overall risk of heart attacks remains
lower due to possible plaque stabilization.

Future Directions and Implications

The insights from MoTrPAC, particularly the wealth of multi-omic data from tissues and
soon from human blood and biopsies, are expected to fuel future research into how exercise
prevents disease and promotes health. The ability to measure thousands of plasma proteins, as
discussed by Eric Topol in Science and his Ground Truths newsletter, will enhance
understanding of how exercise modulates individual organ aging and disease risk, potentially
leading to personalized exercise recommendations tailored to an individual's unique
biological profile. Topol emphasizes that these findings could lead to the identification of
"druggable" targets that mimic some elements of exercise, though he and Ashley agree that
no single pill will ever replicate the comprehensive benefits of exercise.