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

articulated that lifestyle factors are paramount to healthy aging and human health, often
serving as the most powerful interventions available. He introduces the concept of
"lifestyle+" to broaden the traditional understanding of lifestyle beyond diet, exercise, and
sleep, to include critical environmental exposures and social connections.

Here's how these lifestyle factors, as discussed in Topol's sources, significantly impact aging:

Exercise: The "Single Most Potent Medical Intervention"

Topol and Euan Ashley, a leader of the NIH MoTrPAC initiative, emphasize that if a drug
could replicate the benefits of exercise, it would be considered a miraculous breakthrough.
Exercise is seen to profoundly change literally every tissue in the body, a multi-system,
multi-tissue, multi-dimensional response that no single pill can mimic.

 Longevity and Overall Mortality: Regular exercise is unmatched for promoting

longevity. Euan Ashley notably states 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," based on 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.
 Cardiovascular Health: Exercise leads to favorable adaptations of the cardiovascular
system, protecting against atherosclerosis by reducing blood lipids, increasing lipid
oxidation, and lessening body-wide inflammation. Studies show reduced
cardiovascular mortality rates among physically active individuals. Isometric
exercises, such as wall squats, have been shown to lower blood pressure as effectively
as aerobic exercise.
 Brain and Cognitive Health: Exercise reduces brain inflammation. It is also
associated with lowering p-Tau217 levels, a key biomarker for Alzheimer's disease,
suggesting its potential to delay or prevent cognitive decline and dementia. Physical
activity, particularly moderate-to-vigorous exercise, is linked to preserving cognitive
function in older adults and reducing the risk of dementia, tied to increased brain
neurogenesis and plasticity, anti-inflammatory effects, and improved cardiovascular
health.
 Metabolic Health: Exercise improves insulin sensitivity through its impact on
pancreatic, skeletal muscle, and adipose tissues, significantly reducing the risk of
Type 2 diabetes and obesity.
 Immune System Function: Regular exercise enhances immune system
responsiveness. The MoTrPAC study found the immune system to be commonly
upregulated across multiple tissues in exercising rats, including surprising places like
the small intestine.
 Gastrointestinal Health: Exercise leads to favorable adaptations in the
gastrointestinal tract, including enhanced production of short-chain fatty acids
(SCFAs).
 Musculoskeletal System: Exercise is crucial for preserving muscle mass and
strength, which decline significantly with age. Resistance training, even for 60
minutes per week, is associated with a 25% reduction in all-cause mortality and
offers benefits like less visceral fat, better sleep, more bone density, and improved
 mental well-being. Grip strength linearly correlates with reduced all-cause mortality,
with every 5 kilograms making a difference.
 Mental Health: Exercise has dramatic benefits for mental health, reducing
depression, anxiety, and stress. A study cited by Topol showed that dancing, walking,
and jogging outperformed mental health drugs like SSRIs in treating depression.
 Sleep Quality: Physical activity is linked to improved sleep quality.
 Cancer Prevention: Regular exercise is associated with a 50% reduction in the risk
of many cancers. A significant dose-response curve shows that more exercise leads
to less risk across seven cancer types, with vigorous exercise further associated with
reduced head and neck, lung, bladder, and pancreatic cancers.
 Mechanisms: Insights from MoTrPAC reveal exercise as a stressor (hormesis) that
conditions the body, reflected by the prominence of the heat shock response. It also
induces significant changes in mitochondrial function and positively alters adipose
tissue. Sex-specific differences in response to exercise have also been observed,
particularly in adipose tissue.

Topol advocates for a combination of aerobic and strength exercise, suggesting exercising
five or six days a week to build a habit. While there are concerns about over-exercising in
ultra-endurance athletes, such as an increased risk of atrial fibrillation, these are generally
considered exceptions, and the overall benefits are overwhelmingly positive.

Diet: A Foundation for Health and Longevity

Diet plays a crucial role in aging, with poor diet linked to 22% of all deaths globally.

 Ultra-Processed Foods (UPFs): Described as "alien, industrially produced, unnatural

substances," UPFs contain additives and undergo physical changes that accelerate
absorption, leading to spikes in blood glucose and insulin. High UPF intake is
associated with markedly heightened risks of cardiovascular and metabolic diseases,
including an 80% elevated risk of metabolic syndrome, 40% higher risk of Type 2
diabetes, 55% risk of obesity, and 66% risk of cardiovascular death. Among
older adults, even a mere 10% increase in UPF intake is associated with a 16%
increased risk of cognitive impairment. Regular consumption of ultra-processed red
meat is linked to a 14% higher risk of dementia. Overall, a 62% increase in all-cause
mortality is linked to more than four servings per day of UPF.
 Sugary Beverages: These are the biggest source of added sugar and are associated
with a 24% increased all-cause mortality, as well as increased cardiovascular and
cancer-related mortality.
 Salt: Excessive sodium intake is clearly linked to hypertension and increased
cardiovascular risk. High salt diets can also reduce blood flow to the brain and
potentially risk cognitive impairment.
 Carbohydrates, Protein, and Fat: The type of macronutrient matters. Good
carbohydrates, rich in dietary fiber (25-30 grams/day), are associated with a 15-30%
reduced all-cause and cardiovascular mortality, type 2 diabetes, and colon cancer.
Low-quality, fast-digesting carbs are detrimental. For protein, the recommended daily
intake (0.8g/kg) is often underestimated for older adults, but excessive leucine-rich
animal proteins might promote atherosclerosis and inflammation. Regarding fats, a
shift to plant-based unsaturated fats (mono- or polyunsaturated) is associated with
more favorable longevity data and reduced risk of cardiovascular and Type 2 diabetes.
  Red Meat vs. Plant-Based Diets: Processed red meats are deemed carcinogenic by
the WHO, and unprocessed red meats are labeled "probably carcinogenic". High red
meat intake is linked to increased risk of all-cause mortality, cardiovascular disease,
and dementia. Conversely, plant-based diets are associated with 23% lowered risk
of Type 2 diabetes. Substituting processed red meat with plant-based foods offers
substantial protection from all-cause mortality, cardiovascular deaths, and Type 2
diabetes. Plant-based diets promote a healthy gut lining and reduce inflammation via
SCFA production.
 "Good Food" / Mediterranean Diet: This holistic approach, including fruits,
vegetables, legumes, whole grains, nuts, seeds, and healthy fats like olive oil, is
consistently linked to lower cardiovascular, cancer, and neurodegenerative disease
risks. The Mediterranean diet is robustly supported by randomized trials and
observational studies for its association with a reduction of death from any cause,
cardiovascular diseases, cancer, and neurodegenerative diseases. It also favorably
modulates the gut microbiome, fostering diversity and reducing inflammation.
 Caloric Restriction and Time-Restricted Eating: While rigorously studied in model
organisms, the definitive anti-aging properties in humans are still elusive. Benefits
like improved immune response and potential antitumor effects are noted in
experimental models. Practical advice includes eating an early dinner, several hours
before bed, aligning with circadian rhythm.
 Personalized Nutrition ("AI Diet"): The idea of a one-size-fits-all diet is naive due
to individual biological uniqueness. Continuous Glucose Monitors (CGMs) reveal
marked variability in glucose spikes in response to food, exercise, and sleep. The gut
microbiome has emerged as a key determinant of an individual's response to food.
This personalized approach, while still in early stages, holds promise for optimizing
health.

Sleep: Essential for Brain "Waste Clearance"

Sleep is a fundamental biological necessity, on par with air, food, and water. It plays a critical
role in brain health and overall longevity.

 Glymphatic System: During sleep, particularly non-REM sleep, the brain's

glymphatic system actively clears metabolic waste products, including toxic proteins
like beta-amyloid, which are precursors to Alzheimer's disease. One night of sleep
deprivation can lead to a substantial increase in beta-amyloid accumulation.
 Brain Aging: As we age, glymphatic efficiency declines, leading to an accumulation
of metabolic waste and contributing to neurodegenerative diseases like Alzheimer's
and Parkinson's. Reduced non-REM sleep is linked to early Alzheimer's risk, creating
a "vicious loop" where poor sleep leads to more toxic proteins, which in turn interfere
with sleep.
 Overall Health and Mortality: Sleep profoundly impacts all-cause mortality,
cardiovascular and cancer mortality, and the risk of various diseases including Type 2
diabetes, obesity, hypertension, and stroke. Optimal sleep duration is about seven
hours; both less and more sleep are associated with cognitive decline, mental health
issues, and heightened mortality risk.
 Sleep Quality: The challenge for healthy aging is that aging itself compromises sleep
quality, leading to less deep sleep, more fragmented sleep, and regression of circadian
timing.
  Behavioral Factors: Promoting healthy sleep relies on behavioral factors such as
maintaining a regular bedtime and awakening pattern, regular exercise, avoiding late-
night eating, creating a cool and dark bedroom, and avoiding blue light from
electronic devices. Sleep apnea, a common sleep disruption, significantly increases
the risk of cardiovascular and metabolic diseases, highlighting the importance of its
diagnosis and management.

Social Connections: Countering Loneliness and Isolation

Topol includes social connections as part of "lifestyle+" due to their significant impact on
health and aging.

 Mortality Risk: A systematic review of 90 cohort studies involving over 2.2 million
people demonstrated an association between loneliness and a 32% increased all-
cause mortality, a 34% rise in cardiovascular mortality, and a 24% higher
cancer-related mortality. While cause-and-effect is not definitively established, the
link is clear.

Environmental Toxins: An Often-Overlooked "Lifestyle+" Factor

Topol emphasizes that environmental exposures, while often perceived as outside individual
control, are critical modifiable factors that profoundly influence health and aging, falling
under his expanded "lifestyle+" definition.

 Air Pollution: Fine particulate matter (PM2.5) air pollution is the leading contributor
to global disease burden. Even low exposures increase mortality risk, with no safe
threshold identified for chronic effects on cardiovascular health. An estimated
20% of Type 2 diabetes cases are related to chronic exposure to fine particulate
matter. Air pollution is also linked to cognitive decline, reduced immune response,
and increased blood pressure, primarily through body-wide inflammation,
compromised immune function, and increased oxidative stress.
 Microplastics and Nanoplastics (MNPs): These pervasive substances carry
thousands of chemicals and have been found in nearly every organ in the body,
including arteries, brain, blood clots, liver, lungs, placenta, and testes. Their presence
in atherosclerotic plaque was linked to a 4.5-fold heightened risk of heart attack,
stroke, or death. A new study showed brain MNP concentration was 7-30 times
greater than in the liver or kidneys, with significantly higher levels in the brains of
people with dementia. MNPs incite an aggressive inflammatory response across
multiple organ systems.
 "Forever Chemicals" (PFAS): These man-made compounds do not break down and
are widely present in water and consumer products. High exposure has been linked to
kidney and testicular cancer, obesity, increased blood pressure, high cholesterol,
inflammatory bowel disease, and damage to the thyroid, liver, brain, and immune
system.
 Other Toxins: Secondhand smoke, radon, pesticides, and noise pollution are also
associated with various health risks, including increased incidence of cancers,
cardiovascular disease, Type 2 diabetes, and cognitive impairment. Ionizing radiation
from medical imaging and exposure to certain metals also pose risks to cardiovascular
health and overall mortality.
Topol posits that the recent rise in various cancers among younger adults may be attributable
to these environmental factors, emphasizing that these hazards are not adequately recognized
or addressed.

In sum, Topol's view, thoroughly documented in Super Agers and Ground Truths, is that
adopting a comprehensive "lifestyle+" approach – encompassing optimal diet, regular and
varied exercise, sufficient quality sleep, robust social connections, and minimizing exposure
to environmental toxins – represents the most effective strategy for promoting healthy
aging and extending a healthy lifespan, far exceeding the potential of any single medical
intervention or drug. He highlights that these factors are deeply interdependent and their
synergistic impact creates a powerful package for health.