Healthy Ageing by Super Agers

 Healthy Ageing

Eric Topol, a leading voice in medicine and author of the new book Super Agers, has significantly expanded our understanding of healthy aging through his concept of "lifestyle+". This framework, extensively discussed in his book and Ground Truths newsletter, moves beyond the traditional pillars of diet, exercise, and sleep to encompass a broader array of critical factors that profoundly impact our healthspan—the period of life spent in good health. Topol consistently highlights that these elements, ranging from environmental conditions and socioeconomic status to social connections, are powerful determinants that can add many healthy years to our lives, often without the need for expensive technology.

Here's a comprehensive overview of the lifestyle factors Eric Topol emphasizes for healthy aging:

Diet: The Cornerstone of Health

Topol stresses the ancient wisdom "You are what you eat," noting that a poor diet is linked to 22% of all global deaths, surpassing other major health risks like tobacco or hypertension.

• Ultra-Processed Foods (UPFs): These are described as "alien, industrially produced, unnatural substances; they're not even food". UPFs, often found in the middle aisles of grocery stores, contain a long list of additives, artificial sweeteners, and modified starches, and undergo processing that maximises digestibility and accelerates glucose and insulin spikes. Consuming UPFs is consistently linked to a markedly heightened risk of cardiovascular and metabolic diseases, including an 80% elevated risk of metabolic syndrome, 40% higher risk of type 2 diabetes, 23% increased risk of hypertension, 55% risk of obesity, and 66% risk of cardiovascular death. They are also associated with fatty liver disease, most types of cancer, sleep disorders, inflammatory bowel disease, depression, and dementia. More than four servings per day are linked to a 62% increase in all-cause mortality. Chris van Tulleken's self-experiment, increasing UPF intake from 20% to 80%, resulted in a 15-pound weight gain, dramatic brain connectivity changes, and a fivefold rise in hunger hormones. Topol urges that UPFs "must be restricted in your diet to the lowest level possible". He also points out the significant lobbying influence of "Big Food" in the US, which hinders public health guidelines similar to those in other countries.
• "Good Food" and Healthy Eating: This involves fruits, vegetables, legumes, whole grains, nuts, seeds, healthy fats (like olive oil and avocados), and fatty fish rich in omega-3s. These components, particularly when combined in the Mediterranean diet, are robustly supported by evidence for reducing all-cause mortality, cardiovascular diseases, cancer, neurodegenerative diseases, and diabetes. For example, olive oil consumption alone has been tied to about a 20% lower all-cause mortality and a 28% lower risk of dementia with regular intake. Dietary fiber, abundant in unprocessed foods, slows digestion, reduces glucose spikes, and helps lower cholesterol.
• Other Dietary Factors:
  • Sugary Beverages: High consumption, including fruit juices, is associated with a 24% increased all-cause mortality and more than a threefold increase in atrial fibrillation.
  • Carbohydrates: Excessive intake of low-quality, fast-digesting carbs (like refined grains) is associated with increased cardiovascular deaths.
  • Alcohol: While light intake might not be problematic, moderate and heavy drinking "does one no good" and is classified as carcinogenic, with risks increasing exponentially with higher intake levels.
  • Red and Processed Meats: The more red meat, especially processed varieties like hot dogs and bacon, the less healthy one is likely to be, with consistent (albeit small) increases in cardiovascular and cancer risks. Substituting processed red meat with healthier protein sources like nuts and legumes can significantly reduce the risk of dementia and cognitive decline. Plant-based diets are plainly healthier and linked to reduced type 2 diabetes and various forms of mortality.
• Personalised Nutrition: The "one-size-fits-all" diet is naive, given individual variations in genome, metabolism, and gut microbiome. Tools like continuous glucose monitors (CGMs) are helping individuals understand their unique glucose responses to food, exercise, and stress. Topol notes groundbreaking work from the Weizmann Institute and a UK group that leveraged big data and machine learning to demonstrate the gut microbiome's dominant role in predicting individual responses to food. Personalised nutrition programmes have shown improved glucose regulation and reductions in triglycerides, weight, and waist circumference in trials.

Exercise: The "Most Potent Medical Intervention"

Eric Topol, drawing on insights from experts like Euan Ashley (a leader of the NIH MoTrPAC initiative), highlights that exercise "may be the single most potent medical intervention ever known". Its benefits are "comprehensively sweeping across every organ".

• Broad Systemic Benefits: Regular physical activity leads to favourable adaptations across all organ systems, including the cardiovascular system, brain, pancreas, skeletal muscle, gastrointestinal tract, liver, adipose tissue, and immune system. It enhances insulin sensitivity, protects against atherosclerosis, reduces inflammation, and improves mitochondrial function. Ashley noted from the MoTrPAC initiative that regular exercise dramatically changes "literally every tissue," enhancing the body's ability to deal with stress at a cellular level.
• Mortality and Disease Reduction: Exercise is strongly linked to a 31% reduction in all-cause mortality, with a dose-response relationship. It is associated with a 50% reduction in cardiovascular disease and a 50% reduction in the risk of many cancers. Even moderate activities like brisk walking for 450 minutes per week are associated with living 4.5 years longer. Higher intensity exercise may offer even greater returns, with one minute potentially yielding seven or eight minutes of extra life.
• Mental and Cognitive Health: Exercise offers profound positive effects on mental health, often outperforming antidepressant drugs for depression and anxiety. It also helps preserve cognitive function in older adults.
• Intensity and Type: Both aerobic and resistance (strength and balance) training are crucial. Topol notes that decades ago, as a cardiologist, he only stressed aerobic exercise, but now recognises the critical importance of strength and balance training, especially given age-related muscle loss. Isometric exercises have been shown to lower blood pressure as effectively as aerobic exercise.
• No Plateau for Benefits: While some studies suggest a plateau for mortality benefits at high levels of exercise, others show no such plateau, and there is generally no loss of benefits from "too much" physical activity. The main goal for many, as Topol and Ashley suggest, is simply to get off the couch and get moving regularly.
• Dementia Prevention: Physical activity, including steps at high intensity, is linked to protection against dementia.

Sleep: The Brain's "Dishwasher"

Topol describes sleep as a "non-negotiable biological state required for the maintenance of human life," as vital as air, food, and water, providing a "magical sense of restoration and wellness".

• Brain Waste Clearance (Glymphatic System): During non-REM sleep, especially deep slow-wave sleep (Stage N3), the brain's glymphatic system efficiently clears metabolic waste products, including toxic proteins like beta-amyloid. Maiken Nedergaard, who discovered this system, likens it to "turning on the dishwasher before you go to bed and waking up with a clean brain".
• Neurodegenerative Disease Risk: Just one night of sleep deprivation can lead to a substantial increase in beta-amyloid accumulation. Chronically poor sleep is linked to increased risk and progression of Alzheimer's disease; for instance, less than six hours of sleep at ages 50-60 is associated with a 30% increased risk of dementia. This creates a "vicious loop" where decreased sleep leads to more toxic proteins, which then interfere with sleep.
• Optimal Duration: The optimal duration of sleep is approximately seven hours. Both shorter and longer durations are consistently associated with cognitive and mental health decline, as well as heightened all-cause and cardiovascular mortality.
• Medication Impact: Paradoxically, commonly used sleep aids like Ambien (zolpidem) can suppress norepinephrine effects and reduce glymphatic flow, potentially contributing to a heightened risk of Alzheimer's and dementia. Topol notes that no commonly used sleep medications or supplements have been shown to improve waste clearance or promote deep slow-wave sleep without significant side effects.
• Sleep Apnea: This common disruption affects a large percentage of adults and is associated with a twofold or greater risk of cardiovascular and metabolic diseases.

Social Environment and Socioeconomic Status

Topol highlights social isolation and loneliness as a "critical public health concern".

• Increased Mortality Risk: A systematic review of over 2.2 million people found that loneliness is associated with a 32% increased all-cause mortality, a 34% rise in cardiovascular mortality, and a 24% higher cancer-related mortality.
• Socioeconomic Status (SES): Topol includes SES as an independent risk factor for premature mortality, with an impact comparable to smoking, high alcohol intake, hypertension, type 2 diabetes, or physical inactivity. Lower SES is disproportionately associated with less access to unprocessed food ("food deserts"), poorer sleep, higher exposure to air pollution, and less physical activity. Each additional year of education is associated with about a 2% reduction in mortality risk. Addressing these inequities is crucial for population-wide health improvement.

Environmental Toxins: The Invisible Threat

Topol's "lifestyle+" framework critically includes exposure to environmental toxins, which are increasingly understood to pose significant health hazards.

• Air Pollution: Particulate matter air pollution is the leading contributor to the global disease burden, linked to increased all-cause, cardiovascular, and respiratory mortality. No safe threshold has been identified for chronic PM2.5 exposure, and it's estimated that 20% of type 2 diabetes is related to chronic exposure. Air pollution causes body-wide inflammation, compromised immune function, and brain inflammation.
• Microplastics and Nanoplastics (MNPs): These ubiquitous substances carry thousands of chemicals and are found in our environment, food, air, water, and increasingly, human organs including arteries, brain, blood clots, liver, gut, and testicles. Their presence in atherosclerotic plaques is linked to a 4.5-fold heightened risk of heart attack, stroke, or death. A deeply concerning new study shows MNP concentrations in the brain are 7-30 times greater than in the liver or kidneys, with much higher levels found 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, food, and countless products. High exposure is linked to kidney and testicular cancer, obesity, increased blood pressure, high cholesterol, and damage to various organs.
• Other Toxins: Secondhand smoke, radon gas, pesticides, and noise pollution also pose significant health risks. Topol notes that the marked rise of various cancers in younger adults may be attributable to these environmental factors.

The Future of Personalised Healthy Aging

Topol is at the forefront of leveraging new technologies to individualise healthy aging strategies.

• Organ Clocks: Pioneering work from Tony Wyss-Coray and colleagues, discussed by Topol, involves measuring thousands of plasma proteins to develop "organ clocks" that predict and track organ-specific aging. These clocks can identify individuals with accelerated aging in specific organs (e.g., heart, brain, kidney), which is strongly associated with future disease risk and mortality. Importantly, these organ clocks show sensitivity to lifestyle choices like exercise, diet, and alcohol, offering a new way to monitor the impact of interventions.
• Alzheimer's Biomarkers: The p-Tau217 blood biomarker is a significant breakthrough, offering accurate prediction of Alzheimer's disease up to 20 years in advance. Topol highlights that this biomarker is dynamic and responds to interventions like exercise, suggesting it can be used to track treatment response and potentially guide prevention strategies. He envisions a future where p-Tau217 is monitored like cholesterol to assess and mitigate Alzheimer's risk, although he advises against routine screening or premature diagnosis.

In conclusion, Eric Topol's expanded "lifestyle+" perspective from Super Agers underscores that a comprehensive and sustained focus on these interconnected factors—from diet and physical activity to sleep quality, social connections, socioeconomic circumstances, and environmental exposures—is fundamental to promoting healthy aging and significantly extending our healthspan. This holistic approach is often more impactful than any single drug or technological intervention, and addressing inequities in these areas is crucial for population-wide health improvement. As Topol states, our ability to prevent or substantially delay age-related diseases will always "substantially depend on attention to lifestyle+ factors".

Longevity Factors

When considering longevity factors, it's clear that our individual lifestyle choices and environmental exposures play a profoundly significant role in promoting healthy aging and extending our healthspan. Dr. Eric Topol, a leading voice in translational medicine and the author of Super Agers, articulates this through his concept of "Lifestyle+". This framework goes beyond the traditional elements of diet, exercise, and sleep to encompass a broader spectrum, including environmental conditions, socioeconomic status, and social connections. Topol underscores that while cutting-edge biomedical technologies are transforming our understanding of the latter half of life, many more healthy years can be added through these "low tech" lifestyle factors, which often yield effects that even new drugs struggle to match.

Here’s a breakdown of the key longevity factors, drawing from Topol’s insights and the sources provided:

• Dietary Choices: Fueling or Hurting Healthspan

  • The Critical Impact of Diet: A systematic assessment across 195 countries revealed that a poor diet is linked to 22 percent of all deaths globally, surpassing tobacco, cancer, and hypertension. This highlights the long-standing belief in the vital importance of what we eat.
  • Ultra-Processed Foods (UPFs): These industrially produced, "alien" substances are a major concern. Topol, in Super Agers, describes them as "not even food" due to their chemical additives (like artificial sweeteners, hydrogenated oils) and physical alterations that maximise digestibility and accelerate absorption, causing blood glucose and insulin spikes. A randomised trial by Kevin Hall and colleagues showed that participants on an ultra-processed food diet ate an extra 500 calories a day, leading to significant weight gain. Regular UPF consumption is strongly linked to a heightened risk of cardiovascular and metabolic diseases, including an 80% elevated risk of metabolic syndrome, 40% higher risk of type 2 diabetes, and 66% risk of cardiovascular death. It's also associated with cognitive impairment, fatty liver disease, cancer, sleep disorders, depression, and dementia. A high intake of UPFs can increase all-cause mortality by 62% for more than four servings per day. Chris van Tulleken, author of Ultra-Processed People, observed dramatic negative health changes, including significant weight gain and increased inflammation, after increasing his UPF intake to 80% for a month. Topol advises restricting UPFs to the lowest level possible, reading labels, avoiding "health claims" (which can be a red flag), and shopping primarily in the grocery store perimeter for fresh foods. He also points out the concerning lack of US guidelines against UPFs, contrasting with other countries, and the significant lobbying influence of "Big Food".
  • Sweeteners: While sugar provides hedonic value, excessive intake is detrimental. Sugary beverages, including fruit juices, are a major source of added sugar and are linked to increased all-cause and cardiovascular mortality, and a more than threefold rise in atrial fibrillation with high consumption. The picture for non-nutritive artificial sweeteners is more complex; some studies suggest an association with cardiovascular and cerebrovascular disease risk, while others show impaired glucose regulation and changes in the gut microbiome. Overall, the data is "unfavourable" but "not nearly as worrisome as high sugar consumption," with certain sweeteners like stevia appearing less concerning.
  • Salt: High sodium intake is clearly linked to hypertension, although the magnitude of effect varies. Moderate consumption (1-2 teaspoons of salt/day) may not be problematic, but increased cardiovascular risk becomes evident at more than 5 grams of sodium per day, which is above the average American intake. High salt diets can also reduce blood flow to the brain and pose a risk of cognitive impairment. Topol, in Super Agers, suggests avoiding or limiting added salt, checking food labels, and considering potassium chloride salt substitutes (if no kidney disease).
  • Macronutrients (Carbs, Protein, Fat): The type of macronutrient matters significantly.
    • Carbohydrates: Excessive intake is linked to "carbotoxicity." The key is moderation and quality; good carbs include resistant starch, dietary fiber (25-30 grams/day is linked to 15-30% reduced all-cause and cardiovascular mortality), non-starchy vegetables, legumes, fruits, and whole grains. Low-quality, fast-digesting carbs like refined grains are associated with increased cardiovascular deaths.
    • Protein: Current recommended daily intake (0.8g/kg) may underestimate needs for older adults to prevent muscle mass loss (sarcopenia). While some advocate for higher intake (1g/pound), studies warn against high-protein diets (over 1.5g/kg) promoting atherosclerosis and pro-inflammatory gut microbiome metabolites. Topol suggests that increasing protein to 1.2g/kg is reasonable, but avoiding leucine-rich animal proteins.
    • Fat: The quality of fat is crucial, not just the content level. Unsaturated fats (mono- or polyunsaturated) are associated with more favourable longevity data, while trans and saturated fats increase total mortality risk. The ketogenic diet, high in fat, has been linked to higher cholesterol, cardiovascular risk, and fatty liver disease. A plant-based, low-fat diet led to greater weight loss than a ketogenic diet in a randomized trial.
  • Red Meat and Plant-Based Diets: Processed meats (hot dogs, bacon) are linked to the highest risk and deemed carcinogenic by the WHO, also contributing to high greenhouse gas emissions. Unprocessed red meats are labelled "probably carcinogenic" and are associated with increased mortality and cardiovascular disease. Conversely, plant-based foods are generally healthier, linked to reduced risks of type 2 diabetes, all-cause mortality, cardiovascular deaths, and cancer. A plant-based diet was shown to slow the pace of aging in identical twins. Substituting plant protein for animal protein was associated with 40% less cancer-related mortality.
  • Good Food & the Mediterranean Diet: "Healthy eating" consistently shows beneficial effects, reducing cardiovascular risk and all-cause mortality in a dose-dependent manner. This includes fruits, vegetables, legumes, whole grains, nuts, seeds, healthy fats (like olive oil and avocados), and fatty fish. Olive oil consumption alone is tied to about a 20% lower all-cause mortality and reduced risk of dementia. Fiber is crucial, slowing digestion, reducing glucose spikes, and lowering cholesterol; a high-fiber diet is associated with 31% less heart disease and 16% less type 2 diabetes or colon cancer. The Mediterranean diet, a "whole package" of these healthy foods, has robust support from multiple randomized trials and observational studies, demonstrating significant reductions in death from any cause, cardiovascular diseases, cancer, neurodegenerative diseases, and diabetes. It also favourably modulates the gut microbiome, fostering diversity and reducing inflammation.
  • Personalised Nutrition: The idea of a universal optimal diet is naive due to individual biological uniqueness (genome, metabolism, gut microbiome). AI and continuous glucose monitor (CGM) sensors are beginning to enable personalized nutrition by tracking glucose spikes in response to food, exercise, and sleep. The gut microbiome is a key determinant in predicting food response. While in early stages, personalized nutrition algorithms have shown improved glucose regulation and reductions in triglycerides, body weight, and waist circumference in trials.

• Exercise: The Miracle Intervention

  • Unparalleled Benefits: Euan Ashley, a Stanford professor and leader of the NIH MoTrPAC initiative, calls exercise the "single most potent medical intervention ever known". It leads to favourable adaptations across all organ systems, including the cardiovascular system, brain, pancreas, skeletal muscle, liver, adipose tissue, and immune system, enhancing insulin sensitivity and mitochondrial function.
  • Dose-Response: Ashley suggests 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". Briskly walking 450 minutes per week has been associated with living 4.5 years longer. More physical activity generally correlates with more benefit, with a 31% reduction in all-cause mortality seen in a review of 196 studies.
  • Molecular Insights (MoTrPAC): The Molecular Transducers of Physical Activity Consortium (MoTrPAC) is providing a deep molecular map of exercise's effects. Studies in rats showed that regular exercise dramatically changes "literally every tissue". Key findings include a prominent heat shock response (suggesting the body learns to deal with stress), dramatic changes in the adrenal gland, and upregulation of the immune system (especially in surprising places like the small intestine). Exercise upregulates pathways that are the "exact opposite" of disease mechanisms in conditions like liver disease and type 2 diabetes.
  • Beyond Aerobic: Historically, the focus was solely on aerobic exercise. Now, strength, resistance, and balance training are recognised as equally important. Muscle mass and strength decline significantly with age, and resistance training reduces all-cause mortality by about 25% for 60 minutes per week, alongside benefits for cardiovascular health, cancer, visceral fat, bone density, and mental well-being. Grip strength is a prognostic metric, with every 5 kg increase linked to reduced mortality. Balance, assessed by the one-leg stand test, is also crucial, with inability to stand for ten seconds doubling all-cause mortality risk.
  • Sex-Specific Effects: MoTrPAC data consistently showed sex-specific findings, particularly profound in adipose tissue, suggesting that studies need to consider both sexes independently.
  • Mental Health Benefits: Exercise has dramatic positive effects on mental health, often outperforming SSRIs for depression and anxiety.
  • Combatting Sedentary Lifestyles: Prolonged sitting is linked to higher all-cause and cardiovascular mortality, even after adjusting for confounding factors. Limiting sitting time and increasing physical activity are crucial.
  • "Never too late": The inspiring story of Richard Morgan, who took up rowing at 70 and became a world champion at 93, demonstrates that "there's no age limit that precludes getting in shape to counter age effects, and even the potential for using exercise as a means of reversing aging".

• Sleep: The Brain's Cleansing Ritual

  • Essential for Life: As Topol highlights, "Sleep is a non-negotiable biological state required for the maintenance of human life... our needs for sleep parallel those for air, food, and water".
  • Glymphatic System: A major discovery in recent years is the brain's glymphatic pathway, a plumbing system that clears metabolic waste products, including toxic proteins like β-amyloid, from the brain during sleep. This waste clearance primarily occurs during non-rapid eye movement (NREM) sleep, especially deep, slow-wave sleep.
  • Impact of Poor Sleep: Even a single night of sleep deprivation can lead to a substantial increase in β-amyloid accumulation, a precursor to Alzheimer's disease. Chronic poor sleep is prospectively linked to increased risk and progression of Alzheimer's and other neurodegenerative diseases. Sleep disruption also negatively impacts all-cause mortality, cardiovascular and cancer mortality, type 2 diabetes, immune function, obesity, hypertension, stroke, and mental health.
  • Optimal Duration: The optimal duration of sleep is about seven hours. Both too little (less than 6.5 hours) and too much (more than eight hours) sleep are associated with cognitive and mental health decline, unfavourable brain structure changes, and heightened all-cause and cardiovascular mortality.
  • Aging and Sleep: Older adults often face a threefold problem: less deep NREM sleep (significantly reduced by age 70), more fragmented sleep, and regression of circadian timing leading to earlier bedtimes and awakenings. This creates a "vicious loop" where decreased sleep leads to more toxic proteins, which then interfere with sleep.
  • Sleep Aids and Their Risks: Ironically, commonly used sleep medications like Ambien (zolpidem) can suppress glymphatic flow by inhibiting norepinephrine. Many sleep medications have been associated with a heightened risk of Alzheimer's disease and dementia, potentially due to this impairment of brain waste clearance.
  • Promoting Healthy Sleep: Topol advocates for behavioral and lifestyle factors to improve sleep: maintaining a regular bedtime and awakening schedule, consistent exercise, avoiding late eating (early time-restricted eating is beneficial), a cool, dark, quiet bedroom, avoiding blue light from electronics, diagnosing and treating sleep apnea, and relaxation techniques or digital cognitive behavioural therapy. Napping one to two times weekly has been linked to reduced cardiovascular events, but longer afternoon naps may be risky.

• Environmental Toxins: The Silent Threat

  • Pervasive Exposure: Environmental toxins are a crucial, often underestimated, component of Topol's "Lifestyle+". The Institute for Health Metrics identifies particulate matter air pollution as the leading contributor to global disease burden, linked to increased mortality, type 2 diabetes, cognitive decline, and compromised immune function. Phasing out fossil fuels could address over 80% of the 8 million annual premature deaths from outdoor pollution.
  • Other Toxins: Secondhand smoke is linked to heart disease, stroke, type 2 diabetes, and cancer. Radon, an indoor gas, is associated with lung cancer and stroke. Pesticides are linked to various cancers, type 2 diabetes, cognitive impairment, and Parkinson's disease. Noise pollution, at chronic levels above 70 decibels, is associated with increased stress hormones, inflammation, high blood pressure, heart disease, and type 2 diabetes. Medical imaging studies with ionising radiation are performed too frequently and are linked to increased cancer risk.
  • Microplastics and Nanoplastics (MNPs): These "forever chemicals" carry thousands of other chemicals (like bisphenols and phthalates) and are ubiquitous in our environment, food, air, and water. Plastic production has soared to over 400 million tons annually, with over 240,000 particles in an average litre of bottled water, 90% of which are nanoplastics.
    • Presence in the Body: MNPs have been found in almost every human organ, including arteries, the brain, blood clots, liver, gut, lungs, placentas, and testes.
    • Cardiovascular and Inflammatory Impact: A landmark study found MNPs in the atherosclerotic plaque of 58% of patients undergoing carotid artery surgery. Their presence was correlated with marked arterial inflammation and a more than fourfold heightened risk of heart attack, stroke, or death over three years.
    • Brain Accumulation: A deeply concerning new report, highlighted by Topol in Ground Truths, shows MNP concentration in the brain is 7-30 times greater than in the liver or kidneys, increasing significantly over time, and much higher in individuals with dementia. Animal studies demonstrate MNPs crossing the blood-brain barrier, activating the immune system, causing blood flow stagnation, and leading to blood clots and neurological abnormalities.
    • Reproductive and Other Harms: MNPs have been linked to lower sperm count and semen quality, increased risk of asthma, various cancers, and neurodevelopmental delay.
    • Action Needed: Despite overwhelming evidence of toxicity, little is being done to address this "plastic-demic." Topol and others advocate for avoiding plastic food storage, fast foods, high-fat foods in plastic, using glass/steel bottles, and limiting vinyl. More drastically, there's a need for bans, design standards, and reduced production of plastics.
  • PFAS (Per- and Polyfluoroalkyl Substances): These "forever chemicals" do not break down and are found in 31% of EPA-tested water samples. High exposure is linked to kidney and testicular cancer, obesity, high blood pressure, preeclampsia, high cholesterol, inflammatory bowel disease, and damage to various organ systems. Most plastic sandwich bags, for example, contain high levels of toxic PFAS.

• Social Isolation and Socioeconomic Status

  • Loneliness and Social Isolation: These are critical public health concerns. A review of 90 cohort studies, encompassing over 2.2 million people, found an association between loneliness and a 32% increased all-cause mortality, 34% rise in cardiovascular mortality, and 24% higher cancer-related mortality.
  • Socioeconomic Status (SES): Topol highlights SES as a pivotal, independent risk factor for premature mortality, as important as smoking, high alcohol intake, or physical inactivity. Lower SES is disproportionately linked to less unprocessed food intake, poor sleep, more air pollution, and less physical activity. Addressing these inequities, including combating "food deserts" and food insecurity, is crucial for population-wide healthspan improvement.

• Integration and the Future of Longevity

  • Interdependence of Factors: Topol stresses that these lifestyle factors are not isolated but interconnected, forming a comprehensive "lifestyle+ package". Their collective impact is profound, and they have the capacity to mitigate genetic predispositions to over 40 diseases.
  • New Technologies for Tracking: While "low tech" lifestyle interventions are paramount, Topol's work, including his Ground Truths newsletter, also explores high-tech approaches to forecasting health and disease.
    • Proteomic Organ Clocks: Pioneering work by Tony Wyss-Coray and colleagues, discussed by Topol in Ground Truths, involves measuring thousands of plasma proteins to identify organ-specific aging. This allows for the calculation of an "organ age gap" (the difference between biological and chronological age for specific organs). Accelerated heart aging, for instance, is linked to a 5-fold higher risk of heart failure, and brain aging to Alzheimer's disease. These clocks can reveal how lifestyle choices (like smoking, alcohol, exercise, and diet) impact specific organ aging and predict future disease risk.
    • Blood Biomarkers: Topol highlights the breakthrough of the p-Tau217 blood test for Alzheimer's disease, which can predict the disease over 20 years in advance with high accuracy. This dynamic biomarker responds to interventions like exercise and amyloid-reducing treatments, offering a new opportunity for early detection, prognosis, and monitoring treatment response. He envisions a future where p-Tau217 is used to guide individuals in lowering their Alzheimer's risk, similar to cholesterol testing for heart disease.

In conclusion, Topol's work, particularly in Super Agers and Ground Truths, strongly advocates for a holistic "Lifestyle+" approach to longevity. By optimising diet, exercise, and sleep, mitigating exposure to environmental toxins (especially microplastics), fostering social connections, and addressing socioeconomic inequities, individuals can significantly extend their healthspan. Furthermore, emerging high-throughput proteomics and biomarkers like p-Tau217 offer exciting prospects for personalized monitoring and early intervention, providing a "long runway of opportunity to intervene" against age-related diseases. The synergy of these low-tech and high-tech strategies represents the most promising path forward for achieving healthy aging.

SOCIAL ISOLATION AND THE BIG PICTURE

The attention to loneliness and social isolation as a critical public health concern has been mounting. Ninety cohort studies that were systematically reviewed, which included over 2.2 million people, demonstrated an asso-ciation between loneliness and a 32 percent increased all-cause mortality, a 34 percent rise in cardiovascular mortality, and a 24 percent higher cancer-related mortality. It's important to note that the cause-and-effect relationship of loneliness and these adverse outcomes has not been established. Living alone, without having family and friends visit, without weekly groups, con-tributes to social isolation. People with obesity are far more likely to face social isolation and loneliness than those without obesity. A UK Biobank study that included nearly four hundred thousand participants with a mean age of fifty-six years, and thirteen years of follow-up, found that among the 23 percent of people with obesity, the less loneliness and social isola-tion, the lower all-cause mortality. We're in the earliest stages of determin-ing whether generative AI tools can help reduce loneliness, supplementing or substituting for interactions with people, but a study using GPT-3 in a student population with loneliness and suicidal ideation provided some en-couraging preliminary results. We may not like the idea of machines helping our kids avoid suicide, but if such AI works, can we really choose to not use it at least sometimes? Assessing lifestyle+ factors should include the extent to which you or those you care for exhibit social isolation and loneliness, and all the possible countermeasures.

Virtually everything discussed in this chapter has a connection with social determinants of health. A pivotal paper in 2017 on determinants of premature mortality among 1.7 million people provided unequivocal sup-port for the importance of socioeconomic status, an independent risk factor. Socioeconomic status determines one's likelihood of good health as much as cigarette smoking, high alcohol intake, hypertension, type 2 diabetes, or physical inactivity. More unprocessed food in diet, poor sleep, more air pol-lution, and less physical activity are disproportionally found in people with lower socioeconomic status. The first systematic review on the association of education and adult mortality showed a dose-response with a reduc-tion of mortality risk of about 2 percent for every additional year of educa-tion. If we are to see a population-wide improvement in health span, the marked inequities must be reduced. Food deserts are real. More than sixty-five hundred of them are in the United States. Places where it is difficult to get healthy food, populated by a total of twenty-four million people. One study used GPS tracking for ninety-four million visits to 359,000 food retailers over two years. Most people travel beyond their neighborhood to buy food, an average of 3.7 miles. Travel to retailers that sold healthy food had a stronger association with the prevalence of obesity and cardiometabolic conditions than the percentage of retailers in a local area. Food insecurity, affecting more than fifty million Americans, has been linked to all-cause premature deaths in a study of over fifty-seven thousand adults, with about a 50 percent increase compared with people with full food security. Food-as-medicine programs to address food deserts and food insecurity have attracted considerable attention, but randomized trials have not yet borne out improvement in clinical outcomes. So much more dedicated efforts are required to combat inequities so that improvements in health span that are occurring will not be restricted to people of high socioeconomic status.

My expanded view of lifestyle makes a measurable difference to human health span. According to a modeling study for Americans, a sustained change in a typical Western to an optimal diet as we've reviewed, starting at age twenty years, would increase lifespan by more than ten years. Simi-larly, a UK Biobank modeling study for people aged forty calculated that adopting a healthy diet led to a nine-year increase in life expectancy. Among fourteen thousand Americans, those who didn't smoke, were not obese, and drank alcohol in moderation lived an average of seven years longer than their peers without this trio of lifestyle factors.

Another study, of more than seven hundred thousand US veterans, showed there was even more to gain in life expectancy. The cumulative ef-fect of all eight factors tallied in these vets—never smoking, physical ac-tivity, no excessive alcohol consumption, restorative sleep, nutrition, stress management, social connections, and no opioid disorder—was associated with twenty-four years of added life expectancy at age forty for males and 20.5 years for females. A lifestyle score based on those same factors was associated with increased likelihood of becoming a centenarian. A prospec-tive study of healthy lifestyle, consisting of never smoking, BMI less than 25 kg/m2, high-quality diet score, regular exercise, and no more than mod-erate alcohol intake, was associated with marked improvement in healthy aging, of about eight to ten years without cancer, cardiovascular disease, or type 2 diabetes, as seen in figure 3.12 for people at age fifty. A favorable lifestyle was linked to lower risk of dementia across the range of low to high genetic risk. The capacity for lifestyle to mitigate genetic predisposition, cal-culated by polygenic risk score, was highlighted in a UK Biobank study with a thirteen-year follow-up that showed its favorable impact for over forty diseases.

This has been a survey of the lifestyle factors that are critical to healthy aging. The broad, body-wide, marked impact of these factors is also a function of their interdependence. It's not just diet, just exercise, just sleep, or just so-cial isolation. Our environmental exposures are far more important than have been generally acknowledged. All of them come together to create a healthy lifestyle+ package. They may be considered “low tech" since much has been known about some, particularly diet and exercise, for thousands of years, but

Figure 3.12. Relationship of life expectancy (LE) and number of lifestyle risk factors (never smoking, no obesity, diet quality score, physical activity, and level of alcohol intake). Adapted from Yanping Li et al., “Healthy lifestyle and life expectancy free of cancer, cardiovascular disease, and type 2 diabetes: Prospective cohort study,” Brit-ish Medical Journal 368 (January 2020): 16669, https://doi.org/10.1136/bmj.16669.

they have been refined and our knowledge has grown tremendously. My overall sense is that it will be hard for any new drug or intervention to match overwhelming consequences of a well-guided healthy lifestyle, but that doesn't mean it isn't worth reaping the advantages of the combination.

We're ready to go high tech and see why rebooting our approach to dreaded diseases, and diagnosing them earlier, make them eminently more treatable. And even better, with the medical forecasting of high risk of a spe-cific condition in an individual, we can prevent it from occurring. Once determining such risks, our ability to prevent or substantially delay age-related diseases will always substantially depend on attention to lifestyle+ factors.

Eric Topol, in his new book Super Agers and his Substack newsletter Ground Truths, has expanded the traditional view of a healthy lifestyle to what he terms "lifestyle+". This broader definition critically includes environmental conditions, socioeconomic status, loneliness, and social isolation, recognising these as significant factors that profoundly impact healthspan. Indeed, social isolation and loneliness are increasingly being seen as a "critical public health concern".

The risks associated with social isolation are quite stark, even if the direct cause-and-effect relationship hasn't been definitively established in all cases. A systematic review of ninety cohort studies, involving over 2.2 million people, revealed some concerning associations:

• A 32% increased all-cause mortality.
• A 34% rise in cardiovascular mortality.
• A 24% higher cancer-related mortality.

Furthermore, loneliness and social isolation are often intertwined with other health issues. For instance, people with obesity are significantly more likely to experience social isolation and loneliness. A UK Biobank study, which tracked nearly 400,000 participants over thirteen years, found that among the 23% of individuals with obesity, a reduction in loneliness and social isolation was linked to lower all-cause mortality.

The broader context of these risks also ties into what Topol calls "social determinants of health". Factors like lower socioeconomic status disproportionately correlate with conditions that can exacerbate social isolation, such as living in "food deserts" where access to healthy food is limited, or having less physical activity.

While the field is still in its early stages of determining effective countermeasures, some preliminary results suggest that even generative AI tools might eventually play a role in reducing loneliness, potentially supplementing or substituting for human interactions. However, the primary focus remains on addressing and mitigating these factors through comprehensive approaches.

Eric Topol's work underscores that assessing "lifestyle+" factors, including the extent of social isolation and loneliness, and implementing all possible countermeasures, is essential for promoting healthy aging and improving overall population health.

Socio-Economic

Eric Topol, in his new book Super Agers and his Substack newsletter Ground Truths, has profoundly reshaped the discourse around healthy aging by introducing the concept of "lifestyle+". This expanded framework explicitly recognises that socioeconomic status (SES) is not merely an external factor but a critical determinant of human healthspan, alongside diet, exercise, and sleep.

Indeed, socioeconomic status is identified as an independent risk factor for premature mortality, carrying an impact comparable to well-established factors like cigarette smoking, high alcohol intake, hypertension, type 2 diabetes, or physical inactivity.

Topol and the sources highlight several stark connections between lower socioeconomic status and adverse health outcomes:

• Dietary Quality: Individuals with lower socioeconomic status disproportionately consume less unprocessed food. This ties into the issue of "food deserts" in the United States, where over 6,500 such areas exist, affecting 24 million people who struggle to access healthy food. The impact of diet on healthy aging is significant, with higher intake of ultra-processed foods associated with lower odds of healthy aging, and the benefits of healthy dietary patterns (like the Mediterranean diet) being stronger for those with lower socioeconomic status. Food insecurity, affecting more than 50 million Americans, has been linked to about a 50% increase in all-cause premature deaths.
• Physical Activity: Less physical activity is also disproportionately found among people of lower socioeconomic status. As Topol often stresses, exercise is perhaps the single most potent medical intervention, so its deficiency due to socioeconomic barriers has wide-ranging negative effects on health.
• Sleep Quality: Poor sleep, a "non-negotiable biological state required for the maintenance of human life," is more prevalent in populations with lower socioeconomic status.
• Environmental Exposures: While not always explicitly stated as disproportionate, environmental toxins such as air pollution and microplastics are significant health hazards. Socioeconomic status is also noted as a "nonchemical exposure modifier" in the context of the health effects of the plastic life cycle, suggesting its influence on exposure to these pervasive substances.
• Education: A systematic review demonstrated a dose-response relationship between education and adult mortality, with about a 2% reduction in mortality risk for every additional year of education. This underscores how education, often correlated with socioeconomic status, plays a role in health outcomes.

Eric Topol's perspective underscores that for a population-wide improvement in healthspan, the marked inequities in socioeconomic status must be reduced. While "food-as-medicine" programs are gaining attention to address food deserts and food insecurity, their effectiveness in improving clinical outcomes still requires more robust evidence from randomised trials.

In essence, Topol's "lifestyle+" framework urges us to look beyond individual choices and acknowledge the profound, systemic influence of socioeconomic factors on health and healthy aging, calling for dedicated efforts to combat these inequities.

Super Agers Lifestyle

Eric Topol, a leading voice in medicine, has significantly expanded our understanding of healthy aging by introducing the concept of "lifestyle+" in his new book Super Agers and his Ground Truths newsletter. This framework moves beyond the traditional pillars of diet, exercise, and sleep to encompass a broader array of factors including environmental conditions, socioeconomic status, loneliness, and social isolation. Topol emphasises that these elements are not merely external influences but are critical determinants of our healthspan, capable of adding many healthy years to our lives, often without the need for expensive technology.

Here's a breakdown of the profound impact of these lifestyle factors:

• Dietary Choices Topol highlights the enduring belief in the importance of diet, noting that a poor diet is linked to 22% of all deaths globally, surpassing tobacco, cancer, or hypertension.

  • Ultra-Processed Foods (UPFs) are consistently singled out as "alien, industrially produced, unnatural substances". These foods, often found in the middle aisles of grocery stores, are linked to a host of adverse outcomes including a markedly heightened risk of cardiovascular and metabolic diseases, 80% elevated risk of metabolic syndrome, 40% higher risk of type 2 diabetes, 23% increased risk of hypertension, 55% risk of obesity, and 66% risk of cardiovascular death. They also contribute to fatty liver disease, many types of cancer, sleep disorders, inflammatory bowel disease, depression, and dementia, with more than four servings per day linked to a 62% increase in all-cause mortality. Chris van Tulleken's self-experiment, increasing UPF intake from 20% to 80% for a month, resulted in a 15-pound weight gain, dramatic changes in brain connectivity related to habit and reward, and a fivefold rise in hunger hormones.
  • "Good Food" and Healthy Eating involves fruits, vegetables, legumes, whole grains, nuts, seeds, healthy fats like olive oil and avocados, and fatty fish. These components, especially encapsulated in the Mediterranean diet, are strongly associated with a reduction in all-cause mortality, cardiovascular diseases, cancer, neurodegenerative diseases, and diabetes. For instance, olive oil consumption alone has been tied to about a 20% lower all-cause mortality and a 28% lower risk of dementia with regular intake. Dietary fiber, found abundantly in unprocessed foods, slows digestion, reduces glucose spikes, and helps lower cholesterol.
  • Other Dietary Factors: High consumption of sugary beverages, including fruit juices, is linked to a 24% increased all-cause mortality and more than a threefold increase in atrial fibrillation. Excessive carbohydrate intake, especially low-quality, fast-digesting carbs, is associated with increased cardiovascular deaths. While light alcohol intake may not be problematic, moderate and heavy drinking does "no good" and is classified as carcinogenic, with risks increasing exponentially with higher intake levels. The more red meat, especially processed red meat, consumed, the less healthy one is likely to be, with consistent, albeit small, increases in cardiovascular and cancer risks. Substituting processed red meat with healthier protein sources like nuts and legumes can significantly reduce the risk of dementia and cognitive decline. Personalised nutrition, leveraging genomics, metabolomics, and the gut microbiome with AI, holds promise for optimising individual diets, as glucose responses to food vary significantly between people.

• Exercise Eric Topol, supported by experts like Euan Ashley, proclaims that exercise "may be the single most potent medical intervention ever known". Its benefits are "comprehensively sweeping across every organ".

  • Broad Systemic Benefits: Regular physical activity leads to favourable adaptations across all organ systems, including the cardiovascular system, brain, pancreas, skeletal muscle, gastrointestinal tract, liver, adipose tissue, and immune system. It enhances insulin sensitivity, protects against atherosclerosis, reduces inflammation, and improves mitochondrial function.
  • Mortality and Disease Reduction: Exercise is strongly linked to a 31% reduction in all-cause mortality, with a dose-response relationship – more activity generally means more benefit. It leads to a 50% reduction in cardiovascular disease and a 50% reduction in the risk of many cancers.
  • Mental and Cognitive Health: Exercise offers profound positive effects on mental health, often outperforming antidepressant drugs for depression and anxiety. It also helps preserve cognitive function in older adults.
  • Intensity and Type: Both aerobic and resistance (strength and balance) training are crucial. Moderate activities like brisk walking offer significant benefits (450 minutes per week associated with 4.5 years longer life), while higher intensity exercise may offer even greater returns (one minute of high-intensity exercise potentially yielding seven or eight minutes of extra life).
  • "You are a different person": As Euan Ashley noted from the MoTrPAC initiative, regular exercise dramatically changes "literally every tissue," enhancing the body's ability to deal with stress at a cellular level, often by upregulating repair mechanisms.

• Sleep Topol stresses that sleep is a "non-negotiable biological state required for the maintenance of human life," on par with air, food, and water, providing a "magical sense of restoration and wellness".

  • Brain Waste Clearance (Glymphatic System): During non-REM sleep, particularly deep slow-wave sleep (Stage N3), the brain's glymphatic system efficiently clears metabolic waste products, including toxic proteins like beta-amyloid.
  • Neurodegenerative Disease Risk: Just one night of sleep deprivation can lead to a substantial increase in beta-amyloid accumulation. Chronically poor sleep is linked to increased risk and progression of Alzheimer's disease; for instance, less than six hours of sleep at ages 50-60 is associated with a 30% increased risk of dementia. A "vicious loop" is established where decreased sleep leads to more toxic proteins, which then interfere with sleep.
  • Optimal Duration: The optimal duration of sleep is approximately seven hours. Both shorter and longer durations are consistently associated with cognitive and mental health decline, as well as heightened all-cause and cardiovascular mortality.
  • Medication Impact: Paradoxically, commonly used sleep aids like Ambien (zolpidem) can suppress norepinephrine effects and reduce glymphatic flow, potentially contributing to a heightened risk of Alzheimer's and dementia.

• Social Isolation Considered a "critical public health concern," social isolation and loneliness are deeply intertwined with overall health outcomes.

  • Increased Mortality Risk: A systematic review of over 2.2 million people found that loneliness is associated with a 32% increased all-cause mortality, a 34% rise in cardiovascular mortality, and a 24% higher cancer-related mortality.
  • Comorbidity: People with obesity are significantly more likely to experience social isolation and loneliness.

• Socioeconomic Status (SES) Topol includes socioeconomic status as an independent risk factor for premature mortality, with an impact comparable to smoking, high alcohol intake, hypertension, type 2 diabetes, or physical inactivity.

  • Disproportionate Health Disparities: Lower SES is disproportionately associated with a diet of less unprocessed food (e.g., "food deserts" affecting 24 million Americans), poorer sleep, higher exposure to air pollution, and less physical activity.
  • Education Link: Each additional year of education is associated with about a 2% reduction in mortality risk, highlighting its role in health outcomes.

• Environmental Toxins The "lifestyle+" framework also critically includes exposure to environmental toxins such as air pollution, microplastics, and "forever chemicals".

  • Air Pollution: Particulate matter air pollution is the leading contributor to global disease burden. Even short-term exposure is associated with increased all-cause, cardiovascular, and respiratory mortality. No safe threshold has been identified for chronic PM2.5 exposure, and an estimated 20% of type 2 diabetes is related to chronic exposure. Air pollution causes body-wide inflammation, compromised immune function, and brain inflammation.
  • Microplastics and Nanoplastics (MNPs): These ubiquitous substances are found in our environment, food, air, and water, and are increasingly detected in human organs including arteries, brain, blood clots, liver, gut, lungs, and testicles. Their presence in atherosclerotic plaques is linked to a 4.5-fold heightened risk of heart attack, stroke, or death. A deeply concerning new study shows MNP concentrations in the brain are 7-30 times greater than in the liver or kidneys, with much higher levels found 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 due to strong chemical bonds and are widely present in water, food, and countless products. High exposure is linked to kidney and testicular cancer, obesity, increased blood pressure, high cholesterol, and damage to various organs.
  • Other Toxins: Secondhand smoke, radon gas, pesticides, and noise pollution also pose significant health risks.

In conclusion, Eric Topol's expanded "lifestyle+" perspective from Super Agers underscores that a comprehensive and sustained focus on these interconnected factors—from the food we eat and how much we move, to the quality of our sleep, our social connections, our socioeconomic circumstances, and our environmental exposures—is fundamental to promoting healthy aging and significantly extending our healthspan. This holistic approach is often more impactful than any single drug or technological intervention, and addressing inequities in these areas is crucial for population-wide health improvement.