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.