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Supplements for Healthspan & Longevity

While nutrition, exercise, sleep, and stress management form the foundation of any healthspan strategy, targeted supplementation may offer additional benefits by addressing specific aspects of the aging process. This page examines the scientific evidence behind supplements that have shown promise in supporting healthspan and longevity.

Important Considerations:

  • Supplements should complement, not replace, fundamental lifestyle practices
  • Individual responses to supplements vary based on genetics, health status, and other factors
  • The research on many longevity supplements is still emerging and evolving
  • Quality, dosage, timing, and interactions are critical factors in supplement efficacy
  • Consult with healthcare providers before beginning any supplement regimen

This page provides an evidence-based overview of supplements that target various aging mechanisms, including their proposed mechanisms of action, research evidence, potential benefits and risks, and practical considerations for use.

Expert Insight: Dr. David Sinclair

"Supplements are just one tool in the longevity toolkit, and not necessarily the most important one. The foundation should always be lifestyle—exercise, nutrition, sleep, stress management. That said, certain supplements do show promise in addressing specific aspects of aging biology that may be difficult to target through lifestyle alone. The key is to be evidence-based and strategic, focusing on compounds with solid mechanistic rationale and at least some human data. It's also important to recognize that this is a rapidly evolving field—what we know today will likely be refined or even overturned as research advances. The most prudent approach is to prioritize interventions with the strongest evidence base and lowest risk profile." Watch Interview

NAD+ Precursors (NMN and NR)

Nicotinamide adenine dinucleotide (NAD+) is a critical coenzyme involved in hundreds of metabolic processes, including energy production, DNA repair, and the activity of sirtuins—proteins that regulate cellular health and aging. NAD+ levels decline significantly with age, potentially contributing to various aspects of aging.

Research Evidence: A 2018 randomized, double-blind, placebo-controlled clinical trial published in Nature Communications examined the effects of nicotinamide riboside (NR) supplementation in 12 healthy, middle-aged and older adults. The study found that 1000mg of NR daily for 21 days increased NAD+ levels in blood cells by approximately 60% compared to placebo. The intervention was well-tolerated and showed promising effects on markers of cardiovascular health, including reduced blood pressure and arterial stiffness. However, the study was small and short-term, highlighting the need for larger, longer-duration trials to establish clinical benefits.

Key NAD+ Precursors:

Proposed Mechanisms:

Human Research Status:

Outcome Evidence Level Key Findings
NAD+ Increase Strong Multiple studies confirm NR and NMN increase NAD+ levels in humans
Safety Moderate Generally well-tolerated in short-term studies; long-term safety data limited
Cardiovascular Health Preliminary Some evidence for improved blood pressure and arterial function
Metabolic Health Preliminary Mixed results for insulin sensitivity and other metabolic parameters
Muscle Function Preliminary Some evidence for improved mitochondrial function in muscle
Cognitive Function Very Limited Insufficient human data; animal studies show promise
Lifespan/Healthspan None No human data; positive results in model organisms

Practical Considerations for NAD+ Precursors

Dosage Ranges (based on current research):

  • NMN: 250-1200mg daily
  • NR: 250-1000mg daily

Timing:

  • Morning administration may align better with circadian NAD+ patterns
  • Some evidence suggests taking with fasting or before exercise may enhance effects

Form and Quality:

  • Stability is a concern, particularly for NMN
  • Look for products with stability data and third-party testing
  • Some evidence suggests sublingual or liposomal delivery may improve bioavailability

Potential Synergies:

  • Exercise appears to enhance NAD+ response
  • Time-restricted eating may complement NAD+ precursor effects
  • Resveratrol is often combined with NAD+ precursors (though evidence for synergy is primarily from animal studies)

Monitoring:

  • Subjective: Energy levels, sleep quality, recovery from exercise
  • Objective: Blood tests for NAD+ levels are becoming more available but still not standardized

Expert Insight: Dr. Charles Brenner

"NAD+ is fundamentally important for cellular resilience—it's required for cells to resist and repair different types of damage and metabolic stress. What's particularly interesting about NAD+ precursors is that they appear to have tissue-specific effects. For example, some tissues may respond better to NR, while others might preferentially utilize NMN. The field is still working to understand these nuances. One important point is that NAD+ precursors aren't simply providing more 'cellular energy'—they're enabling critical repair and regulatory processes that depend on NAD+. This is why the benefits may be more pronounced in older individuals or those under metabolic stress, where NAD+ has become a limiting factor for these processes." Watch Interview

Senolytics

Cellular senescence—a state where cells stop dividing but remain metabolically active and secrete pro-inflammatory factors—is a hallmark of aging. Senolytic compounds selectively induce death in senescent cells, potentially reducing the "senescence-associated secretory phenotype" (SASP) that contributes to age-related inflammation and tissue dysfunction.

Research Evidence: A 2019 pilot study published in EBioMedicine examined the effects of a senolytic combination (dasatinib plus quercetin) in 14 patients with idiopathic pulmonary fibrosis, a condition associated with increased senescent cell burden. The intervention was administered for three days, with assessments before and after treatment. The researchers observed significant improvements in physical function, including walking distance and chair-rise time, along with decreases in circulating SASP factors. While preliminary, this was the first study to demonstrate potential clinical benefits of senolytic therapy in humans.

Key Senolytic Compounds:

Proposed Mechanisms:

Human Research Status:

Outcome Evidence Level Key Findings
Senescent Cell Reduction Preliminary Limited evidence in humans; well-established in animal models
Safety Limited Short-term use appears tolerable; long-term safety unknown
Physical Function Preliminary Some evidence for improved walking distance and other measures
Inflammatory Markers Preliminary Some evidence for reduced SASP factors
Disease Modification Very Limited Early trials in specific conditions; results pending
Lifespan/Healthspan None No human data; positive results in model organisms

Practical Considerations for Senolytics

Dosage Ranges (based on current research):

  • Fisetin: 500-1500mg daily for 2-3 consecutive days, repeated every few months
  • Quercetin: 500-1000mg daily for 2-3 consecutive days, often combined with dasatinib in clinical studies

Timing:

  • Intermittent "pulse" dosing appears more effective than continuous administration
  • Optimal frequency of administration cycles is unknown (ranges from monthly to quarterly in studies)

Form and Quality:

  • Bioavailability is a significant concern, particularly for fisetin and quercetin
  • Liposomal or phytosomal formulations may improve absorption
  • Taking with fatty meals may enhance absorption of these fat-soluble compounds

Potential Synergies:

  • Combining different senolytics may target different senescent cell populations
  • Senomorphics (compounds that suppress the SASP without killing senescent cells) may complement senolytics
  • Exercise appears to have some senolytic-like effects and may enhance benefits

Cautions:

  • Potential for immune suppression during treatment periods
  • Possible interference with beneficial aspects of senescence (wound healing, cancer suppression)
  • Limited long-term safety data in humans
  • Not recommended during pregnancy, acute illness, or recovery from surgery

Expert Insight: Dr. James Kirkland

"Senescent cells are remarkably potent in their effects—even a relatively small number can cause significant tissue dysfunction through their secretory phenotype. What's particularly interesting about the senolytic approach is that it doesn't require continuous treatment. Unlike most drugs that need to be present to have an effect, senolytics work through a 'hit-and-run' mechanism—they transiently disable pro-survival networks that senescent cells depend on, triggering apoptosis. Once the senescent cells are eliminated, the effect persists until new senescent cells accumulate, which appears to take weeks to months in most tissues. This opens the possibility of intermittent treatment regimens that might minimize side effects while maintaining benefits." Watch Interview

Spermidine

Spermidine is a naturally occurring polyamine found in various foods, particularly wheat germ, aged cheese, mushrooms, and certain legumes. It has gained attention for its ability to induce autophagy—the cellular "recycling" process that removes damaged components and is critical for cellular health and longevity.

Research Evidence: A 2018 prospective population-based study published in The American Journal of Clinical Nutrition followed 829 participants aged 45-84 years for 20 years, assessing dietary spermidine intake through food frequency questionnaires. After adjusting for potential confounding factors, researchers found that higher dietary spermidine intake was associated with a 37% reduction in all-cause mortality risk when comparing the highest to lowest intake tertile. Additionally, a small 2018 pilot trial in 30 elderly subjects with subjective cognitive decline found that 12 months of spermidine supplementation improved memory performance compared to placebo, correlating with positive changes in brain glucose metabolism measured by PET imaging.

Proposed Mechanisms:

Human Research Status:

Outcome Evidence Level Key Findings
Autophagy Induction Moderate Evidence from human cell studies; indirect markers in clinical trials
Safety Moderate Generally well-tolerated in studies; long history of dietary consumption
Cognitive Function Preliminary Small trials show promising effects on memory performance
Cardiovascular Health Preliminary Some evidence for improved blood pressure and arterial function
Mortality Observational Epidemiological evidence links higher intake to reduced mortality
Lifespan/Healthspan None No interventional human data; positive results in model organisms

Practical Considerations for Spermidine

Dosage Ranges (based on current research):

  • Supplemental: 1-2mg daily
  • Dietary sources: Wheat germ (5-6mg per 100g), aged cheese (2-3mg per 100g), mushrooms (1-2mg per 100g)

Timing:

  • No clear evidence for optimal timing
  • Some theoretical basis for taking in the evening or during fasting periods to enhance autophagy

Form and Quality:

  • Wheat germ extract is the most common supplemental form
  • Stability and standardization are important considerations

Potential Synergies:

  • Fasting and caloric restriction enhance autophagy and may complement spermidine
  • Exercise induces autophagy through complementary pathways
  • Other autophagy inducers (e.g., resveratrol) may have additive effects

Dietary Approach:

  • High-spermidine foods: Wheat germ, aged cheese (especially Parmesan), mushrooms, soybeans, peas
  • Meal ideas: Wheat germ added to yogurt or smoothies; mushroom and Parmesan dishes; legume-based meals
  • Cooking considerations: Some spermidine may be lost in cooking; raw or lightly cooked foods retain more

Expert Insight: Dr. Frank Madeo

"What makes spermidine particularly interesting is that it's a natural compound with a long history of human consumption. Unlike many interventions that require drugs or extreme dietary modifications, spermidine can be obtained through specific foods that have been part of traditional diets for centuries. The Mediterranean diet, for instance, is relatively rich in spermidine sources. From a mechanistic perspective, spermidine's primary effect appears to be autophagy induction, but it likely has multiple targets. One fascinating aspect is its potential cardioprotective effect—in animal models, spermidine supplementation can protect against age-related cardiac dysfunction, and our epidemiological data in humans suggests similar benefits. The cognitive effects are also promising, particularly given the role of autophagy in neuronal health and protein aggregate clearance." Watch Interview

Other Promising Compounds

Beyond the more extensively studied compounds discussed above, several other supplements show promise for supporting healthspan and longevity through various mechanisms. These compounds generally have less human research but offer interesting mechanistic rationales and preliminary evidence.

Resveratrol

A polyphenol found in red wine, grapes, and berries that has been studied for its potential to activate sirtuins and mimic some effects of caloric restriction.

Research Evidence: A 2016 meta-analysis published in Nutrition, Metabolism and Cardiovascular Diseases examined 21 randomized controlled trials of resveratrol supplementation involving 958 participants. The analysis found that resveratrol significantly improved systolic blood pressure, glucose control, and total cholesterol levels, particularly at higher doses (≥300mg/day) and in populations with existing health conditions. However, the effects were modest, and significant heterogeneity existed between studies. While these metabolic benefits are promising, direct evidence for resveratrol's effects on longevity in humans remains limited.

Practical Considerations:

Berberine

An alkaloid compound found in several plants used in traditional medicine that has been studied for its metabolic and anti-inflammatory effects.

Research Evidence: A 2015 meta-analysis published in Journal of Ethnopharmacology analyzed 27 randomized controlled trials involving 2,569 participants with type 2 diabetes. The analysis found that berberine was at least as effective as conventional oral diabetes medications in reducing blood glucose levels, with additional benefits for lipid profiles. Berberine reduced HbA1c by an average of 0.71% compared to placebo, a clinically significant effect. While these metabolic benefits are well-established, research specifically examining berberine's effects on aging processes and longevity in humans is limited.

Practical Considerations:

Astaxanthin

A carotenoid pigment found in certain algae and seafood (giving salmon and flamingos their pink color) with potent antioxidant and anti-inflammatory properties.

Research Evidence: A 2018 systematic review published in Nutrients examined 21 randomized controlled trials of astaxanthin supplementation in humans. The analysis found evidence for benefits in several domains, including reduced oxidative stress markers, improved lipid profiles, and enhanced skin health parameters. Particularly notable were studies showing improved endurance performance and reduced exercise-induced muscle damage, suggesting effects on mitochondrial function and recovery. However, most studies were small and relatively short-term, and direct evidence for astaxanthin's effects on aging processes remains limited.

Practical Considerations:

Alpha-Lipoic Acid (ALA)

A naturally occurring antioxidant and cofactor for mitochondrial enzymes that has been studied for its effects on oxidative stress, inflammation, and metabolic health.

Research Evidence: A 2018 meta-analysis published in Clinical Nutrition examined 24 randomized controlled trials involving 1,316 participants. The analysis found that ALA supplementation significantly reduced markers of inflammation and oxidative stress, including C-reactive protein, interleukin-6, and TNF-alpha. These effects were more pronounced in subjects with elevated baseline inflammation. Additionally, several clinical trials have shown benefits for diabetic neuropathy, suggesting neuroprotective effects. While these mechanisms are relevant to aging processes, direct evidence for ALA's effects on longevity in humans is limited.

Practical Considerations:

Coenzyme Q10 (CoQ10)

An essential component of the mitochondrial electron transport chain and an endogenous antioxidant that declines with age and has been studied for its effects on energy production and oxidative stress.

Research Evidence: A 2018 meta-analysis published in Free Radical Biology and Medicine examined 17 randomized controlled trials involving 1,049 participants. The analysis found that CoQ10 supplementation significantly reduced markers of inflammation and oxidative stress, including C-reactive protein and malondialdehyde. Additionally, a 2014 randomized controlled trial (Q-SYMBIO) in 420 patients with heart failure found that CoQ10 supplementation reduced major adverse cardiovascular events by 43% compared to placebo over a two-year period, suggesting significant cardiovascular benefits. While these mechanisms and outcomes are relevant to aging, direct evidence for CoQ10's effects on longevity in humans is limited.

Practical Considerations:

Expert Insight: Dr. Rhonda Patrick

"What's interesting about many of these compounds is that they appear to work through hormetic mechanisms—they induce a mild stress response that activates endogenous protective pathways. This is similar to how exercise works: the acute stress of exercise activates pathways that ultimately make us more resilient. The challenge with supplements is determining the right dose and timing to achieve this hormetic effect without causing excessive stress. Another important consideration is individual variation—genetic differences, gut microbiome composition, and existing health status can all influence how someone responds to a particular compound. This is why personalization is so important, and why we need better biomarkers to track individual responses. In the meantime, focusing on compounds with the strongest safety profiles and mechanistic rationales, while monitoring subjective and objective outcomes, is the most prudent approach." Watch Interview

Supplement Strategy and Implementation

Developing an effective supplement strategy requires careful consideration of individual factors, scientific evidence, and practical implementation. This section provides a framework for approaching supplementation for healthspan and longevity.

Foundational Principles:

Supplement Decision Framework

  1. Identify specific aging mechanisms or health domains you want to target (e.g., mitochondrial function, inflammation, autophagy)
  2. Research compounds that address these targets, focusing on those with:
    • Clear mechanistic rationale
    • Evidence in humans (ideally) or at least multiple model organisms
    • Favorable safety profile
    • Quality products available
  3. Consider your personal context:
    • Age and health status
    • Genetic factors (if known)
    • Existing medications and supplements
    • Budget constraints
    • Lifestyle factors that may enhance or diminish effects
  4. Start with a minimal effective regimen rather than many compounds at once
  5. Monitor effects using both subjective measures and objective biomarkers when possible
  6. Adjust based on response and emerging research

Tiered Approach to Supplementation:

Tier Description Examples
Tier 1: Foundational Essential nutrients that may be suboptimal in many diets Vitamin D, magnesium, omega-3 fatty acids
Tier 2: Targeted Support Compounds with good evidence for specific health domains CoQ10 for cardiovascular health, berberine for metabolic health
Tier 3: Longevity-Specific Compounds targeting aging mechanisms with emerging human evidence NAD+ precursors, spermidine
Tier 4: Experimental Promising compounds with limited human data Senolytics, certain peptides

Quality Considerations:

Important Cautions:

  • Medical consultation: Discuss supplement plans with healthcare providers, especially if you have existing health conditions or take medications
  • Potential interactions: Many supplements can interact with medications or other supplements
  • Individual variation: Response to supplements varies based on genetics, microbiome, and other factors
  • Diminishing returns: More is not always better; excessive supplementation can have adverse effects
  • Evolving evidence: The research landscape is rapidly changing; stay informed about new findings
  • Regulatory limitations: Supplement quality and content are not as tightly regulated as pharmaceuticals

Expert Insight: Dr. Peter Attia

"When it comes to supplements for longevity, I think about them in terms of the magnitude of potential benefit versus the certainty of that benefit versus the risk. Ideally, we want supplements with high potential benefit, high certainty, and low risk. Unfortunately, most longevity supplements currently have either modest potential benefit, low certainty, or both. This doesn't mean they're not worth considering, but it does mean we should be thoughtful and strategic. I generally recommend starting with the basics—ensuring optimal levels of essential nutrients like vitamin D, magnesium, and omega-3s—before moving to more experimental compounds. It's also important to recognize that supplements are just one tool in the longevity toolkit, and often not the most powerful one. Exercise, nutrition, sleep, and stress management typically offer more robust benefits with higher certainty than most supplements." Watch Interview

References

1. Martens CR, et al. (2018). Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults. Nat Commun, 9(1):1286.
2. Elhassan YS, et al. (2019). Nicotinamide Riboside Augments the Aged Human Skeletal Muscle NAD+ Metabolome and Induces Transcriptomic and Anti-inflammatory Signatures. Cell Rep, 28(7):1717-1728.e6.
3. Justice JN, et al. (2019). Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study. EBioMedicine, 40:554-563.
4. Hickson LJ, et al. (2019). Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease. EBioMedicine, 47:446-456.
5. Kiechl S, et al. (2018). Higher spermidine intake is linked to lower mortality: a prospective population-based study. Am J Clin Nutr, 108(2):371-380.
6. Wirth M, et al. (2018). The effect of spermidine on memory performance in older adults at risk for dementia: A randomized controlled trial. Cortex, 109:181-188.
7. Fogacci F, et al. (2019). Effect of resveratrol on blood pressure: A systematic review and meta-analysis of randomized, controlled, clinical trials. Crit Rev Food Sci Nutr, 59(10):1605-1618.
8. Lan J, et al. (2015). Meta-analysis of the effect and safety of berberine in the treatment of type 2 diabetes mellitus, hyperlipemia and hypertension. J Ethnopharmacol, 161:69-81.
9. Ambati RR, et al. (2014). Astaxanthin: sources, extraction, stability, biological activities and its commercial applications--a review. Mar Drugs, 12(1):128-152.
10. Mortensen SA, et al. (2014). The effect of coenzyme Q10 on morbidity and mortality in chronic heart failure: results from Q-SYMBIO: a randomized double-blind trial. JACC Heart Fail, 2(6):641-649.