Supplements for Healthy Aging: A Practical Guide to the Evidence

The global dietary supplement market is vast and exploding (see note). The shelves of pharmacies and online stores are filled with products that blend sophisticated scientific terminology with promises of cellular rejuvenation and extended healthspan. 

For the curious consumer, the challenge is that marketing claims often greatly outpace the slower, more deliberate speed of human clinical trials. A handful of supplements have randomized human data relevant to healthy aging. All of the others rely on a foundation of mechanistic theory, animal models, test tube results or observational data. 

This does not mean emerging supplements are without value. But making informed decisions requires a practical way to weigh the evidence. The goal here is not to tell you what you should or should not take, but to offer a clear-eyed framework for assessing the options—helping you match your personal health goals, budget, and risk tolerance with the realities of current science.

A LADDER OF CONFIDENCE

Not all evidence carries the same weight. When evaluating a supplement, it helps to locate it on a "Ladder of Confidence." 

• Rung 1: Consensus Across Multiple Large Trials. Multiple independent, randomized controlled trials (RCTs) find the same benefit in humans. 

  
  

• Rung 2: A Single Large, Well-Run Trial. A large human trial that measures hard clinical outcomes, like cardiovascular events, rather than just intermediate blood markers. 

  
  

• Rung 3: Small Trials, Typically with Biomarker Endpoints. The compound has been tested in humans (often 50 to 100 people) and shows intriguing, promising, sometimes striking, quantitative improvements in functional measures or biological markers. This is an exciting early chapter, not the final word. 

  
  

• Rung 4: Observational Cohorts. Large populations are tracked over time, showing that people who consume a certain nutrient tend to age better (correlation, not causation). 

  
  

• Rung 5: Preclinical Bench Science. The compound shows extremely interesting results in yeast, worms, mice, or the test tube. 

  
  

• Rung 6: Tradition and Anecdote. Historical use or personal testimonials. Sources for generating hypotheses, but no proof. 

A GRADIENT OF EVIDENCE

TRANSLATING THE DATA

What follows is a look at some supplements with clinical data in or adjacent to the healthy aging space, arranged roughly along a gradient from the more firmly established human data to earlier, more exploratory science.

COCOA FLAVANOLS (CocoVia^®)

Cocoa flavanols boast some of the most rigorous testing in the supplement space, highlighted by the 2022 US COSMOS trial—a study of 21,442 older adults taking 500 mg of daily flavanols for over three years. While the study narrowly missed its primary goal of reducing all cardiovascular events by 10%, the secondary data was striking: cardiovascular deaths dropped by 27%. For participants who actually followed the protocol and took the pills consistently, cardiovascular death fell by 39%. To see an effect of this magnitude from a plant-derived supplement is exceedingly rare.

COQ10 AND SELENIUM (KiSel-10)

This combination offers a rare look at hard cardiovascular outcomes over a long period. A trial of 443 older adults in Sweden found that supplementing with CoQ10 (200 mg) and high-selenium yeast (200 mcg) reduced cardiovascular mortality by a remarkable 54% over five years (5.9% mortality in the supplement group vs. 12.6% in the placebo group). There is one potentially important piece of context: the participants lived in a region with selenium-poor soil. Thus, the supplement may have been effectively correcting a regional deficiency, as an example of how targeted supplementation may be able to dramatically support health if natural levels run low. Whether the supplementation could similarly help people without any deficit is a good question without a definitive answer so far.

CREATINE MONOHYDRATE

Creatine is widely known as a sports supplement, but it holds Rung 1 evidence for preserving muscle function in older adults. A 2024 systematic review of 33 trials found that older adults taking standard doses (3 to 5 grams daily) combined with resistance training showed significant, quantitative improvements over training alone. Specifically, those taking creatine gained an average of 2.1 kilograms (about 4.6 lbs) more on their maximal bench press strength, and showed roughly a 23% improvement in their sit-to-stand performance—meaning they could stand up from a chair significantly faster and more times in a row than the placebo group. While creatine is not a cellular “longevity” molecule, the ability to get up from a chair easily is exactly the kind of functional metric that maps directly onto fall prevention, maintaining independence, and avoiding the frailty spiral.

UROLITHIN A (Mitopure^®)

Urolithin A targets mitophagy—the cellular housekeeping process that clears out damaged mitochondria. While it is derived from compounds in pomegranates and berries, microbiome variations mean that only 30% to 40% of adults can naturally produce clinically meaningful amounts of urolithin A from food alone, giving supplementation a highly coherent biological rationale. In the 2022 US ATLAS trial of 88 older adults, a 12-week course did not hit its primary target of significantly improving VO2 max (peak oxygen consumption), but it did yield a 12% improvement in skeletal muscle endurance (the number of muscle contractions before fatigue) alongside improved mitochondrial biomarkers.

SPERMIDINE

Spermidine is a polyamine found in whole grains and aged cheese that induces autophagy, another vital cellular cleanup process. In the 2021 German SmartAge trial—a 12-month study of 100 older adults with subjective cognitive decline—daily spermidine supplementation was tested for its effect on memory. The group that strictly adhered to the protocol showed a statistically significant improvement in verbal learning and memory scores, while the broader intention-to-treat group trended positive but did not reach strict statistical significance. While dietary spermidine is strongly associated with better brain health in large population studies, translating that into a supplement pill is still in the early stages, making it a promising, though not yet proven, candidate.

GLYNAC

A combination of glycine and N-acetylcysteine, GlyNAC is designed to restore levels of glutathione, a primary cellular antioxidant that declines with age. In a small 2021 US pilot study (n=8) of older adults, GlyNAC corrected glutathione to near-youthful levels and reduced markers of oxidative stress by roughly 50%. This was accompanied by measured improvements in functional endpoints, including roughly a 10% increase in grip strength and a 20% increase in gait speed. These multi-domain improvements have since been echoed in a 60-person trial by the same research group, but larger, independent replication is still needed.

NAD+ PRECURSORS (TruNiagen®, Basis®)

NAD+ precursors (NR and NMN) are incredibly popular, driven by elegant biology showing their role in cellular energy. The human pharmacodynamic data is clear: oral NR and NMN reliably raise blood NAD+ levels, often substantially, within two to four weeks. However, translating those blood levels into functional improvements in healthy older adults has been frustratingly elusive, with meta-analyses showing no significant gains in muscle strength or walking speed. Where they do show potential benefit is in disease-related deficits—for example, a 2024 trial found that peripheral artery disease patients taking NR could walk 31 meters further in a six-minute test than those on placebo.

VITAMIN D

Vitamin D offers a classic example of why correcting a deficit is entirely different from super-dosing for longevity. Its strongest clinical backing comes from the VITAL trial, a massive Rung 2 study of nearly 26,000 older adults. In the VITAL trial, standard daily supplementation (2,000 IU) did not significantly reduce the primary endpoints of major cardiovascular events or overall cancer incidence in generally healthy older adults. However, a deeper dive into the secondary data revealed a significant finding: cancer-related mortality was reduced by approximately 25% (HR 0.75) in the supplemented group—a clinically meaningful result for a 2,000 IU daily dose with an excellent safety profile. Furthermore, large observational cohorts (Rung 4) suggest that severe vitamin D deficiency is associated with premature mortality, with some estimates suggesting several years of life expectancy lost. Thus, while it may not be a magic bullet for extending maximal healthspan in a replete individual, it is foundational for those with a measured deficit.

MAGNESIUM

Magnesium is an essential mineral involved in over 600 enzymatic reactions, including ATP production and cellular energy metabolism. Despite its biological importance, it currently occupies Rung 3 and Rung 4 on the Ladder of Confidence regarding healthy aging. Recent systematic reviews of observational cohorts (Rung 4) reveal a consistent U-shaped association between serum magnesium levels and cognitive impairment, suggesting that maintaining an optimal range is neuroprotective. While small RCTs (Rung 3) have shown some benefits for lowering blood pressure and improving sleep quality in older adults, robust, large-scale RCTs demonstrating definitive prevention of cognitive decline or extended longevity are still lacking. Like vitamin D, the primary value of supplementation lies in correcting age-related absorption declines or dietary shortfalls. 

BERBERINE

Often referred to informally as "over-the-counter metformin," berberine is a plant alkaloid that strongly activates AMPK, a primary cellular energy sensor and metabolic pathway that is also a key target of metformin. While preclinical bench science (Rung 5) demonstrates striking lifespan extensions in animal models alongside reduced oxidative stress, human data rests firmly on Rung 3. Numerous small-to-mid-sized clinical trials confirm its efficacy in improving metabolic biomarkers in populations with metabolic syndrome or type 2 diabetes. A meta-analysis of these trials found that berberine reduced HbA1c by approximately 0.9%, fasting blood glucose by roughly 20 mg/dL, and LDL cholesterol by approximately 12 mg/dL versus placebo—effects broadly comparable to low-dose metformin. Because it fundamentally targets metabolic homeostasis, which degrades with age, it has a highly coherent biological rationale. However, we still lack large, long-term human trials (Rung 2) proving it extends functional healthspan in otherwise healthy older adults.

AKKERMANSIA MUCINPHILA

As evidence for the microbiome’s role in aging continues to grow, Akkermansia muciniphila has emerged as a keystone bacterial strain. The natural abundance of this mucin-degrading microbe tends to decline with age, yet it remains significantly enriched in the guts of healthy centenarians. Animal models (Rung 5) show that supplementing with A. muciniphila improves intestinal barrier integrity, reduces systemic "inflammaging," and extends healthy lifespan. In humans, it currently sits at Rung 3. A landmark proof-of-concept RCT (n=32, three months) in overweight, insulin-resistant adults demonstrated that pasteurized A. muciniphila significantly reduced fasting insulinemia by approximately 27% and lowered LDL cholesterol, while also reducing two gut-permeability markers compared to placebo—with the pasteurized form outperforming both placebo and live bacteria on most endpoints. While clinical applicability is still evolving due to strain variability and the complexities of human microbiome engraftment, it represents the cutting edge of gut-targeted longevity interventions. 

EMERGING FORMULATIONS AND BIOMARKER TARGETS

As the field advances, some interventions with early clinical data are emerging that increasingly target complex metabolic pathways or utilize new measurement tools. Here are several illustrative supplements with Rung 3 data, for comparison with the multitude of other supplements out there in the context of the Ladder of Confidence. 

LEUSIX®

Targeting metabolic health, this specific blend of leucine and vitamin B6 activates pathways similar to those influenced by fasting or certain metabolic drugs. In a 24-week US RCT (n=24 in the caloric restriction arm), the LEUSIX^® cohort lost approximately 9% in body weight (predominantly fat, while preserving lean muscle) and improved cardiometabolic markers such as insulin resistance by about 40%. A separate 28-day US trial (n=20) showed it increased fat oxidation by roughly 300 additional calories per day compared to placebo. This metabolic mechanism is further supported by a 12-week veterinary trial in obese beagles that yielded approximately 22% body weight loss without caloric restriction. (Disclosure: The authors are members of the management team of NuSirt, which developed LEUSIX^®, as well as of Kinexum, the parent company of NuSirt.)

CALCIUM ALPHA-KETOGLUTARATE (Ca-AKG; Rejuvant^®)

Ca-AKG generated considerable interest after a 2021 retrospective study reported an approximately 8-year reduction in biological age among users of the Rejuvant® formulation. The biological rationale is fascinating, but context is crucial: this was a retrospective study of 42 people with no placebo group, and it utilized a proprietary commercial methylation clock (TruAge) rather than more established, validated academic clocks (like GrimAge or PhenoAge). Placebo-controlled trials are currently underway at the National University of Singapore to see if these striking numbers hold up under rigorous testing.

PEPTISTRONG^® (Swiss RX Synthesis)

Using artificial intelligence to identify specific bioactive peptide networks within fava beans, this product was designed to target mTORC1, the cellular pathway that serves as the master biological switch for muscle protein synthesis. Human trials published in 2023 place it on Rung 3 of the Ladder of Confidence for muscle recovery and remodeling. In one randomized, placebo-controlled trial of 30 healthy men, a 2.4-gram daily dose of PeptiStrong significantly improved strength recovery and reduced fatigue over the 72 hours following exhaustive exercise, while simultaneously suppressing myostatin, a protein that acts as a brake on muscle growth. A separate 2023 trial in healthy young men demonstrated that the fava bean peptide network significantly increased muscle protein synthesis rates during a period of remobilization after short-term muscle disuse, outperforming traditional milk protein on this metric. While currently positioned for active exercise recovery, its ability to stimulate anabolic pathways while suppressing muscle breakdown signals gives it high biological coherence for potential future applications in age-related muscle loss.

NOVOS CORE^®

This multi-ingredient formula targets several aging pathways simultaneously using a blend of 12 compounds, including NMN, fisetin, and pterostilbene. A 2025/2026 UK randomized, placebo-controlled crossover trial (the STAMINA trial, approximately 50–60 participants) measured three pre-specified vascular endpoints at six months: arterial stiffness, as assessed by pulse wave velocity (PWV), decreased significantly; endothelial function, as assessed by flow-mediated dilation (FMD), improved significantly; and systolic blood pressure decreased significantly—all versus placebo. In cardiovascular aging research, improved FMD is a validated predictor of future cardiovascular events, and each meaningful reduction in PWV is associated with reduced cardiovascular risk—these are not esoteric biomarkers, but measures that map onto real-world outcomes. The caveat is that a collection of so many ingredients makes it impossible to attribute the benefit to any single compound or subgroup of compounds. Unlike pharmaceutical combinations, where regulators require proof of each component’s specific contribution, supplement blends leave the consumer guessing whether every ingredient in the pill is actually necessary for the observed benefit.

A FRAMEWORK FOR THE INFORMED CONSUMER

When navigating the longevity supplement space, a few practical principles can help guide your decisions: 

• Locate the supplement on the Ladder of Confidence: Before making a purchase, determine what level of human evidence actually supports the product. Is it backed by hard clinical outcomes (Rung 2), small biomarker studies (Rung 3), or just animal data and historical anecdotes (Rungs 5 and 6)? Knowing exactly where a product sits immediately clarifies whether you are paying for proven science or an early-stage biological bet. 

• Look for the deficit: Supplements often work best when they correct a decline—whether that is a lack of a nutrient (selenium, vitamin D, magnesium), a drop in glutathione, or an inability of the microbiome to generate urolithin A. Do you actually have that deficit? If not, it is fair to ask whether paying to ingest more than you need is likely to help. 

• Match the claim to the evidence: Understand what was actually measured. "Reported feeling less hunger" is not the same as a measured 10-pound weight loss compared to a placebo. Raising blood NAD+ levels does not automatically mean NAD+ was raised in brain tissue, nor does reversing an epigenetic clock by 8 years in an uncontrolled study prove an increase in functional lifespan. 

• Do not assume safety: A product being "Generally Recognized as Safe" (GRAS) or sitting on a store shelf does not guarantee safety, especially at higher doses. Manufacturing purity, accuracy of dosing, and the absence of contaminants are critical. Look for products that invest in clinical data and utilize third-party testing (such as NSF or USP certification) to ensure you are actually ingesting what the label claims. 

• Factor in cost and certainty: A highly proven, affordable supplement with a long safety record requires less deliberation than a novel, expensive compound with only early biomarker data. 

The science of healthy aging is progressing steadily. Until the data fully matures, the most rational approach is to stay curious, read past the marketing, objectively assess where a product sits on the Ladder of Confidence, and align your choices with the level of evidence that matches your personal comfort zone.

ABOUT THE AUTHORS

Thomas Seoh, JD is EVP of the Kitalys Institute, a not-for-profit catalyzing the translation of science into public health to extend healthy longevity for all, and CEO of Kinexum, a strategic advisory firm for life science product developers, including longevity biotechnology companies. 

Michael Zemel, PhD, is CSO of Kinexum, founder and CSO of NuSirt Sciences, Inc., a developer of TRIPLN^®, a fixed-dose combination of metformin, sildenafil and leucine, with P2 trials completed in obesity and liver fats and a P2 hypertension trial planned for later in 2026, and LEUSIX^®, and former faculty at the University of Tennessee and Wayne State University. 

NOTES

The global dietary supplement market was valued at approximately $209.5 billion in 2025 and is projected to nearly double by 2033 (Grand View Research, 2026).

For a comprehensive academic review of this market expansion and the concurrent rise in consumer demand for longevity and wellness formulations, see: Djaoudene O, Romano A, Bradai YD, Zebiri F, Ouchene A, Yousfi Y, Amrane-Abider M, Sahraoui-Remini Y, Madani K. A Global Overview of Dietary Supplements: Regulation, Market Trends, Usage during the COVID-19 Pandemic, and Health Effects. Nutrients. 2023; 15(15):3320. https://doi.org/10.3390/nu15153320