Preserving Healthspan After 50: Resistance Exercise, Protein, Creatine, Nutritional Supplements, Telomere Biology, and Cold ExposureA Narrative Review of Human Evidence Published From 2021 to 2026
Ori Scott, M.Sc. Nutrition, Registered Dietitian (Israel), Founder Healthy Habits Coaching
Abstract
Background
Healthy aging is increasingly discussed in relation to nutritional supplements, biological-age biomarkers, telomere preservation, nicotinamide adenine dinucleotide (NAD+) metabolism, and deliberate cold exposure. These approaches differ substantially in the quality and clinical relevance of their supporting evidence. In parallel, age-related losses of skeletal muscle strength and physical function are established threats to mobility and independence and represent modifiable targets of intervention.
Objective
This narrative review examines recent human evidence concerning resistance exercise, dietary protein and protein supplementation, creatine, selected supplements associated with biological-aging claims, telomere-related interventions, NAD+ precursors, resveratrol, and cold-water exposure. Particular attention is given to the distinction between improvements in clinically meaningful functional outcomes and changes in surrogate biomarkers associated with aging.
Methods
A targeted narrative literature search was conducted in PubMed/MEDLINE. Medical Subject Headings (MeSH) and free-text terms were used for concepts related to aging, older adults, sarcopenia, resistance training, dietary protein, creatine, dietary supplements, vitamin D, omega-3 fatty acids, resveratrol, telomeres, telomere shortening, DNA methylation, NAD+, nicotinamide riboside, nicotinamide mononucleotide, cold temperature, cryotherapy, and cold-water immersion. The principal evidence window was 11 September 2021 through 11 September 2026. Human randomized controlled trials, systematic reviews, and meta-analyses were prioritized. Animal and in-vitro studies were not used to establish clinical efficacy. Functional and patient-relevant outcomes were distinguished from intermediate biomarkers such as leukocyte telomere length, DNA-methylation age, and NAD-related metabolites.
Results
Resistance exercise has the most consistent recent evidence among the interventions reviewed for improving muscle strength and physical function in older adults. Protein supplementation may augment selected adaptations to resistance exercise, particularly in older adults with sarcopenia or physical frailty, although effect sizes, heterogeneity, and certainty of evidence limit broad conclusions. Creatine supplementation combined with exercise appears to provide modest additional benefits for selected strength and lean-tissue outcomes.
Evidence that nutritional supplements slow biological aging is substantially less certain. In the VITAL telomere ancillary randomized trial, vitamin D3 supplementation was associated with reduced leukocyte telomere attrition over four years, whereas an ancillary randomized analysis from the D-Health Trial did not demonstrate a significant effect on telomere length. Marine omega-3 fatty acids did not significantly affect telomere attrition in the VITAL analysis. Small randomized studies of Astragalus-based and mixed botanical supplements have reported favorable telomere findings, while a nucleotide-supplementation trial reported a reduction in DNA-methylation age without a significant change in leukocyte telomere length. Human studies of NAD+ precursors consistently demonstrate biochemical target engagement, but evidence for clinically meaningful anti-aging effects remains inconclusive. Cold-water immersion produces acute physiological responses and may affect selected wellbeing outcomes, but current human evidence does not demonstrate delayed biological aging, telomere preservation, increased healthspan, or increased lifespan.
Conclusions
The recent human literature supports a clear distinction between preserving functional capacity and modifying surrogate markers associated with aging. Resistance exercise has substantially stronger evidence for clinically meaningful outcomes than supplements or cold exposure have for slowing biological aging. Adequate protein intake and, in selected circumstances, protein or creatine supplementation may complement resistance exercise. Changes in telomere length, DNA-methylation age, NAD-related metabolites, or other molecular markers should not be interpreted as evidence of extended healthspan or lifespan without corresponding clinical outcomes. No supplement or cold-exposure intervention evaluated in this review can presently be considered proven to slow human aging or extend human lifespan.
Keywords: healthy aging; healthspan; resistance training; skeletal muscle; sarcopenia; dietary protein; creatine; dietary supplements; telomeres; vitamin D; NAD+; resveratrol; cold-water immersion; older adults.
1. Introduction
Longer life expectancy has increased interest in strategies that might preserve health, mobility, cognitive and physical capacity, and independence during later life. At the same time, a rapidly expanding commercial market promotes supplements and lifestyle practices using terms such as “anti-aging,” “longevity,” “biological-age reversal,” and “telomere support.”
These concepts require careful interpretation.
Healthy aging is not adequately represented by a single laboratory measurement. Muscle strength, gait speed, mobility, disability, quality of life, leukocyte telomere length, DNA-methylation age, circulating inflammatory markers, and NAD-related metabolites measure different aspects of physiology. They should not be treated as interchangeable endpoints.
An intervention that changes a biomarker associated with aging has demonstrated an effect on that particular biomarker. It has not necessarily demonstrated slower organismal aging, delayed disability, prolonged healthspan, or increased survival.
This distinction is particularly relevant after midlife because skeletal muscle function becomes an important determinant of physical independence. Sarcopenia involves progressive impairment of muscle strength, muscle quantity or quality, and physical performance. Resistance exercise therefore has direct relevance to healthy aging because it targets outcomes that affect physical capability rather than merely altering a proposed marker of aging.
Nutrition interacts with this process through dietary adequacy, protein intake, and potentially specific nutritional supplements. Protein and creatine are of particular interest because their effects can be evaluated against tangible outcomes including lean tissue, muscle strength, and physical performance.
Other interventions occupy a different evidentiary position. Vitamin D, omega-3 fatty acids, resveratrol, NAD+ precursors, nucleotide preparations, Astragalus-derived products, and other supplements have been studied in relation to molecular or cellular endpoints associated with aging. Deliberate cold exposure has similarly attracted considerable attention because of its acute cardiovascular, autonomic, metabolic, and stress-related effects.
The purpose of this narrative review is to examine these different approaches within a common framework. The principal question is not whether an intervention produces any measurable biological response, but whether recent human evidence supports a meaningful contribution to health and function during aging.
2. Methods
2.1 Review design
A narrative review was undertaken because the interventions, populations, study designs, and outcomes under consideration are heterogeneous. The objective was to critically integrate recent human evidence rather than calculate a new pooled treatment estimate.
The review places particular emphasis on the clinical meaning of reported outcomes and on distinguishing direct functional benefits from changes in surrogate or exploratory biomarkers.
2.2 Database and search approach
The literature search was restricted to PubMed/MEDLINE.
Searches incorporated combinations of MeSH terminology and title/abstract terms including:
“Aging”;
“Aged”;
“Healthy Aging”;
“Sarcopenia”;
“Resistance Training”;
“Exercise”;
“Dietary Proteins”;
“Dietary Supplements”;
“Creatine”;
“Vitamin D”;
“Fatty Acids, Omega-3”;
“Resveratrol”;
“Telomere”;
“Telomere Shortening”;
“DNA Methylation”;
“Cellular Senescence”;
“Nicotinamide Adenine Dinucleotide”;
“nicotinamide riboside”;
“nicotinamide mononucleotide”;
“Cold Temperature”;
“Cryotherapy”; and
“cold-water immersion.”
Search concepts were combined according to the intervention being examined.
The principal publication window was 11 September 2021 through 11 September 2026.
2.3 Eligibility
Priority was given to:
systematic reviews and meta-analyses of human randomized controlled trials;
randomized controlled human trials;
systematic reviews of human intervention studies; and
controlled human intervention studies where higher-level recent evidence was limited.
Studies involving adults aged 50 years and older were prioritized. Research involving adults aged ≥60 or ≥65 years, individuals with sarcopenia or physical frailty, and healthy community-dwelling older adults was considered particularly relevant.
Cold-exposure studies involving younger healthy adults were considered when evaluating the physiological evidence base, but these findings were not assumed to apply directly to older adults.
Animal and in-vitro evidence was not used to establish clinical efficacy.
2.4 Interpretation of outcomes
Outcomes were considered in two broad categories.
Clinical and functional outcomes included muscle strength, walking or gait performance, functional capacity, mobility, lean tissue or muscle mass, quality of life, and other outcomes relevant to physical independence.
Intermediate biological outcomes included leukocyte telomere length, DNA-methylation age, NAD-related metabolites, inflammatory markers, and related molecular measures.
A change in an intermediate biomarker was not considered evidence of delayed human aging unless supported by corresponding evidence for meaningful clinical outcomes.
This distinction was applied consistently when interpreting interventions marketed or discussed as anti-aging strategies.
3. Resistance Exercise and Functional Healthy Aging
Among the interventions considered in this review, resistance exercise has the most direct and consistent relationship with preservation of muscular function.
Shen et al. conducted a systematic review and network meta-analysis of 42 randomized controlled trials involving 3,728 participants with sarcopenia. The median participant age was 72.9 years, and median follow-up was 12 weeks. Resistance exercise, alone or as part of multicomponent programs, was among the most effective approaches for several patient-important outcomes. Moderate- or high-certainty evidence supported resistance-based interventions for quality of life and selected measures of physical function. Resistance and balance exercise with or without nutritional intervention produced favorable effects on gait speed, while adding nutritional intervention appeared to provide greater effects on handgrip strength than exercise alone.[1]
Evidence extends beyond individuals formally diagnosed with sarcopenia. A 2023 systematic review and meta-analysis by Khodadad Kashi et al. included 21 studies and 1,610 adults aged ≥60 years. Resistance training improved upper- and lower-limb strength and handgrip strength and was associated with improvement in several domains of quality of life. However, benefits were not observed for every endpoint, including six-minute walking distance, and the authors characterized the overall evidence as preliminary.[2]
A more recent systematic review and meta-analysis by Hoseinpour et al. included 19 randomized controlled trials involving 728 healthy adults aged ≥60 years. Resistance training improved leg-extension strength and six-minute walk performance. C-reactive protein decreased, whereas significant changes were not demonstrated for tumor necrosis factor-α or interleukin-6.[3]
The importance of these findings lies in the nature of the outcomes. Resistance exercise does not need to alter telomere length, DNA methylation, or another molecular biomarker to be relevant to healthy aging. Strength, mobility, and the ability to perform ordinary physical tasks are themselves clinically meaningful outcomes.
Resistance exercise therefore provides an appropriate reference against which interventions described as anti-aging can be evaluated.
4. Dietary Protein, Supplementation, and Muscle Preservation
Protein intake has an established biological relationship with skeletal muscle protein metabolism, but supplementation trials in older adults require more nuanced interpretation than the general statement that “more protein prevents muscle loss.”
Baseline diet, nutritional status, sarcopenia, exercise participation, supplement composition, intervention duration, and the outcome measured all influence interpretation.
Whaikid and Piaseu evaluated protein supplementation combined with resistance exercise in community-dwelling adults aged ≥60 years with sarcopenia. Seven randomized trials and one quasi-experimental study, involving 854 participants, were included. Intervention periods ranged from 10 to 24 weeks. The pooled analysis favored combined protein supplementation and resistance exercise for muscle mass (SMD 0.95; 95% CI 0.13–1.78) and muscle strength (SMD 0.32; 95% CI 0.08–0.56). The authors nevertheless emphasized that the limited number of randomized trials restricted the robustness of the conclusions.[4]
A 2023 meta-analysis specifically evaluating whey protein during resistance exercise included seven randomized trials and 591 participants with sarcopenia. Five studies contributed to quantitative synthesis. Whey protein plus resistance exercise produced a small improvement in appendicular muscle index (SMD 0.24; 95% CI 0.05–0.42). Handgrip strength also favored supplementation, but heterogeneity was high, and the magnitude of improvement did not exceed the minimally important clinical difference identified by the investigators. Evidence quality was rated low to very low.[5]
A 2025 systematic review and meta-analysis by Yoshimura et al. included 13 randomized trials and 1,057 adults aged ≥65 years with sarcopenia or physical frailty. Protein supplementation combined with exercise improved skeletal muscle index and handgrip strength compared with exercise alone. Protein supplementation without exercise produced more limited effects, particularly for physical performance. Importantly, the authors rated the overall certainty of evidence as very low.[6]
A separate 2024 meta-analysis of 18 randomized controlled trials involving 1,147 older adults reported improved gait-speed outcomes when protein supplementation was combined with resistance training. Substantial heterogeneity, however, limits the precision with which the pooled estimate can be translated into an expected individual benefit.[7]
The recent literature therefore supports protein as an important component of muscle-preservation strategies but does not support a universal conclusion that supplemental protein independently prevents age-related functional decline.
The more defensible interpretation is that protein supplementation may be useful when it addresses inadequate intake or is integrated with resistance exercise in appropriately selected older adults. Exercise remains an important component of the intervention rather than an optional addition to supplementation.
5. Creatine as an Adjunct to Exercise
Creatine is frequently included in discussions of longevity supplements, although its strongest human evidence relates to exercise adaptation rather than aging itself.
A 2025 systematic review and meta-analysis by Sharifian et al. included 20 articles and 1,093 older participants, 69% of whom were women. Creatine supplementation combined with exercise produced a statistically significant additional improvement in one-repetition maximum strength compared with placebo plus exercise (mean difference 2.122 kg; P=0.001). A small reduction in body-fat percentage was also reported, whereas total-body bone mineral density did not significantly improve.[8]
Liu et al. subsequently examined creatine specifically in conjunction with resistance training. Eight randomized controlled trials involving 482 participants were included. Compared with placebo plus resistance training, creatine plus resistance training improved lower-limb strength (SMD 0.29; 95% CI 0.00–0.57) and lean tissue mass (SMD 0.27; 95% CI 0.02–0.53). A significant overall improvement in upper-extremity strength was not demonstrated. Subgroup analyses suggested that intervention duration may modify some outcomes.[9]
These results support a relatively narrow but clinically relevant conclusion: creatine may augment selected adaptations to exercise in older adults.
They do not demonstrate that creatine slows biological aging, prevents telomere attrition, or extends human lifespan.
This distinction is useful. A nutritional supplement can have evidence-supported applications without needing to be described as an anti-aging treatment.
6. Telomere Biology and the Interpretation of “Cellular Aging”
Telomeres are DNA-protein structures located at chromosome ends that contribute to genomic stability. Telomere attrition is associated with cellular replication, aging, and several age-related conditions.
Leukocyte telomere length, however, is not a complete measurement of biological aging.
This limitation is particularly important in supplement research. A statistically significant difference in leukocyte telomere length cannot by itself establish improved mobility, reduced disability, prevention of chronic disease, increased healthspan, or longer survival.
Recent randomized evidence illustrates this problem clearly.
7. Vitamin D, Omega-3 Fatty Acids, and Telomere Attrition
One of the most informative recent studies is the VITAL telomere ancillary randomized trial.
The parent VITAL trial enrolled 25,871 U.S. adults, with women aged ≥55 years and men aged ≥50 years, using a randomized double-blind 2×2 factorial design. The telomere ancillary study included 1,054 participants, and leukocyte telomere length was measured in 2,571 samples from 1,031 participants across baseline, year 2, and year 4.
Vitamin D3 at 2,000 IU/day significantly reduced leukocyte telomere attrition relative to placebo over four years. The between-group difference was 0.14 kilobase pairs (95% CI 0.007–0.27; P=0.039), equivalent to approximately 140 base pairs. The longitudinal trend corresponded to approximately 0.035 kilobase pairs greater leukocyte telomere length per year in the vitamin D group.
Marine omega-3 fatty acids at 1 g/day did not significantly affect leukocyte telomere length at year 2 or year 4.[10]
The vitamin D finding is noteworthy, but it is not sufficient to conclude that vitamin D slows aging.
A separate randomized dataset produced a different result.
The D-Health ancillary study randomly selected 1,519 Australians aged 60–84 years from the larger D-Health Trial. Participants had been allocated to monthly vitamin D or placebo, with 744 individuals in the vitamin D group and 775 in the placebo group for the telomere analysis. Telomere length measured four or five years after randomization did not differ meaningfully between the groups.[11]
These trials therefore do not provide a uniform conclusion regarding vitamin D and telomere maintenance.
Differences in dosing schedule, participant characteristics, baseline nutritional status, laboratory methodology, and other study characteristics could potentially contribute to the divergent findings, but these possibilities should not be presented as established explanations unless directly tested.
The appropriate conclusion is that one substantial randomized ancillary study identified reduced leukocyte telomere attrition with daily vitamin D3, while another randomized analysis did not demonstrate a significant effect.
Neither trial establishes that vitamin D supplementation extends human lifespan.
8. Telomere-Targeted and Botanical Supplements
Small trials have generated interest in supplements specifically promoted in relation to telomere biology.
De Jaeger et al. conducted a six-month randomized, double-blind, placebo-controlled study of an Astragalus-based nutritional supplement in 40 healthy adults with a mean age of 56.1 years. Twenty participants received the supplement and 20 received placebo.
The intervention group demonstrated significantly greater median telomere length and short-telomere length measurements during follow-up, together with a lower proportion of short telomeres. No adverse effects were reported during the six-month trial.[12]
The findings are hypothesis-generating rather than definitive.
The sample consisted of only 40 participants, the intervention lasted six months, and the study was not designed to determine whether the telomere findings translated into prevention of disability, chronic disease, or mortality.
Another randomized double-blind placebo-controlled study evaluated a supplement composed of five edible plant ingredients in 32 adults aged 50–65 years. After eight weeks, mean leukocyte telomere length increased from baseline in the intervention group, while no significant change was reported in the placebo group. Total antioxidant capacity also differed between groups.[13]
Again, the trial was small and short. The findings apply to the specific formulation tested and cannot be generalized to botanical supplements as a category.
Neither study provides sufficient evidence for recommending a commercial supplement as a clinically established method of slowing human aging.
9. DNA-Methylation Age and Nucleotide Supplementation
The increasing use of epigenetic measures introduces another difficulty in interpreting healthy-aging research.
The 2025 Targeting Aging and Longevity with Exogenous Nucleotides (TALENTs) trial randomized 121 adults aged 60–70 years to nucleotide supplementation at 1.2 g/day or placebo for 19 weeks.
At 19 weeks, the intervention group demonstrated a greater reduction in median DNA-methylation age than the placebo group (β −3.08 years; 95% CI −5.07 to −1.10; P=0.0023).
The telomere results were different. Between-group changes in leukocyte telomere length were not statistically significant at either 11 weeks or 19 weeks. The trial also reported improvement in HOMA-IR at 19 weeks.[14]
The study provides a useful demonstration of why biological-aging measures cannot be treated as interchangeable. One proposed biomarker changed while another did not.
It is also important to note that PubMed identifies Zhen-ao Group Co., Ltd. as a funding source for the TALENTs trial. Industry funding does not invalidate a study, but funding source is relevant when appraising emerging supplement evidence and should be reported transparently.
A reduction in a DNA-methylation-age estimate should therefore be described precisely as such. It should not automatically be translated into a statement that participants became biologically younger or gained additional years of healthy life.
Long-term validation against clinical outcomes remains necessary.
10. NAD+, Nicotinamide Riboside, and Nicotinamide Mononucleotide
NAD+ metabolism has become a prominent target in contemporary longevity research.
Nicotinamide adenine dinucleotide participates in cellular energy metabolism and multiple enzymatic reactions. Interest in supplementation has focused particularly on NAD+ precursors such as nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN).
A 2026 PRISMA-guided systematic review identified 113 eligible intervention studies, including 33 human studies—28 randomized and five nonrandomized—and 80 rodent studies.
In humans, oral NR and NMN consistently demonstrated biochemical target engagement through changes in circulating or cellular NAD-related metabolites and were generally well tolerated over the relatively short intervention periods studied. Clinical findings involving metabolic, vascular, physical-performance, and other healthspan-related outcomes were considerably more heterogeneous and were frequently null or specific to individual endpoints.
The review identified no eligible outcomes trials of intravenous or intramuscular NAD+ itself for anti-aging or wellness indications.[15]
This distinction between biochemical target engagement and clinical efficacy is fundamental.
If an intervention increases an NAD-related metabolite, it has demonstrated an effect on NAD metabolism. It has not demonstrated that the individual is aging more slowly.
Current human evidence therefore does not establish that NAD+, NR, or NMN supplementation extends lifespan or produces a clinically validated slowing of aging.
11. Resveratrol
Resveratrol has received sustained interest because of proposed effects on metabolic regulation, inflammation, cellular signaling, and exercise adaptation.
A 2024 systematic review by Yadegar et al. included ten randomized clinical studies of resveratrol supplementation in older adults.
Some trials reported favorable effects on exercise adaptation, muscle-related outcomes, mobility, or selected cognitive measures in specific populations. Other trials did not demonstrate superiority over placebo for relevant outcomes in adults with diabetes or peripheral artery disease. High-dose resveratrol was also associated with unfavorable changes in selected cardiovascular-risk biomarkers in one of the populations considered by the review.
The investigators concluded that optimal dose, long-term effects, and potential medication interactions remain insufficiently established.[16]
The evidence therefore does not support describing resveratrol as a proven anti-aging intervention.
Potential effects in selected populations or endpoints remain worthy of study, but they should not be generalized into claims of slowed aging or extended longevity.
12. Lifestyle Intervention and Telomere Length
Telomere research is not limited to supplements.
A 2022 systematic review and meta-analysis evaluated lifestyle interventions and telomere length. Twenty studies involving 2,995 participants were included in the systematic review, with 19 contributing to meta-analysis.
Physical activity with or without dietary intervention was associated with favorable telomere-length findings compared with control conditions. The authors also reported that combinations of strength and endurance exercise appeared more favorable than either mode alone in meta-regression.[17]
These findings are relevant but require the same caution applied to supplement trials.
The result supports a possible relationship between lifestyle intervention and telomere dynamics. It does not establish that telomere change mediates the known functional benefits of exercise, nor does it demonstrate extension of human lifespan.
Exercise already has clinically meaningful justification based on strength and physical-function outcomes. Telomere findings should be regarded as complementary biological evidence rather than the principal reason for recommending physical activity.
13. Cold-Water Immersion and Deliberate Cold Exposure
Cold-water immersion, ice baths, cold showers, and related practices have become increasingly promoted for recovery, metabolic health, stress resilience, and longevity.
The human evidence supports the existence of substantial physiological responses to cold. It does not establish that those responses constitute delayed aging.
Cain et al. published a 2025 systematic review and meta-analysis of randomized cold-water-immersion studies in healthy adults. Eleven studies involving 3,177 participants were included. Interventions involved cold showers, baths, or plunges at temperatures ≤15°C for at least 30 seconds.
Inflammatory measures increased acutely immediately after exposure (SMD 1.03; 95% CI 0.37–1.68) and one hour later (SMD 1.26; 95% CI 0.59–1.94).
Stress was lower 12 hours after cold-water immersion (SMD −1.00; 95% CI −1.40 to −0.61), but significant effects were not detected immediately or at several other measured time points. Immediate and one-hour immune-function outcomes were also not significantly different.
Narrative findings suggested possible effects on sleep quality, quality of life, and sickness absence, but the authors emphasized the limited number of randomized trials, small samples for several outcomes, and limited diversity of participants.[18]
A 2024 systematic review and meta-analysis by Jdidi et al. evaluated cardiovascular and cardiac autonomic responses to cold-water immersion and cryostimulation. Twenty-seven studies were included in the systematic review and 24 in meta-analysis.
Cold exposure increased several heart-rate-variability measures associated with parasympathetic activity and was accompanied by a small decrease in heart rate and a modest increase in mean blood pressure. Responses depended in part on participant characteristics and cooling methods.[19]
These physiological responses should not be confused with evidence of slowed aging.
A 2025 review by Kunutsor et al. considered cold-water therapy specifically in relation to healthy aging. The review described potential effects involving cardiometabolic factors, brown adipose tissue, energy expenditure, neuroendocrine responses, inflammation, mood, sleep, and exercise recovery. The authors also emphasized that much of the evidence originated from small intervention studies and that definitive intervention evidence remains necessary.[20]
No evidence identified in the eligible recent human literature establishes that ice baths or cold-water immersion preserve telomeres, reverse biological age, prevent age-related disability, extend healthspan, or increase human lifespan.
The most defensible conclusion is therefore that deliberate cold exposure produces measurable physiological effects and may influence selected wellbeing outcomes, while a clinically meaningful anti-aging effect remains unproven.
14. Cold Exposure Is Not Risk-Free
The popularity of cold-water immersion also requires attention to safety.
A 2024 systematic review and meta-analysis of the cold-shock response described cold-water immersion as capable of provoking hyperventilation, cardiovascular responses, and arrhythmias and of increasing drowning risk through impairment of safe behavior. Repeated exposure can produce partial habituation of the cold-shock response, but habituation should not be interpreted as elimination of risk.[21]
This consideration is particularly important when cold exposure is promoted for longevity despite the absence of evidence that it prolongs life.
Older adults and individuals with cardiovascular disease, impaired thermoregulation, limited mobility, or other relevant medical conditions should not assume that protocols studied in young or healthy participants are necessarily appropriate for them.
The present review does not establish a therapeutic cold-water protocol.
15. Biomarkers Are Not Healthspan
The central interpretive problem in much of the anti-aging literature is not an absence of measurable biological effects. It is the tendency to convert those effects into conclusions that extend beyond the outcome actually studied.
The following statements represent different levels of evidence:
“An intervention increased leukocyte telomere length.”
“An intervention reduced a DNA-methylation-age estimate.”
“An intervention increased an NAD-related metabolite.”
“An intervention improved muscle strength.”
“An intervention slowed human aging.”
“An intervention extended human lifespan.”
These statements are not equivalent.
The first three describe biological or molecular measurements. The fourth describes a functional outcome. The final two require substantially stronger and longer-term evidence.
A credible healthspan intervention should ultimately demonstrate benefits that matter to people: preserved mobility, physical independence, cognitive and physical function, reduced disability, delayed clinically important disease, improved quality of life, or potentially reduced mortality.
This distinction explains why resistance exercise occupies a stronger position in this review than many technologically appealing anti-aging interventions.
Resistance training has evidence for outcomes directly related to physical capability. It does not need to be described as a molecular age-reversal therapy to be important.
16. Relative Strength of the Current Evidence
The interventions considered in this review can be placed into broad evidentiary categories.
Resistance exercise
The evidence is comparatively strong for improvements in muscle strength and selected measures of physical function in older adults, including people with sarcopenia.
Protein plus resistance exercise
Evidence supports additional effects on selected muscle-mass and strength outcomes, particularly in older adults with sarcopenia or frailty. However, effect sizes vary, some findings may not reach clinically important thresholds, and recent systematic reviews have rated the certainty of evidence from low to very low.
Creatine plus exercise
Evidence supports modest additional improvements in selected strength and lean-tissue outcomes. Creatine is better characterized as a possible adjunct to exercise than as a longevity intervention.
Vitamin D and telomere maintenance
Randomized evidence is inconsistent. The VITAL ancillary trial identified reduced leukocyte telomere attrition with daily vitamin D3, whereas the D-Health analysis did not demonstrate a significant telomere effect. These results do not establish vitamin D as an anti-aging treatment.
Marine omega-3 fatty acids
Marine omega-3 supplementation did not significantly influence leukocyte telomere attrition in the VITAL telomere analysis. This conclusion is specific to telomere outcomes and should not be generalized to other established or proposed effects of omega-3 fatty acids.
NAD+ precursors
Biochemical target engagement is considerably better established than clinically meaningful slowing of aging.
Resveratrol
Human findings are heterogeneous, population-specific, and insufficient for a general anti-aging conclusion.
Telomere-targeted and botanical supplements
Small randomized trials have generated potentially interesting findings, but sample sizes and intervention durations are insufficient to establish healthspan or longevity effects.
Nucleotide supplementation
One randomized trial demonstrated a change in DNA-methylation age but not leukocyte telomere length. The long-term clinical significance is unknown.
Cold-water immersion
Short-term physiological effects are documented. Evidence for delayed biological aging, telomere preservation, prolonged healthspan, or longevity is absent.
17. Clinical Interpretation
A practical consequence of this evidence hierarchy is the need for precise communication.
Saying:
“Vitamin D reduced leukocyte telomere attrition in one randomized ancillary trial”
is scientifically different from saying:
“Vitamin D slows aging.”
Similarly:
“Creatine provided additional improvement in selected strength outcomes when combined with exercise”
is different from:
“Creatine is an anti-aging supplement.”
And:
“Cold-water immersion produces acute autonomic and inflammatory responses”
is different from:
“Ice baths increase longevity.”
The first statement in each comparison describes the evidence. The second adds a conclusion that has not been established.
This distinction is especially important in public communication because mechanistic terminology can make an intervention appear more clinically established than it is.
18. Safety and Individualization
Evidence supporting an intervention does not establish universal suitability.
Resistance exercise should be adapted to baseline functional capacity, training experience, musculoskeletal limitations, cardiovascular status, and other relevant clinical factors.
Protein intake should be considered in the context of habitual diet, total energy intake, nutritional status, exercise, and medical conditions. Population-level evidence supporting protein supplementation in sarcopenia should not be interpreted as a universal high-protein prescription.
This is particularly relevant for individuals with chronic kidney disease or other conditions requiring individualized medical nutrition therapy.
Creatine and other supplements should likewise be evaluated according to the specific clinical objective, dose, medical history, medication use, and relevant contraindications or precautions.
Vitamin D supplementation should not be prescribed solely for a claimed anti-aging effect on the basis of the telomere evidence reviewed here.
Cold-water immersion deserves particular caution because acute cold exposure can provoke substantial respiratory and cardiovascular responses. The absence of demonstrated longevity benefit makes indiscriminate exposure difficult to justify in individuals at elevated medical or environmental risk.
19. Limitations
This review has several limitations.
First, it is a narrative rather than a systematic review. Although the search was restricted to PubMed/MEDLINE and used predefined concepts and a strict publication window, the review was designed to integrate heterogeneous areas of evidence rather than provide exhaustive quantitative identification of every eligible publication.
Second, the populations represented in the literature vary considerably. Healthy community-dwelling adults, individuals with sarcopenia, people with physical frailty, and participants with chronic diseases should not be considered interchangeable.
Third, many interventions are short relative to the biological process under investigation. Aging develops over decades, whereas numerous supplement trials last only weeks or months.
Fourth, the literature uses heterogeneous outcomes. Lean tissue, muscle mass, grip strength, gait speed, six-minute walk distance, telomere length, DNA-methylation age, inflammatory markers, and NAD-related metabolites answer different questions.
Fifth, publication of a systematic review within the 2021–2026 eligibility window does not mean that all primary trials synthesized by that review were conducted during the same period. Recent secondary evidence frequently incorporates older primary research. This review treats those publications as contemporary evidence syntheses rather than implying that their underlying trials were newly conducted.
Sixth, supplement formulations differ. Findings from a specific formulation cannot automatically be extrapolated to another product containing a similarly named ingredient.
Seventh, several areas—particularly telomere-targeted supplementation, epigenetic-age modification, and deliberate cold exposure—remain supported by relatively small or short studies.
Finally, surrogate biomarkers remain a major limitation. Even a randomized trial cannot establish extended healthspan when its principal outcome is a short-term change in a biomarker whose relationship to future clinical outcomes remains uncertain.
20. Research Priorities
Future healthy-aging research should increasingly connect molecular endpoints with outcomes that matter clinically.
Trials of supplements proposed to modify aging should include validated measures of physical function, mobility, disability, cognition where relevant, quality of life, incident disease, and sufficiently long follow-up.
Studies of telomere length and epigenetic clocks should determine whether intervention-induced biomarker changes predict subsequent clinical benefit.
NAD+-precursor studies require longer and adequately powered randomized trials that move beyond demonstration of biochemical target engagement.
Small trials of botanical or telomere-targeted supplements require independent replication before their findings are used to support clinical recommendations.
Exercise and nutrition studies should continue to examine whether supplements provide meaningful incremental benefit beyond well-designed resistance-training and dietary programs.
Cold-exposure research requires standardized reporting of water temperature, duration, depth of immersion, frequency, acclimatization, participant age, medical status, and adverse events. Long-term studies in older populations are particularly necessary before cold exposure can reasonably be considered a healthy-aging intervention.
Funding source and investigator conflicts should also be reported and considered when interpreting emerging commercial supplement research.
21. Conclusion
Recent human evidence presents a clear contrast between interventions that preserve function and interventions proposed to alter biological aging.
Resistance exercise has the most consistent evidence among the interventions considered here for improving strength and selected measures of physical function in older adults.
Adequate nutrition is integral to maintenance of muscle. Protein supplementation may provide additional benefit in selected older adults, particularly when combined with resistance exercise, although certainty of evidence is not uniformly high. Creatine may modestly augment selected strength and lean-tissue adaptations to exercise.
Evidence becomes substantially less certain when the objective changes from preserving function to slowing biological aging.
Vitamin D has produced conflicting randomized findings for leukocyte telomere maintenance. Marine omega-3 supplementation did not significantly reduce telomere attrition in the VITAL ancillary analysis. Small trials of botanical and telomere-targeted supplements have generated signals that require replication. Nucleotide supplementation has altered a DNA-methylation-age measure without significantly altering leukocyte telomere length. NAD+ precursors demonstrate biochemical activity, but clinically meaningful anti-aging effects remain unestablished. Resveratrol evidence is heterogeneous.
Cold-water immersion produces measurable physiological responses but has not been demonstrated to preserve telomeres, slow biological aging, extend healthspan, or increase human lifespan.
The current evidence therefore does not identify a supplement, biomarker-targeted intervention, or cold-exposure practice that can legitimately be described as a proven method of slowing human aging.
The strongest evidence presently supports a less dramatic but clinically more meaningful objective: preserving strength, muscle-related function, mobility, and physical capability as people age.
Maintaining the distinction between changing a biomarker, improving function, and slowing aging is essential for scientific interpretation, clinical practice, and responsible public communication.
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Declarations
Funding
This work received no external funding. The author received no financial or commercial support for the preparation of this review.
Conflicts of Interest
The author declares no financial or non-financial conflicts of interest relevant to this manuscript.
Author Contributions
Ori Scott conceived the review topic and scope, defined the research questions and eligibility criteria, evaluated and interpreted the literature, critically revised the manuscript, and approved the final version. The author accepts responsibility for the accuracy, integrity, interpretation, and conclusions of the work.
Ethics Approval
Not applicable. This narrative review evaluates previously published literature and involved no recruitment of human participants, collection of identifiable personal information, or original intervention involving human or animal subjects.
Consent to Participate
Not applicable.
Consent for Publication
Not applicable.
Data Availability
No original participant-level dataset was collected or generated for this narrative review. The evidence discussed in the manuscript is derived from peer-reviewed publications indexed in PubMed/MEDLINE and identified in the reference list.
Acknowledgments
None.
Declaration of AI-Assisted Technologies
An AI-assisted language tool was used during manuscript preparation to assist with organization, drafting, and language refinement. The author retains responsibility for literature selection, evaluation of the evidence, interpretation of findings, verification of scientific claims and references, critical revision, and approval of the final manuscript. The AI tool was not used as a scientific source and is not an author.
The author accepts responsibility for the content of the final manuscript.
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