CIHW

Across all ten papers, the interventions with the best current evidence are lifestyle and prevention related — closer to "eat better and move more" than to a pharmaceutical silver bullet. Below is a list of interventions across the prevention-to-treatment-and-care continuum: some with strong evidence (mostly prevention and lifestyle related), others still evolving (mostly related to treatment).

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Population/behavioral level:

 

Closing much of the life-expectancy gap may be achievable through behavioral and policy change — reducing smoking, improving diet, and addressing socioeconomic disparities — without needing any scientific breakthrough in the biology of aging. Some of the strongest human evidence for this at scale comes from large cohort studies (EPIC-Elderly, >75,000 people across 10 countries), which show that adherence to a Mediterranean-style diet predicts lower mortality regardless of country — suggesting diet itself, not geography or genetics, is the key variable. Randomized trials reinforce this: the Lyon Diet Heart Study and PREDIMED both showed Mediterranean-pattern diets reduced cardiovascular events in at-risk people, and the FINGER trial showed a combined diet + exercise + cognitive training + vascular monitoring intervention reduced cognitive decline in older adults.

 

Mechanistic/Nutrition/ Lifestyle:

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-> Caloric restriction (CR) — roughly 25–30% fewer calories without malnutrition — remains the most robust lifespan-extending intervention across model organisms, including primates, working through the AMPK-SIRT1-FOXO-PGC1α network. A 2017 rhesus monkey study and a 2-year human CR trial showed measurable anti-inflammatory and immune benefits, even though full compliance proved difficult. CR carries real risks (bone density loss, sarcopenia) that argue for caution in older adults specifically.

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-> Protein quality and timing matter more than raw calories in some analyses: lower protein/methionine intake mimics several effects of CR in younger and middle-aged adults. After 65 years of age, higher protein intake is needed to protect against sarcopenia and frailty, since IGF-1 (a growth-promoting hormone that's harmful in excess earlier in life) becomes protective for muscle and bone in old age.

 

-> Antioxidant supplementation is inconsistent. The idea of "mitohormesis" — that mild oxidative stress from exercise or fasting is itself a beneficial signal — suggests that blunting it with high-dose antioxidants can reduce the adaptive benefit entirely. Large clinical trials on antioxidant vitamins show mixed-to-null results, and some show harm at high doses.

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-> Caloric restriction mimetics (CRMs) — compounds that reproduce CR's molecular signature without eating less — are an active area of drug and nutraceutical development: rapamycin (direct mTOR inhibitor), metformin (AMPK activator, already used as an antidiabetic and under study as a "geroprotector"), NAD+ precursors (nicotinamide riboside/mononucleotide), resveratrol and other sirtuin activators, and spermidine (shown safe and modestly cognition-supportive in early human trials).

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-> Exercise is repeatedly singled out as the single most reliable non-pharmacological driver of the same mitochondrial-biogenesis and AMPK-SIRT1 pathways that calorie restriction targets — with high-intensity interval training showing particularly strong effects on mitochondrial network health in human trials. A 2026 review maps exercise onto an extended 14-hallmark framework (adding extracellular matrix remodeling and psychosocial isolation to the original 12) and finds that regular physical activity favorably influences all fourteen, with the clearest human evidence for telomere maintenance, reduced cellular senescence markers, and lower chronic inflammation (CRP, IL-6, TNF-α); effects on gut microbiome diversity are also reported, though with a thinner evidence base than the other outcomes. One cited cohort study found that as little as 90 minutes of activity per week (about 15 minutes/day) was associated with a 14% drop in all-cause mortality and roughly 3 additional years of life expectancy, while meeting standard guidelines (150 min/week moderate or 75 min/week vigorous activity) was linked to a 31% mortality reduction versus no leisure-time activity at all. The effects are dose- and modality-specific: in one trial, aerobic exercise and high-intensity interval training both increased telomerase activity and telomere length, while resistance training alone did not; and the review notes a U-shaped relationship between exercise volume and benefit, with extreme endurance training potentially straining cardiac tissue.

 

-> Sleep is emerging as an important lifestyle pillar alongside diet and exercise: a 2026 UK Biobank study using objective accelerometer data tested six sleep patterns against the original nine hallmarks of aging, and found that longer, deeper, more REM-rich sleep was linked to lower risk across most of them (including telomere attrition, cellular senescence, and epigenetic drift), while fragmented and irregular sleep moved the opposite way.

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A wider drug pipeline:

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The Hallmarks review catalogs a much larger set of interventions already tested in humans, organized by which hallmark they target — several with completed or ongoing clinical trials:

• Senolytics (drugs that selectively kill senescent cells) — dasatinib+quercetin and fisetin have shown improved physical performance and reduced inflammatory markers in early-phase human trials for conditions like pulmonary fibrosis and diabetic kidney disease.

• Anti-inflammatory therapy — the phase 3 CANTOS trial found that canakinumab (an anti-IL-1β antibody) reduced not just recurrent cardiovascular events but also diabetes incidence and lung cancer mortality in a high-risk population, offering human proof that targeting a single hallmark (chronic inflammation) can shift multiple, seemingly unrelated disease outcomes at once.

• NAD+ precursors — human trials report improved insulin sensitivity in prediabetic women and reduced inflammation in Parkinson's disease patients.

• Urolithin A — improved muscle strength and reduced inflammatory markers (CRP) in a phase 3 trial of middle-aged adults.

• Gut microbiome interventions — oral Akkermansia muciniphila supplementation improved metabolic markers in a randomized human pilot study, mirroring the fecal-transplant experiments that reverse aging-related decline in mice.

 

Key implication: the most defensible, well-evidenced interventions for the general population today are still dietary pattern (Mediterranean-style), exercise, sleep, and avoiding excess calories/obesity, not any single supplement or drug. But this is an evolving scenario: several hallmark-targeted drugs (senolytics, anti-inflammatories, NAD+ precursors) have cleared early human trials, even though none is yet an approved "anti-aging" treatment in its own right. Current trials must still be framed around preventing specific diseases, since aging itself is not yet a recognized regulatory target for drug approval.