What interventions are effective for promoting anti-aging or longevity?

Evidence-Based Anti-Aging and Longevity Interventions

The most effective interventions for promoting longevity and reducing age-related disease are calorie restriction, regular exercise (particularly aerobic and high-intensity interval training), and dietary modifications that minimize mTOR/insulin/IGF-1 pathway activation, with emerging pharmaceutical options including mTOR inhibitors like rapamycin and senolytic drugs. 1

Primary Lifestyle Interventions

Dietary Approaches

Calorie restriction remains the most well-established longevity intervention, demonstrating reduced frailty in naturally aging mice, genetically manipulated mice, and nonhuman primates 1. In humans, long-term calorie restriction improves cardiometabolic parameters, reduces atherosclerosis, and improves diastolic dysfunction 2.

• Intermittent fasting (fasting every other day or several days per week with up to 75% calorie reduction) offers a more achievable alternative, improving LDL cholesterol and insulin sensitivity, though effects appear more pronounced in males 2, 1
• Protein restriction, particularly limiting methionine, reduces mTOR activation and extends lifespan in rodent models 1
• Mediterranean diet substantially reduces cardiovascular disease risk more than standard low-fat diets by providing low-glycemic index foods with mithormetic, anti-amyloidogenic, and anti-inflammatory compounds from vegetables, fruits, red wine, olive oil, and nuts 2
• Vegetarian diets are associated with reduced all-cause mortality, providing more plant-based proteins and lower methionine content 2

Exercise Interventions

Regular exercise, particularly aerobic exercise and high-intensity interval training, consistently reduces frailty in animal models 1. Voluntary wheel running improves physical performance and reverses frailty phenotypes in aging mice 1.

Pharmaceutical Interventions

mTOR Inhibitors

Rapamycin extends healthspan and reduces frailty indices in multiple animal models by targeting a key nutrient-sensing pathway involved in aging 1. This represents one of the most promising pharmacological approaches currently under investigation.

Senolytic Drugs

Senolytics that target senescent cells are emerging as promising interventions, with human clinical trials currently underway 1. These drugs address cellular senescence, one of the fundamental hallmarks of aging 2.

Supplements and Nutraceuticals

While less robust than dietary and pharmaceutical interventions, certain supplements show promise:

• Resveratrol reduces frailty in naturally aging mice 1
• Alpha-ketoglutarate attenuates frailty in aging mice 1
• Allicin (from garlic) inhibits inflammation and reduces frailty markers 1

Important caveat: Antioxidant dietary supplements do not increase lifespan based on biogerontological knowledge, despite popular belief 2.

Optimal Dietary Principles

Future optimized diets should 2:

• Avoid overstimulation of mTOR, insulin, and IGF-1 receptors
• Deliver mithormetic substances that stimulate cellular stress resistance pathways
• Provide substances that beneficially influence protein/amyloid aggregation, autophagy, lipid peroxidation, and mitochondrial dysfunction

Combination Approaches

Drug treatment plus exercise regimens may better attenuate or even reverse frailty accumulation than single interventions 1. This is critical because addressing only one disease of aging would add merely 2.87 years to average lifespan, as patients remain afflicted by other aging-related diseases 2, 1.

Critical Pitfalls and Caveats

Sex-Specific Effects

Many longevity interventions show sex-specific effects, with some treatments being more effective in males versus females 1. This must be considered when implementing interventions.

Timing Considerations

Timing of interventions is critical, with some showing greater benefits when started earlier in life while others can be effective even when initiated later 1.

Avoid High Animal Protein Diets

Diets high in animal protein (like Atkins or some paleo interpretations) are probably not healthy long-term based on biogerontological predictions 2.

Polypharmacy Risks

De-prescribing unnecessary medications can be a viable strategy to combat frailty, as polypharmacy increases frailty scores 1.

Monitoring Intervention Effectiveness

• Frailty indices provide translational measures of health in aging and can monitor intervention effectiveness 1
• Biological age markers including DNA methylation clocks and telomere length assess the impact of interventions on aging processes 1
• Epigenetic clocks (PhenoAge and GrimAge indices) are strongly predictive of mortality, disability, and dementia 3

Mechanistic Targets

Effective interventions target the fundamental hallmarks of aging 2, 3:

• Genomic instability and DNA damage
• Telomere shortening
• Cellular senescence and SASP (senescence-associated secretory phenotype)
• Epigenetic alterations
• Mitochondrial dysfunction
• Loss of proteostasis
• Deregulated nutrient sensing

The geroscience hypothesis posits that failure in this network of homeostatic mechanisms affects the pace of aging and causes growing susceptibility to diseases 2. Therefore, interventions must address aging itself rather than only specific aging-related diseases 2.