Dietary and Pharmacological Modulation of Aging-Related Metabolic Pathways: Molecular Insights, Clinical Evidence, and a Translational Model.

Advances in geroscience suggest that aging is modulated by molecular pathways that are amenable to dietary and pharmacological intervention. We conducted an integrative critical review of caloric restriction (CR), intermittent fasting (IF), and caloric restriction mimetics (CR-mimetics) to compare shared mechanisms, clinical evidence, limitations, and translational potential. Across modalities, CR and IF consistently activate AMP-activated protein kinase and sirtuins, inhibit mTOR (mechanistic target of rapamycin) signaling, and enhance autophagy, aligning with improvements in insulin sensitivity, lipid profile, low-grade inflammation, and selected epigenetic aging measures in humans. CR-mimetics, such as metformin, resveratrol, rapamycin, and spermidine, partially reproduce these effects; however, long-term safety and efficacy in healthy populations remain incompletely defined. Methodological constraints-short trial duration, selective samples, intermediate (nonclinical) endpoints, and limited adherence monitoring-impede definitive conclusions on hard outcomes (frailty, disability, hospitalization, mortality). We propose the Active Management of Aging and Longevity (AMAL) model, a three-level biomarker-guided framework that integrates personalized diet, chrono-nutrition, exercise, and the selective use of CR-mimetics, along with digital monitoring and decision support. AMAL emphasizes epigenetic clocks, multi-omics profiling, inflammatory and microbiome metrics, and adaptive protocols to enhance adherence and clinical relevance. Overall, CR, IF, and CR mimetics constitute promising, complementary strategies to modulate biological aging; rigorous long-term trials with standardized biomarkers and clinically meaningful endpoints are needed to enable their scalable implementation.