The hallmarks of protein and amino acid restriction in aging and longevity.

Despite widespread recommendations for higher protein intake during aging, increasing evidence suggests that dietary protein restriction (PR) promotes metabolic health, healthspan, and lifespan across diverse organisms. Mechanistic studies further demonstrate that restriction of specific amino acids, particularly methionine, isoleucine, and valine, recapitulates many of the benefits of PR, highlighting the specific amino acid composition of the diet as a key determinant of aging. Here, we define the hallmarks of PR through the lens of aging, examining how PR and restriction of specific essential amino acids impact metabolic health, nutrient sensing, senescence, mitochondrial function, and the epigenome. We also discuss the known and unknown roles of non-essential amino acids in healthy aging. Overall, this review provides a comprehensive overview of current knowledge regarding the benefits of PR and amino acid restriction for healthy aging and highlights the therapeutic potential of interventions based on these diets to promote healthspan and longevity.