Amino Acid Regulation of Cellular Aging Pathways and Therapeutic Perspectives for Healthspan and Lifespan Enhancement

Abstract

While amino acids have traditionally been viewed primarily as the building blocks of proteins, accumulating evidence indicates that they play critical roles in metabolic regulation and cellular homeostasis. These functions span several key biological pathways implicated in aging, including mechanistic target of rapamycin (mTOR) signaling, proteostasis, cellular senescence, mitochondrial function, and epigenetic regulation. This review used a structured analytical approach to critically evaluate scientific literature on the role of amino acids in cellular aging, with a focus on healthspan and lifespan regulation. Peer-reviewed studies published between 2000 and 2024 were systematically selected from major databases based on relevance and methodological quality. Evidence from both animal models and human studies was synthesized to identify shared mechanisms and potential therapeutic implications. Although this review highlights leucine, methionine, and glycine as illustrative examples of amino acids that influence aging pathways, the broader analysis encompasses multiple amino acids and dietary protein patterns to provide a more comprehensive perspective on their collective and context-dependent roles in human aging. We propose that targeted manipulation of amino acid availability represents a more specific and mechanistically precise intervention than general caloric restriction, and that imbalances in amino acid signaling, rather than absolute intake levels alone, may be key drivers of aging-related dysfunction. Leucine, a branched-chain amino acid, is well known for its anabolic effects mediated through mTOR activation; however, chronic mTOR stimulation has been linked to impaired autophagy and increased oxidative stress, potentially accelerating age-associated pathologies. Methionine, an essential amino acid central to one-carbon metabolism and DNA methylation, exerts dual effects by supporting epigenetic stability while promoting metabolic stress when present in excess. Notably, dietary methionine restriction has been shown to extend lifespan in multiple model organisms, likely through enhanced stress resistance and metabolic reprogramming. In contrast, glycine has emerged as a cytoprotective amino acid that supports redox homeostasis and collagen synthesis, with growing evidence suggesting that glycine supplementation may improve healthspan by enhancing cellular resilience. By integrating the unique physiological contributions of these amino acids within aging-associated molecular pathways, this review highlights the importance of amino acid balance and context-dependent signaling in the regulation of aging. These insights underscore the potential of precision nutritional strategies aimed at modulating amino acid metabolism to promote healthier aging and improve quality of life across the lifespan.