The Role of Ketogenic Diet and β-Hydroxybutyrate in the Prevention of Muscle Catabolism and Sarcopenia in Aging Populations: Mechanisms, Evidence, and Clinical Perspectives.

Abstract

Sarcopenia, characterized by the progressive loss of skeletal muscle mass, strength, and function, represents a growing public health challenge in aging populations. Emerging mechanistic evidence suggests that ketogenic diets (KDs) and elevated circulating β-hydroxybutyrate (βOHB) levels may offer selective and context-dependent nutritional strategies to support muscle health during aging. This review summarizes current evidence on the effects of ketogenic diets and ketone body metabolism on muscle mass and function, with a focus on underlying molecular mechanisms and clinical relevance in older adults. βOHB acts not only as an alternative energy substrate but also as a signaling molecule, notably through histone deacetylase inhibition and modulation of inflammatory pathways. Nutritional ketosis in humans typically results in circulating βOHB concentrations of approximately 0.5-3.0 mM, which may be sufficient to engage some of these signaling pathways, although the extent of these effects in human tissues remains incompletely defined. Preclinical studies indicate that long-term ketogenic diets preserve muscle mass, strength, and mitochondrial function in aging models. Limited clinical evidence, largely derived from populations with sarcopenic obesity or metabolic comorbidities, suggests that protein-adequate ketogenic diets, when implemented as an adjunct to physical exercise, may help preserve fat-free mass and improve functional outcomes, while exogenous ketones show potential to augment post-exercise anabolic signaling. Overall, the integration of mechanistic and preliminary clinical data provides a supplementary and exploratory framework suggesting that ketogenic diets may represent a promising adjunctive strategy for sarcopenia prevention, although well-designed long-term randomized controlled trials are required to define their efficacy, safety, and optimal clinical application.