Epigenetic mechanisms underlying lifespan and age-related effects of dietary restriction and the ketogenic diet

Aging constitutes the central risk factor for major diseases including many forms of cancer, neurodegeneration, and cardiovascular diseases. The aging process is characterized by both global and tissue-specific changes in gene expression across taxonomically diverse species. While aging has historically been thought to entail cell-autonomous, even stochastic changes, recent evidence suggests that modulation of this process can be hierarchal, wherein manipulations of nutrient-sensing neurons (e.g., in the hypothalamus) produce peripheral effects that may modulate the aging process itself. The most robust intervention extending lifespan, plausibly impinging on the aging process, involves different modalities of dietary restriction (DR). Lifespan extension by DR is associated with broad protection against diseases (natural and engineered). Here we review potential epigenetic processes that may link lifespan to age-related diseases, particularly in the context of DR and (other) ketogenic diets, focusing on brain and hypothalamic mechanisms.