The metabolic-epigenetic landscape of aging: interplay between histone acetylation, lactylation, and glycation
Abstract
Background: The aging epigenome is shaped by three mechanistically distinct histone post-translational modifications-acetylation, lactylation, and glycation-each driven by a different metabolic flux: mitochondrial oxidative phosphorylation, glycolytic lactate production, and reactive carbonyl stress, respectively. Understanding their interplay is central to a molecular physiology of epigenetic aging.
Scope: This mini review synthesizes current evidence on the mechanisms of histone acetylation, lactylation, and glycation in aging; their crosstalk and convergence on shared regulatory nodes; and their modulation by environmental, nutritional, and behavioral factors. Key controversies and research gaps are critically appraised.
Key findings: NAD + decline in aging disables the sirtuin deacetylase family, dysregulating the histone acetylation landscape and impairing autophagy, mitochondrial biogenesis, and DNA repair. Histone lactylation, written by p300 at H3K18 and related lysine residues, is context-dependent: physiological pulses during exercise and sleep are adaptive, while chronic accumulation in diabetic microglia drives neuroinflammation via TLR4/NF-κB, and excess in tumor cells enables senescence bypass. Histone glycation by methylglyoxal irreversibly displaces regulatory marks and inactivates sirtuin proteins; pharmacological induction of glyoxalase I and glycation-lowering interventions reduce this burden and extend healthspan. These three axes may converge on a…
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