Histone lactylation and glycation drive aging; NAD+ restoration and carbonyl stress reduction show promise

Photo by Odile / Unsplash

Frontiers in Medicine Published June 3, 2026 Medically reviewed June 3, 2026 DOI ↗ By Dr. Sofia Müller, MD · Lifespan & Whole-Person Care

Key Takeaway

Consider combinatorial NAD+ restoration, lactylation modulation, and carbonyl stress reduction as emerging strategies for slowing metabolic-epigenetic aging.

This mini review examines the roles of histone acetylation, lactylation, and glycation in the aging process, focusing on their crosstalk and convergence on shared regulatory nodes. The authors synthesize evidence that these epigenetic modifications are modulated by environmental, nutritional, and behavioral factors, and that their dysregulation contributes to aging. Key findings include the potential of combinatorial interventions targeting NAD+ restoration, modulation of lactylation, and reduction of carbonyl stress as the most evidence-based approach to slowing metabolic-epigenetic aging. However, the review acknowledges several limitations: lactylation erasers remain uncharacterized, the pro-versus anti-senescence duality of H3K18la is unresolved, and genome-wide histone glycation mapping in human tissues is absent. These gaps highlight the need for further research before clinical application. The review is narrative in nature and does not provide pooled effect sizes or quantitative synthesis. Clinicians should interpret these findings as hypothesis-generating rather than practice-changing.

Study Details

Study typeSystematic review

EvidenceLevel 1

PublishedJun 2026

View Original Abstract ↓

BackgroundThe 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.ScopeThis 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 FindingsNAD + 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 unified metabolic-epigenetic collapse that we propose constitutes the cellular basis of an ‘aging’ metabolic memory.Controversies and GapsLactylation erasers remain uncharacterized; the pro-versus anti-senescence duality of H3K18la is unresolved; and genome-wide histone glycation mapping in human tissues is absent.ConclusionCombinatorial interventions targeting NAD + restoration, modulation of lactylation, and reduction of carbonyl stress offer the most evidence-based approach to slowing metabolic-epigenetic aging.