Targeting of Protein Persulfidation in Aging and Age-Related Disorders

Aging is associated with a progressive loss of proteostasis and increased susceptibility to neurodegenerative and metabolic disorders. Among the molecular mechanisms implicated in these processes, protein persulfidation, a hydrogen sulfide (H₂S)-mediated cysteine modification, has emerged as a critical regulator of protein function and redox homeostasis. Recent studies demonstrate that aging is accompanied by a decline in persulfidation and a concomitant increase in irreversible cysteine hyperoxidation, leading to protein dysfunction and aggregation. Beyond its established role in protecting proteins from oxidative damage, persulfidation has recently been shown to regulate biomolecular condensation and liquid-liquid phase separation, suppressing the formation of pathological protein assemblies linked to aging and neurodegenerative diseases. Moreover, pharmacological approaches that enhance persulfidation, including stimulation of endogenous H₂S production and treatment with ergothioneine, improve metabolic resilience, increase NAD⁺ levels, and promote healthspan in experimental models. In this review, we discuss emerging evidence linking loss of persulfidation to protein aggregation, biomolecular condensates, and age-related functional decline, and highlight therapeutic strategies aimed at restoring persulfidation as a promising avenue for healthy aging and disease intervention.