The glycolytic metabolite phosphoenolpyruvate restricts cGAS-driven inflammation to promote healthy aging.

Aging involves multiple detrimental changes in the systemic milieu, leading to functional deterioration and age-related diseases. However, the potential self-protective adaptive alterations during aging remain underexplored. Here we show that phosphoenolpyruvate (PEP), a glycolytic metabolite, acts as a protective factor against age-related chronic inflammation. Longitudinal analyses in mice and humans reveal a biphasic PEP trajectory, characterized by initial accumulation followed by progressive decline. Blocking PEP accumulation exacerbates inflammation and accelerates aging phenotypes, whereas PEP administration before its decline promotes healthy aging in mice. In aged humans, high PEP levels strongly correlate with lower inflammation and healthier traits. Mechanistically, PEP acts as an endogenous inhibitor of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway by competitively binding to cGAS. Moreover, PEP alleviates neuroinflammation and improves cognitive function in an Alzheimer's disease mouse model. Thus, our findings define PEP accumulation as an evolutionarily conserved geroprotective mechanism, positioning PEP as a promising intervention for aging and associated diseases.