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

  • Nat Aging. 2026 Apr;6(4):831-848. doi: 10.1038/s43587-026-01087-1.
Zengqing Song  #  1 ,  Huaibin Hu  #  2 ,  Wanpeng Zhang  #  2 ,  Xincheng Zheng  #  2 ,  Liyun Liang  2  3 ,  Bing Zhao  2 ,  Guangping Song  2  3 ,  Jianing Li  2 ,  Sen Li  2 ,  Yuqi Wen  2 ,  Biyu Zhang  2 ,  Wen Wang  2 ,  Guozhen Deng  4 ,  Cunjin Zhang  4 ,  Hua Jiang  5 ,  Supei Hu  6 ,  Haiqing Tu  2 ,  Min Wu  2 ,  Huiyan Li  7
Affiliations
  • 1. Nanhu Laboratory, State Key Laboratory of Biomedical Analysis (SKLBA, formerly known as National Center of Biomedical Analysis (NCBA), Beijing, China. [email protected].
  • 2. Nanhu Laboratory, State Key Laboratory of Biomedical Analysis (SKLBA, formerly known as National Center of Biomedical Analysis (NCBA), Beijing, China.
  • 3. School of Basic Medical Sciences, Tsinghua University, Beijing, China.
  • 4. Department of Neurology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.
  • 5. Department of General Practice, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
  • 6. Ningbo No. 2 Hospital, Ningbo, China.
  • 7. Nanhu Laboratory, State Key Laboratory of Biomedical Analysis (SKLBA, formerly known as National Center of Biomedical Analysis (NCBA), Beijing, China. [email protected].
  • # Contributed equally.
PMID: 41792330 DOI: 10.1038/s43587-026-01087-1
Abstract

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.

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