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

Nature Aging (2026)Cite this article

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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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Fig. 1: Elevated PEP in the aging systemic milieu inhibits the activation of the cGAS−STING pathway.
Fig. 2: PEP disrupts the DNA binding and activation of cGAS independently of its role in glycolysis.
Fig. 3: The age-induced accumulation of PEP is an adaptive response to inhibit cGAS-driven inflammation and promotes healthy aging.
Fig. 4: Administration of systemic PEP mitigates inflammation and promotes healthspan and lifespan in naturally aged mice.
Fig. 5: PEP supplement mitigates brain aging in naturally aged mice.
Fig. 6: PEP supplement ameliorates the pathology of Alzheimer’s disease in 5×FAD mice.
Fig. 7: The PEP levels in human blood affect the activation of the cGAS−STING pathway and correlate with healthy indicators during the aging process.

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Data availability

All RNA sequencing files were deposited in the short-read sequence archive under BioProject ID PRJNA1405939. Source data and supplementary information are available for this paper. Correspondence and requests for materials should be addressed to H.Y.L. and Z.Q.S.

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Acknowledgements

This work was partially funded by the National Key Research and Development Program of China (2022YFC2505001 (H.Y.L)) and the National Natural Science Foundation of China (32341003 (H.Y.L), 82301990 (H.B.H) and U24A20692 (C.J.Z.)).

Author information

Author notes

  1. These authors contributed equally: Zengqing Song, Huaibin Hu, Wanpeng Zhang, Xincheng Zheng.

Authors and Affiliations

  1. Nanhu Laboratory, State Key Laboratory of Biomedical Analysis (SKLBA, formerly known as National Center of Biomedical Analysis (NCBA), Beijing, China

    Zengqing Song, Huaibin Hu, Wanpeng Zhang, Xincheng Zheng, Liyun Liang, Bing Zhao, Guangping Song, Jianing Li, Sen Li, Yuqi Wen, Biyu Zhang, Wen Wang, Haiqing Tu, Min Wu & Huiyan Li

  2. School of Basic Medical Sciences, Tsinghua University, Beijing, China

    Liyun Liang & Guangping Song

  3. Department of Neurology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China

    Guozhen Deng & Cunjin Zhang

  4. Department of General Practice, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China

    Hua Jiang

  5. Ningbo No. 2 Hospital, Ningbo, China

    Supei Hu

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Contributions

All authors contributed to the paper. H.Y.L. conceived the initial hypothesis and experimental design and supervised the project. Z.Q.S., H.B.H., W.P.Z. and X.C.Z. built the experimental system and performed most of the experiments. B.Y.Z. and W.W. performed the animal genotyping experiments. G.P.S. and J.N.L. performed histopathological evaluations. G.Z.D., C.J.Z., H.J. and S.P.H. collected samples and provided suggestions. L.Y.L., B.Z., S.L. and Y.Q.W. analyzed the data and amended the original draft of the paper. Z.Q.S., H.B.H., H.Q.T., M.W. and H.Y.L. wrote the paper. All authors discussed the results and commented on the paper.

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Correspondence to Zengqing Song or Huiyan Li.

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Nature Aging thanks Jianxiong Zeng and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 Aging systemic milieu inhibits the activation of cGAS-STING pathway.

(a,b) qPCR analysis of Cxcl10 (a) and Mx1 (b) mRNA in the brain and lung from mice infected with or without HSV-1 for 36 h as in Fig. 1a. (n = 4 per group). (c,d) ELISA analysis of cGAMP production (c) and immunoblot assays of p-STING, p-TBK1, and p-IRF3 (d) in BMDMs treated with young or aged mice serum followed by ISD transfection. (n = 6 per group). (e) qPCR analysis of Ifnb, Cxcl10 and Mx1 mRNA in BMDMs treated with young or aged mice serum followed by vehicle or ISD transfection. (n = 6 per group) (f) ELISA analysis of IFN-β secretions in BMDMs cultured with different serum fractions as indicated for 2 h before transfected with HT-DNA. (n = 3). (g) Heat-map of significantly changed metabolites in aged mice plasma compared with those in young mice plasma. (h) The effect of PEP on the activation of cGAS-STING pathway, RIG-I-like receptor pathway and Toll-like receptor pathway induced by different stimulators as indicated. (n = 3). (i) Analysis of the PEP changes in Macaca fascicularis from a published dataset (Aging Atlas, C. Nucleic Acids Res 49, D825-D830. 10.1093/nar/gkaa894). (j) qPCR analysis of ISG15 and IFIT1 in THP-1 cells transfected with dsDNA upon PEP treatment. (n = 3). (k) The effect of pH of PEP on the dsDNA-induced IFN-β secretions. The pH of RPIM 1640 Medium at the presence of Veh or PEP was adjusted by NaOH. (n = 3). (l-n) qPCR analysis of Cxcl10 (l), Mx1 (m) mRNA levels, and immunoblot of p-STING, p-TBK1, and p-IRF3 (n) in BMDMs cultured with different serum for 2 h before transfected with HT-DNA. (n = 3). (o) ELISA analysis of IL-1α, CXCL1 and CCL2 levels in plasma from mice on day 6 after ionizing irradiation. (n = 3 in ctrl group; n = 6 in IR group).Data show the mean ± SD; Each dot represents one independent biological replicate; Two-way ANOVA with Sidak post hoc test in (a,b,e,k,o); Two-tailed unpaired t test in (c,i); One-way ANOVA with Turkey post hoc test in (f,h,j,l,m).

Source data

Extended Data Fig. 2 PEP inhibits the activation of cGAS-STING pathway during cell senescence by disrupting the formation of cGAS-DNA complex.

(a) Immunoblot of Pkm in BMDMs from Pkmfl/fl-LysMcre−/− (n = 5), Pkmfl/fl-LysMcre+/− (n = 5) or Pkmfl/fl-LysMcre+/+ (n = 6) mice. (b) The effect of PKM knockout on the activation of cGAS-STING pathway. Immunoblot of p-IRF3 in BMDMs from Pkmfl/fl-LysMcre−/−, Pkmfl/fl-LysMcre+/−or Pkmfl/fl-LysMcre+/+ mice upon HT-DNA transfection. (c) Heatmap showing levels of glycolytic metabolites in senescent WI-38 cell upon PEP or vehicle (Veh) treatment measured by LC-MS. (d) The effect of PEP on HT-DNA-induced the cGAMP synthesis in THP-1 cells. (n = 3). (e) Experimental workflow of Sepharose and PEP coupled. (f) Quantification of cGAS foci in THP-1 cells transfected with HT-DNA (2 μg·ml−1) for 3 h with PEP or vehicle (Veh) treatment. (n = 3). (g,h) Cytokine-array analysis of secreted factors in replication-induced senescent WI-38 cells treated with PEP or vehicle (Veh). (n = 2). Data show the mean ± SD; Each dot represents one independent biological replicate; One-way ANOVA with Turkey post hoc test in (d); Two-way ANOVA with Sidak post hoc test in (f); Two-tailed unpaired t test in (h).

Source data

Extended Data Fig. 3 Activating pyruvate kinase by DASA-58 reduces the PEP levels in aged mice and promotes the activation of cGAS-pathway.

(a) The PEP levels in plasma from male or female mice with different ages. (n = 4 per group). (b-d) The activity of pyruvate kinase activity (b), phosphoenolpyruvate carboxykinase activity (c) and the concentration of enolase (d) in plasma from mice with different ages. (n = 8 per group). (e) The pyruvate kinase activity in plasma of 15-month-old mice treated with vehicle or DASA-58 for 3 months. (n = 8 per group). (f) Body weight in the mice treated with DASA-58 or vehicle for 3 months. (n = 8 per group). (g) The PEP relative levels in plasma of 20-month-old mice treated with vehicle or DASA-58 for two weeks. (n = 8 per group). (h) ELISA analysis of cGAMP production in plasma from the 20-month-old mice treated with or without DASA-58 for two weeks. (n = 8 per group). Data show the mean ± SD; Each dot represents one independent biological replicate; One-way ANOVA with Dunnett post hoc test in (b,c,d); Two-tailed paired t test in (e,g); Two-tailed unpaired t test in (f,h).

Source data

Extended Data Fig. 4 PEP supplement promotes healthy aging in naturally aged mice.

(a) Heat-map of protein levels of inflammatory factors in plasma or mRNA levels of inflammatory genes in tissues (liver, kidney, brain) from mice with different ages (3, 20, 26 months). (n = 8 per group). (b,c) qPCR analysis of mRNA levels of inflammatory factors in kidney (b) and liver (c) from the mice treated with PEP or vehicle (Veh) for 6 months. (n = 8 per group). (d,e) HE staining of immune cells infiltration in liver (d) and kidney (e) from the mice treated with PEP or vehicle (Veh) for 6 months. Scale bar, 100 μm. (f) SA-β-gal staining of lung from the mice treated with PEP or vehicle (Veh) for 6 months. Scale bar, 100 μm. (g) The body weight of mice treated with PEP or vehicle for 6 months in grip strength test. (n = 8 per group). (h) Quantification of circulating PEP levels in 20-month-old mouse from the Veh or PEP treatment groups before the lifespan assay. (i-j) Survival analysis of the Veh group mice stratified based on high or low PEP levels. (k) Correlation analysis between the concentration of PEP and frailty index. (l) SA-β-gal staining of brain from the mice treated with PEP or vehicle (Veh) for 6 months. Scale bar, 200 μm. (m) Total arms of Y maze test in 26-month-old mice treated with PEP or vehicle (Veh). (n = 8 per group). Data show the mean ± SD; Each dot represents one independent biological replicate; Two-tailed unpaired t test in (b,c,g,h,i left,j left,m); Two-sided log-rank (Mantel–Cox) and Gehan-Breslow-Wilcoxon test in (i right,j right); Simple linear regression in (k).

Source data

Extended Data Fig. 5 PEP supplement ameliorates the pathology of 5×FAD mice.

(a-c) The representative images (a) and quantification of GFAP+ cells (b) or C3+GFAP+ A1 astrocytes (c) in the brain from 5×FAD mice treated with PEP or vehicle (Veh). Scale bars, 1 mm (left), 100 μm (right). (n = 6 per group). (d) Immunostaining of Aβ with Thioflavine S (Ths) and anti-Aβ in the brain from 5×FAD mice treated with PEP or vehicle (Veh). Scale bars, 1 mm (upper), 200 μm (lower). (e) Total arms of Y maze test in 5×FAD mice treated with PEP or vehicle (Veh). (n = 10 in Veh group; n = 13 in PEP group). (f) Central/Total distance, total distance and speed of open field test in 5×FAD mice treated with PEP or vehicle (Veh). (n = 10 in Veh group; n = 13 in PEP group). Data show the mean ± SD; Each dot represents one independent biological replicate; Two-tailed unpaired t test in (b,c,e,f).

Source data

Extended Data Fig. 6 Tendency of PEP in human blood and its effect on the activation of cGAS.

(a,b) The PEP levels in plasma from male (a) or female (b) human donors with different ages. (c) The PEP levels in plasma from human donors with different age group. (d,e) Correlation analysis between the concentration of PEP and ages (ages 20-56 (d) or ages ≥ 65 (e)). (f) Quantification of cGAS-DNA foci in THP-1 cells cultured with different pooled human serum. (n = 3). Data show the mean ± SD; Each dot represents one independent biological replicate; Simple linear regression in (d,e); One-way ANOVA with Dunnett post hoc test in (f).

Source data

Extended Data Fig. 7 The glycolytic metabolite phosphoenolpyruvate is a protective factor for healthy ageing via restricting cGAS-STING-mediated inflammation.

(a) Schematic showing that the glycolytic metabolite PEP accumulates at the early stages of aging, while gradually decreases with advanced aging, serving as a beneficial factor in curbing inflammaging and promoting healthy aging by inhibiting the cGAS-STING pathway.

Supplementary information

Reporting Summary (download PDF )

Supplementary Table 1. (download XLSX )

Significant changed metabolites in aged mouse plasma compared to young mouse plasma (P < 0.05, fold change > 1.5 and P < 0.05, fold change < 0.5).

Supplementary Table 2. (download XLSX )

Detailed information of the human donors.

Supplementary Table 3. (download XLSX )

Chemicals used in this study and their effects on Ifnβ productions induced by HT-DNA.

Supplementary Table 4. (download XLSX )

Quantitative PCR primer sequences.

Source data

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Statistical source data.

Source Data Fig. 1 (download PDF )

Unprocessed western blots.

Source Data Fig. 2 (download XLSX )

Statistical source data.

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Unprocessed western blots.

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Song, Z., Hu, H., Zhang, W. et al. The glycolytic metabolite phosphoenolpyruvate restricts cGAS-driven inflammation to promote healthy aging. Nat Aging (2026). https://doi.org/10.1038/s43587-026-01087-1

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