Aging-rewired metabolic cues promote autophagy and senescence via DRAM1

  • Autophagy. 2025 Oct 14:1-23. doi: 10.1080/15548627.2025.2568487.
Jinghong Yang  1  2 ,  Haobin Sun  1  2 ,  Keqing Xu  1  2 ,  Xiaomei Zhang  1  2  3  4 ,  Mudan Huang  2 ,  Guanghui Jin  1  2  5 ,  Yasong Liu  1  2 ,  Weizhao Chen  1  2 ,  Shunan Lin  1  2 ,  Juan Shen  2 ,  Chuan-Qi Zhong  6 ,  Yan Xu  2  7 ,  Qi Zhang  2  7  8 ,  Wei Liu  2 ,  Yang Yang  1  2 ,  Jingxing Ou  1  2
Affiliations
  • 1. Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital, Organ Transplantation Institute, Sun Yat-Sen University; Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation Medicine, Guangzhou, China.
  • 2. Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
  • 3. Department of Cancer Biology, Dana-Farber Cancer Institute.
  • 4. Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
  • 5. State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
  • 6. State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, China.
  • 7. Biotherapy Centre, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
  • 8. Cell-Gene Therapy Translational Medicine Research Center, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
PMID: 41037659 DOI: 10.1080/15548627.2025.2568487
Abstract

Being a major contributor to cell senescence and aging, DNA damage activates macroautophagy/Autophagy, but how this process is affected by aging-rewired metabolism in normal biological systems remains to be explored. Here in cultured human umbilical cord-derived mesenchymal stem cells (HsMSCs) and the mouse liver that accumulate DNA damage during aging, we found an elevation of DRAM1 (DNA damage regulated Autophagy modulator 1) and DRAM1-mediated pro-senescent Autophagy (DMPA). Confirming that DRAM1 activated AMPK, we sought DMPA-associated metabolic features and noted substantial enrichment of N-acetylhistamine (N-AcHA) and phosphatidylethanolamine (PE) products in the aging HsMSCs and mouse liver. Elevating DNA damage and senescence, N-AcHA supplements were sufficient to upregulate DRAM1 and DMPA in primary hepatocytes from young mice but not even in pre-senescent HsMSCs, hence reflecting the differential tolerance of these cell models toward cytotoxic metabolic cues. The effects of N-AcHA were further verified in mouse aging and post-hepatectomy liver regeneration models. In contrast, accumulating cellular PE contents via ethanolamine supplements augmented Autophagy but not DNA damage and senescence despite tending to induce DRAM1. Combined treatments with N-AcHA and ethanolamine were sufficient to trigger DMPA in HsMSCs. Despite their differential cellular responses toward N-AcHA and ethanolamine supplements, in primary HsMSCs and mouse hepatocytes DMPA did not notably downregulate SQSTM1/p62 proteins, which differed from general macroautophagy and may constitutively support the fusion of SQSTM1-modified cargo-containing autophagosomes with lysosomes. Overall, this study reveals DMPA-promoting metabolic and molecular features. Thus, targeting certain metabolic pathways and DMPA may promote DNA repair and delay senescence/aging.Abbreviations: ATM: ATM serine/threonine kinase; ATG5: Autophagy related 5; ACTB: actin beta; BaFA1: bafilomycin A1; CDKN1A/p21: cyclin dependent kinase inhibitor 1A; DDR: DNA damage response; DEGs: differentially expressed genes; DRAM1: DNA damage regulated Autophagy modulator 1; DMPA: DRAM1-mediated pro-senescent autophagy; DPMPs: differentially presented metabolic products; ETO: etoposide; Eth: ethanolamine; GL: glycerolipids; GP: glycerophospholipids; γ-H2AX: phosphorylated H2A.X variant histone; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HsMSC: human mesenchymal stem cell; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MSA: methanesulfonic acid; N-AcHA: N-acetylhistamine; PE: phosphatidylethanolamine; PHx: partial hepatectomy; PCYT2: phosphate cytidyltransferase 2, ethanolamine; SASP: senescence-associated secretory phenotype; SA-GLB1/β-gal: senescence-associated galactosidase beta 1; SQSTM1/p62: sequestosome 1; TAF: telomere-associated foci; TP53/p53: tumor protein p53.

Keywords
Aging; DNA damage; DRAM1; autophagy; metabolism; senescence.
Products