Aging-rewired metabolic cues promote autophagy and senescence via DRAM1 - Research paper

Sep 28, 2026

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DNA damage driven by aging activates macroautophagy/autophagy, yet the impact of aging-rewired metabolism in normal systems remains unclear. In cultured human umbilical cord-derived mesenchymal stem cells and aging mouse liver, DRAM1 levels increased and DRAM1-mediated prosenescent autophagy (DMPA) was elevated. DRAM1 activation of AMPK linked DMPA to enriched N-acetylhistamine and phosphatidylethanolamine products. N-AcHA promoted DRAM1 and DMPA and enhanced DNA damage and senescence in young hepatocytes, validated in aging and regeneration models, whereas ethanolamine augmented autophagy without matching DNA damage/senescence, though N-AcHA plus ethanolamine triggered DMPA. DMPA did not markedly downregulate SQSTM1/p62, indicating distinct molecular routing.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages23

Reading Time58 min

AccessFree to download

Abstract

Key findings

Metabolic cues and DMPA

Models and validations

Molecular differences (SQSTM1/p62)

AUTOPHAGY 2025, VOL. 21, NO. 12, 3142–3164 [https://doi.org/10.1080/15548627.2025.2568487](https://doi.org/10.1080/15548627.2025.2568487) | RESEARCH PAPER
Aging-rewired metabolic cues promote autophagy and senescence via DRAM1
Jinghong Yang a,b*, Haobin Sun a,b*, Keqing Xu a,b*, Xiaomei Zhang a,b,c,d, Mudan Huangb, Guanghui Jin a,b,e, Yasong Liua,b, Weizhao Chen a,b, Shunan Lina,b, Juan Shenb, Chuan-Qi Zhongf, Yan Xub,g, Qi Zhangb,g,h, Wei Liu b, Yang Yang a,b, and Jingxing Ou a,b

aDepartment 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; bGuangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China; cDepartment of Cancer Biology, Dana-Farber Cancer Institute; dDepartment of Cell Biology, Harvard Medical School, Boston, MA, USA; eState 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; fState Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, China; gBiotherapy Centre, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China; hCell-Gene Therapy Translational Medicine Research Center, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China | | | --- | --- | | 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 prosenescent 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. | ARTICLE HISTORY
Received 21 April 2025 Revised 8 September 2025 Accepted 26 September 2025
KEYWORDS
Aging; autophagy; DNA damage; DRAM1; metabolism; senescence | | 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

FAQs

What is the main focus of this study?

The study investigates how aging-rewired metabolic cues regulate DRAM1-mediated prosenescent autophagy and how this relates to DNA damage and cellular senescence.

How does DRAM1 influence the aging-related autophagy pathway?

DRAM1 activation of AMPK is associated with metabolic features enriched during aging and supports DRAM1-mediated prosenescent autophagy (DMPA).

What roles do N-acetylhistamine and ethanolamine play in senescence and autophagy?

N-acetylhistamine upregulates DRAM1 and DMPA and is sufficient to increase DNA damage and senescence in young hepatocytes. Ethanolamine increases autophagy but does not similarly drive DNA damage and senescence, although combined treatment with N-acetylhistamine plus ethanolamine triggers DMPA in HsMSCs.

Sep 28, 2026

Uploaded by SANS