Aging-associated metabolites promoted -mediated pro-senescent autophagy in human mesenchymal stem cells and mouse liver models.
Evidence
This cell and mouse mechanistic study examined aged HsMSCs, mouse liver, primary hepatocytes, aging mice, and post-hepatectomy liver regeneration models, focusing on DRAM1, N-acetylhistamine, phosphatidylethanolamine, DNA damage, autophagy, and senescence.
Caveat
The findings come from cell and mouse systems, and the proposed anti-aging targeting implications were not tested as human clinical outcomes.
Simplified
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 (DNA damage regulated autophagy modulator 1) and DRAM1-mediated pro-senescent autophagy (). 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.ATM: ATM serine/threonine kinase; ATG5: autophagy related 5; ACTB: actin beta; BaFA1: bafilomycin A; 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. Abbreviations: 1
Key numbers
N/A
Increase in Levels
Observed in cultured and mouse hepatocytes.
N/A
N-AcHA Induced Senescence
Demonstrated through assays measuring senescence-associated markers.
N/A
PE Effects on Autophagy
Assessed in both and mouse hepatocytes.
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