Aging and obesity prime the methylome and transcriptome of adipose stem cells for disease and dysfunction

Abstract

The epigenome of stem cells occupies a critical interface between genes and environment, serving to regulate expression through modification by intrinsic and extrinsic factors. We hypothesized that aging and obesity, which represent major risk factors for a variety of diseases, synergistically modify the epigenome of adult adipose stem cells (ASCs). Using integrated RNA-and targeted bisulfite-sequencing in murine ASCs from lean and obese mice at 5-and 12-months of age, we identified global DNA hypomethylation with either aging or obesity, and a synergistic effect of aging combined with obesity. The transcriptome of ASCs in lean mice was relatively stable to the effects of age, but this was not true in obese mice. Functional pathway analyses identified a subset of genes with critical roles in progenitors and in diseases of obesity and aging. Specifically, Mapt, Nr3c2, App, and Ctnnb1 emerged as potential hypomethylated upstream regulators in both aging and obesity (AL vs. YL and AO vs. YO), and App, Ctnnb1, Hipk2, Id2, and Tp53 exhibited additional effects of aging in obese animals. Furthermore, Foxo3 and Ccnd1 were potential hypermethylated F I G U R E 7 Heat map (A) and normalized counts (B) for seven genes differentially expressed (padj < .05) with diet and age identified by DESeq2 analysis.

Latent transforming growth factor beta binding protein 4: A regulator of mitochondrial function in acute kidney injury

“…Notably, in lung tissue, antioxidant protein Sestrin 2 can restore against pathology caused by knockout of LTBP4, suggesting that lung remodeling is similarly protected against LTBP4 through pathways involving modulating the oxidative stress response (Tomasovic et al., 2017 ). Finally, a study in adult murine adipose stem cells demonstrates that while aging alone did not increase LTBP4, the confluence of aging and obesity increased LTBP4 expression (Xie et al., 2023 ). Notably, DRP1 is affected by both aging (Sharma et al., 2019 ) and diet, with high‐fat diets having modulated DRP1‐dependent responses to mitophagy in cardiac tissues (Tong et al., 2023 ).…”