Free Radical Biology and Medicine
Aging is a critical risk factor for numerous chronic diseases, and it presents a rising clinical problem as approximately 19 percent of the US population is predicted to be 65 y and older by 2030 (U.S. Census Bureau). However, the mechanisms that regulate the process of aging are still not well understood. Results from RNA sequencing and bioinformatics analysis showed a significant difference in global gene expression between old (58 - 70 y) compared to young (3 d – 12 y) Normal Human Fibroblasts (NHFs). Gene set enrichment analysis ranked lipid metabolism as the top pathway that is altered in older NHFs. Significant changes in the expression of more than 40 genes related to lipid metabolism including Hypoxia inducible Factor 1 alpha (HIF-1α) and its target gene G0-G1 Switch 2 (G0S2; negative regulator of lipolysis) were observed. Results from RT-qPCR and immunoblotting analysis showed a significant decrease in HIF-1α expression in older (>50 y) compared to young (<50 y) NHFs that correlated with decreases in its target gene, G0S2 expression. Live cell imaging of NHFs using BODIPY 493/503 fluorescent probe showed approximately 100% increase in lipid droplets in older NHFs. Results from live cell imaging of proliferation of NHFs showed a significant decrease in the cell growth index of NHFs from donors of older (>50 y) compared to young (<50 y) healthy donors. Whereas the involvement of HIF-1α in carbohydrate metabolism and switching to anaerobic glycolysis under hypoxia is well established, to the best of our knowledge, we were the first to report a novel role of HIF-1α in lipid metabolism and proliferative capacity of NHFs during aging.
Hiremagalore S, Pearson K, Son J, Kalen A, Goswami P, Sarsour E. An Inverse Correlation Between Hypoxia Inducible Factor-1α Expression and Lipid Droplets Associated with a Decline in the Proliferative Index of Aging Normal Human Fibroblasts. Free Radical Biology and Medicine. 2022; 180(S1).