Session
Session 1
Board Number
30
Reactive lipids induce cellular senescence through DNA and protein alteration
Senescence is a cellular fate marked by disruption in normal function and production of inflammatory factors. In aging, senescent cells accumulate in various tissues in the body. This increase in senescent cells is thought to cause or contribute to several age-related diseases. Recent findings point to senescence burden in fat tissue as a potential cause of insulin resistance (i.e. type 2 diabetes) associated with obesity and aging. However, the mechanism that would explain enhanced senescence in fat depots during obesity and aging remains unknown. We hypothesize that a class of reactive byproducts from lipids (i.e. fats) build up in fat depots over time and may be the link between inflammation, obesity/aging, and increased senescence in fat tissue. When these reactive lipids are added to cells, we’ve found they cause those cells to become senescent. Our work is aimed at characterizing this new type of senescence, which we’ve termed Biogenic Lipid Induced Senescence (BLIS), and unraveling its underlying mechanisms. After a weeklong exposure to reactive lipids, we found that cultured cells exhibit classic hallmarks of senescence, including compromised nuclear envelope integrity, withdrawal from normal cell division, and enhanced senescence-associated β galactosidase activity. Concomitant with cellular senescence on lipid exposure, we found an accumulation of lipid-modified protein adducts, particularly in mitochondria. Also coincident with the development of BLIS, we observed signs of DNA double-stranded breaks, damage to mitochondrial function, and aberrant metabolism. Taken together, our results suggest that modification of proteins and DNA lead to BLIS through complex underlying mechanisms.