Fight Aging!

It may turn out to be the case that many mechanisms of cellular regulation that slow aspects of aging function, at least in part, by slowing the pace at which senescent cells accumulate. Senescent cells induce tissue dysfunction via inflammatory signaling. Studies in which senescent cells are selectively destroyed in old tissues via senolytic drugs have resulted in rejuvenation, showing that the accumulation of these errant cells has a sizable role in the progression of degenerative aging. Atherosclerosis is a condition that is sensitive to chronic inflammation, as the behavior of macrophage cells is the primary determinant of the rate at which atherosclerotic lesions grow in blood vessel walls. More inflammation means that more macrophage cells abandon their task of repairing these lesions.

Atherosclerosis (AS) is a complex vascular disease that seriously harms the health of the elderly. It is closely related to endothelial cell aging, but the role of senescent cells in atherogenesis remains unclear. Studies have shown that peroxisome proliferator-activated receptor alpha (PPARα) inhibits the development of AS by regulating lipid metabolism. Our previous research showed that PPARα was involved in regulating the repair of damaged vascular endothelial cells. Detecting senescent cells in atherosclerosis-prone apolipoprotein E-deficient (Apoe-/-) mice, we found that PPARα delayed atherosclerotic plaque formation by inhibiting vascular endothelial cell senescence, which was achieved by regulating the expression of growth differentiation factor 11 (GDF11).

We demonstrated a likely causal role for PPARα in vascular endothelial cell senescence and occurrence of AS, where PPARα inhibited cell aging and plaque formation by directly targeting GDF11. Pharmacologic stimulation of PPARα alleviated atherosclerotic plaque formation, vascular endothelial cell damage, and senescence, as well as increasing GDF11 expression in Apoe-/- model mice. At the same time, we proved that PPARα directly targeted the aging-related protein GDF11, thereby affecting the aging, proliferation, apoptosis, and angiogenesis of vascular endothelial cells in vitro. Our findings are consistent with the general hypothesis that inhibiting the aging of vascular endothelial cells helps prevent the formation of atherosclerotic plaques. Our work suggests that targeting PPARα or senescent vascular endothelial cells could be a promising avenue for delaying, preventing, alleviating, or treating AS.

Link: https://doi.org/10.1155/2021/2045259