Cellular Senescence in Aging-related Metabolic Diseases

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Cellular senescence causes inflammation, oxidative stress, and mitochondrial dysfunction, which have been implicated in the pathogenesis of age-related diseases. Accordingly, genetic depletion of senescent cells has recently been shown to extend lifespan and attenuate aging-related diseases. However, the cellular mechanisms underlying senescence and how it may promote diseases of aging are unclear. Recent work from my laboratory has implicated a role for ALCAT1 in linking cellular senescence with aging-related diseases. ALCAT1 is an enzyme that catalyzes pathogenic resynthesis of cardiolipin (CL) with aberrant fatty acids in response to oxidative stress. CL is a mitochondrial signature phospholipid required for oxidative phosphorylation, mitophagy, and mitochondrial biogenesis. Aging is associated with remodeling of CL by polyunsaturated fatty acids (PUFA) that are highly sensitive to oxidative damage by reactive oxygen species (ROS). Our prior work has revealed a key role for ALCAT1 in catalyzing the pathological remodeling of CL by PUFA in aging-related diseases, such as obesity, T2DM, and cardiovascular diseases. ALCAT1 promotes the development of the disorders of aging because its expression is significantly upregulated by ROS, leading to a vicious cycle of oxidative stress, CL oxidation, and mitochondrial dysfunction. Other recent studies from my laboratory also demonstrate a striking role for ALCAT1 in cellular senescence. Our preliminary data indicate that: 1) replicative senescence significantly increases ALCAT1 protein expression; 2) upregulated ALCAT1 expression in cell lines and mice causes mitochondrial DNA (mtDNA) mutation and dysfunction, leading to cellular senescence; and 3) targeted deletion of ALCAT1 delays cellular senescence and prevents the onset of various aging-related diseases, including T2DM, diabetic nephropathy, and cardiomyopathy. Based upon our prior studies and recent findings, we hypothesize that mitochondrial dysfunction by ALCAT1 links cellular senescence to the pathogenesis of aging-related metabolic diseases, which will be tested by three Aims. Aim 1 will elucidate how ALCAT1 promotes mitochondrial dysfunction in replicative senescence, Aim 2 will determine whether mtDNA mutations induced by ALCAT1 links senescence to aging, and Aim 3 will identify the role of ALCAT1 in linking cellular senescence to diet-induced obesity. The results from the proposed studies are expected to provide key insights on targeting ALCAT1 enzyme as a paradigm shifting treatment for aging-related diseases through depletion of senescent cells.