My research focuses on the study of aging in the context of cellular metabolism, particularly as it pertains to the process known as cellular senescence. Cellular senescence is a stress response by which cells adopt a state of permanent mitotic arrest. More than simple arrest, the senescent phenotype is complex and includes a senescence-associated secretory phenotype (SASP) that leads to secretion of multiple biologically-active molecules, including proinflammatory cytokines, matrix metalloproteinases, and growth factors, that can have potent effects on the tissue microenvironment.
We are currently addressing two areas. First, I identified compromised mitochondrial function as a potentially important inducer of senescence. Unlike other inducers of senescence, mitochondrial dysfunction drives senescence with a distinct SASP. This new paradigm for senescence highlights the plasticity of the senescent phenotype and reveals an unexplored vector by which mitochondrial dysfunction can drive aging phenotypes such as lipodystrophy, thinning skin, and cancer. Second, I found that senescent cells alter their lipid metabolism, including secretion of several signaling lipids that promote inflammation, fever, hair loss, parturition, asthma, fibrosis, and other conditions. This senescence-associated oxylipin biosynthesis acts to promote the SASP, reinforce mitotic arrest, and promote pulmonary fibrosis. Finally, my studies have allowed me to identify new avenues for the selective elimination of senescent cells by targeting their unique metabolic characteristics. Together, my findings reveal new insights regarding the nature of cellular senescence and offer alternative avenues for intervention for associated disorders, such as cancer, diabetes, and aging.