Regulation of cellular senescence and metabolic health by dietary protein

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PROJECT SUMMARY The number of people over age 65 has more than tripled over the past century, placing great burdens on families and the healthcare system. Extending healthspan, the portion of the life that is relatively free from major deficits that impair quality of life, may be the most efficacious way to prevent or delay aging and age- related diseases to reduce such burdens. However, without fully understanding the mechanisms driving aging, identifying and developing effective and translatable interventions to improve health and longevity in humans will likely remain limited. A hallmark of aging, cellular senescence (CS), is an apoptotic-resistant, cell-cycle arrested state induced by various stressors. Senescent cells release pro-inflammatory soluble factors collectively called the senescence- associated secretory phenotype (SASP), which can induce premature CS in healthy cells and promote age-related pathologies. CS can be cleared by genetic or pharmacological (i.e., senolytic drugs) methods, which leads to improvements in metabolic health and reductions age-related diseases. Protein restriction (PR) improves many aspects of metabolic health in both humans and mice, and extends mouse lifespan, specifically through the reduced consumption of the branched-chain amino acids (i.e. leucine, isoleucine and valine; BCAAs). In preliminary studies, I have found that a diet low in BCAAs (BCAA-R) reduces CS in aged and diet-induced obese mice as well as cell culture. The mechanisms by which protein promotes CS, and conversely the mechanisms by which PR and BCAA-R promote healthy aging and reduce CS, are unknown. One mechanism by which BCAA-R may function to reduce CS is the protein kinase mTORC1, which is stimulated by protein and BCAAs. mTORC1 activity promotes the SASP, while the mTOR inhibitor rapamycin inhibits the SASP. BCAA-R has been shown to reduce mTORC1 signaling in the liver and muscle of male mice. Another factor required for PR is fibroblast growth factor 21 (FGF21), which is also induced by BCAA-R. In vitro, FGF21 has been shown to protect against CS burden. In this proposal, I will test if diet affects CS clearance by assessing if senolytics will have the greatest effect on metabolic health and frailty in aged mice eating a high protein diet. I also will test if BCAAs drive high-protein-induced CS and metabolic dysfunction through activation of mTORC1 in vivo and in vitro. Finally, I will test if the action of BCAA-R on FGF21 in the whole body or in specific tissues mediates the effects of a BCAA-R on metabolic health and CS in diet-induced obese mice. Together, these aims will examine multiple mechanisms by which dietary protein and the BCAAs modulate to impact CS burden. I will be completing this fellowship under the mentorship of my sponsor, Dr. Dudley Lamming, an expert in aging biology and metabolism, and my co-sponsor, Dr. Paul Robbins, a world-leading expert in CS. Completing these aims and the accompanying individualized training plan will help me develop the skills necessary to become a successful tenure track faculty member focused on the biology of aging and cellular senescence.