Kathleen Markan, Ph.D. (Year 1)

ABSTRACT

Aging-related pathologies lead to an abbreviated health- and lifespan. Cellular senescence, which is an irreversible cessation of the cell cycle, occurs during aging and with associated metabolic dysfunction. The p16INK4a protein is a key regulator of the cell cycle and its activation leads to a block of the cell cycle and proliferation. While exercise exerts an anti-senescent effect, whether progressive resistance training has this effect and whether the mechanism involves p16INK4a remains undetermined. Furthermore, while targeted pharmacogenetic methods to ablate p16INK4a expressing cells improve lifespan and metabolic dysfunction, the anti-senescent effects of genetically deleting p16INK4a specifically in adipose tissue stem cells remains untested.

The work proposed in this application is based on findings that p16INK4a expression is increased in adipose and adipose tissue stem cells during aging and its associated metabolic dysfunction. To test this association, we will study whether or not an anti-senescent effect occurs with resistance exercise in concert with decreased adipose and adipose stem cell p16INK4a expression. Furthermore, we will test the effects of p16INK4a genetic deletion in adipose tissue stem cells on metabolic dysfunction across the lifespan. Overall, the findings from the proposed studies should enhance our understanding of the relationship between cellular senescence and aging-related metabolic dysfunction.

Lay Summary
Aging contributes to many pathologies including metabolic disease and the dysfunction of fat tissue. Typically, in a healthy fat pad, fat stem cells grow, proliferate and differentiate into mature fat cells. However, during aging, these fat stem cells cease to grow and proliferate, a process termed cellular senescence. Since cellular senescence is a symptom of aging, targeting senescence could be an attractive therapeutic avenue for treating the deleterious effects of aging. To this end, we will study the effects of progressive resistance exercise training and of the protein named p16INK4a on senescence in fat tissue and in fat-tissue-resident stem cells of mice. In Specific Aim 1 of this proposal, we will characterize the effects of progressive resistance training on cellular senescence and p16INK4a expression in adipose tissues and adipose tissue stem cells of wild-type mice. In Specific Aim 2, we will characterize the effects of genetically deleting p16INK4a specifically in mice’s fat stem cells over their lifespan. Overall, our proposed studies will provide novel mechanistic insight that could potentially be used to develop new countermeasures for aging and improve metabolic function and health span for the life span.