Research

Why are we interested in the biology of aging?

The developed world is undergoing an unprecedented shift in age-demographics, featuring a decline in reproduction rates, an increase in the percentage of people over the age of 65, and a growing prevalence of individuals suffering multiple age-related morbidities. This change in age-demographics is expected to strain US healthcare systems and result in complex global economic changes.

Recent scientific advances have shown that diet, exercise, social connectivity, and other lifestyle factors can extend human lifespan and also extend the healthy portion of human life that is free of late-life disease (healthspan). Mice (and other laboratory animals) can also enjoy significant increases in lifespan and healthspan, resulting from single gene mutations, transgenes, dietary interventions, and drug treatments. These findings have fueled the rise of an entire industry of biotechs seeking to identify drug treatments and dietary supplements that can further slow the human aging process and prevent or delay the onset of late-life diseases.

What have we learned about aging from mice?

The endocrine system plays a critical role in regulating the pace of aging. Mutations dampening signaling through the insulin (INS) and insulin-like growth factor 1 (IGF1) signaling pathway dramatically extend lifespan and healthspan in C. elegans, D. melanogaster, and mice. Mouse mutants with reduced growth hormone (GH) signaling have reductions in circulating INS and IGF1 and have a >40% lifespan extension, lower rates of cancer, and improved insulin-sensitivity.  We investigate the changes to metabolism and cell biology in long-lived endocrine mutant mice. By understanding these changes, we hope to develop and refine treatments to extend the lifespan of normal mice, and eventually people.

Chaperone-mediated autophagy

Protein turnover via the lysosome/autophagy system is a crucial regulator of aging. Chaperone-mediated autophagy (CMA) is the most selective form of lysosomal proteolysis, where proteins bearing consensus motifs are individually selected for lysosomal degradation. CMA degrades proteins that are damaged or present in excess, maintaining a “clean” proteome, but CMA also regulates the abundance of proteins whose overaccumulation contributes to age-related diseases, including Parkinson’s disease, Alzheimer’s disease, fatty-liver disease, cancer, and others.. Our own work has shown that long-lived mutant mice with reduced growth hormone signaling have elevated CMA, with decreased abundance of several CMA-sensitive proteins. There is currently intense interest in characterizing the mechanisms of CMA regulation, with the long-term goal of identifying and refining interventions for activating CMA therapeutically. 

We have recently reported that CMA is negatively regulated by the insulin (INS)/PI3K/AKT signaling pathway, and that clinically safe inhibitors of class I PI3K activate CMA in mice. Using a combination of quantitative proteomics, genetics, mouse studies, and cell biology, we are further characterizing the mechanisms through which the INS/PI3K/AKT pathway regulates CMA, and attempting to understand how enhanced CMA affects the proteome.