All ETDs from UAB

Advisory Committee Chair

Steven N Austad

Advisory Committee Members

Andrew M Pickering

Constanza J Cortes

Dan E Berkowitz

Farah Lubin

Liou Y Sun

Document Type

Dissertation

Date of Award

2022

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Protein translation (PT) is an essential cellular process playing crucial roles in growth and development. PT precipitously declines with age in multiple animal species, including humans. It has been implicitly assumed that elevated PT at young ages is beneficial to health while PT ends up dropping as a passive byproduct of aging. However, whether this holds true and how dynamic fluctuations in PT over time impact aging remain unknown. In Drosophila, we show that a transient PT spike in early-adulthood drives aging by triggering dysfunction in protein homeostasis (proteostasis) at old ages. We propose the early-adulthood spike in PT to represent an antagonistic pleiotropic effect, enhancing reproductive fitness early in life at the expense of proteostasis late in life. To maximize reproductive outcomes at young ages, the early-adulthood PT spike stimulates juvenile hormone/germline stem cell signaling, which ends up exerting long-lasting negative impacts on aging trajectories and proteostasis in later life. Our findings indicate that PT is thus rapidly suppressed after early-adulthood/fertility peak in order to alleviate proteostatic burden, slow down aging, and optimize lifespan; this suggests that agedependent decline in PT may not simply be a passive byproduct of aging as previously thought but rather an adaptive response to promote healthy aging. We propose that the rise and fall in PT over time impact aging in the opposite direction from what was assumed in the past. Our work helps resolve so-called protein synthesis paradox and iii provides a new theoretical framework for understanding how lifetime PT dynamics shape aging trajectories. To maintain proteostasis, it is essential to precisely control not only PT but also protein degradation. The ubiquitin-proteasome system (UPS) is the major pathway for degrading misfolded/damaged proteins. Proteasome dysfunction is a prominent feature of aging and age-related diseases, including Alzheimer’s disease (AD). We generated a novel transgenic mouse with neuronal-specific proteasome overexpression. We also developed a set of novel TAT-based proteasome activating peptidomimetics which stably penetrate the blood brain barrier and enhance 20S/26S proteasome activity. We showed that genetic and pharmacologic augmentations of proteasome activity ameliorate ADrelated cognitive deficits and mortality in cell culture, Drosophila, and mouse AD models.

Share

COinS