R01AG074551

Dissecting the Integrated Mechanisms of Protein Turnover to Prevent Proteostatic Decline with Aging - Summary

Proteostatic mechanisms fail with advancing age, resulting in the accumulation of damaged and dysfunctional proteins. Protein breakdown and replacement with newly synthesized proteins (protein turnover) is the primary mechanism to mitigate the accumulation of damaged proteins over time. However, there are several conflicting findings related to protein turnover, aging, and treatments that slow aging, which leave the field with fundamental contradictions regarding protein turnover as a proteostatic mechanism.

The current project seeks to understand the fundamental mechanisms that regulate proteostatic maintenance so that we can overcome a barrier to targeting this pillar of aging to slow age-related decline. Our studies indicate that:

1) Aging does not universally decrease protein turnover, and in fact, it increases the turnover of many proteins.
2) Aging decreases the number of proteins that turnover (for which we introduce the term dynamic pool size).
3) Treatments that extend lifespan have nearly an equal number of proteins that increase and decrease protein synthesis, which contradicts the notion that treatments that extend lifespan slow protein synthesis.
4) Some treatments that increase lifespan decrease cell proliferation, which by itself decreases protein turnover in a non-determinant manner.

To date, these studies have been limited to tissue samples, which has restricted the understanding of how individual cell types within a tissue influence overall tissue proteostasis. To overcome these unknowns, the proposed studies use mouse models that allow cell-specific isolation of proteins and nuclei in skeletal muscle and brain.

The project will use both discovery-based and targeted proteomics with novel deuterium oxide (D2O) labeling to examine cell-type-specific individual protein turnover and cell replication. Through loss of proteostatic maintenance (aging) and gain of proteostatic maintenance (treatments that slow aging), we will address the following specific aims:

1) To determine cell-type-specific proteins susceptible to proteostatic decline with aging.
2) To determine how a treatment that inhibits mTOR improves proteostasis.
3) To determine how a treatment that does not directly inhibit mTOR improves proteostasis.

The hypotheses are that:

1) The loss of proteostasis with aging results from cell-type-specific changes in individual protein turnover rates and decreases in the dynamic protein pool size.
2) Inhibiting mTOR improves proteostatic maintenance by decreasing cell proliferation while increasing turnover and dynamic pool size of proteins that are susceptible to proteostatic decline.
3) A lifespan-extending treatment that does not directly inhibit mTOR improves proteostatic maintenance by mechanisms that do not include slowed cell proliferation.

Progress toward targeting age-related proteostatic deterioration has been hindered by contradictory and paradoxical results from protein turnover studies. We expect that our approaches will narrow the scope of proteins susceptible to proteostatic decline and, more importantly, will make significant advancements toward strategies to target these proteins to maintain proteostasis with age.

Oklahoma Medical Research Foundation

NOT APPLICABLE

93.866 - Aging Research

National Institute on Aging (NIA) [HHS - NIH]

Oklahoma City, Oklahoma 731045005 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 401% from $660,106 to $3,307,452.