All humans age, though the rate of aging is highly variable and likely influenced by one's genetic composition; our cells accumulate damage over time, and this damage can lead to increased disease susceptibility, decreased ability to respond to injury, reduction in sensory systems, among many other detrimental changes. While not necessarily deadly on their own, they lead to a greatly increased risk of death. In order to begin the clinical work in reducing the effects of aging, research must first elucidate the biochemical interactions causing such effects. This project will identify and describe pathways containing conserved longevity-related protein synthesis genes using the model organism, C. elegans. The nematode C. elegans is an excellent model for aging due to its short lifespan, small number of cells, ease of genetic manipulation, and large fraction (>80%) of conserved genes. The reduced expression of protein synthesis genes post-developmentally increases worm lifespan, even up to 50% higher, but the reasons for this lifespan increase are unknown. It has recently been described that reducing protein synthesis cause developmental arrest if given during the larval stage. Given this connection, and multiple previous studies describing similar longevity-related antagonistic pleiotropy, we seek to characterize the protein synthesis pathways involved in both phenotypes; this includes testing the hypothesis that these two phenotypes may use the same pathway as we have recently determined both of these states share a stress resistance phenotype (a metric of increased healthspan).
Aim 1 will compile a list of deregulated genes via RNA-seq when worms undergo arrest or longevity in response to reduced protein synthesis. Using this list, and three previously-identified genes that can control the arrest phenotype, we will characterize their spatiotemporal expression patterns, using GFP-bound promoters, and how they correlate with the longevity, arrest, and stress resistance phenotypes. Finally, we will determine if rescuing wild type expression levels of these deregulated genes rescues any of the same phenotypes, indicating their importance in that response.
Aim 2 will determine the effects of reducing protein synthesis in a tissue-specific manner (hypodermal, intestinal, muscular, or neuronal) using tissue-specific RNAi strains, which will identify where in the worm the longevity pathway is taking place, including revealing how the signaling and cell-cell crosstalk interacts between cell types to confer longevity, arrest, and stress resistance. The second part of Aim 2 involves coalescing information from our spatiotemporal analysis and tissue-specific studies in order to rescue genes found to be important in conferring these survival-promoting phenotypes in order to determine their importance on a cell or tissue-based level. The description of these protein synthesis genes, particularly in relation to their physiological effects, discovered pathways, and correlation with arrest states and stress resistance, will establish a better connection between enhanced longevity and how that longevity is conferred in order to enable the eventual treatment of aging-related ailments and disease.

Public Health Relevance

The effects of aging cause many ailments, and genes that affect aging have been linked to human diseases38, 39. Reducing the associated cellular damage or activating longevity-inducing pathways will help to delay or eliminate these age-associated deaths40. This project focuses on conserved, lifespan-affecting protein synthesis genes in order to uncover the mechanisms involved in the aging process, including which factors could be modulated to have the most impact on relieving aging-related ailments and which tissue types are most associated with each pathway1.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31AG051382-01A1
Application #
9192920
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Velazquez, Jose M
Project Start
2016-12-10
Project End
Budget Start
2016-12-10
Budget End
Support Year
1
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Southern California
Department
Type
Other Specialized Schools
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90032