Aging is a fundamental biological process that occurs in all eukaryotic organisms. Despite intensive research, the molecular and cellular mechanisms underlying this complex process remain poorly understood. Altering mitochondrial function and nutrient composition in diets are two life span- extension conditions that are drawing considerable interests in the aging field due to their occurrence in all model organisms tested so far. Changes in mitochondrial morphology and function have been intimately associated with aging in diverse organisms. Moreover, genetic and dietary manipulations that extend life span in various species are dependent on normal mitochondrial function. Paradoxically, certain perturbations of mitochondrial function can also extend life span in yeast, worms, flies, and mammals. Thus, the exact role of mitochondria in life span regulation remains enigmatic. Recent studies have also implicated epigenetic regulators in controlling life span in multiple organisms. Despite the strong evidence supporting the importance of mitochondrial and epigenetic regulations in life span determination, the relationship, if any, between these two longevity-regulating axes in the aging process has not been established in metazoans. Our preliminary studies in the model organism Drosophila have uncovered a novel connection between mitochondrial function and epigenetic modifications. We found that the functional status of mitochondria can directly affect histone H3 acetylation, an epigenetic regulation that can strongly influence gene transcription in the nucleus. Our genetic studies strongly implicated the histone acetyltransferase GCN5 as a key enzyme mediating mitochondria-induced H3 acetylation. Moreover, our results implicated the involvement of target of rapamycin complex-2 (TORC2) in this process. These findings led logically to our central hypothesis that mitochondrial and dietary alterations (e.g., dietary restriction-DR) extend life span by impinging on GCN5-mediated acetylation of histone H3 to activate the transcription of longevity promoting genes, and that this process is mediated by TORC2. The proposed work will employ the powerful tools uniquely available in Drosophila to test this novel hypothesis concerning the relationship between mitochondrial and epigenetic changes in promoting longevity. There are two specific Aims in this proposal.
In Aim 1, we will examine the role and tissue- specific requirement of GCN5 in mitochondrial and dietary alteration-induced life span extension.
In Aim 2, we will determine the relationship between GCN5 and TORC2 in mediating the effects of mitochondrial and dietary alterations on life span extension. These studies will offer novel insights into the mechanisms of a prolongevity signaling network underlying the effects of mitochondrial metabolism and diet on life span by elucidating the roles of TORC2 and GCN5 in the process. This will ultimately offer new ways to interfere with the aging process and provide novel therapeutic strategies to treat a battery of age-related diseases.

Public Health Relevance

Aging is a fundamental biological process that occurs in virtually all eukaryotic organisms. The molecular and cellular mechanisms underlying this complex process remain poorly understood. The goal of this project is to establish the relationship between altered mitochondrial function and epigenetic regulation, two newly emerged cellular mechanisms that confer life span extension in all model organisms tested so far. A positive outcome from this study could help elucidate a prolongevity signaling network and provide novel strategies to treat devastating age-related disorders such as neurodegenerative diseases and cancer, where mitochondrial dysfunction and epigenetic dysregulation have been widely implicated.

Agency
National Institute of Health (NIH)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AG045753-01A1
Application #
8698065
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Finkelstein, David B
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Stanford University
Department
Pathology
Type
Schools of Medicine
DUNS #
City
Stanford
State
CA
Country
United States
Zip Code
94304