The long-term goal of this research is to understand the regulation of gene expression during aging using the model organism Drosophila melanogaster. Aging in both flies and humans is found to be associated with a tissue-specific induction of oxidative stress response genes, including members of the hsp70 family and hsp22 (alpha-crystallin) family. Heat shock proteins (hsps) are induced in all species in response to heat and other stresses. hsps appear to be involved in prevention and repair of protein damage and can confer increased heat and oxidative stress resistance to many cell types. Drosophila hsp70 and hsp22 genes are induced in a characteristic, tissue-specific pattern during aging. This aging-associated upregulation involves both transcriptional and posttranscriptional mechanisms, and appears to be in part a response to oxidative stress. hsp22 exhibits one of the largest aging-related increases known for a eukaryotic protein (>150-fold). Homologs of hsp70 and hsp22 are upregulated in humans during normal aging and in numerous pathophysiological and aging-related disease states. We hypothesize that altered hsp gene expression is a species-general biomarker of aging and results from a breakdown in normal nuclear-mitochondrial signaling. We propose to study the aging-related transcriptional regulation of Drosophila hsp70 and hsp22 in detail. The research involves genetic and transgenic manipulation of gene expression and life span in Drosophila. The experiments will test several specific hypotheses relating aging and hsp gene expression. The metabolism and detoxification/repair of cells is coordinated across tissues, occurs in diurnal (24 hour or circadian) cycles, and involves hsp and """"""""Phase I/II"""""""" gene products similar to those implicated in life span extension downstream of the C. elegans insulin-like signaling pathway. Our preliminary data suggests a model in which mitochondrial MnSOD and retrograde ROS (H2O2) signaling coordinately regulates hsp22 and Phase I/II gene expression, metabolic cycles and life span. We have also implicated the tumor suppressor p53 and the sex-determination pathway in the regulation of hsp22 expression during aging. The dynamic nature of these processes requires that we assay fly aging and gene expression longitudinally to address basic mechanisms. We have developed novel 3D video technology to facilitate longitudinal assay of cyclical gene expression patterns during aging.

Public Health Relevance

In humans and in the model research organism Drosophila, aging is associated with the expression of oxidative stress-response genes. For example, heat shock protein genes such as hsp70 and hsp22 are induced in tissue-specific patterns that are similar between humans and flies, and the level of hsp gene expression correlates with life span in both humans and flies. By studying gene expression in aging Drosophila, we hope to better understand the basic mechanisms of aging, and to ultimately develop interventions for human aging-related diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG011833-15
Application #
8416371
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Guo, Max
Project Start
1993-12-01
Project End
2015-02-28
Budget Start
2013-04-01
Budget End
2015-02-28
Support Year
15
Fiscal Year
2013
Total Cost
$254,938
Indirect Cost
$97,569
Name
University of Southern California
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Pomatto, Laura C D; Wong, Sarah; Tower, John et al. (2017) Sexual dimorphism in oxidant-induced adaptive homeostasis in multiple wild-type D. melanogaster strains. Arch Biochem Biophys 636:57-70
Tower, John (2017) Sex-Specific Gene Expression and Life Span Regulation. Trends Endocrinol Metab 28:735-747
Shen, Jie; Landis, Gary N; Tower, John (2017) Multiple Metazoan Life-span Interventions Exhibit a Sex-specific Strehler-Mildvan Inverse Relationship Between Initial Mortality Rate and Age-dependent Mortality Rate Acceleration. J Gerontol A Biol Sci Med Sci 72:44-53
Pomatto, Laura C D; Wong, Sarah; Carney, Caroline et al. (2017) The age- and sex-specific decline of the 20s proteasome and the Nrf2/CncC signal transduction pathway in adaption and resistance to oxidative stress in Drosophila melanogaster. Aging (Albany NY) 9:1153-1185
Pomatto, Laura C D; Carney, Caroline; Shen, Brenda et al. (2017) The Mitochondrial Lon Protease Is Required for Age-Specific and Sex-Specific Adaptation to Oxidative Stress. Curr Biol 27:1-15
Tower, John; Landis, Gary N; Shen, Jie et al. (2017) Mifepristone/RU486 acts in Drosophila melanogaster females to counteract the life span-shortening and pro-inflammatory effects of male Sex Peptide. Biogerontology 18:413-427
Fear, Justin M; León-Novelo, Luis G; Morse, Alison M et al. (2016) Buffering of Genetic Regulatory Networks in Drosophila melanogaster. Genetics 203:1177-90
Tower, John (2015) Programmed cell death in aging. Ageing Res Rev 23:90-100
Tower, John (2015) Mitochondrial maintenance failure in aging and role of sexual dimorphism. Arch Biochem Biophys 576:17-31
Fear, Justin M; Arbeitman, Michelle N; Salomon, Matthew P et al. (2015) The Wright stuff: reimagining path analysis reveals novel components of the sex determination hierarchy in Drosophila melanogaster. BMC Syst Biol 9:53

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