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 #
5R01AG011833-14
Application #
8223218
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Guo, Max
Project Start
1993-12-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
14
Fiscal Year
2012
Total Cost
$269,775
Indirect Cost
$103,247
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
Tower, John (2015) Mitochondrial maintenance failure in aging and role of sexual dimorphism. Arch Biochem Biophys 576:17-31
Tower, John; Landis, Gary; Gao, Rebecca et al. (2014) Variegated expression of Hsp22 transgenic reporters indicates cell-specific patterns of aging in Drosophila oenocytes. J Gerontol A Biol Sci Med Sci 69:253-9
Pickering, Andrew M; Vojtovich, Lesya; Tower, John et al. (2013) Oxidative stress adaptation with acute, chronic, and repeated stress. Free Radic Biol Med 55:109-18
Pickering, Andrew M; Staab, Trisha A; Tower, John et al. (2013) A conserved role for the 20S proteasome and Nrf2 transcription factor in oxidative stress adaptation in mammals, Caenorhabditis elegans and Drosophila melanogaster. J Exp Biol 216:543-53
Ardekani, Reza; Biyani, Anurag; Dalton, Justin E et al. (2013) Three-dimensional tracking and behaviour monitoring of multiple fruit flies. J R Soc Interface 10:20120547
Tower, John (2011) Lactobacillus plantarum gives Drosophila the grow signal. Cell Metab 14:283-4
Hoe, Nicholas; Huang, Chung M; Landis, Gary et al. (2011) Ubiquitin over-expression phenotypes and ubiquitin gene molecular misreading during aging in Drosophila melanogaster. Aging (Albany NY) 3:237-61
Tower, John (2011) Heat shock proteins and Drosophila aging. Exp Gerontol 46:355-62
Tower, John (2010) The genetic architecture of aging: sexual antagonistic pleiotropy of p53 and foxo. Cell Cycle 9:3840-1
Shen, Jie; Tower, John (2010) Drosophila foxo acts in males to cause sexual-dimorphism in tissue-specific p53 life span effects. Exp Gerontol 45:97-105

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