Laboratory of Experimental Gerontology
Functional Genomics Unit |
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Sige Zou, Ph.D., Head
Investigator |
| Research Overview: Aging is a fundamental biological process that occurs in most eukaryotic organisms. Genetic analyses of model organisms have uncovered mutations in a number of genes that can affect lifespan. These findings suggest that the genetic mechanisms govern the rate of many aging processes. The goal of the Functional Genomics Unit (FGU) is to understand molecular and cellular mechanisms of aging with focus on the following questions: (1) What are the molecular changes in aging? (2) What factors influence the age-related changes? (3) How do these changes affect aging? |
| Tissue-specific Expression Profile of Aging in Drosophila Melanogaster: Changes in gene expression in aging have been observed in a number of eukaryotic organisms, including nematodes (C. elegans), fruit flies (D. melanogaster), mouse and human. Within an organism, there is evidence indicating that different tissues show different gene expression patterns. To systematically identify tissue-specific factors that affect lifespan and aging processes, researchers in the FGU are investigating the expression profile of aging for different tissues from D. melanogaster, including brain, muscle and tissues in the digestive and reproductive systems (Figure 1). Furthermore, to search for factors influencing age-related and tissue-specific changes, expression patterns are being analyzed for mutant flies with increased lifespan and for flies under oxidative stress and dietary restriction (DR). Increased oxidative stress has been shown to decrease lifespan; whereas, DR has been shown to extend lifespan in most of species tested so far. This work will help to elucidate molecular and cellular mechanisms controlling how different tissues age and how different tissues affect lifespan. |
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| Figure 1-Influence of Aging at the Tissue Level |
| Evolutionarily Conserved Pathways in Aging: Evolutionarily conserved pathways have been discovered in many biological processes. Pathways affecting aging processes are not an exception. For example, conserved components in the insulin/IGF signaling pathways affect lifespan in several species, including worms, flies and mice. With the completion of genome sequences of several model organisms, researchers can now systematically identify the evolutionarily conserved pathways in aging. In collaboration with the laboratories of Drs. Hao Li, Cynthia Kenyon and Cornelia Bargmann at the University of California at San Francisco (UCSF), we developed a bioinformatic method to identify conserved expression patterns using microarray data from different organisms. Using this method to compare C. elegans and D. melanogaster expression data, we found that repression of genes functioning in mitochondrial oxidative respiration starting in early adulthood was a conserved feature of aging. This work supports the importance of mitochondria and energy production pathways in aging. To extend this work and improve the sensitivity to identify conserved patterns of expression, researchers in the FGU are investigating expression profiles of aging for rat and monkey tissues and those under CR in collaboration with other members in the LEG. Based on analysis of expression data from different species, evolutionarily conserved patterns of expression will be identified at the tissue level. Furthermore, attempts are being made to identify transcription factors that regulate expression of genes with conserved expression patterns in D. melanogaster. This project will shed light on universal mechanisms of aging at molecular and cellular levels. |
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| Figure 2-Conserved Insulin/IGF Signaling Pathway and Lifespan |
| Temporal and Spatial Regulation of Lifespan: Temporal and spatial alteration of gene expression was found to extend lifespan in worms, flies and mice. For example, misexpression of a superoxide dismutase (SOD1) in motor neurons or misexpression of a fork-head transcription factor (dFOXO) in fat body of adult heads extends lifespan in D. melanogaster. This suggests that lifespan is regulated at the tissue level. FGU researchers will take advantage of expression data obtained from experiments as proposed above to systematically investigate spatial and temporal regulation of lifespan. It is reasonable to assume that genes showing evolutionarily conserved expression patterns are likely candidates affecting lifespan. Researchers in the FGU will use genetic approaches to characterize these candidates. Loss-of-function mutations or misexpression of candidates in D. melanogaster will be generated in the FGU or obtained from other sources, such as public stock centers. Lifespan of these stocks will be measured to identify genes which can extend lifespan when modified. Based on tissue-specific expression patterns of these lifespan-related genes, how and when these genes affect lifespan at the tissue level will be investigated. In addition, researchers in the FGU in collaboration with researchers at UCSF have identified a subset of neurons that can regulate body size in D. melanogaster. Whether and how these neurons can affect lifespan are now under investigation to gain insights into mechanisms involved in systematic regulation of aging processes. |
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