Longevity is influenced by genetic pathways and environmental factors. The goals of this project are to (a) elucidate mechanisms by which some genes enhance longevity and (b) identify environmental and physiological factors that can slow aging. These studies focus on aging in the nematode, Caenorhabditis elegans, which is one of the premier organisms for studying aging. The current popularity of C. elegans as a focus for studies of aging comes from its short lifespan (2-3 weeks), ease of cultivation and amenability to genetic manipulation.? ? Insulin-like signaling pathways are important regulators of longevity in several species, from worms to flies to mice, and could also affect human longevity. In C. elegans, lifespan can be increased dramatically by mutations that disrupt signaling downstream of the insulin receptor-like (IR) protein, DAF-2. In addition to regulating lifespan, DAF-2/IR signaling regulates larval development and adult stress resistance and metabolism. Extended lifespan in mutants with disrupted insulin signaling results from activation of DAF-16, a FOXO transcription factor which is a conserved target of insulin-like pathways in many animals. When active, DAF-16/FOXO controls expression of an array of genes that promote longevity and stress resistance. Thus, FOXO transcription factors may be evolutionarily conserved regulators of longevity. ? ? Current work aims to define how FOXO transcription factors affect longevity and to identify FOXO-interacting pathways. First, we have described how DAF-2/insulin receptor signaling within a variety of cell types can promote normal lifespan. These findings led to the hypothesis that DAF-2 signaling regulates longevity and development through an endocrine-like output. Using microarray-based analysis of gene expression, we compared global gene expression profiles in long-lived animals lacking insulin signaling and two strains with insulin-signaling restored to specific tissues. This analysis revealed specific transcriptional targets of the insulin pathway that are regulated in response to tissue-restricted insulin signaling. Current work is focused on elucidating the signaling pathways that couple with insulin signaling to regulate these targets. ? ? We are also working to identify compounds with prolongevity activity in C. elegans. Lead compounds that clear this screen can be further studied for their effects on aging in mammals, which requires more time-consuming and costly procedures. Previous work focused on polyphenolic proanthocyanins from blueberries. We also recently completed analysis of a panel of stilbene molecules differing in methoxylation at the R groups. Stilbenes are also polyphenolic compounds found in a variety of plants. In contrast to the prolongevity effects of blueberry proanthocyanins, the methoxylated stilbenes were toxic to adult C. elegans. Methoxylated stilbenes also inhibited germline tumor growth in animals carrying a mutation resulting in uncontrolled mitotic proliferation of germcells. This is the first systematic demonstration that stilbene methoxylation can increase bioactivity in a whole animal. Future work will focus on identifying the biological targets of methoxylated stilbenes in C. elegans.? ? These studies are complemented by structural studies of aging-related changes in the C. elegans pharynx, a neuromuscular organ responsible for food ingestion and mechanical disruption. Using computer-based image classification, we examined patterns of structural change in the pharynx during aging. The analysis revealed the existence of several stable morphology states that were associated with characteristic points of the C. elegans lifespan. Particular ages were associated with transitions between sequential morphology states. We hypothesize that the stability of aging morphology states reflects the activity of cellular homeostatic mechanisms coping with aging-related ceellular changes. The identification of these stable aging morphology states introduces a novel biomarker of aging that may be useful for studying the mechanisms leading to aging-related declines.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Intramural Research (Z01)
Project #
1Z01AG000320-07
Application #
7732203
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
2008
Total Cost
$1,129,153
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Hunt, Piper R; Son, Tae Gen; Wilson, Mark A et al. (2011) Extension of lifespan in C. elegans by naphthoquinones that act through stress hormesis mechanisms. PLoS One 6:e21922
Iser, Wendy B; Wilson, Mark A; Wood 3rd, William H et al. (2011) Co-regulation of the DAF-16 target gene, cyp-35B1/dod-13, by HSF-1 in C. elegans dauer larvae and daf-2 insulin pathway mutants. PLoS One 6:e17369
Wilson, Mark A; Rimando, Agnes M; Wolkow, Catherine A (2008) Methoxylation enhances stilbene bioactivity in Caenorhabditis elegans. BMC Pharmacol 8:15
Iser, Wendy B; Wolkow, Catherine A (2007) DAF-2/insulin-like signaling in C. elegans modifies effects of dietary restriction and nutrient stress on aging, stress and growth. PLoS One 2:e1240
Iser, Wendy B; Gami, Minaxi S; Wolkow, Catherine A (2007) Insulin signaling in Caenorhabditis elegans regulates both endocrine-like and cell-autonomous outputs. Dev Biol 303:434-47
Zou, Sige; Sinclair, Jason; Wilson, Mark A et al. (2007) Comparative approaches to facilitate the discovery of prolongevity interventions: effects of tocopherols on lifespan of three invertebrate species. Mech Ageing Dev 128:222-6
Wolkow, Catherine A (2006) Identifying factors that promote functional aging in Caenorhabditis elegans. Exp Gerontol 41:1001-6
Lee, Garrick D; Wilson, Mark A; Zhu, Min et al. (2006) Dietary deprivation extends lifespan in Caenorhabditis elegans. Aging Cell 5:515-24
Wilson, Mark A; Shukitt-Hale, Barbara; Kalt, Wilhelmina et al. (2006) Blueberry polyphenols increase lifespan and thermotolerance in Caenorhabditis elegans. Aging Cell 5:59-68
Wolkow, Catherine A; Iser, Wendy B (2006) Uncoupling protein homologs may provide a link between mitochondria, metabolism and lifespan. Ageing Res Rev 5:196-208

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