Genetic analysis of lifespan by insulin-like signaling

Wolkow, Catherine A.

Abstract

Lifespan in the nematode, Caenorhabditis elegans, is determined by genetic pathways and by environmental conditions. One of the most dramatic genetic effects on longevity is observed in animals with mutations inactivating the nematode's insulin-like signaling pathway. In particular, defects in the DAF-2/insulin-like pathway can triple the adult lifespan. Previous studies showed that DAF-2/insulin signaling affects lifespan non-cell autonomously from different cells in the body. Using a transgenic approach, we have found that cells throughout the nervous system have the capability of promoting normal lifespan through the DAF-2/insulin pathway. This finding suggests that a DAF-2/insulin signaling produces a diffusible signal that coordinates aging in the body. We are currently conducting genetic screens, using RNA-interference, to identify genes involved in the production and reception of this diffusible signal. A second focus of this work is to study how DAF-2/insulin signaling affects metabolism in C. elegans. In humans, insulin is an important controller of metabolism and health, as cellular insulin resistance is a hallmark of type II diabetes. Therefore, we are working to identify how the DAF-2 pathway interacts with known metabolic control pathways, including the TOR kinase pathway that senses nutrient availability. These studies may reveal ways to modify cellular insulin sensitivity. In addition, we are characterizing how mitochondrial function is altered in animals with defective DAF-2/insulin signaling. Ultimately, we hope to understand the metabolic changes that promote long lifespan in daf-2 pathway mutants.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Institute on Aging (NIA)
• Type: Intramural Research (Z01)
• Project #: 1Z01AG000320-04
• Application #: 7132246
• Study Section: (LN)
• Support Year: 4
• Fiscal Year: 2005

Institution

• Name: Aging
• Country: United States

Publications

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