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An insulinlike signaling pathway controls Caenorhabditis elegans aging, metabolism, and development. Mutations in the daf-2 insulin receptor-like gene or the downstream age-1 phosphoinositide 3-kinase gene extend adult life-span by two- to threefold. To identify tissues where this pathway regulates aging and metabolism, we restored daf-2 pathway signaling to only neurons, muscle, or intestine. Insulinlike signaling in neurons alone was sufficient to specify wild-type life-span, but muscle or intestinal signaling was not. However, restoring daf-2 pathway signaling to muscle rescued metabolic defects, thus decoupling regulation of life-span and metabolism. These findings point to the nervous system as a central regulator of animal longevity.
Each species has a characteristic life-span, ranging from 10 days for the nematode Caenorhabditis elegans to 80 years for humans. Despite these vast differences in life-span, shared features of aging in diverse species support the existence of a common mechanism for life-span determination (1). Reductions in caloric intake, insulin/insulinlike growth factor-I (IGF-I) signaling, and free radical levels can lengthen the life-span of animals as divergent as nematodes, Drosophila, and mammals (1-3). Mutations that decrease C. elegans daf-2 insulin/IGF-I-like receptor or age-1 phosphoinositide 3-kinase signaling result in severalfold extension of adult life-span (2, 4, 5) and increased accumulation of fat (2, 6-8). Null mutations in daf-2 or age-1 cause constitutive arrest at the dauer larval stage; dauer larvae have slowed metabolic rates, store large amounts of fat, express high levels of antioxidant enzymes such as catalase and superoxide dismutase (SOD), and live longer than reproductive adults (9). One reasonable hypothesis is that free radicals generated as by-products of metabolism damage cellular components (10). The lower level of free radicals in daf-2 insulinlike signaling mutants is essential for life-span extension: The life-span extension in a daf-2 mutant requires the activity of a cytosolic catalase ctl-1 (11).
The cells where daf-2 pathway signaling is required for signaling normal life-span are not known. Insulinlike signaling may regulate metabolism and free radical production directly in aging skin or muscle, or these pathways may act in key signaling centers that then coordinately control the senescence of the entire organism. In addition, it is not clear whether insulin/IGF-I regulation of life-span is simply coregulated with metabolism or whether the metabolic shifts are mechanistically connected to the life-span regulation. Several...