Stabilization of the hypoxia-inducible factor-1 (HIF-1) increases lifespan and healthspan in nematodes through an unknown mechanism. We report that neuronal stabilization of HIF-1 mediates these effects in C. elegans through a cell non-autonomous signal to the intestine resulting in activation of the xenobiotic detoxification enzyme flavin-containing monooxygenase-2 (FMO-2). This pro-longevity signal requires the serotonin biosynthetic enzyme TPH-1 in neurons and the serotonin receptor SER-7 in the intestine. Intestinal FMO-2 is also activated by dietary restriction (DR) and necessary for DR-mediated lifespan extension, suggesting that this enzyme represents a point of convergence for two distinct longevity pathways. FMOs are conserved in eukaryotes and induced by multiple lifespan-extending interventions in mice, suggesting that these enzymes may play a critical role in promoting health and longevity across phyla.
SummaryFibroblast cell lines were developed from skin biopsies of eight species of wild-trapped rodents, one species of bat, and a group of genetically heterogeneous laboratory mice. Each cell line was tested in vitro for their resistance to six varieties of lethal stress, as well as for resistance to the nonlethal metabolic effects of the mitochondrial inhibitor rotenone and of culture at very low glucose levels. Standard linear regression of species-specific lifespan against each species mean stress resistance showed that longevity was associated with resistance to death induced by cadmium and hydrogen peroxide, as well as with resistance to rotenone inhibition. A multilevel regression method supported these associations, and suggested a similar association for resistance to heat stress. Regressions for resistance to cadmium, peroxide, heat, and rotenone remained significant after various statistical adjustments for body weight. In contrast, cells from longer-lived species did not show significantly greater resistance to ultraviolet light, paraquat, or the DNA alkylating agent methylmethanesulfonate. There was a strong correlation between species longevity and resistance to the metabolic effects of low-glucose medium among the rodent cell lines, but this test did not distinguish mice and rats from the much longer-lived little brown bat. These results are consistent with the idea that evolution of long-lived species may require development of cellular resistance to several forms of lethal injury, and provide justification for evaluation of similar properties in a much wider range of mammals and bird species.
Transcriptional regulation of the antioxidant response element (ARE) by Nrf2 is important for the cellular adaptive response to toxic insults. New data show that primary skin-derived fibroblasts from the long-lived Snell dwarf mutant mouse, previously shown to be resistant to many toxic stresses, have elevated levels of Nrf2 and of multiple Nrf2-sensitive ARE genes. Dwarf-derived fibroblasts exhibit many of the traits associated with enhanced activity of Nrf2/ARE, including higher levels of glutathione and resistance to plasma membrane lipid peroxidation. Treatment of control cells with arsenite, an inducer of Nrf2 activity, increases their resistance to paraquat, hydrogen peroxide, cadmium, and UV light, rendering these cells as stress resistant as untreated cells from dwarf mice. Furthermore, mRNA levels for some Nrf2-sensitive genes are elevated in at least some tissues of Snell dwarf mice, suggesting that the phenotypes observed in culture may be mirrored in vivo. Augmented activity of Nrf2 and ARE-responsive genes may coordinate many of the stress resistance traits seen in cells from these long-lived mutant mice.The discovery of single gene mutations that extend life span, first in invertebrates (43,48,60) and then in mice (9, 14, 19), has provided new momentum for defining the molecular mechanisms that control the aging process. Since Harman first proposed the free radical theory of aging (23), many lines of evidence have suggested that oxidative stress plays an important role in aging. In roundworms (Caenorhabditis elegans) (44, 52) and fruit flies (Drosophila melanogaster) (7, 67, 109), mutations resulting in resistance to toxic stresses, both oxidative and otherwise, tend to result in increases in longevity. The relative importance of oxidation damage as a regulator of life span is more controversial. Longevity is often associated with resistance to oxidative injury within and among species, but most attempts to retard aging by antioxidant treatments have failed to show beneficial effects, and mutations that promote oxidative damage in mice have often had little impact on life span (25,72,81,86,96). Utilizing cells from the Snell dwarf mouse, a model of extended longevity, we are attempting to find the mechanism behind cellular stress resistance in hopes of relating this resistance to the delayed aging of the Snell dwarf animal.Snell dwarf mice are homozygous for a mutation at the Pit-1 locus which causes improper development of the anterior pituitary, leading to low levels of growth hormone, thyroid stimulating hormone, and prolactin in young and adult mice (10, 30). These pituitary defects lead to diminished circulating levels of insulin-like growth factor 1 (IGF-1) and thyroxine, which in turn result in reduced size and hypothermia. Snell dwarf mice, like the closely related Prop1 mutant Ames dwarf (9), live approximately 40% longer than littermate controls on several different background stocks (19,20) and show delay in many forms of aging-related pathologies (1,3,19).Previous work has shown that pr...
SUMMARY The hypoxia-inducible factor HIF-1 has recently been identified as an important modifier of longevity in the roundworm Caenorhabditis elegans. Studies have reported that HIF-1 can function as both a positive and negative regulator of lifespan, and several disparate models have been proposed for the role of HIF in aging. Here, we resolve many of the apparent discrepancies between these studies. We find that stabilization of HIF-1 increases life span robustly under all conditions tested; however, deletion of hif-1 increases life span in a temperature-dependent manner. Animals lacking HIF-1 are long-lived at 25°C but not at 15°C. We further report that deletion or RNAi knock-down of hif-1 impairs healthspan at lower temperatures due to an age-dependent loss of vulval integrity. Deletion of hif-1 extends life span modestly at 20°C when animals displaying the vulval integrity defect are censored from the experimental data, but fails to extend life span if these animals are included. Knock-down of hif-1 results in nuclear relocalization of the FOXO transcription factor DAF-16, and DAF-16 is required for life span extension from deletion of hif-1 at all temperatures regardless of censoring.
Stabilization of the hypoxia-inducible factor (HIF-1) protein extends longevity in Caenorhabditis elegans. However, stabilization of mammalian HIF-1α has been implicated in tumor growth and cancer development. Consequently, for the hypoxic response to benefit mammalian health, we must determine the components of the response that contribute to longevity, and separate them from those that cause harm in mammals. Here, we subject adult worms to low oxygen environments. We find that growth in hypoxia increases longevity in wild-type worms but not in animals lacking HIF-1 or DAF-16. Conversely, hypoxia shortens life span in combination with overexpression of the antioxidant stress response protein SKN-1. When combined with mutations in other longevity pathways or dietary restriction, hypoxia extends life span but to varying extents. Collectively, our results show that hypoxia modulates longevity in a complex manner, likely involving components in addition to HIF-1.
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