Curr Biol 2006 (Feb 7); 16 (3): 296–300 ~ FULL TEXT
Dario R. Valenzano, Eva Terzibasi, Tyrone Genade, Antonino Cattaneo, Luciano Domenici, Alessandro Cellerino
Scuola Normale Superiore,
56100 Pisa, Italy
Resveratrol, a natural phytoalexin found in grapes and red wine, increases longevity in the short-lived invertebrates Caenorhabditis elegans and Drosophila and exerts a variety of biological effects in vertebrates, including protection from ischemia and neurotoxicity. Its effects on vertebrate lifespan were not yet known. The relatively long lifespan of mice, which live at least 2.5 years, is a hurdle for life-long pharmacological trials. Here, the authors used the short-lived seasonal fish Nothobranchius furzeri with a maximum recorded lifespan of 13 weeks in captivity. Short lifespan in this species is not the result of spontaneous or targeted genetic mutations, but a natural trait correlated with the necessity to breed in an ephemeral habitat and tied with accelerated development and expression of ageing biomarkers at a cellular level. Resveratrol was added to the food starting in early adulthood and caused a dose-dependent increase of median and maximum lifespan. In addition, resveratrol delays the age-dependent decay of locomotor activity and cognitive performances and reduces the expression of neurofibrillary degeneration in the brain. These results demonstrate that food supplementation with resveratrol prolongs lifespan and retards the expression of age-dependent traits in a short-lived vertebrate.
From the FULL TEXT Article:
In the present paper we tested the effects of resveratrol on the lifespan and on the onset of age-related markers in the short-lived fish Nothobranchius furzeri, a seasonal fish whose recorded median lifespan in captivity is 9 weeks . This short captive lifespan is a natural trait observed also in one wild-derived population collected by the authors in 2004 (D.R.V., E.T., and A. Cellerino, unpublished data). Other longer-living natural populations of Nothobranchius furzeri exist, and they originate from a more humid habitat (unpublished data), in line with the relationship between length of the rain season and captive lifespan observed in Nothobranchius species . The biological action of resveratrol, we report here, extend8B0000 to vertebrates the longevity effect of resveratrol originally described in yeast, Drosophila, and C. elegans 3 and 5. The effects of resveratrol were not coupled to loss of fertility, in agreement with the effects found by others in C. elegans and Drosophila . More importantly, this effect was observed with treatments starting in early adult life and effected functional parameters such as locomotor activity and cognitive deficit, which are observed during vertebrate and human aging 21, 22, 23 and 24. A complex dietary supplement was shown to cause a small extension of longevity in mice , and supplementation of L-Acetyl-Carnitine was shown to retard rat locomotor and cognitive aging 22 and 23.
The natural polyphenol resveratrol has received much attention for its possible pharmacological use. It was reported to have anticancer and antiinflammatory action in vitro 26 and 27 and neuroprotective action in vitro 6, 7, 9, 10 and 28 and in vivo . The mechanisms of action of resveratrol are multiple . It inhibits mitochondrial ATPase in mammals 29 and 30 and was reported to activate the NAD-dependent hystone deacetylase sirtuins in nematodes, flies, and rodents 5 and 6. The effects of resveratrol in nematodes and flies require the presence of a functional Sir2 gene . Overexpression of the mammalian homolog of sir2, SIRT1, has reported to be neuroprotective in a variety of models, and this effect is mimicked by resveratrol 6, 7 and 28. Finally, dietary restriction, the best-studied life-extension treatment, causes overexpression of SIRT1 , and its effects on lifespan are not additive to those of resveratrol in Drosophila . All these data raise the possibility that resveratrol mimics dietary restriction by decreasing the aging rate though activation of SIRT1. However, more recent results have shown that resveratrol increases Sir2 or SIRT1 activity only if the substrate is conjugated to a nonphysiological fluorescent moiety 32 and 33. So, at present, the mechanism underlying the life-extension property of resveratrol and its relationship with calorie restriction remain unclear. The effect of resveratrol is mimicked by overexpression of sirtuins 6, 7 and 28, but does not seem to be mediated by direct action on sirtuins 32 and 33.
Life extension by resveratrol is associated with a change in the slope of the mortality trajectory, i.e., the time-dependent increase in death risk is lowered in resveratrol-fed fishes compared to control-fed ones. A similar effect is observed in Drosophila when the temperature is reduced and was linked to a reduction in the age-dependent accumulation of biochemical irreversible damage . This effect is different from the life extension induced by dietary restriction, which, at least in Drosophila, is tied to time-restricted reduction in the acute risk of death without changes in the slope of the mortality rate . If this interpretation can be extended to N. furzeri, it would further suggest caution when equating the effects of resveratrol with dietary restriction. We observed that resveratrol induced an early increase in death rate after administration, suggesting a possible hormetic role, i.e., its weakly toxic action would stimulate a stress response and eventually increase lifespan and retard ageing. This view is in agreement with the resveratrol-dependent activation of detoxification enzymes observed in in vitro studies .
Resveratrol has shown neuroprotective activity in a variety of paradigms both in vivo and in vitro 6, 7, 9, 10 and 28. Invertebrate studies have revealed the importance of the nervous system in regulating lifespan, as neuronal-specific gene manipulations and neuroprotective drugs can change the longevity of both worms and flies 2, 36, 37 and 38. Resveratrol-fed fishes showed remarkable preservation of operant learning and prevention of age-dependent neurodegeneration. The possibility cannot be excluded that life extension induced by resveratrol is secondary to a protective action on the nervous system.
The mechanisms by which resveratrol prolongs lifespan in model organism are not clear, but the observation that its supplementation with food extends vertebrate lifespan and delays motor and cognitive age-related decline could be of high relevance for the prevention of aging-related diseases in the human population.