Extending healthy life span--from yeast to humans
1 When the food intake of organisms such as yeast and rodents is reduced (dietary restriction), they live longer than organisms fed a normal diet. A similar effect is seen when the activity of nutrient-sensing pathways is reduced by mutations or chemical inhibitors. In rodents, both dietary restriction and decreased nutrient-sensing pathway activity can lower the incidence of age-related loss of function and disease, including tumors and neurodegeneration. Dietary restriction also increases life span and protects against diabetes, cancer, and cardiovascular disease in rhesus monkeys, and in humans it causes changes that protect against these age-related pathologies. Tumors and diabetes are also uncommon in humans with mutations in the growth hormone receptor, and natural genetic variants in nutrient-sensing pathways are associated with increased human life span. Dietary restriction and reduced activity of nutrient-sensing pathways may thus slow aging by similar mechanisms, which have been conserved during evolution. We discuss these findings and their potential application to prevention of age-related disease and promotion of healthy aging in humans, and the challenge of possible negative side effects.
Mechanistic target of rapamycin pathway comes of age
2 Dietary restriction reduces mTORC1 activity in invertebrate organisms and in some mammalian tissues, and pharmacological or genetic disruption of mTORC1 is sufficient to extend lifespan in both invertebrates and mice under non-dietary restriction conditions
Rapamycin fed late in life extends lifespan in genetically heterogeneous mice.
3 Inhibition of the TOR signalling pathway by genetic or pharmacological intervention extends lifespan in invertebrates, including yeast, nematodes and fruitflies; however, whether inhibition of mTOR signalling can extend lifespan in a mammalian species was unknown. Here we report that rapamycin, an inhibitor of the mTOR pathway, extends median and maximal lifespan of both male and female mice when fed beginning at 600 days of age. On the basis of age at 90% mortality, rapamycin led to an increase of 14% for females and 9% for males. The effect was seen at three independent test sites in genetically heterogeneous mice, chosen to avoid genotype-specific effects on disease susceptibility. Disease patterns of rapamycin-treated mice did not differ from those of control mice. In a separate study, rapamycin fed to mice beginning at 270 days of age also increased survival in both males and females, based on an interim analysis conducted near the median survival point. Rapamycin may extend lifespan by postponing death from cancer, by retarding mechanisms of ageing, or both. To our knowledge, these are the first results to demonstrate a role for mTOR signalling in the regulation of mammalian lifespan, as well as pharmacological extension of lifespan in both genders. These findings have implications for further development of interventions targeting mTOR for the treatment and prevention of age-related diseases.
Mechanistic target of rapamycin is a key modulator of ageing and age-related disease
4 Reduction in nutrient intake in the absence of malnutrition, or dietary restriction (also referred to as calorie restriction), extends lifespan in many different species. In fact, other than mTORC1 inhibition, dietary restriction is currently the only intervention known to extend lifespan in yeast ageing models and in worms, flies and mice. mTORC1 is thought to play a part in mediating longevity and health benefits as a result of dietary restriction, which is intuitive given its function in responding to nutrient and growth cues. Dietary restriction reduces mTORC1 activity in invertebrate organisms and in some mammalian tissues, and pharmacological or genetic disruption of mTORC1 is sufficient to extend lifespan in both invertebrates and mice under non-dietary restriction conditions