Extending healthy life span--from yeast to humans

Abstract

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.

Figure 1

A) A model for the conserved nutrient signaling pathways that regulate longevity in various organisms and mammals (see text). The role of the TOR-S6K pathway in promoting aging appears to be conserved from yeast to mammals. By contrast, both the AC-PKA pathways and the and TOR-S6K pathway promote aging in yeast and mammals, whereas an insulin/IGF-I-like receptor accelerates aging in worm, flies, and possibly mice. Similar transcription factors (GIS1, MSN2/4, DAF-16, FOXO) affect either stress resistance or aging in all the major model organisms. Notably, in the multicellular worms, flies and mice, it is the function of these genes and pathways in particular cell types that affect aging and stress resistance, as depicted for mammals in panel B (see text). B) Deficiency in GH/IGF-I signaling leads to life span extension and increased stress resistance in various mouse cell types (see text).

Figure 2

Food level, fecundity and longevity. Median life span and fecundity are negatively affected by a very low nutrient concentration in higher eukaryotes. However, life span but not fecundity is optimized by DR.

Figure 3

A) Mortality from age-related causes for control and DR rhesus monkeys. Monkeys were DR for 15-20 years. B) Mortality from all causes (adapted from (63)).

Figure 4

A) Jaime Guevara, MD (left) and a GHR deficient subject in the mountains of Southern Ecuador (right) b) Composite photograph of a DR practitioner before starting DR with adequate nutrition (on the left: weight 180 lb or 81.6 kg; BMI 26.0 kg/m2), and after 7 years of DR (on the right: weight 134 lb, or 60.8 kg; BMI 19.4 kg/m2). Total cholesterol and LDL cholesterol declined from 244 mg/dl and 176 mg/dl (pre-DR) to 165 mg/dl and 97 mg/dl respectively, while HDL cholesterol increased from 37 mg/dl to 57 mg/dl. Fasting blood glucose and blood pressure declined also from 87 mg/dl and 144/87 mmHg to 74 mg/dl and 94/61 mmHg, respectively.