Interventions that might delay ageing have long attracted interest, but the majority of more recent studies in this field have used short-lived organisms as models, such as yeast, nematode worms and fruit flies. Two recent papers — published in Science and Nature — offer insights into the ageing process in higher organisms.

The first paper, by Colman and colleagues, described a study of calorie restriction — which has been shown to extend lifespan in several model organisms — in adult Rhesus macaques over a 20-year period. The authors examined age-associated con-ditions that are prevalent in humans, including diabetes, cancer, cardio-vascular disease and brain atrophy, in primates that were subjected to a 30% restriction of calorie intake.

When deaths due to age-related causes were distinguished from those due to acute conditions that are unre-lated to ageing, it was found that 37% of the control animals died of age-related causes, compared with 13% of the calorie-restricted group. In this group, body weight was reduced (primarily owing to a decrease in total fat mass) compared with the control group and there was no impairment of glucose homeostasis; furthermore, diabetes was prevented. The incidence of neoplasia and cardiovascular disease were both reduced by 50% in the animals on a calorie-restricted diet, compared with the control group. Moreover, calorie restriction reduced age-associated brain atrophy — a characteristic of human ageing that is not accurately reproduced in smaller mammals — in key regions that promote motor function and executive function.

The overall incidence of age-associated disease was approximately three times greater in control animals

than in animals on the calorie-restricted diet. This indicates that the calorie-restricted animals were biologically younger than animals that were fed normally.

The second study, by Harrison and colleagues, examined the effect of rapamycin — an inhibitor of mam-malian target of rapamycin (mTOR) — on lifespan in mice, as genetic deletion of mTOR in short-lived organism models had been found to extend lifespan. To avoid genotype-specific effects on disease suscepti-bility, a genetically heterogeneous mouse population was studied. Mice were fed rapamycin beginning at 600 days of age, which is approximately equivalent to a 60-year-old human.

At each of the three institutions at which these studies were inde-pendently conducted, rapamycin increased lifespan in males and females. Life expectancy at 600 days was increased by 28% for males and 38% for females. Maximum lifespan, defined on the basis of age at 90% mortality, was also increased by

rapamycin: by 14% for females and 9% for males. Although rapamycin enhanced lifespan, it did not change the distribution of the presumed causes of death. It also reduced mid-life mortality risk, as assessed in mice that were fed rapamycin from 270 days of age.

The authors suggested that the increase in lifespan that is observed with rapamycin treatment may be due to a combination of anticancer effects, and effects on resistance to cellular stress and response to nutrients. Rapamycin is unlikely to be suitable as an anti-ageing drug because it is a potent immunosup-pressant; however, this study high-lights the role of the mTOR pathway in the control of ageing in mammals.

Charlotte Harrison

ORIGINAL RESEARCH PAPERS Colman, R. J. et al. Caloric restriction delays disease onset and mortality in Rhesus monkeys. Science 325, 201–204 (2009) | Harrison, D. E. et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460, 392–395 (2009)

AG E I N G

Secrets of a long life

R e s e a R c h h i g h l i g h t s

nATuRe RevIeWs | Drug Discovery vOLuMe 8 | sepTeMbeR 2009

© 2009 Macmillan Publishers Limited. All rights reserved