Monday, April 19, 2010

Two routes to slowing aging...

Fontana et al. offer a nice article in the April 16 issue of Science Magazine, a review of experiments indicating that caloric restriction and reduced activity of nutrient-sensing pathways may slow aging by similar mechanisms. I am passing on the excellent summary of the article's main points provided by the magazine, as well as the final section of the article on the outlook for the future (well worth a look for resveratrol enthusiasts.  A previous mindblog post on resveratrol side effect has drawn multiple comments):
Nutrient-sensing pathways are central to the aging process
Both dietary restriction -- a reduction of food intake without malnutrition -- and manipulation of nutrient-sensing pathways through mutations or drugs can increase life span and reduce age-related disease in several model organisms. These pathways are conserved during evolution.

Single-celled yeast provides a simple model system for studying aging
The life span of yeast can be increased substantially through both dietary restriction and mutation or drugs. Reduced activity in two major nutrient-sensing pathways is involved.

C. elegans worms are a simple multicellular model system for aging
Life-span increases in C. elegans are similar to those in yeast. As in yeast, aging in C. elegans is delayed by the activation of pathways normally turned on by starvation/food restriction.

Flies provide a more complex model system that allows e.g. sex differences to be studied
The damage response pathways in some unicellular eukaryotes, such as yeast, differ from those in mammals. Their telomeres are tailored to respond to these differences. The way in which telomeres solve the end protection problem thus differs widely between eukaryotes.

Studies of rodents may yield leads for human clinical trials
Both dietary restriction and manipulation of nutrient-sensing pathways through mutation or drugs can reduce the occurrence of age-related diseases and extend life span in rodents. However, dietary restriction in rodents can also have negative effects. Differences in metabolism, life span, and susceptibility to diseases must be taken into account when extrapolating these results to humans.

Limited data exist on life-span extension in primates
Naturally occurring mutations in humans or monkeys help to understand the role of nutrient-sensing pathways in aging. Experimental studies are complicated by the long life spans of primates. The protective effects of dietary restriction against cancer, cardiovascular disease, and diabetes in primates must be weighed against potentially negative long term effects.

A key question is how we can extend the life span without unwanted side effects
The identification of a common set of genes in yeast, worms, flies, and mice that can extend the healthy life span will accelerate progress toward human clinical trials testing drugs that activate these conserved anti-aging pathways. Further mammalian studies are needed to understand whether dietary restriction and the pharmacological modulation of anti-aging pathways can extend life span and reduce pathologies.

Extreme dietary restriction can lead to several detrimental health effects such as amenorrhea, infertility, sarcopenia, osteoporosis, and immune deficiencies. Thus, it will be important to examine these negative side-effects in dietary-restricted subjects that are not malnourished. Indeed, experimental studies are required to evaluate the optimal calorie intake and macro- and micronutrient composition needed for healthy aging in humans, on the basis of age, sex, genotype, and energy expenditure.

Although adjustment of dietary intake and composition may be realistic and beneficial, the severe dietary restriction that induces major health benefits is not a desirable option for most people. Drugs that target nutrient-sensing pathways to obtain the health benefits of dietary restriction are realistic, but the effects of chronic administration require study. For instance, rapamycin, the TOR (target of rapamycin) inhibitor that extends mouse life span, is an immunosuppressant and may not produce an overall health benefit in humans living in an environment with pathogens. However, genetic deletion of the GH receptor or of the downstream S6 kinase in mice extends life span and induces a broad-spectrum improvement in health. More testing of potential disadvantages is required and many open questions remain, but these seem promising drug targets and are hopefully the first of many.

1 comment:

  1. What is being manipulated on the nutrient-sensing pathways?