Slicing Calorie Restriction Ever Finer

Over the past few years, researchers have designed and carried out interesting and ingenious experiments that try to narrow down which of the biological effects of calorie restriction are important when it comes to the resulting benefits to health and longevity. That calorie restriction notably lengthens healthy life span in almost all species tested to date is beyond doubt: eat less while still obtaining the necessary nutrients for survival and live longer as a consequence. The challenge for the scientific community is that the practice of calorie restriction changes an enormous range of metabolic processes and measures: levels of visceral fat tissue, expression patterns of genes known to be involved in aging, cell cycle behavior, body temperature, and so on down a long, long list. All of these factors are interdependent, and very hard to change in isolation of one another.

So what to do? The answer is to design and run experiments such as this one, and step by step aim at narrowing the field:

Calorie restriction (CR) reduces the rate of cell proliferation in mitotic tissues. It has been suggested that this reduction in cell proliferation may mediate CR-induced increases in longevity. The mechanisms that lead to CR-induced reductions in cell proliferation rates, however, remain unclear.

To evaluate the CR-induced physiological adaptations that may mediate reductions in cell proliferation rates we altered housing temperature and access to voluntary running wheels to determine the effects of food intake, energy expenditure, percent body fat and body weight on proliferation rates ... We found that ~20% CR led to a reduction in cell proliferation rates in all cell types. However, lower cell proliferation rates were not observed with (a) reductions in food intake and energy expenditure in female mice housed at 27°C, (b) reductions in percent body fat in female mice provided running wheels, or (c) reductions in body weight in male mice provided running wheels, compared to ad libitum-fed controls. In contrast, reductions in insulin-like growth factor-1 were associated with decreased cell proliferation rates.

Taken together, these data suggest that CR-induced reductions in food intake, energy expenditure, percent body fat and body weight do not account for the reductions in global cell proliferation rates observed in CR. In addition, these data are consistent with the hypothesis that reduced cell proliferation rates could be useful as a biomarker of interventions that increase longevity.

It is interesting that the hot environment CR mice have this distinctive difference in cellular behavior from those raised in a normal environment. The results that point at cell proliferation rates as something peculiar to the core processes of CR rather than any of its secondary effects, such as weight loss, are also interesting. It would be perhaps enlightening to revisit the twenty or more methods known to extend mouse life span and see what they are all doing to cell proliferation rates. If it turns out that a simple measurement could be used to quickly quantify the prospects of any potential new therapy to slow down the aging process, that would be a big deal.

Another item worth noting is the investigation of drugs that can slow cell proliferation - the cancer research community has developed a few of these, but it is a long way from here to something that could be made safe to give to healthy people. All such efforts are made challenging by the enormous complexity of metabolism: changing it safely is very hard, and changing any one aspect of metabolism in isolation is next to impossible.

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