Eat less, live long?

Caloric restriction delays disease onset and mortality in rhesus monkeys.

Colman RJ, Anderson RM, Johnson SC, Kastman EK, Kosmatka KJ, Beasley TM, Allison DB, Cruzen C, Simmons HA, Kemnitz JW, Weindruch R.

Science. 2009 Jul 10;325(5937):201-4.

Caloric restriction has been proposed to increase the lifespan of a number of animals. However, this is for the first time that the benefits of calorie restriction have been shown in a primate. Preliminary results of study started in 1989 (and extended in 1994)on 76 Rhesus monkeys have shown that a 30% calorie restricted diet had many beneficial effects, including an increased disease-free lifespan and delayed onset of senility-associated diseases like diabetes mellitus, cardiovascular diseases, cancer and brain atrophy.

The authors claim that calorie-restricted monkeys "look" younger than their counterparts who were given a free rein at feeding time. In addition they show that there was significantly less mortality due to senility-associated diseases in the calorie restricted animals. These animals were also less prone to developing diabetes and colon adenocarcinoma which is known to be common in aged Rhesus monkeys. Functional MRI images of the brain showed that areas of the brain related to movement and memory were protected from age-related atrophic changes.

This study is interesting because this is probably as near as we can get to doing a large-scale experiment on caloric restriction in a species that is a close relative of man. Although a few descriptive studies in humans do suggest the beneficial effects of a calorie restricted diet in the elderly, ethical considerations virtually preclude a randomized controlled trial of the nature described in this study. The authors say that the study is on-going and the results at the conclusion of the study will reveal more interesting facts.

There have been a number of theories that have tried to explain the apparent ability of calorie restriction to extend life span. A few of the current theories are given below.

1. The "hormesis" theory
The term "hormesis" refers to a wide variety of phenomena where intentional application of a mild stress on an organism elicits a response that enables it to withstand a much stronger stress to which it may be subjected to in future. This kind of response is analogous to the effects of vaccination with a live, attenuated pathogen on the immune system.

I has been shown that when Caenorhabditis elegans is subjected to restriction of glucose availability for metabolism, it induces a state of mild oxidative stress. This elicits a robust antioxidant response in the organism which ultimately resulted in an increased resistance to further oxidative stress. This was probably the first experimental evidence for hormesis being the reason for extended life span following CR.

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2. Sir2/SIRT1 and resveratrol
Sir2 or "silent information regulator 2" is a longevity gene, discovered in baker's yeast cells, that extends lifespan by suppressing DNA instability. In mammals Sir2 is known as SIRT1. Recent discoveries have suggested that the gene Sir2 might underlie the effect of CR. David Sinclair at Harvard Medical School, Boston, showed that in mammals the SIRT1 gene is turned on by a CR diet, and this protects cells from dying under stress.

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Sirtris Pharmaceuticals, Inc., a GlaxoSmithKline-owed biotechnology company based in Cambridge, MA co-founded by Sinclair, is developing resvertrol and other SIRT1 activators for human use. Because life-span extension is not an FDA-approvable indication, the company is developing SIRT1 activators for the treatment of diseases associated with aging including type 2 diabetes and cancer.

3. Free radicals and glycation

A calorie restricted diet provides lesser amounts of energy, thus decreasing the flux through the mitochondrial electron transport chain (ETC). It is known that the ETC is "leaky" and 1-2% of oxygen normally gets converted to superoxide, a free radical that can cause oxidative tissue damage (oxidative stress). Decreased calorie intake can therefore lead to reduced oxidative stress.

Reduced caloric intake will also result in reduced mean glucose levels in blood. It is known that glucose can form adducts with a variety of macromolecules by a non-enzymatic, spontaneous process called "glycation". Glycation of proteins is one of the major mechanisms of pathogenesis of long-term diabetes mellitus. A reduced mean glucose levels would result in decreased glycation and tissue abnormalities associated with protein glycation.

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4. Longevity and subclinical hypothyroidism

A recent study in Ashkenazi Jews has shown that a low thyroid activity as evidenced by moderately elevated TSH levels is associated with extreme longevity. The authors suggest that lowered metabolism associated with low thyroid hormone levels is probably responsible for this effect. They cite the example of the elephant with a very low basal metabolism having a long average lifespan as compared to a mouse with a very high basal metabolism having a very short lifespan.

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5. Neuropeptide Y

One popular hypothesis suggests that the neuroendocrine response to low energy availability mediated by neuropeptide Y released by the arcuate nucleus of the hypothalamus plays a primary role in calorie restriction mediated lifespan extension. A recent review published in Molecular and Cellular Endocrinology explains the scientific basis of this hypothesis.

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References:
Wikipedia article on "Caloric restriction"