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Model for CR Effects on Mammalian Aging
Posted on: May 21, 2003

For almost 70 years, calorie restriction has been known to extend life span. Despite the extensive physiological characterisation of this dietary regimen, the molecular basis for the slowing in aging remains unsolved. Several classical models for CR propose a mechanical basis for the slowing of aging and extension of life span. For example, the accumulation of damage by oxidation or glycation may be expected to slow down because of reducing calories in the diet. However, experiments in yeast showed that the added life span during CR is not a mechanical output of low calories, but a process that is highly regulated. In this organism, CR triggers a metabolic shift toward respiration that activates the regulator SIR2. Could the extension in mammalian life span by CR also be a regulated process?

The chain of events that follows the imposition of CR in mammals could be modelled (Fig.).

Figure. Model of how calorie restriction may extend life span in mammals. Effects occur at two levels: (1) sensing CR to adjust hormonal levels and (2) executing a slowing of aging on all organs. Roles for Sir2 genes are proposed at both levels, as discussed in the text.

Scientists speculate that the altered physiology resulting from lower levels of calories induces primary changes in the neuroendocrine system. As already known, glucose-sensing neurons in the hypothalamus, as well as 13-cells in the pancreas, somehow recognize a slowing in the rate of conversion of NAD to NADH during CR. This metabolic change likely results in a reduction in the secretion of growth hormone from the pituitary and insulin from the pancreas. Low GH would in turn reduce levels of IGF-1 made by the liver. In addition to affecting IGF-l, the lowering of other pituitary hormones, the gonadotropins, slows reproductive capabilities of the animal.

It could be stated that mammalian Sir2 proteins may play roles at two critical positions in the pathway of CR effects on aging. The first would occur during the sensing of CR, leading to changes in levels of hormones in the blood stream. Because Sir2 proteins are NAD-dependent deacetylases, they are well suited to this regulatory function and may play key roles in the pituitary and pancreas in sensing the conversion of NAD to NADH and resetting the levels of insulin and IGF-l that are released. Such a mechanism would bespeak a conserved role of Sir2 proteins as sensors of CR from yeast to mammals. The resulting endocrinological changes would allow the animal to mount a coordinated regulatory response to CR in different tissues.

Any hormonal changes must execute their effects by slowing aging in the animal. This execution phase is likely mediated, at least in part, by the insulin and IGF-l signalling pathways in receptor-bearing cells. The precise effects of the hormone-receptor interaction may vary from organ to organ, because different cells bear different constellations of regulators. In general, however, longevity-promoting effects are expected to result from decreasing the insulin and IGF-l pathways. In both C. elegans and mammals, these pathways impinge on transcription factors of the forkhead family. The worm factor is Daf-16 and the mammalian homologs are FOXO1-FOXO3. Decreased signalling by insulin/IGF-l activates forkhead transcription factors, which in turn increase resistance to stress in mammalian cells and worms. An increase in stress resistance is a hallmark of CR in a wide variety of organisms.

Changes that are not mediated by hormones may also be important. For example, metabolic changes on their own may directly slow aging in organs. In this regard, mammalian Sir2 proteins may play a pivotal role in some organs by recognizing the altered metabolism. If the metabolic shift during CR increases the activity of SIR2 in tissues with nondividing cells, it may directly slow apoptosis and age-dependent degeneration of organs such as the brain and perhaps the heart. Finally, metabolism-mediated changes in cells may synergize with changes in the levels of circulating insulin/IGF-1 hormones. In this regard, it is interesting that the worm sir- 2.1 extends life span by down regulating the insulin/IGF-1 responsive signalling pathway. It is tempting to speculate that mammalian Sir2 proteins play second role during this execution phase of CR by modulating the insulin and IGF-1 signalling pathways in hormone- responsive cells.

Extension of life span by CR in mammals is a multidimensional phenomenon, which has ramifications ranging from endocrinology to metabolism to cell biology. The studies in yeast imply that the extension of life span by CR is a regulated process. It is important therefore to consider regulatory mechanisms in any discussion of how CR slows aging in mammals.

SIR2: gene regulates the life span in yeast mother cells; mutations that inactivate SIR2 shorten the life span, and overexpression of SIR2 extends it.

Source: Jana Koubova and Leonard Guarente; How does calorie restriction work?; Genes & Development 17:313-321, 2003
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