Calorie Restriction And Aging
Until recently thought to prolong life was a fantasy, however, since it was discovered that the mutation of genes in the worm C. elegans could extend life, began to think that was possible plasticity of aging, as well as that aging could be affected by diet (caloric restriction) or pro-longevity mutations, especially when considering the results of some studies showing the existence of some genes that regulate growth, energy metabolism, signal nutrients and playback and encoding factors such as growth factor similar to insulin / insulin (IIS) or the target of rapamycin (TOR). If caloric restriction has an effect on aging, the progress in the development of strategies and therapies for better aging could be faster, enabling them to improve health, reduce the most common chronic diseases in advanced stages of life and have aging longer with a better quality of life.
Numerous articles from the 70 related caloric restriction (CR) with the extension of life and delay age-related diseases in multiple species, including yeast, nematode worms, flies and rodents.
CR is the only environmental intervention that has shown to prolong life in invertebrates and vertebrates lessening or modifying the changes of aging. Caloric restriction is defined as one that induces “undernourishment”, but without malnutrition and would correspond to an evolutionary adaptive mechanism to protect individuals in times of famine by allowing accommodate the scarce energy resources. The discovery of specific transcription factors related to the RC is allowing progress in understanding this phenomenon.
The identification of genes that regulate pathways of CR in different species and determining the pathways and signals involved, will know the mechanisms operating. For example, it was found that mutations of genes encoding growth factor signals like insulin / insulin (ISS) results in an increase of life. However, this has been attributed exclusively to IIS in flies has not been replicated in worms (C. elegans), and apparently other systems participate.
Sirtuins (SIR) are the first described that induce histone longevity regulated by CR and whose overexpression would increase the life (studies in yeast). However, all these results should be viewed with caution as other studies show that other transcription factors exist which depend on their action (FOX O3a in mammals and in worms DAF16 equivalent), or IIS. This has opened the door to research that seeks to increase the amount of sirtuins and observe the effect of this intervention. The revesratrol a polyphenol plant in vitro increase the SIR2, a type sirtuin, yeast, worms, flies and small fish. The action of the RC has been shown to depend not only increase sirtuins, but activate other pathways, such as AMP protein kinase (AMPK), or the path of ISS.
In relation to oxidative stress and free radical theory, it is estimated that CR would reduce oxidative damage by reducing the damage of macromolecules (lipids and DNA), decreasing the formation of ROS in mitochondria or by enhancing the capacity reparation of the damage. This diet does not act by reducing the metabolism, as was postulated several years ago. Although it is not proven to be the reduction of ROS and damage the mechanism by which CR works by prolonging the life, increased receptor “scavengers” has been reported in studies in worms. We have also found a change in the expression of superoxide dismutase (SOD antioxidant enzyme) in worms, suggesting that regulation of ROS toxicity might be the mechanism by which the DR induced longevity.
The route of the serine protein kinase (TOR), an amino acid sensing pathway, also present in eukaryotic cells and regulates protein synthesis and growth in response to nutrient intake is proposed as a candidate mechanism through RC which could act. And the reduction of amino acids (AA) extends life in yeast, has also been observed that reducing TOR signals it also lengthens. TOR can be inhibited by an antibiotic, rapamycin.
In relation to TOR could say that would be a mechanism by altering the nutritional intake, could change the profile of life. The protein kinase activated by AMP (AMPK) is a switch signal of nutrients, acts as a sensor of cellular energy and may act in the RC. At low energy (AMPalto / ATPbajo) also activates AMPK and inhibits the consumption of energy, for example, decreasing protein synthesis and also inhibiting TOR.
In mammals, TOR acts on the hypothalamus to promote food and regulate glucose in the liver works by increasing gluconeogenesis. Also involved in aging, stress resistance and tumor formation. The RC may act to reduce tumorigenesis by decreasing the activity of TOR. There are studies that have used as an anticancer therapy, such as using rapamycin inhibits TOR in skin cancers and hamartomas. Research findings are contradictory, so cannot say whether the extension of life is produced by reduction of TOR signals or simultaneously silencing other genes or other genes.
According to numerous studies, the reduction of IIS and the lengthening of life and the transcription factor DAF-16 would not be the mechanism through which it operates longevity. Other factors PH-4 and SKN-1 have been observed in studies in worms as essential to induce longevity. The PH-4 is the ortholog of transcription factors called head rakes, “forkhead” (Foxa) observed in mammals, involved in early development and also maintain metabolic homeostasis. In this way, PH-4 would act one way in which the RC, since studies (worms) show that its blockade would nullify the effect of prolonging the life given by the DR, although the mechanism is regulated as PH-4 in response to DR is not clearly established.
SKN-1 in worms and its equivalent in mammalian Nrf1 and 2 are transcription factors that induce detoxifying enzymes that act early in the throat and intestinal development play a role in these stages. During adult life involved in resistance to oxidative damage. It is thought that SKN-1 (worm and its equivalent in mammals) could be the key to regulate the response to the RC, together with a decrease in signal IIS. It is not known whether they act directly between the cytoplasm and nucleus of intestinal cells in response to CR, but when they are deleted, their restoration, for example in neurons, allows the extension of life when there is this type of diet. The mechanisms by which these factors are regulated in response to a low intake of nutrients are not yet known.
Apparently a reduction in food intake (RC) induces physiological changes in organisms for which it acts by modifying the response of a number of factors signaling pathways of these nutrients and signals. As most studies have been developed in worms (C. elegans) and other lower species, is also one of the great challenges of research to show whether the factors described comply with the same or similar functions in more complex organisms.
Although the genetic basis of how CR works in the prolongation of life has not been identified, many of these investigations have led to progress in understanding the complexity of the aging process and may allow in future to develop therapies that improve human health by changing or stopping some of the pathways or mechanisms described.
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