6. RESULTADOS
6.4. Determinación del perfil de citocinas en contenido intestinal de ratones de los
As summarized above, CR is the most reproducible manipulation that extends life span in mammals. It has beneficial effects at the molecular, cellular, and homeostatic systems levels in rodents. Ongoing studies in nonhuman primates have suggested that CR has similar beneficial effects at the systems level in monkeys.65 These primate studies have been too brief to see an effect on longevity. All of this makes CR a potentially attractive nutritional intervention for humans. However, the restrictedness of the diet and its composition would make it impractical as a general intervention in a food-conscious Western society. This has led to the search for CR mimetics, dietary or pharmacological compounds that mimic the biological effects of CR without restricting diet itself.66
Information on many CR mimetic studies is minimal due to the proprietary nature of the work. However, there have been some reviews of noncommercial strategies.59 The first candidate mimetics have targeted energy metabolism, since this appears to be a fundamental trigger of the CR response. The first compound to be tested was 2-deoxyglucose, a glycolytic inhibitor. In one study, the effects of feeding 2-deoxyglucose were compared to the effects of intermittent feeding, a type of dietary restriction, over a 6-month period in young rats.67 Feeding 2-deoxyglucose decreased blood pressure, heart rate, and serum and insulin levels in a manner similar to intermittent feeding. Both treatments also raised stress hormone levels.
In addition to glucose metabolism, lipid metabolism may also be a target for CR mimetics.59 The compounds alpha-lipoic acid and carnitine have been discussed previously in the context of antioxidants (see above). However, in addition to being antioxidants, they also have effects on fatty acid oxidation in mitochondria. Ulti-mately, a combination of compounds may be required to mimic the many effects of CR. Feeding a diet composed of vitamins, minerals, herbs, and antioxidants has been reported to extend longevity in mice.68
2.3.4.2 Hormesis
Masoro defines hormesis in the context of aging research as “the beneficial action resulting from the response of an organism to a low-intensity stressor.”58 Masoro has argued that CR is a low-intensity stressor. It increases stress hormone levels even as it increases life span and improves physiological functioning. In the context of brain aging, this has been referred to as the glucocorticoid paradox of CR. In their review of the literature, Patel and Finch64 concluded that the positive neuroprotective effects of CR outweighed the increase in glucocorticoids that it also produced.
However, Masoro proposes that the increase in glucocorticoids itself may be bene-ficial, perhaps by reducing inflammation.58
In addition to CR, other stressors that may work through hormesis include pro-oxidants, irradiation, heat shock, and exercise.69 From a nutritional standpoint, the most interesting of these is dietary pro-oxidants. As an example, curcumin, an antioxidant derived from turmeric, a curry spice, also induces heat shock proteins, a stress response.70 This compound has been cited as contributing to the reduced
incidence of Alzheimer’s disease in India. This raises the interesting possibility that dietary intake of small amounts of compounds normally considered harmful may induce antioxidant defenses and have long-term beneficial effects.
2.4 SUMMARY
This review has highlighted our knowledge of aging at the molecular level and its interaction with nutrition. Recent studies suggest why certain nutrients may be beneficial and also suggest new strategies. Some of the nutritional interventions are very familiar, such as the antioxidant vitamins. However, even here there are some surprises, as antioxidants such as vitamin E seem to have specific actions in cells that go far beyond their antioxidant properties. These multiple actions are also seen in studies of the Ginkgo preparation EGb761. In recent years, it has become clearer how fruit polyphenols may have beneficial effects at the molecular level. These studies are exciting because this class of compounds is found in fruits such as strawberries, spinach, and blueberries.
Studies of mitochondrial aging have suggested new nutritional interventions such as L-carnitine and lipoic acid. These compounds appear to have specific effects on mitochondrial energy production and antioxidant capability. They have not yet been demonstrated to have an effect on longevity, but they do have an effect on cognitive function in old animals. This would have important implications if they were found to have the same effects in humans.
Finally, recent studies suggest that a mechanism exists in rodents, probably in nonhuman primates and possibly in humans, that responds to caloric stress. This provides a new target for nutritional intervention. This target is particularly attractive since the response to caloric stress is so robust. It may be that true caloric mimetics will be found given the great commercial interest. On the other hand, caloric stress may be just one of broader classes of stress responses. Activating these by nutritional means could potentially give the benefits of an enhanced stress response while minimizing the unpleasant side effects (i.e., hunger) of the stressor itself.
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