Abstract
It has been shown that caloric restriction (CR) delays aging and possibly delays the development of Alzheimer's disease (AD). We conjecture that the mechanism may involve interoceptive cues, rather than reduced energy intake per se. We determined that hunger alone, induced by a ghrelin agonist, reduces AD pathology and improves cognition in the APP-SwDI mouse model of AD. Long-term treatment with a ghrelin agonist was sufficient to improve the performance in the water maze. The treatment also reduced levels of amyloid beta (Aβ) and inflammation (microglial activation) at 6 months of age compared to the control group, similar to the effect of CR. Thus, a hunger-inducing drug attenuates AD pathology, in the absence of CR, and the neuroendocrine aspects of hunger also prevent age-related cognitive decline.
Highlights
Caloric restriction (CR), a reduction in food intake without malnutrition, increases longevity in many invertebrate and vertebrate species [1]
It has been suggested that Sirt1 contributes to the beneficial impact of caloric restriction, which may be mediated, in part, through mechanisms involving the regulation of cellular metabolism, and inflammatory and antioxidant responses [6]
All groups were examined using normal quantile plots for normality, and Levene’s test was used to test for homoscedasticity. Both the control and LY-treatment group were fed ad libitum, and the calorically restricted (CR) group was fed 20% less than the control group
Summary
Caloric restriction (CR), a reduction in food intake without malnutrition, increases longevity in many invertebrate and vertebrate species [1]. It has been suggested that Sirt (a mammalian member of the sirtuin gene family) contributes to the beneficial impact of caloric restriction, which may be mediated, in part, through mechanisms involving the regulation of cellular metabolism, and inflammatory and antioxidant responses [6]. It has been shown that a high caloric intake based on saturated fat promotes AD type Beta-amyloidosis; it has been demonstrated that dietary restriction based on reduced carbohydrate intake is able to prevent it [7] This evidence is consistent with current epidemiological studies suggesting that obesity and diabetes are associated with a .4-fold increased risk of developing AD. The clarification of the mechanisms through which dietary restriction may beneficially influence AD neuropathology and the eventual discovery of future ‘‘mimetics’’ capable of anti-Beta-amyloidogenic activity will help in the development of ‘‘lifestyle therapeutic strategies’’ in aging, AD, and other neurodegenerative disorders
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