The practice of calorie restriction is demonstrated to slow near every aspect of aging in laboratory species, and in humans it greatly improves measures of health related to risk of age-related disease. Here researchers look specifically at effects on the molecular biochemistry of cells in the brain, protective mechanisms that slow the progression and impact of age-related neurological disorders:
Mechanisms that increase longevity and, perhaps most importantly, promote longer health spans (lower or delayed incidence of age-related diseases) have always attracted attention. The most effective intervention known to date to prevent age-related decline and promote better health spans in a wide variety of organisms, ranging from yeast to primates, is caloric restriction (CR). This dietary intervention typically consists of a 20-40% reduction in caloric intake without micronutrient limitation relative to an ad libitum diet. Perhaps the most striking group of age-related diseases prevented by CR is in the brain. A large number of neurological disorders are age-related, and CR has been demonstrated to effectively prevent these disorders. CR also improves age-related declines in memory and learning abilities observed in elderly animals. Although the mechanisms by which CR exerts its effects are poorly understood, mitochondria, as master regulators of cellular metabolism, are believed to play an important role in the cellular adaptations that take place with the diet.
In the brain, increases in mitochondrial activity may change the susceptibility to excitotoxicity, a pathological process associated with many age-related neurological conditions such as stroke, Alzheimer's disease and Parkinson's disease, in which excessive activation of postsynaptic receptors results in cell death. This neurodegenerative process involves the binding of glutamate or glutamate analogues to NMDA and AMPA receptors, resulting in pathological increases in cytosolic calcium levels and a rapid decrease in ATP levels due to the activation of ionic balance restoration pathways. Mitochondria are the main site for ATP production in neurons and contribute toward cellular calcium buffering by accumulating this ion in a membrane potential-dependent manner. Indeed, interventions that increase mitochondrial calcium buffering capacity protect against excitotoxicity and related conditions. Interestingly, while intermittent fasting (a dietary intervention that consists in offering food ad libitum on alternate days) has been found to be neuroprotective under excitotoxic conditions, the effects of CR on excitotoxicity have not been well explored to date. Furthermore, mechanistic insights toward possible neuroprotective effects of this diet are still scarce. The aim of this study was to determine the effects of CR on excitotoxicity and dissect the molecular mechanisms involved.
We show that CR is also effective in preventing direct excitotoxic damage. Our data show that mitochondria in the brains of CR animals have enhanced electron transport capacity, accompanied by higher levels of some electron transport proteins and proteins involved in mitochondrial morphology and dynamics. Interestingly, the increase in electron transport chain (ETC) enzyme activities does not seem to affect the respiratory rates of isolated mitochondria. Cells seem to be able to regulate independently many different mitochondrial features. In our case, CR increases the levels of cardiolipin in the brain, while the activity of citrate synthase remains constant. Moreover, some, but not all, mitochondrial proteins are enriched in a per mitochondrion basis after CR. Some of the metabolic adaptations that CR induces in the brain seem to be mediated by molecule(s) present in the bloodstream. Indeed, CR serum promotes mitochondrial adaptations in primary neurons analogous those observed in vivo, namely protection against glutamate excitotoxicity. Previous reports in other tissues indicate that metabolic effects observed with CR can be partly reproduced in vitro using serum from animals subjected to the diet. These results support the notion that the metabolic remodeling that takes place with CR can be triggered by circulating molecules. A possible candidate is adiponectin, which is elevated in CR animals. Adiponectin protects against excitotoxicity both in vivo and in vitro.
Our results in brain mitochondria show that CR promotes sizable increases in both the rate and the accumulation capacity for calcium. As a result, under excitotoxic conditions, CR neurons possess a largely enhanced ability to buffer cytosolic calcium levels, which explains the strong resistance toward excitotoxic damage conferred by this dietary intervention both in vitro and in vivo. Overall, we demonstrate that CR is a highly effective intervention to prevent excitotoxic neuronal cell death by enhancing antioxidant capacity, mitochondrial respiratory rates, preventing mitochondrial permeability transition and thus enhancing calcium accumulation capacity, resulting in lower cell death. These properties may be central to the mechanism through which this dietary intervention promotes its many beneficial neurological effects.