Abstract
By about eight decades it has been suggested that the longevity in rodent is increased when animals are treated with caloric restriction diet (CR), since this seems to play a primary control and maintenance of basal cell states at various levels. In the brain, one of the factors of aging is oxidative stress, generating neurodegenerative processes, especially in mitochondrial level. Among important generators of oxidative stress, nitric oxide (NO) is notable for also play a key role on stimulating spontaneous activity, along with other hypothalamic protein, the orexin. This neuropeptide, in turn, also controls the sleep/wake and other behaviors and has their activity affected by age (with reduction) and caloric restriction (with increase). Interestingly, both orexin and NO are reduced in aging and the CR can promote increased mitochondrial biogenesis (modulated by NO), increase the orexin, improving cellular respiration and attenuating the reduction of the spontaneous activity. The SIRT3 is a mitochondrial sirtuin what appears to play protective function of this organelle and is reduced in aging, which is attenuated when animals are kept with CR diet. Moreover, it seems that the reduction of degenerative process promoted by CR, and therefore the increase in longevity, only succeeds in the presence of SIRT3. Based on these aspects, the objectives of this project are to determine the spontaneous activity of SIRT3 knockout mice maintened at CR diet, at 5 months (young animals), 15 months (middle age) and 25 months (old), in an analysis that aims to establish relations of CR and SIRT3 on hypothalamic mitochondrial metabolic processes (mitochondrial respiration) in these ages, as well as the concentrations of NO (mitochondrial) and expressions and protein amounts of orexins A and B, their receptors (OXR1 and OXR2 ), and hypothalamic NO synthases as nNOS, eNOS and iNOS. Our hypothesis is that mice which do not express SIRT3 will have reduced their spontaneous activity at all ages as well as severe metabolic mitochondrial disorders, with marked reduction of expression and amount of orexins, their receptors, and the mitochondrial nitric oxide and hypotahalamic NO synthases.
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