Caloric restriction (CR) is a dietary regimen known to promote lifespan by slowing down the occurrence of age-dependent diseases. The greatest risk factor for neurodegeneration in the brain is age, from which follows that CR might also attenuate the progressive loss of neurons that is often associated with impaired cognitive capacities. In this study, we used a transgenic mouse model that allows for a temporally and spatially controlled onset of neurodegeneration to test the potentially beneficial effects of CR. We found that in this model, CR significantly delayed the onset of neurodegeneration and synaptic loss and dysfunction, and thereby preserved cognitive capacities. Mechanistically, CR induced the expression of the known lifespan-regulating protein SIRT1, prompting us to test whether a pharmacological activation of SIRT1 might recapitulate CR. We found that oral administration of a SIRT1-activating compound essentially replicated the beneficial effects of CR. Thus, SIRT1-activating compounds might provide a pharmacological alternative to the regimen of CR against neurodegeneration and its associated ailments.
Wednesday, June 05, 2013
The chemistry of protecting our brains by fasting.
Actually, I'm making a big assumption in the post title... namely that the results obtained by Gräff et al. in mice would extrapolate to similar finding in the human brain. In several animal models, a reduced consumption of calories seems to protect against cognitive deficits such as memory loss, in addition to acting on many different cell types and tissues to slow down aging. They found that caloric restriction effectively delays the onset of neurodegeneration and preserves structural and functional synaptic plasticity as well as memory capacities. Fasting activates the expression and activity of the nicotinamide adenine dinucleotide (NAD)–dependent protein deacetylase SIRT1, a known promoter of neuronal life span. (A deacetylase is an enzyme that cleaves acetate groups - think acetic acid or vinegar - from their attachment to proteins.) Surprisingly, this effect of reduced consumption of calories is mimicked by a small-molecule SIRT1-activating compound. (Just in case you were curious, the compound is SRT3657 [tertα-butyl 4-((2-(2-(6-(2-(tert-butoxycarbonyl(methyl)amino)ethylamino)-2-butylpyrimidine-4- carboxamido)phenyl)thiazolo[5,4-b]pyridin-6-yl)methoxy)piperidine-1-carboxylate])!! Mice treated with this substance recapitulated the beneficial effects of caloric restriction against neurodegeneration-associated pathologies. If this mechanism also applies to humans, SIRT1 may represent an appealing pharmacological target against neurodegeneration. Here is the abstract: