Protection against age-related neuronal frailty by sirtuin 1 enhancement

Abstract

In aging and in the diseases associated with the elderly occurs a progressive cognitive loss caused by deteriorating brain function. Sirtuin 1, a member of the sirtuin family of protein deacetylases, is involved in lifespan extension and is considered a neuroprotective protein. The senescence-accelerated prone 8 (SAMP8) mouse, an accelerated aging model, presents an early age-related pattern and shows overproduction of Aß and p-tau. In this study, we performed functional assays of mitochondrial activity and oxidative stress in cultures of neurons from SAMP8 and senescence-accelerated-resistant (SAMR1) mice models to examine the status of neurons with emphasis in the mitochondrial function. The SAMP8 mitochondria presented lower membrane potential and higher vulnerability to mitochondrial damaging agents than SAMR1 mitochondria. This increased vulnerability indicated the presence of a senescence-associated frailty stage in SAMP8 neurons. We assayed the neuroprotective effects of resveratrol, a known Sirtuin 1 enhancer agent, and that of melatonin, also effective in anti-aging mechanisms. Here we show that both, resveratrol and melatonin, protected against the senescence-associated mitochondrial frailty stage in SAMP8 mouse neurons. Mechanisms involved included the enhancement of sirtuin1 expression and antioxidant mechanisms. The beneficial neuronal effects of Sirtuin 1 promoting agents makes this molecule a promising anti-aging target. New studies of Sirtuin 1 overexpression by using lentiviral vectors are ongoing.