Dietary Restriction and Epigenetics: Part I.

Biological aging occurs concomitantly with chronological aging and is commonly burdened by the development of age-related conditions, such as neurodegenerative, cardiovascular, and a myriad of metabolic diseases. With a current global shift in disease epidemiology associated with aging and the resultant social, economic, and healthcare burdens faced by many countries, the need to achieve successful aging has fueled efforts to address this problem. Aging is a complex biological phenomenon that has confounded much of the historical research effort to understand it, with still limited knowledge of the underlying molecular mechanisms. Interestingly, dietary restriction (DR) is one intervention that produces anti-aging effects from simple organisms to mammals. Research into DR has revealed robust systemic effects that can result in attenuation of age-related diseases via a myriad of molecular mechanisms. Given that numerous age-associated diseases are often polygenic and affect individuals differently, it is possible that they are confounded by interactions between environmental influences and the genome, a process termed 'epigenetics'. In part one of the review, we summarize the different variants of DR regimens and their corresponding mechanism(s) and resultant effects, as well as in-depth analysis of current knowledge of the epigenetic landscape.

Pin1 promotes neuronal death in stroke by stabilizing Notch intracellular domain.

OBJECTIVE: Stroke is a leading cause of mortality and disability. The peptidyl-prolyl cis/trans isomerase Pin1 regulates factors involved in cell growth. Recent evidence has shown that Pin1 plays a major role in apoptosis. However, the role of Pin1 in ischemic stroke remains to be investigated. METHODS: We used Pin1 overexpression and knockdown to manipulate Pin1 expression and explore the effects of Pin1 in cell death on ischemic stress in vitro and in a mouse stroke model. We also used Pin 1 inhibitor, γ-secretase inhibitor, Notch1 intracellular domain (NICD1)-deleted mutant cells, and Pin1 mutant cells to investigate the underlying mechanisms of Pin1-NICD1-mediated cell death. RESULTS: Our findings indicate that Pin1 facilitates NICD1 stability and its proapoptotic function following ischemic stroke. Thus, overexpression of Pin1 increased NICD1 levels and enhanced its potentiation of neuronal death in simulated ischemia. By contrast, depletion or knockout of Pin1 reduced the NICD1 level, which in turn desensitized neurons to ischemic conditions. Pin1 interacted with NICD1 and increased its stability by inhibiting FBW7-induced polyubiquitination. We also demonstrate that Pin1 and NICD1 levels increase following stroke. Pin1 heterozygous (+/-) and knockout (-/-) mice, and also wild-type mice treated with an inhibitor of Pin1, each showed reduced brain damage and improved functional outcomes in a model of focal ischemic stroke. INTERPRETATION: These results suggest that Pin1 contributes to the pathogenesis of ischemic stroke by promoting Notch signaling, and that inhibition of Pin1 is a novel approach for treating ischemic stroke.