New Drug Targets for Slowing Vascular Ageing: Sirt1, Sirt5, Jund and P66Sch

Abstract

Western societies are aging due to an increasing life span, decreased birth rates, and improving social and health conditions. On the other hand, the prevalence of cardiovascular (CV) and cerebrovascular (CBV) diseases rises with age. Thus, in view of the ongoing aging pandemic, it is appropriate to better understand the molecular pathways of aging as well as age-associated CV and CBV diseases. Oxidative stress contributes to aging of organs and the whole body by an accumulation of reactive oxygen species promoting oxidative damage. Indeed, increased oxidative stress produced in the mitochondria and cytosol of heart and brain is a common denominator to almost all CV and CBV diseases. Accordingly, different aging/longevity genes have been described as potential drug targets being involved in lifespan determination, oxidative stress modulation and CV disease pathophysiology. Among those, the mitochondrial adaptor protein p66(Shc) is deeply involved in age-related CV dysfunction by mediating reactive oxygen species production and translating oxidative stress into apoptotic signals. Furthermore, p66(Shc) was shown to be a potential target to blunt post-ischemic damage in both myocardial infarction and ischemic stroke. Also, the family of deacetylase enzymes, the sirtuins, regulates the aging process, determine lifespan of many species and are involved in oxidative stress modulation and CV diseases. Similarly, the longevity gene JunD, by enhancing antioxidant pathways and reducing the inflammatory response was reported as a critical modulator of ischemia/reperfusion in brain and heart.