SIRT3: Striking at the heart of aging.

摘要: Ever since the realization that aging is a regulated process, intense research has gone into uncovering key players underlying its regulation. Among most intriguing molecular factors have been uncovered are sirtuins, family of NAD+-dependent deacetylases implicated in lifespan extension model organisms ranging from yeast to flies[1]. Mammals contain seven members sirtuin family, SIRT1-7, which SIRT1 extensively characterized. Although exact role sirtuins mammalian awaits further elucidation, barrage recent studies shown mitochondrial SIRT3 an important play warding off vicissitudes aging. In previous issue Aging, Hafner et al.(2010) add growing body evidence by showing mice lacking develop severe age-related pathologies heart [2]. Aging characterized hypertrophy and fibrosis, although causes unknown. Employing SIRT3−/− mice, al. present linking these phenotypes dysfunction SIRT3[2]. The authors show hearts more prone less resistant stress. They also note mitochondria significantly susceptible swelling, hallmark permeability transition pore (mPTP), multi-protein complex, thought be one main culprits driving pathology mitochondria[3]. Thus, inhibition mPTP could potentially major therapeutic value. found interacts with deacetylates cyclophilin D (CypD), component target prescription drug cyclosporine A (CsA) [4]. Interestingly, lysine residue on CypD targeted adjacent CsA binding site, raising possibility deacetylation might regulate function. Whereas inhibits structurally-related cyclophilins, leading suppression immune system, findings open up tantalizing targeting specifically suppress pernicious effects CypD. This study combined work Someya (2010), Kim Sundaresan (2009) can delay onset multiple tissues [2,5-7]. comes heels Qiu Tao (2010) implicating protection against oxidative stress, cause pathologies[6,8,9]. One targets uncovered, antioxidant superoxide dismutase 2 (SOD2), linked numerous longevity models. strong case built for as protector ravages However, whether actually extend still Also, while activity decrease age due lower levels NAD+, only apparent when older [2,10]. It mystery why phenotypically normal they young. Much remains done understand plays but floodgates opened, emerging increasingly attractive small molecule activators healthspan or even lifespan.