Mitochondrial Maintenance Mechanisms of Stem Cells and Aging

摘要： 了解导致衰老的机制可能会导致增加健康寿命的创新策略，以及 这一努力将带来巨大的人类和经济利益。事实上，许多物种(尽管通常是 不仅是发育较慢、寿命较长和体型较大的物种)拥有能够 自我更新和组织再生的理论让人质疑为什么这些生物和它们的体细胞干细胞 确实会变老，而生殖系显然不会。躯体干细胞的功能随着年龄的增长而下降， 这种下降至少部分是由细胞内在机制解释的。虽然经常被视为一种退化的 在这种情况下，体细胞的老化实际上可能是保护性干细胞普遍作用的反映 与成熟细胞相比，对压力和损伤具有不同敏感性的维持机制。 然而，不朽的种系经历了极端的选择，只有最适合的配子才能传递他们的 基因组传给下一代。有证据表明，线粒体功能的质量是一种机制 根据其选择配子。与配子相反，体细胞干细胞主要依赖于 糖酵解ATP的产生，而大多数成熟细胞使用线粒体呼吸。可能是因为他们的 依赖糖酵解，有证据表明，造血干细胞是最具特征的成人干细胞 类型的人比祖细胞更不容易受到线粒体功能受损的影响。因此，我们假设 线粒体在HSC的维持中起着重要的作用，而不是直接依赖于ATP的产生。我们 确实观察到HSCs具有较高的线粒体质量，并且不执行有丝分裂。此外， 线粒体动力学的损害减少了具有广泛淋巴潜能的HSCs的数量 诱导了整个HSC隔室的循环。这些数据表明，线粒体确实在 HSC维护。在这项建议中，我们研究了线粒体维持的机制 HSCs及其对HSCs衰老的影响。我们将检验线粒体受损的假设 HSC的维持将对幼鼠的HSC功能产生负面影响，但可能导致更长时间的维持 HSC在衰老小鼠体内的功能。体细胞维持是机体衰老的一种机制 将与衰老的进化论--对抗多效性理论--惊人地一致 提出在生命早期提供生殖或生存益处的机制在生命后期是有害的 并导致衰老。

Summary: Understanding the mechanisms driving aging may lead to innovative strategies to increase health span, an effort that would carry enormous human and economic benefit. The fact that many species (typically, though not exclusively, more slowly developing, longer-lived and larger species) possess somatic stem cells capable of self-renewal and tissue regeneration calls into question why these organisms and their somatic stem cells do age whereas the germline apparently does not. The function of somatic stem cells declines with age, and this decline is at least in part explained by cell-intrinsic mechanisms. While often viewed as a degenerative condition, aging of somatic stem cells may in fact be a reflection of the pervasive action of protective stem cell maintenance mechanisms that confer differential susceptibility to stress and injury compared to mature cells. The `immortal' germline, however, undergoes extreme selection so that only the fittest gametes transmit their genome to the next generation. Evidence suggests that the quality of mitochondrial function is one mechanism based on which gametes are selected. In contrast to gametes somatic stem cells rely predominantly on glycolytic ATP production, while most mature cells use mitochondrial respiration. Likely because of their reliance on glycolysis, evidence suggests that hematopoietic stem cells, the best characterized adult stem cell type, are less susceptible to impaired mitochondrial function than progenitors. We therefore hypothesize that mitochondria play an important role in HSC maintenance that is not directly dependent on ATP production. We indeed observed that HSCs have high mitochondrial mass and do not perform mitophagy. Furthermore, impairment of mitochondrial dynamics decreases the number of HSCs with extensive lymphoid potential and induced cycling of the entire HSC compartment. These data show that mitochondria do play specific roles in HSC maintenance. In this proposal, we examine the mechanisms underlying mitochondrial maintenance of HSCs, and its implication for the aging of HSCs. We will test the hypothesis that impairment of mitochondrial maintenance of HSCs will negatively affect HSC function in young mice, but may lead to longer maintenance of HSC function in aged mice. Somatic stem cell maintenance as a mechanism underlying organismal aging would be remarkably consistent with an evolutionary theory of aging, the antagonistic pleiotropy theory, which proposes that mechanisms that provide reproductive or survival benefit early in life are detrimental late in life and contribute to aging.