Mitochondrial Maintenance Mechanisms of Stem Cells and Aging

干细胞的线粒体维持机制与衰老

• 批准号: 9751137
• 负责人: HANS-WILLEM E SNOECK
• 金额: $ 38.87万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9751137
• 关键词: Affect; Age; Aging; Automobile Driving; Biology of Aging; Blood; Bone Marrow; Bone Marrow Transplantation; Calcium; Cell Aging; Cell Compartmentation; Cell Cycle; Cell Cycle Regulation; Cell Maintenance; Cell physiology; Cells; Cellular biology; Data; Degenerative Disorder; Deterioration; Development; Economics; Frequencies; Genes; Genome; Germ Cells; Glycolysis; Goals; Hematopoietic Stem Cell heterogeneity; Hematopoietic Stem Cell subsets; Hematopoietic System; Hematopoietic stem cells; Human; Immune response; Immune system; Impairment; Individual; Injury; Interferons; Lead; Life; Lymphoid; Maintenance; Mitochondria; Mitochondrial DNA; Mus; Myelogenous; Organism; Physiological; Play; Predisposition; Process; Production; Quality Control; Regulation; Resistance; Respiration; Role; Signal Transduction; Stem cells; Stress; Testing; Viral; adult stem cell; age related; aged; antiviral immunity; base; cell type; healthspan; hematopoietic stem cell quiescence; innovation; leukemia; mitochondrial DNA mutation; mitochondrial dysfunction; negative affect; next generation; overexpression; pleiotropism; progenitor; reproductive; selective expression; self-renewal; theories; tissue regeneration

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.

概括： 了解导致衰老的机制可能会带来延长健康寿命的创新策略， 的努力将带来巨大的人类和经济利益。事实上，许多物种（通常，尽管 不仅是发育更慢、寿命更长和体型更大的物种）拥有成体干细胞 自我更新和组织再生的能力令人质疑为什么这些生物体及其成体干细胞 会衰老，而种系显然不会。成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。虽然经常被视为退化 在这种情况下，成体干细胞的衰老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，维持机制赋予对压力和损伤的不同敏感性。 然而，“永生”的种系经历了极端的选择，因此只有最适合的配子才能传播它们的后代。 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 基于选择配子。与配子相反，成体干细胞主要依赖 糖酵解 ATP 产生，而大多数成熟细胞使用线粒体呼吸。很可能是因为他们 依赖于糖酵解，有证据表明造血干细胞，特征最好的成体干细胞 类型，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 维持中发挥着重要作用，但不直接依赖于 ATP 的产生。我们 确实观察到 HSC 具有较高的线粒体质量并且不进行线粒体自噬。此外， 线粒体动力学受损会减少具有广泛淋巴潜能的 HSC 数量， 诱导整个 HSC 室的循环。这些数据表明线粒体确实在 HSC 维护。在本提案中，我们研究了线粒体维持的机制 HSC 及其对 HSC 衰老的影响。我们将检验线粒体损伤的假设 HSC 的维持会对年轻小鼠的 HSC 功能产生负面影响，但可能会导致更长时间的维持 老年小鼠的 HSC 功能。成体干细胞维持作为机体衰老的机制 与衰老的进化理论，即拮抗多效性理论非常一致，该理论 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 并有助于衰老。