Department of Pharmacology, Faculty of Pharmacy, Health and Science Center, University of Debrecen, Debrecen, Hungary.
J Cell Mol Med. 2013 Aug;17(8):936-57. doi: 10.1111/jcmm.12074. Epub 2013 Jun 22.
Progressively sophisticated understanding of cellular and molecular processes that contribute to age-related physical deterioration is being gained from ongoing research into cancer, chronic inflammatory syndromes and other serious disorders that increase with age. Particularly valuable insight has resulted from characterization of how senescent cells affect the tissues in which they form in ways that decrease an organism's overall viability. Increasingly, the underlying pathophysiology of ageing is recognized as a consequence of oxidative damage. This leads to hyperactivity of cell growth pathways, prominently including mTOR (mammalian target of rapamycin), that contribute to a build-up in cells of toxic aggregates such as progerin (a mutant nuclear cytoskeletal protein), lipofuscin and other cellular debris, triggering formation of senescent cellular phenotypes, which interact destructively with surrounding tissue. Indeed, senescent cell ablation dramatically inhibits physical deterioration in progeroid (age-accelerated) mice. This review explores ways in which oxidative stress creates ageing-associated cellular damage and triggers induction of the cell death/survival programs' apoptosis, necrosis, autophagy and 'necroapoptophagy'. The concept of 'necroapoptophagy' is presented here as a strategy for varying tissue oxidative stress intensity in ways that induce differential activation of death versus survival programs, resulting in enhanced and sustained representation of healthy functional cells. These strategies are discussed in the context of specialized mesenchymal stromal cells with the potential to synergize with telocytes in stabilizing engrafted progenitor cells, thereby extending periods of healthy life. Information and concepts are summarized in a hypothetical approach to suppressing whole-organism senescence, with methods drawn from emerging understandings of ageing, gained from Cnidarians (jellyfish, corals and anemones) that undergo a unique form of cellular regeneration, potentially conferring open-ended lifespans.
正在进行的癌症、慢性炎症综合征和其他随年龄增长而增加的严重疾病的研究，使人们对导致与年龄相关的身体恶化的细胞和分子过程有了日益复杂的认识。通过描述衰老细胞如何以降低生物体整体活力的方式影响它们形成的组织，特别有价值的见解已经产生。衰老的潜在病理生理学越来越被认为是氧化损伤的结果。这导致细胞生长途径的过度活跃，特别是包括 mTOR（哺乳动物雷帕霉素靶蛋白），这导致毒性聚集体（如 progerin（一种突变核细胞骨架蛋白）、脂褐素和其他细胞碎片）在细胞中积累，触发衰老细胞表型的形成，这些表型与周围组织发生破坏性相互作用。事实上，衰老细胞消融可显著抑制早衰（加速衰老）小鼠的身体恶化。这篇综述探讨了氧化应激如何导致与衰老相关的细胞损伤，并触发细胞死亡/存活程序凋亡、坏死、自噬和“坏死凋亡”的诱导。本文提出了“坏死凋亡”的概念，作为一种通过改变组织氧化应激强度的策略，以诱导死亡与存活程序的差异激活，从而增强和持续代表健康功能细胞。这些策略是在具有与间质基质细胞协同作用潜力的专门间质基质细胞的背景下讨论的，这些细胞具有稳定植入祖细胞的潜力，从而延长健康寿命。信息和概念在抑制整个生物体衰老的假设方法中进行了总结，方法来自对刺胞动物（水母、珊瑚和海葵）的新兴衰老理解中获得，这些动物经历了一种独特的细胞再生形式，可能赋予了无限制的寿命。
