Sah Eric, Krishnamurthy Sudarshan, Ahmidouch Mohamed Y, Gillispie Gregory J, Milligan Carol, Orr Miranda E
Department of Internal Medicine, Section on Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
Bowman Gray Center for Medical Education, Wake Forest School of Medicine, Winston-Salem, NC 27101, USA.
Life (Basel). 2021 Mar 11;11(3):229. doi: 10.3390/life11030229.
In 1960, Rita Levi-Montalcini and Barbara Booker made an observation that transformed neuroscience: as neurons mature, they become apoptosis resistant. The following year Leonard Hayflick and Paul Moorhead described a stable replicative arrest of cells in vitro, termed "senescence". For nearly 60 years, the cell biology fields of neuroscience and senescence ran in parallel, each separately defining phenotypes and uncovering molecular mediators to explain the 1960s observations of their founding mothers and fathers, respectively. During this time neuroscientists have consistently observed the remarkable ability of neurons to survive. Despite residing in environments of chronic inflammation and degeneration, as occurs in numerous neurodegenerative diseases, often times the neurons with highest levels of pathology resist death. Similarly, cellular senescence (hereon referred to simply as "senescence") now is recognized as a complex stress response that culminates with a change in cell fate. Instead of reacting to cellular/DNA damage by proliferation or apoptosis, senescent cells survive in a stable cell cycle arrest. Senescent cells simultaneously contribute to chronic tissue degeneration by secreting deleterious molecules that negatively impact surrounding cells. These fields have finally collided. Neuroscientists have begun applying concepts of senescence to the brain, including post-mitotic cells. This initially presented conceptual challenges to senescence cell biologists. Nonetheless, efforts to understand senescence in the context of brain aging and neurodegenerative disease and injury emerged and are advancing the field. The present review uses pre-defined criteria to evaluate evidence for post-mitotic brain cell senescence. A closer interaction between neuro and senescent cell biologists has potential to advance both disciplines and explain fundamental questions that have plagued their fields for decades.
1960年，丽塔·列维-蒙塔尔奇尼和芭芭拉·布克做出了一项改变神经科学的观察：随着神经元成熟，它们变得对细胞凋亡具有抗性。次年，伦纳德·海弗利克和保罗·莫尔黑德描述了细胞在体外的一种稳定的复制停滞现象，称为“衰老”。近60年来，神经科学和衰老这两个细胞生物学领域并行发展，各自分别定义表型并揭示分子介质，以分别解释其各自领域的创始人在20世纪60年代所观察到的现象。在此期间，神经科学家一直观察到神经元具有非凡的存活能力。尽管处于慢性炎症和退化的环境中，就像在许多神经退行性疾病中发生的那样，但往往是病理程度最高的神经元抵抗死亡。同样，细胞衰老（以下简称为“衰老”）现在被认为是一种复杂的应激反应，最终导致细胞命运的改变。衰老细胞不是通过增殖或凋亡来应对细胞/DNA损伤，而是在稳定的细胞周期停滞中存活。衰老细胞同时通过分泌对周围细胞产生负面影响的有害分子，导致慢性组织退化。这两个领域终于交汇了。神经科学家已经开始将衰老的概念应用于大脑，包括有丝分裂后细胞。这最初给衰老细胞生物学家带来了概念上的挑战。尽管如此，在大脑衰老、神经退行性疾病和损伤的背景下理解衰老的努力已经出现，并正在推动该领域的发展。本综述使用预先定义的标准来评估有丝分裂后脑细胞衰老的证据。神经科学家和衰老细胞生物学家之间更密切的互动有可能推动这两个学科的发展，并解释困扰它们几十年的基本问题。
