Blagosklonny Mikhail V
Cell Cycle. 2006 Sep;5(18):2087-102. doi: 10.4161/cc.5.18.3288. Epub 2006 Sep 15.
While ruling out programmed aging, evolutionary theory predicts a quasi-program for aging, a continuation of the developmental program that is not turned off, is constantly on, becoming hyper-functional and damaging, causing diseases of aging. Could it be switched off pharmacologically? This would require identification of a molecular target involved in cell senescence, organism aging and diseases of aging. Notably, cell senescence is associated with activation of the TOR (target of rapamycin) nutrient- and mitogen-sensing pathway, which promotes cell growth, even though cell cycle is blocked. Is TOR involved in organism aging? In fact, in yeast (where the cell is the organism), caloric restriction, rapamycin and mutations that inhibit TOR all slow down aging. In animals from worms to mammals caloric restrictions, life-extending agents, and numerous mutations that increase longevity all converge on the TOR pathway. And, in humans, cell hypertrophy, hyper-function and hyperplasia, typically associated with activation of TOR, contribute to diseases of aging. Theoretical and clinical considerations suggest that rapamycin may be effective against atherosclerosis, hypertension and hyper-coagulation (thus, preventing myocardial infarction and stroke), osteoporosis, cancer, autoimmune diseases and arthritis, obesity, diabetes, macula-degeneration, Alzheimer's and Parkinson's diseases. Finally, I discuss that extended life span will reveal new causes for aging (e.g., ROS, 'wear and tear', Hayflick limit, stem cell exhaustion) that play a limited role now, when quasi-programmed senescence kills us first.
在排除程序性衰老的同时，进化理论预测存在一种衰老的准程序，即发育程序的延续，该程序不会关闭，而是持续运行，功能亢进并造成损害，引发衰老疾病。能否通过药物手段将其关闭？这需要识别参与细胞衰老、机体衰老和衰老疾病的分子靶点。值得注意的是，细胞衰老与雷帕霉素靶蛋白（TOR，一种营养和丝裂原感应途径）的激活有关，尽管细胞周期被阻断，但它仍能促进细胞生长。TOR是否参与机体衰老？事实上，在酵母中（细胞即机体），热量限制、雷帕霉素以及抑制TOR的突变都能减缓衰老。在从蠕虫到哺乳动物的动物中，热量限制、延长寿命的物质以及众多延长寿命的突变都汇聚于TOR途径。而且，在人类中，通常与TOR激活相关的细胞肥大、功能亢进和增生会导致衰老疾病。理论和临床考量表明，雷帕霉素可能对动脉粥样硬化、高血压和高凝状态（从而预防心肌梗死和中风）、骨质疏松症、癌症、自身免疫性疾病和关节炎、肥胖症、糖尿病、黄斑变性、阿尔茨海默病和帕金森病有效。最后，我讨论了延长寿命将揭示新的衰老原因（例如活性氧、“磨损”、海弗利克极限、干细胞耗竭），这些原因在准程序性衰老首先导致我们死亡时，目前发挥的作用有限。
