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纵观人的一生,随着年龄增加,干细胞中的 DNA 损伤不断积累,端粒不断缩短。正常情况下,这些损伤的干细胞会退出细胞周期,进入生长停滞阶段,之后程序性死亡或成为衰老细胞。当越来越多的干细胞退出细胞周期,组织的稳态将被打破,其正常功能难以维持,再生能力也会下降,这就导致了衰老表型及衰老相关疾病。与此同时,可能存在极少数的细胞获得关键性的基因突变,在 DNA 受到损伤的情况下仍然能够继续分裂,这样的细胞就将有可能进一步发展为癌细胞,从而增加个体的患癌概率。
癌症和衰老最直接的相同点,就是基因组的不稳定增加。我们生存的环境中到处都是造成 DNA 损伤的诱变剂,而人体内的干细胞一生中要进行数以亿计的分裂,每次分裂都可能带来基因突变的风险。虽然大部分的突变都会被 DNA 修复系统所修复,但仍有一部分突变累积下来。在癌细胞中,基因组的不稳定性可以帮助癌细胞获得更多癌变所需的关键性突变;与此同时,基因组的不稳定性也通过多种不同的方式促进了衰老表型的产生,例如改变蛋白的氨基酸序列使其丧失正常功能,导致组织稳态被打破等。
虽然现在断定热量限制可以延长人类的寿命还为时过早,但我们已经发现,对肥胖的人群进行热量限制可以减少其心脏病的风险因素,提高胰岛素敏感性,增强线粒体功能并且减少 DNA 的氧化损伤。因此,未来对于热量限制机制的进一步阐明以及模拟热量限制作用的小分子(CRM,Caloric restriction mimetics)的发现,有望帮助我们加深对衰老和癌症的理解,提供强有力的干预手段。
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