Lansdorp Peter M
Terry Fox Laboratory, BC Cancer Research Institute, Vancouver, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, Canada.
Arch Med Res. 2022 Dec;53(8):741-746. doi: 10.1016/j.arcmed.2022.10.004. Epub 2022 Nov 3.
Telomeres and telomerase play a crucial role in human aging and cancer. Three "drivers" of human aging can be identified. The developmental program encoded in DNA is the primary determinant of lifespan. Faithful execution of the developmental program requires stability of the (epi-)genome which is challenged throughout life by damage to DNA as well as epigenetic 'scars' from error-free DNA repair and stochastic errors made during the establishment and maintenance of the "epigenome". Over time (epi-)mutations accumulate, compromising cellular function and causing (pre-)malignant alterations. Damage to the genome and epigenome can be considered the second "driver" of aging. A third driver of the aging process, important to suppress tumors in long-lived animals, is caused by progressive loss of telomeric DNA. Telomere erosion protects against cancer early in life but limits cell renewal late in life, in agreement with the Antagonistic Pleiotropy theory on the evolutionary origin of aging. Malignant tumors arise when mutations and/or epimutations in cells (clock 2) corrupt the developmental program (clock 1) as well as tumor suppression by telomere erosion (clock 3). In cancer cells clock 3 is typically inactivated by loss of p53 as well as increased expression of telomerase. Taken together, aging in humans can be described by the ticking of three clocks: the clock that directs development, the accumulation of (epi-)mutations over time and the telomere clock that limits the number of cell divisions in normal stem and immune cells.
端粒和端粒酶在人类衰老和癌症中起着至关重要的作用。可以确定人类衰老的三个“驱动因素”。DNA中编码的发育程序是寿命的主要决定因素。发育程序的忠实执行需要（表观）基因组的稳定性，而在整个生命过程中，DNA损伤以及无差错DNA修复产生的表观遗传“疤痕”和“表观基因组”建立与维持过程中出现的随机错误都会对其构成挑战。随着时间的推移，（表观）突变不断积累，损害细胞功能并导致（癌前）恶性改变。基因组和表观基因组的损伤可被视为衰老的第二个“驱动因素”。衰老过程的第三个驱动因素是端粒DNA的逐渐丢失，这对长寿动物抑制肿瘤很重要。端粒缩短在生命早期可预防癌症，但在生命后期会限制细胞更新，这与衰老进化起源的拮抗多效性理论相一致。当细胞中的突变和/或表观突变（时钟2）破坏发育程序（时钟1）以及端粒缩短导致的肿瘤抑制（时钟3）时，恶性肿瘤就会出现。在癌细胞中，时钟3通常因p53缺失以及端粒酶表达增加而失活。综上所述，人类衰老可以用三个时钟的滴答声来描述：指导发育的时钟、随着时间推移（表观）突变的积累以及限制正常干细胞和免疫细胞中细胞分裂次数的端粒时钟。
