Department of EAPS, Massachusetts Institute of Technology, Cambridge, MA 02138, USA.
Biochemistry (Mosc). 2013 Sep;78(9):1054-60. doi: 10.1134/S0006297913090125.
It has been a decade since the first surprising discovery that longer telomeres in humans are statistically associated with longer life expectancies. Since then, it has been firmly established that telomere shortening imposes an individual fitness cost in a number of mammalian species, including humans. But telomere shortening is easily avoided by application of telomerase, an enzyme which is coded into nearly every eukaryotic genome, but whose expression is suppressed most of the time. This raises the question how the sequestration of telomerase might have evolved. The predominant assumption is that in higher organisms, shortening telomeres provide a firewall against tumor growth. A more straightforward interpretation is that telomere attrition provides an aging clock, reliably programming lifespans. The latter hypothesis is routinely rejected by most biologists because the benefit of programmed lifespan applies only to the community, and in fact the individual pays a substantial fitness cost. There is a long-standing skepticism that the concept of fitness can be applied on a communal level, and of group selection in general. But the cancer hypothesis is problematic as well. Animal studies indicate that there is a net fitness cost in sequestration of telomerase, even when cancer risk is lowered. The hypothesis of protection against cancer has never been tested in animals that actually limit telomerase expression, but only in mice, whose lifespans are not telomerase-limited. And human medical evidence suggests a net aggravation of cancer risk from the sequestration of telomerase, because cells with short telomeres are at high risk of neoplastic transformation, and they also secrete cytokines that exacerbate inflammation globally. The aging clock hypothesis fits well with what is known about ancestral origins of telomerase sequestration, and the prejudices concerning group selection are without merit. If telomeres are an aging clock, then telomerase makes an attractive target for medical technologies that seek to expand the human life- and health-spans.
自从人类的端粒较长与预期寿命较长存在统计学关联这一令人惊讶的发现出现以来，已经过去了十年。从那时起，已经确凿无疑地表明，端粒缩短会给许多哺乳动物物种（包括人类）带来个体适应度成本。但是，通过应用端粒酶可以轻松避免端粒缩短，端粒酶是一种几乎存在于每个真核生物基因组中的酶，但大多数时候其表达受到抑制。这就提出了一个问题，即端粒酶的隔离是如何进化而来的。主要假设是，在高等生物中，缩短端粒可以形成阻止肿瘤生长的防火墙。更直接的解释是，端粒磨损提供了衰老时钟，可靠地编程寿命。大多数生物学家通常会拒绝后一种假设，因为编程寿命的好处仅适用于社区，实际上个体要付出相当大的适应度成本。长期以来，人们一直对将适应度概念应用于社区层面以及群体选择的概念持怀疑态度。但是，癌症假说也存在问题。动物研究表明，即使降低了癌症风险，隔离端粒酶也会导致净适应度成本。在实际上限制端粒酶表达的动物中，从未对针对癌症的保护假说进行过测试，而只是在老鼠中进行了测试，老鼠的寿命不受端粒酶限制。人类医学证据表明，从端粒酶的隔离中会加剧癌症风险，因为端粒较短的细胞发生肿瘤转化的风险很高，而且它们还会分泌细胞因子，从而加剧全球炎症。衰老时钟假说与已知的端粒酶隔离的祖先起源以及有关群体选择的偏见是一致的，而且这些偏见是没有根据的。如果端粒是衰老时钟，那么端粒酶就成为寻求延长人类寿命和健康跨度的医学技术的有吸引力的目标。
