Institute of Healthy Ageing, and Research Department of Genetics, Evolution and Environment, University College London, London WC1E 6BT, UK.
Ageing Res Rev. 2022 Feb;74:101557. doi: 10.1016/j.arr.2021.101557. Epub 2022 Jan 3.
The process of senescence (aging) is predominantly determined by the action of wild-type genes. For most organisms, this does not reflect any adaptive function that senescence serves, but rather evolutionary effects of declining selection against genes with deleterious effects later in life. To understand aging requires an account of how evolutionary mechanisms give rise to pathogenic gene action and late-life disease, that integrates evolutionary (ultimate) and mechanistic (proximate) causes into a single explanation. A well-supported evolutionary explanation by G.C. Williams argues that senescence can evolve due to pleiotropic effects of alleles with antagonistic effects on fitness and late-life health (antagonistic pleiotropy, AP). What has remained unclear is how gene action gives rise to late-life disease pathophysiology. One ultimate-proximate account is T.B.L. Kirkwood's disposable soma theory. Based on the hypothesis that stochastic molecular damage causes senescence, this reasons that aging is coupled to reproductive fitness due to preferential investment of resources into reproduction, rather than somatic maintenance. An alternative and more recent ultimate-proximate theory argues that aging is largely caused by programmatic, developmental-type mechanisms. Here ideas about AP and programmatic aging are reviewed, particularly those of M.V. Blagosklonny (the hyperfunction theory) and J.P. de Magalhães (the developmental theory), and their capacity to make sense of diverse experimental findings is assessed.
衰老（老化）的过程主要取决于野生型基因的作用。对于大多数生物来说，这并不能反映衰老所具有的任何适应性功能，而是生命后期具有有害影响的基因随着选择压力下降而在进化上的影响。要理解衰老，就需要解释进化机制如何导致致病性基因作用和晚年疾病，将进化（终极）和机制（近因）原因整合到一个单一的解释中。G.C.威廉姆斯提出的一个有充分依据的进化解释认为，衰老可以通过对适应性和晚年健康有拮抗作用的等位基因的多效性作用而进化（拮抗多效性，AP）。尚不清楚的是基因作用如何导致晚年疾病的病理生理学。一个终极-近因解释是 T.B.L.柯克伍德的可抛弃体细胞理论。该理论基于随机分子损伤导致衰老的假设，认为衰老与生殖适应性相关，因为资源更倾向于投入到生殖中，而不是体细胞维持。另一种更近期的终极-近因理论认为，衰老在很大程度上是由程序性、发育类型的机制引起的。在这里，我们回顾了关于 AP 和程序性衰老的观点，特别是 M.V.布拉戈斯克洛嫩（超功能理论）和 J.P.德马加利斯（发育理论）的观点，并评估了它们对各种实验结果的解释能力。
