Institute of Healthy Ageing, and Research Department of Genetics, Evolution and Environment, University College London, London WC1E 6BT, United Kingdom.
Institute of Healthy Ageing, and Research Department of Genetics, Evolution and Environment, University College London, London WC1E 6BT, United Kingdom.
Ageing Res Rev. 2024 Nov;101:102527. doi: 10.1016/j.arr.2024.102527. Epub 2024 Oct 5.
Maximum lifespan differs greatly between species, indicating that the process of senescence is largely genetically determined. Senescence evolves in part due to antagonistic pleiotropy (AP), where selection favors gene variants that increase fitness earlier in life but promote pathology later. Identifying the biological mechanisms by which AP causes senescence is key to understanding the endogenous causes of aging and its attendant diseases. Here we argue that the frequent occurrence of AP as a property of genes reflects the presence of constraint in the biological systems that they specify. This arises particularly because the functionally interconnected nature of biological systems constrains the simultaneous optimization of coupled traits (interconnection constraints), or because individual traits cannot evolve (impossibility constraints). We present an account of aging that integrates AP and biological constraint with recent programmatic aging concepts, including costly programs, quasi-programs, hyperfunction and hypofunction. We argue that AP mechanisms of costly programs and triggered quasi-programs are consequences of constraint, in which costs resulting from hyperfunction or hypofunction cause senescent pathology. Impossibility constraint can also cause hypofunction independently of AP. We also describe how AP corresponds to Stephen Jay Gould's constraint-based concept of evolutionary spandrels, and argue that pathologies arising from AP are bad spandrels. Biological constraint is a conceptual missing link between ultimate and proximate causes of senescence, including diseases of aging.
寿命的长短在不同物种间存在着巨大的差异，这表明衰老的过程在很大程度上是由遗传决定的。衰老在一定程度上是由于拮抗多效性（AP）进化而来的，在这种情况下，选择有利于那些在生命早期增加适应性但在后期促进病理的基因变异。确定 AP 导致衰老的生物学机制是理解衰老的内在原因及其相关疾病的关键。在这里，我们认为，AP 作为基因的一个特性频繁出现，反映了它们所指定的生物系统中存在约束。这主要是因为生物系统的功能相互关联的性质限制了耦合特征的同时优化（连接约束），或者因为单个特征无法进化（不可能约束）。我们提出了一种衰老的解释，将 AP 和生物约束与最近的程序性衰老概念（包括代价性程序、准程序、超功能和低功能）结合起来。我们认为，代价性程序和触发的准程序的 AP 机制是约束的结果，其中超功能或低功能导致衰老的病理。不可能约束也可以独立于 AP 导致低功能。我们还描述了 AP 如何对应于斯蒂芬·杰伊·古尔德（Stephen Jay Gould）基于约束的进化副现象概念，并认为 AP 引起的病理是不良副现象。生物约束是衰老的终极和近因之间的一个概念缺失环节，包括与衰老相关的疾病。
