University of Exeter Medical School, Exeter, UK.
Faculty of Health and Life Sciences, University of Exeter, Exeter, UK.
Ageing Res Rev. 2024 Sep;100:102456. doi: 10.1016/j.arr.2024.102456. Epub 2024 Aug 15.
Understanding mechanisms of ageing remains a complex challenge for biogerontologists, but recent adaptations of evolutionary ageing theories offer a compelling lens in which to view both age-related molecular and physiological deterioration. Ageing is commonly associated with progressive declines in biochemical and molecular processes resulting from damage accumulation, yet the role of continued developmental gene activation is less appreciated. Natural selection pressures are at their highest in youthful periods to modify gene expression towards maximising reproductive capacity. After sexual maturation, selective pressure diminishes, subjecting individuals to maladaptive pleiotropic gene functions that were once beneficial for developmental growth but become pathogenic later in life. Due to this selective 'shadowing' in ageing, mechanisms to counter such hyper/hypofunctional genes are unlikely to evolve. Interventions aimed at targeting gene hyper/hypofunction during ageing might, therefore, represent an attractive therapeutic strategy. The nematode Caenorhabditis elegans offers a strong model for post-reproductive mechanistic and therapeutic investigations, yet studies examining the mechanisms of, and countermeasures against, ageing decline largely intervene from larval stages onwards. Importantly, however, lifespan extending conditions frequently impair early-life fitness and fail to correspondingly increase healthspan. Here, we consolidate multiple evolutionary theories of ageing and discuss data supporting hyper/hypofunctional changes at a global molecular and functional level in C. elegans, and how classical lifespan-extension mutations alter these dynamics. The relevance of such mutant models for exploring mechanisms of ageing are discussed, highlighting that post-reproductive gene optimisation represents a more translatable approach for C. elegans research that is not constrained by evolutionary trade-offs. Where some genetic mutations in C. elegans that promote late-life health map accordingly with healthy ageing in humans, other widely used genetic mutations that extend worm lifespan are associated with life-limiting pathologies in people. Lifespan has also become the gold standard for quantifying 'ageing', but we argue that gerospan compression (i.e., 'healthier' ageing) is an appropriate goal for anti-ageing research, the mechanisms of which appear distinct from those regulating lifespan alone. There is, therefore, an evident need to re-evaluate experimental approaches to study the role of hyper/hypofunctional genes in ageing in C. elegans.
理解衰老的机制仍然是生物老年学家面临的一个复杂挑战，但最近对衰老理论的适应性进化的研究为观察与年龄相关的分子和生理衰退提供了一个引人注目的视角。衰老通常与生化和分子过程的逐渐衰退有关，这些过程是由于损伤的积累而导致的，但人们对持续发育基因激活的作用认识不足。在年轻时期，自然选择压力最大，目的是通过改变基因表达来最大限度地提高生殖能力。性成熟后，选择压力减弱，个体容易受到曾经有利于发育生长但后来在生命后期变得致病的多效性基因功能的影响。由于衰老过程中的这种选择性“阴影”，不太可能进化出对抗这些超/低功能基因的机制。因此，针对衰老过程中基因超/低功能的干预措施可能代表一种有吸引力的治疗策略。秀丽隐杆线虫是研究生殖后机制和治疗方法的有力模型，但研究衰老衰退机制和对策的研究主要从幼虫阶段开始干预。然而，重要的是，延长寿命的条件常常会损害生命早期的适应性，并不能相应地增加健康寿命。在这里，我们综合了多种衰老理论，并讨论了支持秀丽隐杆线虫在全球分子和功能水平上的超/低功能变化的数据，以及经典的寿命延长突变如何改变这些动态。讨论了这些突变模型在探索衰老机制方面的相关性，强调生殖后基因优化代表了一种更具转化潜力的方法，适用于不受进化权衡限制的秀丽隐杆线虫研究。虽然秀丽隐杆线虫中一些促进晚年健康的遗传突变与人类的健康衰老相对应，但其他广泛使用的延长线虫寿命的遗传突变与人类的限制寿命的病理有关。寿命已成为量化“衰老”的金标准，但我们认为，生殖间隔压缩（即“更健康”的衰老）是抗衰老研究的一个适当目标，其机制与单独调节寿命的机制不同。因此，显然需要重新评估实验方法，以研究秀丽隐杆线虫中超/低功能基因在衰老中的作用。
