Brief Funct Genomics. 2022 Jan 25;21(1):13-23. doi: 10.1093/bfgp/elab005.
Many of the leading causes of death in humans, such as cardiovascular disease, type 2 diabetes and Alzheimer's disease are influenced by biological mechanisms that become dysregulated with increasing age. Hence, by targeting these ageing-related mechanisms, we may be able to improve health in old age. Ageing is partly heritable and genetic studies have been moderately successful in identifying genetic variants associated with ageing-related phenotypes (lifespan, healthspan and longevity). To decipher the mechanisms by which the identified variants influence ageing, studies that focus on their functional validation are vital. In this perspective, we describe the steps that could be taken in the process of functional validation: (1) in silico characterisation using bioinformatic tools; (2) in vitro characterisation using cell lines or organoids; and (3) in vivo characterisation studies using model organisms. For the in vivo characterisation, it is important to focus on translational phenotypes that are indicative of both healthspan and lifespan, such as the frailty index, to inform subsequent intervention studies. The depth of functional validation of a genetic variant depends on its location in the genome and conservation in model organisms. Moreover, some variants may prove to be hard to characterise due to context-dependent effects related to the experimental environment or genetic background. Future efforts to functionally characterise the (newly) identified genetic variants should shed light on the mechanisms underlying ageing and will help in the design of targeted interventions to improve health in old age.
许多导致人类死亡的主要原因，如心血管疾病、2 型糖尿病和阿尔茨海默病，都受到生物机制的影响，这些机制随着年龄的增长而失调。因此，通过针对这些与衰老相关的机制，我们也许能够改善老年时的健康状况。衰老是部分遗传的，遗传研究已经成功地识别出与衰老相关表型（寿命、健康寿命和长寿）相关的遗传变异。为了解释已识别的变异如何影响衰老的机制，专注于其功能验证的研究至关重要。在这篇观点文章中，我们描述了在功能验证过程中可以采取的步骤：（1）使用生物信息学工具进行计算机模拟特征分析；（2）使用细胞系或类器官进行体外特征分析；（3）使用模式生物进行体内特征分析。对于体内特征分析，重要的是要关注能够反映健康寿命和寿命的转化表型，如虚弱指数，以便为后续的干预研究提供信息。遗传变异的功能验证深度取决于其在基因组中的位置和在模式生物中的保守性。此外，由于与实验环境或遗传背景相关的上下文相关效应，某些变异可能难以进行特征分析。未来对（新）鉴定的遗传变异进行功能特征分析的努力将有助于阐明衰老的机制，并有助于设计有针对性的干预措施，以改善老年时的健康状况。
