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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.

From mutation to mechanism: deciphering the molecular function of genetic variants linked to human ageing