David Gems and Alexander Carver of University College London, working alongside Yuan Zhao from Queen Mary University of London, introduce a fresh conceptual model for understanding how ageing contributes to the onset of chronic disease. Rather than attributing age-related illness to a single biological cause, the authors draw together insights from evolutionary theory and modern biology to argue that ageing reflects the interaction of damage incurred earlier in life and genetic processes that become detrimental in later years. Their approach offers a coherent explanation for why conditions such as cancer, arthritis, and infectious diseases disproportionately affect older people, while also pointing towards new avenues for prevention.
Ageing is widely recognised as the strongest risk factor for most chronic diseases, yet the biological basis of this relationship remains contested. To address this gap, the authors propose a two-stage model that links events across the life course. In the first stage, individuals accumulate disruptions early in life, including infections, physical injuries, and genetic mutations. Although the body is often able to repair or contain these disturbances, they are rarely eliminated completely. As a result, a hidden burden of unresolved damage persists beneath the surface of apparent health.
The second stage emerges later in life, when ordinary genetic activity begins to have harmful rather than beneficial effects. Processes that support growth, reproduction, or survival in youth may gradually undermine tissue maintenance and immune function as the body ages. According to the model, these late-life genetic effects weaken the mechanisms that previously kept early damage under control. Once this balance is lost, earlier disruptions are able to progress into overt disease, transforming long-standing vulnerabilities into clinical illness.
A key strength of the review is its emphasis on ageing as a multifactorial process shaped by interacting causes rather than a single underlying mechanism. The authors illustrate how early-life damage and late-life genetic activity act together to produce age-related disease. For instance, viruses acquired earlier in life may remain dormant for decades, only to re-emerge as conditions such as shingles when immune function declines. Likewise, joint injuries sustained in youth can set the stage for osteoarthritis later on, as ageing tissues lose their ability to compensate for past damage. Genetic mutations may also lie dormant for many years before contributing to cancer or fibrotic disease in older age.
The proposed framework is firmly grounded in evolutionary biology, particularly the idea that natural selection becomes less effective at shaping traits expressed later in life. Because survival and reproduction typically occur earlier, there is weaker evolutionary pressure to prevent harmful effects that arise in old age. The authors reinforce this perspective with evidence from studies of the roundworm Caenorhabditis elegans, where early mechanical damage can lead to lethal infections in later life, suggesting that similar principles may apply across species, including humans.
Overall, the review offers a unifying framework for understanding how diverse biological processes converge to drive age-related disease. By distinguishing between early-life damage and late-life genetic activity, the two-stage model clarifies how health trajectories are shaped over time. Importantly, it also highlights opportunities for promoting healthier ageing, suggesting that preventing or limiting early damage, as well as targeting harmful late-life processes, could reduce the burden of chronic disease and extend the period of life spent in good health.
More information: David Gems et al, Aging as a multifactorial disorder with two stages, Aging-US. DOI: 10.18632/aging.206339
Journal information: Aging-US Provided by Impact Journals LLC
