image: Figure 2. Two-stage model for interactions between earlier and later etiologies. Diverse disruptions of normal biological function resulting from insults are contained and lie dormant within the youthful physiological milieu. In the senescent milieu, containment of such disruptions fails, and they form foci for the development of diverse senescent pathologies. Such contained, latent disruptions are analogous to seeds lying dormant within the host; later, pathogenic wild-type gene action stimulates the seeds to grow; this analogy captures the developmental nature of senescent pathogenesis [20]. The early etiologies are those typical of disease causes prior to aging, including infection, mechanical damage, and mutation (somatic and inherited). The main, late-life etiology, wild-type gene action, is predominantly (but not entirely) restricted to senescence. The model encompasses both evolutionary theories of aging. Mutation accumulation (MA): inherited, late-acting deleterious mutations can be understood as those unmasked by later programmatic changes. Antagonistic pleiotropy (AP): this determines the late-life programmatic changes themselves. Note that this model does not argue against a role for molecular damage accumulation in aging, but rather that it is a relatively minor contributory factor (e.g. DNA damage in cancer development).
Credit: Copyright: © 2025 Gems et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
“Here we propose a general account of how different determinants of aging can interact to generate late-life disease.”
BUFFALO, NY — January 20, 2026 — A new review was published in Volume 17, Issue 12 of Aging-US on December 30, 2025, titled “Aging as a multifactorial disorder with two stages.”
“This article is a contribution to the special issue of Aging celebrating the life and work of Misha Blagosklonny (more formally, Mikhail Vladimirovich Blagosklonny), who died in October 2024.”
In this review, David Gems and Alexander Carver from University College London, together with Yuan Zhao from Queen Mary University of London, present a new theoretical model to explain how aging leads to the development of chronic diseases. Drawing on evolutionary theory and biological research, the authors propose that aging is driven by a combination of early-life damage and harmful genetic activity in later life. This framework helps explain why diseases such as cancer, arthritis, and infections often appear in old age and offers insight into how they might be prevented.
Aging is the biggest risk factor for most chronic diseases, but the biological reasons for this association are still debated. The authors address this by introducing a two-stage model. In the first stage, individuals experience disruptions early in life, such as infections, injuries, or genetic mutations. Although the body can often contain or repair this damage, it does not fully eliminate it. In the second stage, which begins in later life, normal genetic processes begin to act in ways that are no longer beneficial. These late-life changes weaken the body’s ability to contain earlier damage, allowing it to develop into disease.
The review emphasizes that aging is a multifactorial process, shaped by many interacting causes rather than a single underlying mechanism. The model suggests that early-life disruptions and later-life genetic activity work together to drive age-related diseases. For example, dormant viruses can re-emerge as infections like shingles due to weakened immunity in older adults. Similarly, injuries to joints in youth can lead to osteoarthritis as tissues change with age. Inherited mutations may also remain silent for decades before contributing to conditions such as cancer or fibrosis later in life.
This two-stage model builds on long-standing ideas from evolutionary biology, particularly the theory that aging occurs because natural selection has less influence in later life. The authors also draw on studies in the roundworm Caenorhabditis elegans, where early mechanical damage can lead to fatal infections in old age, suggesting similar patterns may occur in humans.
Overall, this review presents a new framework for understanding how different causes of aging interact over time. By identifying two key stages, early-life damage and late-life genetic activity, it highlights potential strategies for promoting healthier aging through prevention and targeted intervention.
Paper DOI: https://doi.org/10.18632/aging.206339
Corresponding author: David Gems – david.gems@ucl.ac.uk
Abstract video: https://www.youtube.com/watch?v=d4TSI4Ot3yM
Keywords: aging, C. elegans, disease, hyperfunction, multifactorial model
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Journal
Aging-US
Method of Research
Literature review
Subject of Research
Not applicable
Article Title
Aging as a multifactorial disorder with two stages
Article Publication Date
30-Dec-2025
COI Statement
The authors declare no conflicts of interest.