“Aging (senescence) is characterized by development of diverse senescent pathologies and diseases, leading eventually to death.”
Aging has long been explained in different ways. One traditional view is that it results from the gradual accumulation of molecular damage over time. Another perspective, based on evolutionary theory, suggests that natural selection strongly protects health during youth and reproductive years but becomes less effective later in life. As a result, biological effects that appear in older age may persist because they have little impact on reproduction.
Over the past two decades, researchers have also explored the idea that biological programs beneficial early in life may continue operating later in ways that become harmful. Processes that once supported growth, repair, and reproduction may, with time, contribute to chronic disease.
A recent review article, titled “Aging as a multifactorial disorder with two stages,” published in Aging-US by researchers at University College London and Queen Mary University of London, brings these different perspectives together into a unified model, to propose a broader explanation of how aging-related diseases develop. The review appears in a special issue honoring the late scientist Misha Blagosklonny, whose theoretical work on programmatic aging significantly influenced the field.
The Two-Stage Model
The review by David Gems, Alexander Carver from University College London, and Yuan Zhao from Queen Mary University of London, brings together evidence from evolutionary biology, laboratory research, and human disease. It argues that most diseases associated with aging are multifactorial, meaning they arise from multiple interacting causes rather than a single trigger. The authors describe aging as a process that often develops in two main stages.
The first occurs earlier in life and involves disruptions in normal biological functions. It can include infections, physical injuries, environmental exposures, or DNA mutations. In many cases, the body repairs the damage or contains it effectively. However, not all disruptions are fully eliminated. Some remain in tissues in a controlled or dormant state without causing immediate symptoms.
The second stage takes place later in life, when normal age-related biological changes alter the body’s internal environment. Immune function tends to decline, inflammatory activity may increase, and tissue repair processes shift. Cells may enter a state known as senescence, in which they stop dividing but release signaling molecules that influence surrounding tissues. According to the review, these later-life changes can weaken the body’s ability to contain earlier disruptions. As a result, previously silent injuries or latent conditions may begin to develop into clinically recognizable disease.
In this model, aging is not explained only by accumulated damage or exclusively by genetic programming. Instead, disease emerges from the interaction between earlier disruptions and later biological changes.
Evidence from Laboratory and Human Studies
Part of the conceptual foundation for this model comes from studies in the roundworm Caenorhabditis elegans. In this organism, early mechanical damage to tissue can later contribute to fatal infections in old age, illustrating how early disruption and later biological change may interact. The authors suggest that similar patterns may occur in humans.
Several human conditions also fit this model. In shingles, the virus responsible for chickenpox remains dormant in nerve cells after childhood infection and may reactivate decades later as immune control weakens. Tuberculosis provides another example, as latent infections can become active in older age when immune defenses decline.
Osteoarthritis is more common in individuals who experienced joint injury earlier in life. Although the joint may initially recover, age-related changes in cartilage and surrounding tissues may allow earlier structural damage to progress. Traumatic brain injury in youth has also been associated with increased risk of dementia later in life, suggesting that early injury may interact with aging processes.
Cancer risk rises sharply with age as well. While genetic mutations accumulate over time, changes in the aging tissue environment, including altered inflammatory signaling and the presence of senescent cells, may increase the likelihood that mutated cells progress into tumors.
Across these examples, the recurring theme is the interaction between earlier contained disruption and later biological vulnerability.
Implications for Prevention and Intervention
The authors outline two broad approaches to reduce age-related disease. One approach focuses on preventing or minimizing early disruptions, for example through vaccination, injury prevention, and reduction of harmful environmental exposures. The other aims to modify later-life biological processes that contribute to loss of containment, including pathways involved in inflammation or excessive cellular activity.
At present, the most reliable and widely implemented measures in humans focus on preventing early disruptions. Interventions that directly target fundamental aging processes remain under investigation and require further research to establish their safety and effectiveness.
Future Perspectives and Conclusion
The two-stage model does not claim to provide a complete explanation of aging. Rather, it offers a structured model for understanding how multiple causes may combine over time to produce late-life disease. By integrating evolutionary theory, laboratory findings, and clinical observations, the review clarifies how early-life events and later biological changes may interact.
This perspective suggests that aging is neither purely passive decline nor solely genetically programmed deterioration. Instead, it may reflect a lifelong interaction between accumulated disruptions and evolving biological conditions. Continued research will be needed to determine how broadly this model applies and how it might guide future efforts to reduce the burden of chronic disease in older adults.
Click here to read the full review published in Aging-US.
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Aging-US is indexed by PubMed/Medline (abbreviated as “Aging (Albany NY)”), PubMed Central, Web of Science: Science Citation Index Expanded (abbreviated as “Aging‐US” and listed in the Cell Biology and Geriatrics & Gerontology categories), Scopus (abbreviated as “Aging” and listed in the Cell Biology and Aging categories), Biological Abstracts, BIOSIS Previews, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science).
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