Childhood chickenpox returns decades later as shingles, and an old knee injury leads to osteoarthritis: biologist David Gems and colleagues describe a shared mechanism behind different age-related diseases
Childhood chickenpox returns decades later as shingles, and an old knee injury leads to osteoarthritis: biologist David Gems and colleagues describe a shared mechanism behind different age-related diseases
On 30 December 2025, David Gems and colleagues published the review “Aging as a multifactorial disorder with two stages” in Aging, in an issue dedicated to the memory of Mikhail Blagosklonny. Blagosklonny, who died in October 2024, first proposed that existing genes begin to cause harm as we age. The authors explain why different age-related diseases can remain dormant for decades before emerging in old age.
The chickenpox virus causes the familiar childhood rash, which clears within two weeks. In some people who recover, the virus persists for decades in clusters of nerve cells near the spine, held in check by the immune system. As immune control weakens with age, the virus reactivates, causing shingles: incidence rises from 0.74 cases per thousand children aged 0–9 to 10.1 per thousand people aged 80–89.
Gems and colleagues argue that this reflects a shared two-stage mechanism. During the first stage, before old age, the body encounters various disturbances, such as infection, injury or mutation, and almost always keeps them from developing into disease. During the second stage, in old age, a deeper cause comes into play: the “selection shadow.” In evolutionary theory, this describes the weakening of selection against a gene whose harmful effects appear only after its carrier has reproduced. This has allowed growth and reproductive programs to persist: they are useful in youth, but become overactive with age and undermine the mechanisms that keep these disturbances in check. The authors compare these sites of damage to dormant seeds:
“These sites of latent damage resemble seeds that, later in life, germinate and develop into disease as aging brings changes in biological programs.”
The idea grew out of Gems’s observations in the roundworm C. elegans. In young worms, the hard pharyngeal grinder damages the cuticle, allowing intestinal bacteria to enter. The immune system contains the bacteria within cells, and the cuticle heals. Only in old age does the contained infection spread and kill the worm, in roughly 40% of individuals. The same pattern occurs in humans: Finnish data show that a knee injury in youth raises the risk of osteoarthritis in that knee in old age fivefold; a mild concussion in youth is associated with a sixfold risk of dementia decades later.
The same selection shadow also explains hereditary diseases. The mutation that causes Huntington’s disease is present from birth, but symptoms emerge only in midlife. In 1941, geneticist John Haldane used this example to show why selection had failed to eliminate a harmful mutation from the population.
The model distinguishes two types of treatment. The first prevents early damage through vaccination, protection against injury and embryo screening for mutations. An example is the shingles vaccine, which reduces dementia risk according to findings published in Nature in 2025. The second limits the later decline in control, for example with rapamycin, which blocks the mTOR signaling pathway. So far, only the first type has been shown to work in humans; evidence for the second is limited to mice. The same vaccine was recently associated with a lower incidence of cardiovascular disease in another natural experiment in the US. For osteoarthritis, the authors acknowledge an uncertainty: disease may emerge because the body becomes less able to contain the effects of an injury, or because changes in gait caused by that injury accelerate joint wear.
Infection, injury and hereditary disease thus become instances of a shared process: an early disturbance that the aging body can no longer keep in check.