How your brain controls ageing — and why zombie cells could be key

Research is revealing the cellular mechanisms that link mental well-being and longevity

There might be a paradox in the biology of ageing. As humans grow older, their metabolisms tend to slow, they lose muscle mass and they burn many fewer calories. But certain cells in older people appear to do the exact opposite — they consume more energy than when they were young.

These potential energy hogs are senescent cells, older cells that have stopped dividing and no longer perform the essential functions that they used to. Because they seem idle, biologists had assumed that zombie-like senescent cells use less energy than their younger, actively replicating counterparts, says Martin Picard, a psychobiologist at Columbia University in New York City.

But in 2022, Gabriel Sturm, a former graduate student of Picard’s, painstakingly observed the life course of human skin cells cultured in a dish¹ and, in findings that have not yet been published in full, found that cells that had stopped dividing had a metabolic rate about double that of younger cells.

For Picard and his colleagues, the energetic mismatch wasn’t a paradox at all: ageing cells accumulate energetically costly forms of damage, such as alterations in DNA, and they initiate pro-inflammatory signalling. How that corresponds with the relatively low energy expenditure for ageing organisms is still unclear, but the researchers hypothesize that this tension might be an important driver of many of the negative effects of growing old, and that the brain might be playing a key part as mediator². As some cells get older and require more energy, the brain reacts by stripping resources from other biological processes, which ultimately results in outward signs of ageing, such as greying hair or a reduction in muscle mass (see ‘Energy management and ageing’).

Picard and his colleagues call this concept the ‘brain–body energy-conservation model’. And although many parts of the hypothesis are still untested, scientists are working to decipher the precise mechanisms that connect the brain to processes associated with ageing, such as senescence, inflammation and the shortening of telomeres — the stretches of repetitive DNA that cap the ends of chromosomes and protect them. This work, some researchers say, is also beginning to illuminate how psychological stress can accelerate ageing at a molecular level. Although once at the fringes of ageing research, this idea is now becoming mainstream, says Alessandro Bartolomucci, a biologist at the University of Minnesota in Minneapolis. “The science speaks for itself. The field cannot dismiss it.”

Wear and tear

Some of the earliest pieces of evidence pointing to the brain’s role in ageing came from studies that revealed the effects of psychological stress on individual cells.

In the early 2000s, Elissa Epel, who was then a postdoctoral researcher at the University of California, San Francisco (UCSF), set out with her colleagues to examine whether chronic stress could leave behind a cellular signature. At the time, there was already a “very impressive literature” linking long-term stress to poor health, says Epel, who is now a health psychologist at UCSF. “But we didn’t know as much about what was happening at the cellular level.”

So, the researchers decided to look at telomere length. Telomeres progressively shorten over the lifespan of an organism, and this process has been linked to senescence and other forms of age-related changes in cells.

The team recruited a group of 58 healthy women: 19 of whom had a healthy child; and 39 of whom had a child with a chronic illness. The researchers reasoned that the latter group often experienced increased levels of stress compared with the women who had healthy children³. Epel’s team found that the women with a chronically ill child had shorter telomeres than those who did not — and that telomere length correlated with the number of years spent as a carer. These findings suggested that exposure to chronic stress can introduce molecular changes that are important for ageing, says biologist Noah Synder-Mackler at Arizona State University in Tempe.

Since then, teams have also found evidence of telomere shortening in people exposed to other stressors, such as adverse experiences in childhood and work-related exhaustion⁴. Although some of the results have been mixed when it comes to telomere length, researchers have also amassed evidence linking stress to other molecular markers of ageing.

For example, Anthony Zannas, a physician–scientist at the University of North Carolina at Chapel Hill, and his colleagues have shown, through studies of large cohorts of people, that high levels of stress throughout life were associated with signs of accelerated ageing in the epigenome, the patterns of chemical modifications to the genome, such as DNA methylation, that help to regulate what genes are expressed. These changes might be mediated by stress hormones such as cortisol. Zannas’s team found that, in women, higher levels of cortisol were linked to lower levels of DNA methylation, as well as an increase in the expression of the gene coding for tumour necrosis factor (TNF), a signalling molecule associated with inflammation⁵.

Exercise can help to mitigate some of the effects of stress on ageing. Credit: Kevin Frayer/Getty

Others have been studying these processes in animals. Although animal models of stress have their limitations — for one, humans stressors are much more complex and can include a variety of social, psychological and biological factors — this work has provided mechanistic insights that are difficult to obtain in human studies. Bartolomucci and his team have discovered that chronic social stress in rodents, such as being subjected to aggressive behaviour from a dominant animal, can damage heart health and lead to a shorter lifespan⁶. They’ve also found that exposure to this type of adversity is linked to an increase in age-related molecular changes, such as a build-up of signals associated with senescence.

For example, in one 2024 study of male mice, Bartolomucci’s team demonstrated that social stress during a relatively brief period in early life led to an increase in levels of a key marker of cellular senescence, called p16, in the brain, fat tissue and immune cells⁷. These changes occurred only in response to social stress: animals exposed to stress in the form of physical restraint, which involved placing them in small tubes for three hours per day for a month, did not experience a build-up of p16.

Synder-Mackler’s team have been conducting similar studies in rhesus macaques. These animals tend to form hierarchies within groups, with newcomers dropping to lower social ranks. So, by sequentially introducing animals into groups, the researchers were able to examine the effects of social status on health. They found that social stress affects the immune system in multiple ways. In the immune cells of monkeys with lower social status, it led to an increase in the expression of inflammation-associated genes⁸. These effects were at least partially reversible: when the animals’ social rankings were rearranged, the gene expression patterns in their immune cells also changed to match their standings. The team has yet to look at how these alterations affect lifespan — macaques can live for around 30 years, which makes it difficult to address this issue, Synder-Mackler says.