BY MARIA BURKE
Ageing is a natural part of life. Understanding how it occurs could be the key to preventing or even reversing a plethora of age-related diseases – as well as increasing longevity. Maria Burke reports
Two major theories explain ageing at the molecular level. The somatic mutation theory suggests ageing results from the accumulation of mutations – permanent, random changes in DNA sequences. The epigenetic clock theory involves the accumulation of minor changes that don’t alter the underlying DNA sequence. Unlike mutations, epigenetic modifications can sometimes be reversed.
Scientists favour the epigenetic clock theory to measure biological ageing because epigenetic modifications only occur at specific sites on the genome, making them easier to quantify. However, a team at the University of California San Diego School of Medicine, US, has now reported a link between the two theories.
‘Major research institutions and companies are betting on turning back the epigenetic clock as a strategy to reverse the effects of ageing, but our research suggests that this may only be treating a symptom of ageing, not the underlying cause,’ says team leader Trey Ideker. ‘If mutations are responsible for the observed epigenetic changes, this fact could fundamentally change the way we approach anti-ageing efforts in the future.’
The team compared genetic mutations to epigenetic modifications in 9331 patients and found they correlated with changes in DNA methylation, one type of epigenetic modification[1]. They report that a single mutation could cause a cascade of epigenetic changes across the genome, not just where the mutation occurred. The researchers say their study demonstrates that epigenetic changes are ‘intricately and predictably’ tied to random genetic mutations, with significant implications for developing new therapies.
‘If somatic mutations are the fundamental driver of ageing and epigenetic changes simply track this process, it’s going to be a lot harder to reverse ageing than we previously thought,’ adds co-corresponding author Steven Cummings. ‘This shifts our focus from viewing ageing as a programmed process to one that’s largely influenced by random, cumulative changes over time.’
However, researchers from The Rockefeller University argue their work suggests ageing is a synchronised, body-wide process. They’ve created an atlas of 7m cells showing how ageing reshapes the body across 21 mammalian organs and unfolds in a coordinated way.
To map ageing at this scale, Junyue Cao’s team refined a method known as single-cell ATAC-seq. This approach looks at how DNA is packaged inside each cell, revealing which regions of the genome are active, a key indicator of a cell’s state and function. The researchers applied this technique to millions of cells from 21 organs in 32 mice at one months, five months and 21 months. They identified more than 1800 cell subtypes and tracked how their numbers changed as the mice aged. About one quarter of all cell types showed significant changes in abundance over time[2]. For example, certain muscle and kidney cell populations declined sharply, while immune cells expanded considerably.
‘The system is far more dynamic than we realised,’ says Cao. ‘And some of these changes begin surprisingly early. By five months of age, some cell populations had already begun to decline. This tells us ageing isn’t just something that happens late in life; it’s a continuation of ongoing developmental processes.’
One striking finding was that many age-related shifts happen in sync across multiple organs, suggesting shared signals, possibly circulating in the bloodstream, help coordinate ageing throughout the body.
‘This challenges the idea that ageing is random genomic decay,’ Cao says. ‘Instead, we see specific regulatory hotspots that are particularly vulnerable, and these are precisely the regions we should be studying if we want to understand what drives the ageing process.’
Ageing process
As we age, our blood and immune systems gradually lose strength. One reason is the decline of hematopoietic stem cells (HSCs), responsible for producing blood. Under healthy conditions, HSCs renew themselves and create a balanced mix of blood cells. But over time, they generate fewer new cells and are less able to support strong immune responses. Several factors could drive this decline, including chronic low-level inflammation, and changes in gene activity. But how they combine to reduce HSC function is not well understood.
To explore how age-related stress affects HSCs, researchers from the University of Tokyo, Japan, and St Jude’s Children’s Research Hospital, US, focused on how cells interact with a specific protein associated with necroptosis, a form of programmed cell death, through a ‘signalling axis’ called MLKL. Necroptosis is regulated by three key proteins: receptor-interacting serine/threonine-protein kinase (RIPK)-1, RIPK3, and mixed-lineage kinase domain-like protein (MLKL). Studies on mice revealed a previously unknown role for MLKL in stem cell ageing. When activated under stress, MLKL briefly moved to the mitochondria where it caused damage and reduced energy production. This led to key features of ageing in HSCs, including reduced ability to renew themselves[3]. HSCs lacking MLKL retained their ability to regenerate, produced healthier immune cells, showed less DNA damage, and maintained better mitochondrial function.
The team suggests MLKL influences ageing through processes at the level of cellular structures, rather than through changes in DNA regulation or inflammation. Identifying MLKL as a key link could lead to new strategies for slowing ageing at its source, says study leader Masayuki Yamashita.
Ageing and disease
Ageing increases the risk of many chronic illnesses. But Kris Burkewitz’s team at Vanderbilt University, US, is investigating whether the biological process of ageing can be separated from the development of disease. Recently, his team reported a new way cells respond to ageing. ‘Where many prior studies have documented how levels of different cellular machineries change with age, we are focusing instead on how ageing affects the way cells house and organise these machineries,’ Burkewitz says.
The researchers showed that cells reshape the endoplasmic reticulum (ER), a complex network of membranes inside the cell, which undergoes controlled ‘remodelling’ as organisms age[4]. They found that remodelling occurs when cells selectively break down specific regions of the ER. This process appears to be part of the ageing process, suggesting it could one day become a target for drugs.
In studies on worms, the team found ageing cells significantly reduce the amount of ‘rough’ ER associated with protein production. In contrast, the tubular form of ER linked to lipid or fat production declines only slightly. This pattern aligns with well-known features of ageing, such as reduced ability to maintain healthy proteins and metabolic changes contributing to fat accumulation in new tissues.
‘Changes in the ER occur relatively early in the ageing process,’ Burkewitz says. ‘One of the most exciting implications is that it may be one of the triggers for what comes later: dysfunction and disease.’ If researchers can pinpoint what initiates early ER changes, they may be able to prevent the cascade of events leading to age-related disease.
Ageing in specific organs can contribute to numerous diseases. Now University College London researchers have devised a way to predict diseases affecting particular organs, and across the body.
‘Our organs function as an integrated system, but they can age at different rates,’ says UCL’s Mika Kivimäki. ‘We found that a quick and easy blood test can identify whether a specific organ is ageing faster than expected. In future, blood tests like this could play a crucial role. Preventing age-related diseases could begin much earlier, prioritising those who would benefit most and tailoring interventions to individual risk profiles.’
The researchers analysed blood samples collected in the late 1990s from over 6200 middle-aged adults to determine the biological age of nine organs and the entire body. They measured the gap between a person’s chronological age and assessed biological age for each of their organs and tracked the participants for 20 years.
The team found accelerated organ ageing predicted the risk of 30 diseases in initially healthy people[5]. For example, a heart that aged rapidly predicted significantly increased risk of cardiovascular diseases. People with accelerated kidney ageing were more likely to develop vascular disease, diabetes and liver diseases, while biological ageing of nearly all organs predicted increased risk of kidney disease.
Surprisingly, the highest risk of dementia occurred in those whose immune system aged faster than usual, not those whose brains aged more rapidly in midlife, suggesting a link between inflammation and neurodegenerative diseases.
US researchers, meanwhile, have produced a map showing which brain cells may be most affected by ageing. Some brain cells, such as a group of hormone-controlling cells, may undergo more age-related changes in genetic activity than others.
‘Ageing is the most important risk factor for Alzheimer’s and many other devastating brain disorders,’ says Richard Hodes of NIH’s National Institute on Ageing. ‘This new map may fundamentally alter the way scientists think about how ageing affects the brain and also provide a guide for developing new treatments.’
The team used genetic analysis tools to study brain cells in two-month-old and 18-month-old mice. For each age, researchers analysed the genetic activity of cell types located in 16 brain areas. They found decreased activity of genes associated with neuronal circuits involving neurons and glial cells[6]. In contrast, ageing increased the activity of genes associated with the brain’s immunity, inflammatory systems and blood vessel cells.
Most sensitive to ageing were cells lining the third ventricle, a major pipeline enabling cerebrospinal fluid to reach the hypothalamus. Ventricle-lining cells control the passage of hormones and nutrients between the brain and the body. Neighbouring neurons in the hypothalamus also showed significant changes in genetic activity with age.
Slowing ageing
Scientific evidence suggests periods of fasting trigger cellular pathways that shift the body from growth and storage to maintenance and repair. This metabolic reprogramming affects the molecular and cellular markers that define biological age which is why fasting has become a focus for longevity research.
In a recent literature review, however, researchers note the benefits of intermittent fasting have not been proven in people[7]. The review concludes that: ‘the current state of evidence is limited and not sufficient to justify widespread adoption of fasting practices, nor is it sufficient to exclude the possibility that fasting holds a key to a longer life.’
While the jury is out on fasting, researchers at King’s College London have uncovered a surprising link with dark chocolate. After examining data from 1600 people, they found higher amounts of theobromine – a natural cocoa compound – in the bloodstream of people biologically younger than their real age[8]. They didn’t find any similar patterns with other cocoa or coffee metabolites.
‘While we’re not saying people should eat more dark chocolate [as it contains sugar and fat], this research can help us understand how everyday foods may hold clues to healthier, longer lives,’ says senior author Jordana Bell.
Exercise might be an even better bet. In 2025, a literature review concluded that regular physical activity produces measurable reductions in biological age and could potentially reverse it[9]. Benefits were seen not only in muscles but in the heart, liver, fat tissue, and gut. Planned, repetitive, and goal-directed exercise, such as aerobics and strength training, have stronger effects than walking or housework. Such exercise reduced biological age markers in blood and skeletal muscle.
Building strong relationships as well as fitness may also slow ageing. Anthony Ong’s team at Cornell University, US, discovered that people with greater ‘cumulative social advantage’ tended to show slower biological ageing and reduced chronic inflammation[10].
‘Cumulative social advantage is really about the depth and breadth of your social connections over a lifetime,’ Ong says. This includes parental warmth and support, community connections, involvement in religious or faith-based groups, and ongoing emotional support from friends and family. The team found higher social advantage was linked to lower levels of interleukin-6, a pro-inflammatory molecule implicated in heart disease, diabetes and neurodegeneration.
‘People with richer, more sustained social connections literally age more slowly at the cellular level,’ says Ong. ‘Ageing well means both staying healthy and staying connected – they’re inseparable.’
References
- Z. Koch et al, Nature Ageing, 2025; DOI: 10.1038/s43587-024-00794-x
- Z. Lu et al, Science, 2026; DOI: 10.1126/science.adw6273
- Y Yamada et al, Nature Communications, 2026; DOI: 10.1038/s41467-026-71060-4
- E. Donahue et al, Nature Cell Biology, 2026; DOI: 10.1038/s41556-025-01860-1
- M. Kivimäki et al, The Lancet Digital Health, 2025; DOI: 10.1016/j.landig.2025.01.006
- K Jin et al, Nature, 2025; DOI: 10.1038/s41586-024-08350-8
- ML Steinhauser et al, Biogerontology, 2026, 27, 93
- 8 R Saad et al, Ageing, 2025, 17, 2902
- T Kawamura, Ageing, 2025; DOI: 10.18632/ageing.206278
- AD Ong et al, Brain, Behavior, & Immunity – Health, 2025; DOI: 10.1016/j.bbih.2025.101096
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