Calorie restriction slowed the accumulation of age-related DNA mutations in mice by 30%.

Calorie restriction may have a more profound impact on aging than previously thought. In a new study published September 9, 2026, in the journal Cell, scientists showed that mice fed approximately 30% fewer calories accumulated fewer somatic DNA mutations in cells across several organs. The effect extended not to a single gene, but to large swaths of the genome and affected multiple types of genetic changes. [1]

The researchers found reductions in both single-nucleotide substitutions, in which one DNA "letter" is replaced by another, and small insertions and deletions, in which individual fragments of the genetic sequence are added or lost. The magnitude of the effect varied significantly between tissues: the reduction in mutational load was most pronounced in the liver, while it was weaker in the kidneys and brain. [2]

Even more surprising was the question of where exactly in the genome the number of mutations was reduced. In the liver and kidneys, calorie restriction was more protective of inactive regions of DNA—areas where genes are absent or are barely used by a given cell. The authors suggest that active regions of the genome already receive more attention from DNA repair systems, so the additional reduction in damage is particularly noticeable in areas where such protection is typically weaker. [3]

The work is important for another reason: somatic mutations gradually accumulate in virtually all tissues with age. Most of them cause no noticeable harm, but some can disrupt gene function, promote tumor transformation, or impair the function of aging cells. The new study is the first to directly link a well-known geroprotective intervention in animals—calorie restriction—to a reduction in the genome-wide rate of accumulation of such changes. [4]

Key parameter	Result
Object of study	mice
Intervention	approximately 30% fewer calories
Comparison	free access to feed
Main outcome	somatic mutational load
Single nucleotide substitutions	decreased
Insertions and deletions	decreased
The most pronounced effect	liver
More moderate effect	kidney and brain
Cell types studied	including hepatocytes and cerebellar neurons
Age-related mutation signature	SBS5 activity decreased
An unexpected find	maximum effect in low-activity regions of the genome
Human study	No
DOI	10.1016/j.cell.2026.08.013

Why are somatic mutations associated with aging at all?

The DNA of most cells in the body does not remain unchanged at birth. It is constantly exposed to chemical damage, oxidative stress, copying errors, and imperfect repair systems. If damage is repaired incorrectly or goes undetected, the change can become fixed as a somatic mutation—that is, a mutation that occurs after conception and is present only in some cells.

The number of such changes gradually increases with age. Moreover, mutations accumulate not only in actively dividing tissues but also in long-lived cells, including neurons. Different tissues have their own rate of accumulation and their own set of predominant mutational processes, which depend on metabolism, cell division frequency, environmental exposure, and the efficiency of various DNA repair systems. [5]

Most somatic mutations occur in regions of the genome where they have virtually no effect. However, sometimes a change occurs in a critical gene or regulatory region. The accumulation of certain combinations of mutations underlies the development of many types of cancer. Furthermore, increasing genetic heterogeneity in cells is considered a potential component of age-related tissue loss. [6]

However, one should not oversimplify the conclusion that aging is caused solely by mutations. Modern aging biology examines multiple interconnected processes: epigenetic changes, energy metabolism disruptions, protein imbalance, cellular senescence, inflammation, mitochondrial dysfunction, and genomic damage. New research shows that calorie restriction impacts yet another of these processes: the rate of accumulation of genetic errors.

Where do somatic mutations come from?

Source	Possible consequence
DNA copying errors	substitution of individual nucleotides
Oxidative damage	chemical change of bases
Spontaneous chemical reactions	DNA misreading
DNA repair errors	reinforcing the wrong sequence
External mutagens	specific mutational signatures
Age-related processes	gradual accumulation of mutations
Cell division	additional possibility of errors
Damage in non-dividing cells	mutations are possible even in neurons

How Scientists Measured Extremely Rare Mutations

One of the main technical challenges of such studies is that conventional sequencing inherently introduces errors. If a true somatic variant is present in only one cell among thousands, it can easily be mistaken for a technical error in the instrument. Therefore, assessing age-related mutations requires methods that are significantly more accurate than those used in conventional genetic variant searches.

The new study utilized high-precision double-stranded DNA sequencing. Its principle is that both complementary strands of a single DNA molecule are analyzed independently. A true mutation should be consistently detected in both strands, whereas most sample preparation or reading errors appear in only one. This approach dramatically reduces technical noise and enables the detection of extremely rare somatic variants. [7]

The researchers analyzed several tissues and cell populations, including liver and kidney, as well as isolated hepatocytes and cerebellar neurons. This allowed them to test whether caloric restriction had the same effects on the actively metabolizing liver, kidney tissue, and long-lived brain cells. The results were not uniform, which was one of the key findings of the study. [8]

Importantly, the authors analyzed more than just the total number of changes. They classified the types of mutations and studied their distribution across the genome. This allowed them to move beyond the simple statement "there are fewer mutations" to the question of which specific mutational processes are changing and which regions of the genome are most protected.

What was analyzed	For what
Single nucleotide substitutions	evaluate the main class of point mutations
Inserts	detect the appearance of additional nucleotides
Deletions	identify the loss of DNA regions
Mutation signatures	determine probable mechanisms of damage
Location in the genome	understand which areas are more strongly protected
Various organs	evaluate the tissue-specific effect
Individual cell types	eliminate the influence of the composition of the entire fabric

30% fewer calories - and fewer mutations of several types at once

The main experimental result was that the overall somatic mutational load was reduced in mice on a restricted calorie diet. This applied not only to a single pre-selected gene, as in some earlier studies, but to significantly broader regions of the genome. The authors consider this scale of analysis to be the key distinction of the new study. [9]

The number of single-nucleotide substitutions (SNSs)—the most common class of small somatic changes—decreased. If you imagine a DNA sequence as a giant text, such a mutation corresponds to a situation where one letter in a random location is replaced by another. Millions of such changes in an organism can be neutral, but a few can alter protein structure or the regulation of an important gene.

At the same time, the number of small insertions and deletions decreased. These changes are particularly interesting because, when occurring within the coding region, they sometimes shift the reading frame of the gene and can significantly alter the protein than a simple replacement of a single "letter." In the new study, calorie restriction also affected this class of mutations. [10]

However, the authors don't offer a single, universal figure, such as "30% less food leads to 30% fewer mutations." The magnitude of the effect varied depending on the tissue, cell type, mutation type, and genomic region. This heterogeneity is crucial for understanding the mechanism: the intervention apparently doesn't simply slow down all genetic processes uniformly throughout the body.

The liver reacted more strongly than the kidneys and brain.

The most pronounced reduction in mutational load was found in liver cells. This is biologically plausible, as the liver is one of the main metabolic centers and is highly sensitive to changes in energy balance, nutrient availability, and hormonal signaling. During calorie restriction, it is here that particularly large-scale metabolic changes occur. [11]

The effect was also observed in kidney tissue, but was less pronounced. The authors attribute the differences between the organs to the fact that liver and kidney cells differ in metabolism, the intensity of DNA damage, their ability to divide, and the activity of their genome repair systems. Therefore, the same systemic intervention can alter the "damage-repair-mutation fixation" balance in different organs in completely different ways. [12]

In brain neurons, the reduction in mutational load was even more modest. Neurons differ fundamentally from hepatocytes: most mature neurons practically do not divide, so their age-related mutations are less associated with errors in normal DNA copying. Nevertheless, somatic changes continue to accumulate in these cells, as previously demonstrated in an analysis of human cerebellar neurons. [13]

The tissue specificity makes the study's conclusion more interesting, but also complicates its translation to humans. It cannot be assumed that a conditional reduction in mutations in the liver automatically translates to a similar reduction in the heart, intestine, skin, hematopoietic system, or human brain. The authors explicitly point to the need to study additional organs and cell types. [14]

How did the effect differ?

Tissue / cells	The effect of calorie restriction
Liver	the most pronounced reduction in mutation load
Hepatocytes	pronounced effect
Bud	decreased mutations, but weaker than the liver
Cerebellar neurons	the effect was present, but more moderate
Other organs	require further study

Caloric restriction reduced the age-related SBS5 mutation signature

Scientists paid special attention to mutational signatures. These are characteristic combinations of various types of nucleotide substitutions that allow statistically reconstructing the processes that left their mark on the genome. For example, ultraviolet radiation, tobacco smoke, and disruptions to certain DNA repair systems create their own recognizable mutation patterns.

One of the most common age-related signatures is SBS5. It is found in a wide variety of normal tissues and tumors and typically increases with age. Unlike some mutational processes with a well-known cause, the precise source of SBS5 remains complex: it likely reflects the cumulative effects of endogenous damage and its subsequent processing by cellular repair systems. [15]

In the new study, SBS5 activity was reduced by calorie restriction. This is particularly interesting because it is not a question of preventing a single, specific external mutagen, but rather of influencing a background aging process that operates throughout life. [16]

However, a decrease in SBS5 cannot automatically translate into "biological age decreased by a certain percentage." The mutational signature represents only one molecular layer of aging. The study demonstrates that the rate of a specific age-related mutational process can be modified by dietary intervention in mice, but it does not establish a universal "genetic age" for the organism.

The most unexpected effect was discovered in a low-activity region of the genome.

The cellular genome functions extremely heterogeneously. Some genes are actively transcribed almost constantly, others are activated only under certain conditions, and large sections of DNA in a given cell remain relatively inactive. This difference also affects damage repair.

Actively transcribed regions enjoy additional protection. When the RNA synthesis machinery encounters DNA damage, the cell can activate specialized repair processes. Therefore, actively transcribed regions of the genome are often repaired more efficiently than regions that are rarely used.

Scientists expected that if calorie restriction generally improved the cells' ability to repair DNA, the benefit would be particularly pronounced in functionally important, active genes. However, in the liver and kidneys, the opposite pattern was observed: the reduction in mutations was most pronounced in regions of low activity. [17]

The authors offer an intriguing explanation. Perhaps calorie restriction doesn't so much dramatically enhance the repair of active genes as it reduces the sheer number of damages occurring throughout the genome. Active regions are already well repaired and therefore receive a relatively small additional benefit, while less active regions, previously less well protected, exhibit a much more significant reduction in mutations. This is currently a working hypothesis, not a proven mechanism. [18]

Genome region	Expected initial situation	The effect of calorie restriction
Actively working genes	more intense DNA repair	the additional effect is less
Inactive genes	repairs may be less intensive	the reduction in mutations is more noticeable
Non-coding regions	low transcriptional activity	pronounced effect in the liver and kidneys
General conclusion	the effect is distributed unevenly across the genome	possible reduction of DNA damage itself

How Calorie Reduction Can Protect DNA

One possible explanation is related to metabolic stress. The more active cellular metabolism, the more reactive molecules and intermediates are produced that can chemically damage DNA. Energy restriction alters glucose and fat utilization, insulin sensitivity, mitochondrial function, and numerous signaling systems, potentially altering the severity of such damage.

A second possible pathway is alteration of cellular maintenance and repair systems. Calorie restriction affects pathways associated with insulin, nutrient signaling, autophagy, and the cellular stress response. All of these pathways can indirectly alter a cell's ability to remove damaged molecules or repair genomic damage. Animal studies have previously repeatedly linked calorie restriction to a reduction in oxidative DNA damage and changes in the activity of DNA repair systems. [19]

A third mechanism may be related to the frequency of cell division. In proliferating tissues, each additional copy of the genome creates the potential for error. If a change in the energy environment reduces unnecessary proliferation of certain cell populations or alters cell selection, the resulting mutational load may also decrease.

But the new study has not yet determined which of these mechanisms is the primary one. Moreover, the relatively small effect in non-dividing neurons suggests that common replication errors cannot be the sole explanation. Therefore, the authors plan to compare other dietary and potentially drug interventions to understand which biological changes are truly responsible for the reduction in mutations. [20]

Can Reducing Mutations Reduce Cancer Risk?

Theoretically, the connection is quite logical. For a normal cell to become malignant, it typically needs to accumulate several genetic changes that provide advantages in growth, survival, and evasion of the body's defense mechanisms. The more mutations that appear in a tissue over decades, the greater the likelihood that at least some dangerous combinations will arise by chance.

If the intervention does reduce the rate of somatic mutations, it could potentially reduce the number of opportunities for tumor clones to emerge. This is why the authors consider the effect they found as a possible part of the explanation for the long-known association between calorie restriction and a lower incidence of certain tumors in animal experiments. [21]

However, the new study is not a cancer prevention study. Its primary outcome was mutational burden, not tumor incidence, cancer mortality, or life expectancy. Even a significant reduction in background mutations does not guarantee a proportional reduction in cancer risk, because tumor development also depends on immune surveillance, inflammation, epigenetics, hormones, and competitive cell selection.

Furthermore, not every mutation is equally harmful. A million changes in functionally insignificant regions may have fewer consequences than a single mutation in a key oncogene or tumor suppressor gene. Therefore, the next important question is not only whether the number of mutations is decreasing, but also whether the likelihood of the emergence of functionally harmful clones is decreasing.

Could this be one of the mechanisms for slowing down aging?

Caloric restriction is one of the most reproducible interventions for increasing lifespan in many laboratory animals. However, its mechanism of action has never been pinpointed to a single molecule. It alters energy metabolism, inflammation, the activity of cellular damage-recovery systems, hormonal signaling, and the function of numerous genes.

New work adds another layer to this picture: a reduced accumulation of genetic errors. If cells in an old organism retain their genome closer to its original state, this could theoretically reduce the risk of dysfunctional clones and certain age-related diseases. [22]

However, the somatic mutation theory of aging remains a subject of debate. In some long-lived cells, the absolute number of mutations appears to be relatively small to explain the full diversity of age-related changes. It is more likely that genomic damage interacts with other aging mechanisms rather than being the sole underlying cause.

Therefore, the new study does not prove that mice live longer because they have fewer mutations. It reveals a much more specific, yet important, causal pathway: changes in energy intake can alter the genome-wide somatic mutation load. The next step should demonstrate the extent to which this effect actually contributes to increased healthy lifespan.

What is known about calorie restriction in humans?

Humans can't be automatically compared to laboratory mice. However, there is a randomized trial, CALERIE, in which 220 healthy, non-obese adults were assigned to either a normal diet or an attempt to reduce calorie intake by approximately 25% over two years. In practice, participants in the restricted group achieved an average reduction in energy intake of approximately 12%, much less than the 30% in the new mouse study. [23]

In CALERIE analyses, moderate caloric restriction affected several markers associated with biological aging. Changes were found in individual markers of DNA methylation, inflammation, metabolic health, and markers of cellular aging. More recent studies of CALERIE samples also revealed changes in small non-coding RNAs in blood, muscle, and adipose tissue.

However, this doesn't confirm Cell's new human results. CALERIE failed to demonstrate that moderate calorie restriction reduces the accumulation of nuclear somatic mutations throughout the genome. The new experiment examined precisely this question, and only in mice.

Therefore, it's impossible to take the result "30% fewer calories = fewer mutations" and turn it into a recommendation for a person to permanently eat a third less. Even the authors themselves note that such a significant and long-term dietary restriction is difficult to implement in humans. They consider the main translational goal to be the search for biological mechanisms that will reduce mutational load without the need to maintain an extreme diet. [24]

What we know about mice and humans

Question	Mice in new work	People
Calorie restriction	30%	in CALERIE actually ≈12% on average
Somatic mutations of the genome	decreased	such a result has not yet been established
Metabolic changes	Yes	Yes
Markers of cellular aging	previously shown	changed in CALERIE
DNA methylation	the influence is known	changes detected
Life extension	well demonstrated in many animal models	not proven
Can a 30% limit be recommended?	experimental model	No

Why a new study doesn't support fasting

In aging research, the term "calorie restriction" refers to reducing energy intake while maintaining adequate levels of essential nutrients. It's not the same as fasting, chronic malnutrition, or eliminating large quantities of foods without monitoring their vitamin, mineral, and protein levels.

Furthermore, a 30% calorie restriction in laboratory mice cannot be simply translated to human calories. Mice and humans differ dramatically in lifespan, metabolic rate, energy reserves, and physiological response to food deprivation. Even between different mouse strains, the effect of calorie restriction on lifespan can vary. [25]

The human CALERIE study also demonstrates the practical difference well: participants were prescribed a 25% reduction in calories, but over the long term, the actual average reduction was about 12%. Moreover, the program was conducted within the framework of a controlled study of healthy people, not as a stand-alone extreme diet. [26]

Therefore, the practical significance of the new study lies not in recommending a third-less diet, but in identifying a new biological mechanism that can potentially be replicated in other ways. If we understand why calorie restriction reduces mutational load, we can search for drugs or less drastic dietary interventions that target the same process.

Main limitations of the study

The first and most important limitation is that the study was conducted on mice. Although the basic mechanisms of DNA damage and repair are largely common in mammals, the quantitative response to energy restriction can differ significantly between short-lived rodents and humans.

A second limitation is that only a few tissues and cell types have been studied. The strongest response in the liver demonstrates the importance of organ-specific context. It is still unknown what happens in intestinal epithelium, skin, hematopoietic stem cells, the heart, or other tissues particularly important for age-related diseases.

Third, the study demonstrates a reduction in mutational load, but does not prove its clinical consequences. It was not shown that the reduction in mutations specifically leads to fewer tumors, a delayed onset of age-related diseases, or an increase in lifespan in specific animals in the study group.

Fourth, the mechanism itself remains unclear. It is unclear whether DNA damage formation is reduced, whether its repair is improved, whether the rate of cell division is altered, whether cell lineage selection is affected, or whether several processes are simultaneously at play. The unexpected advantage of inactive regions of the genome provides an important clue, but does not yet allow one explanation to be chosen. [27]

Limitation	Why is it important?
Only mice	the effect in humans is unknown
30% calorie restriction	much harsher than most human interventions
Several organs	cannot be extrapolated to the entire organism
Mutations are an intermediate indicator	are not equal to clinical disease
Risk of cancer as a primary outcome was not assessed	tumor prevention has not been proven
Life extension through this mechanism has not been proven.	the causal chain has not been established
The mechanism for reducing mutations is unknown.	there is no specific drug target yet

What scientists need to find out next

The first obvious question is whether the results are reproducible with more moderate caloric restriction. If a reduction in mutational load is observed with just a 10-15% reduction in energy intake, this would be much more interesting in terms of translation to humans.

The second question is whether calorie restriction itself is required, or whether the associated fasting periods, circadian feeding patterns, and changes in specific metabolic pathways are important. The authors intend to analyze additional nutritional interventions and a larger number of tissues to disentangle these components. [28]

The third direction is the search for direct molecular mediators. If it turns out that the key factor is, for example, the reduction of a certain type of endogenous DNA damage or the enhancement of a specific repair system, this target could potentially be replicated pharmacologically.

Finally, a direct human experiment will be required. Modern high-precision sequencing methods theoretically allow for comparison of somatic mutational load before and after long-term dietary interventions. Such an analysis, whether in CALERIE or future randomized trials, could answer the key question: can moderate, safe calorie restriction truly slow mutation accumulation in human tissues?

The main conclusion

A study in Cell demonstrates for the first time at the genome-wide level that an organism's energy status can alter the rate of accumulation of somatic mutations. Mice fed approximately 30% fewer calories had reduced rates of single-nucleotide substitutions, small insertions, and deletions in several tissues. [29]

The effect was not uniform across different organs: it was most pronounced in the liver and less pronounced in the kidneys and brain neurons. Simultaneously, one of the key age-related mutational signatures, SBS5, was reduced, linking the dietary intervention to the background processes of genetic change accumulation during aging. [30]

The most unexpected finding was the preferential reduction in mutations in low-activity regions of the liver and kidney genome. This result supports the hypothesis that calorie restriction may reduce the formation of DNA damage throughout the genome, while active regions are already protected by more intensive repair. However, this mechanism remains speculative. [31]

Therefore, the most accurate interpretation of the study is that calorie restriction in mice doesn't simply alter metabolism; it can reduce the accumulation of age-related genetic errors. However, it is still unknown whether the same occurs in humans and whether this effect is one of the reasons for the animals' increased lifespan. Clarifying these two questions is now the next stage of the study.

News source

Grońska-Pęski M. et al. Caloric restriction modulates genome-wide somatic mutation in mice. Cell. Published online September 9, 2026. The work was carried out by researchers from New York University, University Hospitals Cleveland, and Case Western Reserve University in collaboration with the National Institute on Aging and the University of Texas Southwestern Medical Center. DOI: 10.1016/j.cell.2026.08.013.

This is an original, peer-reviewed experimental study on animals, not a human study or a clinical trial. Therefore, its primary scientific conclusion concerns the ability of 30% calorie restriction to alter somatic mutational load in mice; claims about cancer prevention, slowing genetic aging in humans, or the need for a similar diet in humans do not directly follow from this study.