Supercentenarians over 110 years old have been found to have an unusual immune system restructuring: rare killer T cells become much more numerous.

People who have surpassed the age of 110 represent a rare model of exceptionally successful aging. Despite their extreme age, many supercentenarians remain relatively free of severe infections, cancer, and other age-related diseases. A new study published in Cell Reports points to one possible component of this resilience: supercentenarians exhibit a sharp increase in an unusual population of immune cells—cytotoxic CD4-positive T lymphocytes, which are capable of directly killing other cells.

Researchers led by Kosuke Hashimoto from the Institute for Protein Research at Osaka University analyzed T cells from 28 healthy individuals in three age groups. The study included eight individuals aged 70-99, ten centenarians aged 100-109, and ten supercentenarians aged at least 110. A combination of modern single-cell technologies was used to characterize the cells: RNA sequencing of individual cells, simultaneous detection of surface proteins, and sequencing of T cell receptors.

The differences were significant. Cytotoxic CD4-positive T lymphocytes accounted for a median of approximately 4.0% of CD4-positive T cells in people aged 70-99, 9.6% in people aged 100-109, and 17.6% in supercentenarians over 110. In other words, in the oldest group, the proportion of this unusual immune population was more than four times higher than among participants under 100.

But it wasn't just the number of these cells that proved more important. Analysis of T-lymphocyte receptors revealed signs of clonal expansion—the proliferation of individual cell clones, which typically occurs after recognizing a specific target. This suggests that the immune system of supercentenarians doesn't simply passively accumulate unusual cells with age, but actively selects and expands specific populations in response to antigens encountered throughout life. Therefore, the authors view this finding as an example of adaptive immune restructuring during exceptionally successful aging.

Research in numbers

Indicator	Result
Total number of participants	28
Age 70-99 years	8 people
Age 100-109 years	10 people
Age ≥110 years	10 people
Proportion of cytotoxic CD4-positive T cells in 70-99 year olds	4.0%
At 100-109 years old	9.6%
At ≥110 years	17.6%
Basic methods	Single-cell ribonucleic acid sequencing, CITE-seq, T-cell receptor sequencing
The material under study	Peripheral blood T-lymphocytes
The main find	Age-dependent increase and clonal expansion of cytotoxic CD4-positive T cells

[1]

Why these cells are unusual: CD4-positive lymphocytes are not usually considered the main "killers"

To understand the significance of this discovery, it's important to recall the classical division of T-lymphocyte functions. CD4-positive T-cells are traditionally called T-helper cells: they coordinate the immune response, secrete signaling molecules, help B-lymphocytes produce antibodies, and regulate the activity of other immune cells. The primary function of directly destroying virus-infected or malignant cells is usually attributed to CD8-positive cytotoxic T-lymphocytes.

However, there is a less common subtype of CD4-positive cells that acquires cytotoxic properties. These cells are capable of expressing molecules characteristic of cellular "weapons," including perforin, granzymes, and granulysin. After recognizing a suitable target cell, they can initiate programmed cell death. Therefore, in terms of functional behavior, these CD4-positive lymphocytes become significantly closer to classical killer cells than to conventional T-helper cells.

Cytotoxic CD4-positive T cells are not exclusively "longevity cells." They are found in viral infections, some tumors, autoimmune diseases, transplants, and a number of other conditions. Depending on the context, their activity can be beneficial—for example, by promoting the destruction of infected or tumor cells—or they can contribute to pathological tissue damage. Therefore, the mere presence of a large number of these lymphocytes does not automatically mean a stronger or healthier immune system.

This is precisely what makes the new study particularly interesting. The participants were selected as healthy elderly individuals, and the official study database explicitly states that the project's goal was to study the molecular features of immune aging in centenarians. Thus, the scientists observed an unusual expansion of cytotoxic CD4-positive cells not in the context of severe illness, but in individuals who had managed to live to an exceptionally old age.

What are the differences between the main types of T lymphocytes?

Cell type	Typical function	Can directly destroy target cells
Normal CD4-positive T cell	Coordination of the immune response	Usually no
CD8-positive cytotoxic T lymphocyte	Destruction of infected and altered cells	Yes
Cytotoxic CD4-positive T lymphocyte	Combines regulatory and cytotoxic properties	Yes
Regulatory T cell	Inhibits excessive immune response	Usually no
Memory T cell	Stores information about a previously encountered antigen	Depends on the subtype

[2]

From 4% to 17.6%: The immune system changed especially noticeably after 100 years

In the youngest of the study groups, which included people aged 70 to 99, cytotoxic CD4-positive T cells remained a relatively small portion of the CD4-positive population—a median of about 4%. Among centenarians aged 100 to 109, this proportion more than doubled—to approximately 9.6%. Among those who reached 110 years of age, the figure rose to 17.6%.

This sequence is important because it suggests not a simple distinction between "ordinary elderly" and a few exceptional supercentenarians, but a gradual change in the immune profile as we approach extreme ages. However, the study was cross-sectional: the scientists compared different people of different ages, rather than observing the same participants from 70 to 110 years old. Therefore, it cannot be assumed that the proportion of these cells in a given individual will necessarily increase steadily with each decade.

The traditional concept of immune aging largely focuses on the loss of function. With age, the number of naive T cells decreases, receptor diversity diminishes, responses to new antigens are impaired, and chronic inflammation becomes more pronounced. However, data from supercentenarians show that compensatory changes can occur alongside these losses, in which the body expands certain specialized cell populations.

Kosuke Hashimoto therefore proposes considering immunity in extreme longevity not only as a system that slowly "wears out," but also as one capable of reorganization. The immune cell repertoire of a supercentenarian may be less similar to that of a younger person, but certain specialized clones potentially compensate for the age-related loss of other functions. The new study provides cellular and molecular evidence for this model.

How did the proportion of cytotoxic CD4-positive cells change?

Age group	Number of participants	Median CD4-CTL proportion	Change from 70-99 years
70-99 years old	8	4.0%	Reference
100-109 years	10	9.6%	approximately 2.4 times higher
≥110 years	10	17.6%	approximately 4.4 times higher

Multiplicity calculations are based on published proportions and are intended to provide illustrative comparisons rather than being a separate statistical outcome of the study.[3]

Scientists looked not only at the cells, but also at their “immune passports”

One of the study's greatest strengths was the use of single-cell sequencing. In a typical blood test, numerous lymphocytes are analyzed as a single mixture, easily missing rare populations. Here, the scientists studied the molecular profile of individual T cells, determining which genes are active in them and which surface proteins they carry. The official study repository lists the use of single-cell RNA sequencing and CITE-seq, which analyzed 16 surface proteins.

Sequencing of the T-cell receptor has become particularly important. Each T-lymphocyte carries a receptor with a virtually unique structure, formed during the cell's development. It can be thought of as a molecular identifier or "barcode." If a sample reveals multiple cells with the same receptor, the most likely explanation is that they all originated from a single original clone that once recognized a specific antigen and began actively replicating.

This type of clonal expansion was previously observed by Hashimoto's team in supercentenarians, and the new study extends this finding to a larger, age-stratified sample. The research project specifically sequenced the CDR3 regions of the alpha and beta chains of the T-cell receptor—the regions that largely determine antigen recognition specificity.

This significantly changes the interpretation of the finding. If cytotoxic CD4-positive cells simply accumulated non-specifically with age, a wide variety of independent cells would be expected. The predominance of repeating receptor sequences, on the contrary, indicates the selection of distinct clones. This doesn't necessarily indicate what these clones recognize, but it does indicate that their expansion bears the hallmarks of an acquired, antigen-dependent immune response.

What technologies did the researchers use?

Method	What does it measure?	Why was it needed?
Single-cell sequencing of ribonucleic acid	Gene activity in each cell	Determine the functional state of T-lymphocytes
CITE-seq	Ribonucleic acid + surface proteins	To differentiate cell subtypes more precisely
T-cell receptor sequencing	Unique receptor sequences	Detect clonal expansion
Analysis of CDR3 of alpha and beta chains	The most variable part of the receptor	Trace the origin of individual cell clones
Stimulation with PMA and ionomycin in some samples	Functional cellular response	Assess the ability of cells to activate

For the functional set, cells from six participants were used - two people from each age group. [4]

Clonal expansion suggests that cells may have encountered the same target many times.

In adaptive immunity, clonal expansion is one of the fundamental principles of defense. When a rare T cell recognizes a suitable antigen, the body doesn't limit itself to this single cell: it begins dividing, creating a large number of progeny with the same receptor. After the threat is eliminated, some cells may persist as long-lived immunological memory. Therefore, a large clone serves as a kind of remnant of a past or ongoing immune response.

This is a particularly interesting phenomenon for supercentenarians. Their immune systems exist for over a century and, during this time, are exposed to a huge number of infectious and other antigenic challenges. Theoretically, a long lifespan could lead to excessive depletion of the immune repertoire. However, the data of Hashimoto and colleagues suggest an alternative: some clones do not disappear, but rather become extremely numerous and acquire pronounced cytotoxic properties.

Such expansion cannot be automatically considered beneficial. Clonal T-cell populations are also found in chronic viral infections, autoimmune diseases, and other conditions. The key question is which antigens support these cells and how effectively they perform their functions. The authors of the new study have not yet identified their specific targets, so the biological significance of the expansion remains a central challenge for further research.

Nevertheless, the combination of two features—a high number of cytotoxic CD4-positive cells and pronounced clonality—supports the main idea of the article, as expressed in its title: "signs of adaptive expansion during healthy aging." The official Japanese repository directly links the published work to projects devoted to the mechanism of CD4-killer cell expansion in late life and the study of antigenic memory in T cells of centenarians.

The most intriguing finding: some of the cells resembled T cells from cancer patients.

The researchers were particularly interested in comparing the T-cell profiles of the supercentenarians with data previously obtained in younger individuals with cancer. Some characteristics of the cytotoxic CD4-positive cells in the oldest participants were similar to cell populations observed in lung, breast, and liver cancers. Moreover, the centenarians and supercentenarians in the study had not previously been diagnosed with these cancers.

This similarity suggests an intriguing hypothesis: perhaps certain cytotoxic CD4-positive clones are able to detect transformed cells even before they form a clinically detectable tumor. If the immune system regularly removes isolated potentially malignant cells, the tumor may never reach a stage at which it can be diagnosed. This is consistent with the general concept of immune surveillance of tumors, but the new study does not prove that this process occurred in the supercentenarians.

There are other possible explanations. Identical or similar T-cell functional programs may arise in response to chronic viruses, damaged tissue, or senescent cells. Cytotoxic CD4-positive lymphocytes have already been linked to the removal of cells that have entered a state of cellular senescence, which is potentially especially relevant in humans over 100 years of age. Therefore, antitumor activity is only one possible function of the discovered population.

Hashimoto emphasizes that the next task is to determine the specific molecular targets these clones recognize. Only then will it be possible to determine whether they are directed against tumor antigens, viruses, senescent cells, or other structures. If specific protective targets are indeed discovered, the idea of artificially reproducing a similar immune response may arise in the future, but the current work is still a long way from therapeutic conclusions.

What targets can supercentenarian cells potentially recognize?

Possible target	Why is it being considered?	Proven in new research?
Tumor cells	There are similarities to T cells found in several types of cancer	No
Virus-infected cells	CD4-CTL are capable of participating in antiviral immunity	No
Senescent cells	Such T cells can destroy cells with signs of senescence.	No
Other chronic antigens	Clonal expansion usually requires repeated antigenic stimulation.	Not installed
Several types of targets at the same time	The CD4-CTL population is heterogeneous	Possible, but not proven

Perhaps healthy aging does not mean maintaining a “youthful” immune system, but rather a successful restructuring

One of the conceptually important implications of this study is that the immune system of a supercentenarian need not appear youthful. On the contrary, it may differ significantly from that of a middle-aged person. A high proportion of cytotoxic CD4-positive cells is an example of a characteristic that is relatively rare in young people but becomes noticeable at extreme ages.

This challenges the conventional understanding of "immune rejuvenation." If certain age-related changes are compensatory and help us survive past 100, simply trying to restore the immune system to the state of a 30-year-old may be an overly simplistic strategy. It would be more useful to understand which changes represent pathological decline and which are adaptations to decades of accumulated infections, damage, and cellular aging.

Supercentenarians are particularly valuable for this type of research precisely because they represent an extreme natural experiment. To live to 110, a person must endure decades of increasing risk of cardiovascular disease, cancer, infections, and other causes of death. Therefore, the biological characteristics of these individuals may not reflect a "lack of aging," but rather effective mechanisms for compensating for its consequences.

The new data fits well with this model. The increase in specialized cytotoxic clones may indicate that part of the adaptive immune system is becoming less diverse, but simultaneously more focused on constantly encountering threats. The authors formulate this as a possible reorganization of the immune system, rather than a simple linear decline in its performance.

Two models of immune aging

Simplified model	A model supported by new data
With age, immunity only weakens.	Some functions are weakened, while other specialized populations may expand
Better immunity = as close to youth as possible	Successful aging may require specific age-related adaptations
Clonal expansion is always undesirable.	Some clones may potentially be protective
Growth of unusual T cells = a sign of disease	In healthy supercentenarians, such cells may be part of an adaptation
All age-related changes should be reversed	First, it is necessary to distinguish between harmful and compensatory changes.

[5]

The new work follows on from a discovery made by the same group back in 2019.

The topic of cytotoxic CD4-positive cells in supercentenarians is not new. In 2019, Hashimoto and colleagues published a study in the Proceedings of the National Academy of Sciences analyzing over 61,000 individual immune cells from seven supercentenarians and five younger individuals. The scientists demonstrated for the first time that people over 110 years old have an extremely high number of CD4-positive T cells with a cytotoxic program.

Already in that study, signs of massive clonal expansion emerged. However, the sample was very small and consisted primarily of two sharply different age groups. It was difficult to determine exactly when in the aging process such a profile emerges: whether it is a characteristic that persists for decades, or develops immediately upon reaching extreme ages.

The new study expands the age spectrum and includes a separate group of centenarians aged 100-109 years, an intermediate stage between normal old age and age over 110 years. This allows us to identify the sequence 4.0% → 9.6% → 17.6%, which suggests a gradual restructuring of late immune aging. At the same time, more modern single-cell methods allow us to more closely integrate the transcriptome, surface phenotype, and receptor structure of a single cell.

Therefore, the new study should be viewed more as a development and deepening of the previous discovery than as a completely unexpected discovery of a new cell type. In 2019, scientists identified the phenomenon; they are now attempting to understand its dynamics, clonal structure, and potential antigenic significance. The next logical step will be to directly determine the target of the expanded T-cell clones.

How the study changed from 2019 to 2026

Characteristic	Work of 2019	New job 2026
The main question	Do supercentenarians have unusual cytotoxic CD4 cells?	How do they expand with age and what is their clonal structure?
Supercentenarians	7	10
Intermediate group 100-109 years	No	Yes, 10 people
Single-cell transcriptome	Yes	Yes
Analysis of surface proteins	Limited	CITE-seq
T cell receptors	Yes	Advanced single-cell analysis
Main interpretation	Massive expansion of CD4-CTL	Adaptive clonal rearrangement in healthy aging

[6]

Why can't we say that these cells "give" a person 110 years of life?

The study's most significant limitation is its very small sample size. Twenty-eight participants is a reasonable number for a study of supercentenarians, as people over 110 years of age are extremely rare, but statistically, such a sample size remains limited. A few participants with unusual immune profiles could significantly impact the final results, so the results need to be confirmed in independent cohorts.

The second limitation is related to the survivor selection effect. The researchers analyzed people who had already lived to 100 or 110 years of age. Therefore, it is impossible to determine whether the unusual T cells emerged long before reaching this age and contributed to their survival, or whether they are a consequence of extreme age, accumulated infections, and years of immune stimulation. Proving the former would require observing a large group of people over decades.

The third problem is that the specificity of the expanded clones remains unknown. Similarities to T cells found in cancer cells are extremely interesting, but they do not prove the existence of hidden antitumor defenses. The same functional programs can emerge under completely different immune stimuli. Until it is demonstrated that superlong-lived cells actually recognize specific tumor or senescent antigens and destroy the corresponding targets, the anticancer interpretation will remain hypothetical.

Finally, the results do not suggest that artificially increasing CD4-CTL counts will prolong life. These cells are capable of participating not only in defense but also in inflammatory, autoimmune, and pathological responses. If a therapeutic strategy based on this finding is ever developed, it will be necessary to reproduce not just the cell count, but also the correct specificity, activation state, and control of their activity.

What the study shows—and what it doesn't show

It can be concluded	It is impossible to conclude
The supercentenarians studied had more CD4-CTL	These cells are the cause of longevity
The proportion of cells increased between the three age groups	In every person it inevitably grows with age.
There are signs of clonal expansion.	It is already known which antigens the clones recognize
Some cells are similar to populations found in cancer	They have been proven to prevent cancer.
Immune aging may involve adaptive remodeling	The immune system of supercentenarians is "younger" than the normal one
The results provide new therapeutic hypotheses	There is already a way to create super-long-liver immunity

[7]

What do scientists want to find out next?

The first question is to identify the antigens recognized by the largest T-cell clones. This requires linking a specific T-cell receptor sequence to a specific molecular target. If it turns out that several independent superlong-lived cells carry cells that respond to similar tumor, viral, or senescent antigens, this will provide a significantly stronger argument for the functional role of the discovered phenomenon.

The second direction is to understand when these cells begin to expand. The presence of an intermediate group of 100-109-year-olds already indicates a gradual increase in their proportion, but larger longitudinal studies of people aged 70, 80, and 90 are needed. Then it will be possible to establish whether a certain T-cell profile is an early predictor of future healthy longevity or whether it only appears in those who have already reached old age.

The third objective is to directly assess cell function. The official dataset already includes an experiment in which T cells from six participants were stimulated for six hours with phorbol 12-myristate 13-acetate and ionomycin, allowing us to study their ability to activate effector programs. However, to prove specific protection, we will need to demonstrate the destruction of specific target cells and establish the molecular mechanism behind this process.

In the long term, the researchers suggest the possibility of using knowledge about such cells for immunological interventions against cancer, chronic infections, or the accumulation of senescent cells. However, this is still a fundamental research area. At this stage, the main significance of the work lies elsewhere: it demonstrates that record-breaking human longevity may be accompanied not by the preservation of an unchanged immune system, but by its profound and highly selective adaptation.

Key results

Conclusion	What was discovered
Supercentenarians have an unusual immune profile.	The proportion of cytotoxic CD4-positive T cells is sharply increased
70-99 years old	4.0%
100-109 years	9.6%
≥110 years	17.6%
Number of participants	28
Research approach	Single-cell multi-level analysis of T lymphocytes
Important feature	Pronounced clonal expansion
Possible role	Control of infections, senescent or tumor cells
Antitumor effect	It is assumed, but not proven.
Causal relationship with longevity	Not proven
Main concept	Healthy extreme aging may be accompanied by adaptive restructuring of the immune system

[8]

News source

Hashimoto K. et al. CD4 CTLs in Supercentenarians: Signs of Adaptive Expansion in Healthy Aging. Cell Reports. 2026;45:117728. The official Japanese repository NBDC Human Database links this publication to datasets JGAD000957, E-GEAD-1107, and E-GEAD-1108, containing single-cell data from 28 healthy participants in three age groups.

DOI: 10.1016/j.celrep.2026.117728.

The article corresponds to the provided Cell Reports identifier S2211-1247(26)00806-5. The main conclusion of the study is that in people who have reached 110 years of age, cytotoxic CD4-positive T lymphocytes not only become significantly more numerous, but their receptor repertoire also exhibits signs of selective clonal expansion. This supports the hypothesis that immunity in exceptionally long-lived individuals may undergo specialized adaptive restructuring, potentially helping to control chronic threats even in extreme old age.