Immune remodeling in extreme old age: how supercentenarians reshape their immune system
Researchers from the University of Osaka uncover an unusual immune cell that expands in supercentenarians and may help protect against cancer and other age-related threats
image:
Percentage of CD4-positive cytotoxic T cells by age group.
view moreCredit: Kosuke Hashimoto, The University of Osaka
Osaka, Japan – Aging while maintaining good health is a priority for many populations. This is often difficult considering that the risk of certain diseases increases with age, alongside weakened immunity to illnesses that younger individuals could easily overcome. This has raised an important question for researchers: why do some people live to a very old age while avoiding major diseases?
However, answers may come from new research, conducted by a team at the University of Osaka, involving Japanese supercentenarians aged 110 years and older. The findings suggest that a rare type of immune cell becomes increasingly abundant with extreme age. The findings are set to be published in Cell Reports.
One class of immune cells, called T cells, are traditionally divided into two groups: helper cells that coordinate immune responses, and killer cells that destroy infected or cancerous cells. However, supercentenarians accumulate an unusual hybrid known as CD4 cytotoxic T lymphocytes, or CD4 CTLs. These rare cells have the ability to both recognize threats and destroy dangerous cells.
To understand exactly how rare these hybrid cells are, immune cells from various age groups were analyzed. This included people in their 70s to 90s, centenarians, and supercentenarians. The hybrid cells remain uncommon throughout most of life but were found to expand dramatically around the age of 100. In supercentenarians, these cells make up nearly one-fifth of all T cells in the blood, whereas they only comprise about 4% of total cells in the younger study participants.
"We analyzed a rare cell population that is enriched in supercentenarians and found signs of immune remodeling in extreme old age," says lead author, Kosuke Hashimoto. "Rather than showing signs of exhaustion, they remain highly active and may help the body cope with persistent threats that increase with age."
Many of these cells had expanded into large populations of identical cells, suggesting that they had repeatedly encountered the same targets over the years. Remarkably, their molecular sensors closely matched those found on immune cells from patients with cancer, even though the supercentenarians had no history of the disease.
“The similarity between these receptor sequences and those found in T cells from tumors suggests that these cells may help recognize tumors before they become clinically detectable," says Hashimoto. "It may be that immune changes in extreme old age are better understood as the immune system reorganizing itself rather than just wearing out."
The researchers caution that their study does not prove that CD4 CTLs directly cause longevity. However, the findings provide one of the clearest pictures yet of how the immune system adapts in people who achieve exceptional lifespans, offering insight into healthy aging and potentially contributing to protection against disease in supercentenarians.
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The article, “CD4 CTLs in Supercentenarians: Signs of Adaptive Expansion in Healthy Aging,” will be published in Cell Reports at DOI: https://doi.org/10.1016/j.celrep.2026.117728
About The University of Osaka
The University of Osaka was founded in 1931 as one of the seven imperial universities of Japan and is now one of Japan's leading comprehensive universities with a broad disciplinary spectrum. This strength is coupled with a singular drive for innovation that extends throughout the scientific process, from fundamental research to the creation of applied technology with positive economic impacts. Its commitment to innovation has been recognized in Japan and around the world. Now, The University of Osaka is leveraging its role as a Designated National University Corporation selected by the Ministry of Education, Culture, Sports, Science and Technology to contribute to innovation for human welfare, sustainable development of society, and social transformation.
Website: https://resou.osaka-u.ac.jp/en
Journal
Cell Reports
Method of Research
Data/statistical analysis
Subject of Research
Human tissue samples
Article Title
CD4 CTLs in Supercentenarians: Signs of Adaptive Expansion in Healthy Aging
Article Publication Date
19-Aug-2026
Supercentenarians have an abundance of cancer-killing immune cells
The human immune system has specialized cells called CD4 cytotoxic T lymphocytes (CD4 CTLs), which have been shown to kill tumor cells in some cancers. When a person gets sick, these cells multiply in a process called clonal expansion to help fight infection. In a study publishing in the Cell Press journal Cell Reports on August 19, researchers show that these immune cells also may play a role in healthy aging among supercentenarians.
“Immune aging is not simply a process of decline,” says first author Kosuke Hashimoto, an associate professor at the University of Osaka in Japan. “The selective expansion of certain T cells suggests that, even in extreme old age, the immune system may continue to adapt to age-related challenges.”
CD4 CTLs are a cellular signature of supercentenarians—people who live to age 110 and beyond. In this study, the researchers discovered that these cells expand and adapt within this older population.
“CD4 CTLs are an atypical and relatively rare T cell population,” Hashimoto says. “So, their marked increase in supercentenarians may provide important clues as to how the immune system is maintained in extreme old age.”
The researchers analyzed the blood samples of 28 adults who had been divided into three age groups: 70–99, 100–109, and 110 and older. The proportion of CD4 CTLs increased with age, with median percentages of 4%, 9.6%, and 17.6%, respectively.
While the results suggest CD4 CTL expansion begins around 100, this phenomenon was not unique to centenarians and supercentenarians; one participant younger than 100 had the highest proportion of these cells.
The team then looked at participants’ T cell receptors and determined that clonal expansion helps drive this increase. CD4 CTLs clone themselves when the immune system is under attack. In the study, the most prominent clone accounted for an average 33.3% of CD4 CTLs, indicating that older adults may be responding to persistent immune threats. In one centenarian’s blood sample, a single clone accounted for 53.8% of their CD4 CTLs.
Next, the researchers matched the receptor sequences of each participant’s top CD4 CTL clone to those in a public database. Nearly three dozen matches belonged to people with cancer—namely lung, breast, and liver cancers. Because none of the centenarians or supercentenarians studied had been diagnosed with these cancers, the researchers theorized that their CD4 CTL expansion may reflect early immune responses.
“Some CD4 CTLs may recognize cancer-related targets, although their exact targets remain unknown,” Hashimoto says.
The study, which focused on T cells circulating in the blood, does not prove that having an abundance of CD4 CTLs prevents cancer or causes a person to live longer. Hashimoto says the team’s next step is to research how these cells behave in human tissues.
“As we age, abnormal cells, including senescent and cancerous cells, become more common,” Hashimoto says. “Our findings suggest that immune adaptation to these changes may contribute to exceptional longevity.”
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This work was supported by Japan Society for the Promotion of Science KAKENHI grants, the Promotion Program for Frontier Protein Research from the Institute for Protein Research, the University of Osaka, the Takeda Science Foundation, the Mochida Memorial Foundation for Medical and Pharmaceutical Research, research grants for Keio University Global Initiative Research Projects, and a research grant from the Ministry of Education, Culture, Sports, Science and Technology to the RIKEN Center for Integrative Medical Sciences.
Cell Reports, Hashimoto et al., “CD4 CTLs in supercentenarians: Signs of adaptive expansion in healthy aging” https://www.cell.com/cell-reports/fulltext/S2211-1247(26)00806-5
Cell Reports (@CellReports), published by Cell Press, is a weekly open-access journal that publishes high-quality papers across the entire life sciences spectrum. The journal features reports, articles, and resources that provide new biological insights, are thought-provoking, and/or are examples of cutting-edge research. Visit http://www.cell.com/cell-reports. To receive Cell Press media alerts, contact press@cell.com.
Journal
Cell Reports
Method of Research
Observational study
Subject of Research
People
Article Title
CD4 CTLs in Supercentenarians: Signs of Adaptive Expansion in Healthy Aging
Article Publication Date
19-Aug-2026
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