Rare cancer-killing T cells expand markedly in some exceptionally old adults, suggesting the immune system may continue adapting even at extreme ages.
Among people who live past 100, the immune system may not simply weaken with age. Instead, rare immune cells known as CD4 cytotoxic T lymphocytes (CD4 CTLs), which can kill tumor cells in some cancers, appear to become increasingly prominent. These cells multiply through a process called clonal expansion when the immune system responds to threats, and research published August 19 in the Cell Press journal Cell Reports suggests they may also be involved 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 have emerged as a cellular feature of supercentenarians, people who reach age 110 or beyond. In the new study, researchers found evidence that these uncommon cells continue expanding and adapting in this exceptionally old 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.”
CD4 killer T cells rise with age
Researchers examined blood samples from 28 adults divided into three age groups: 70–99, 100–109, and 110 and older. Median CD4 CTL levels rose steadily across those groups, from 4% to 9.6% and then 17.6%, respectively.
The pattern suggests that expansion of these cells may begin around age 100, although it was not limited to centenarians and supercentenarians. One participant younger than 100 actually had the highest proportion of CD4 CTLs in the study.
The researchers next analyzed participants’ T cell receptors and found that clonal expansion was helping drive the increase. CD4 CTLs can make copies of themselves when the immune system encounters a threat. Across the study, the largest clone represented an average of 33.3% of all CD4 CTLs, suggesting that some older adults may be responding to persistent immune challenges. In one centenarian, a single clone made up 53.8% of the CD4 CTLs in the blood sample.
Cancer protection remains an open question
To investigate what these dominant cells might be responding to, researchers compared receptor sequences from each participant’s leading CD4 CTL clone with sequences stored in a public database. Nearly three dozen matches came from people with cancer, including lung, breast, and liver cancers.
None of the centenarians or supercentenarians in the study had been diagnosed with those cancers, leading the researchers to propose that the expansion of these cells might represent early immune responses to abnormal targets.
“Some CD4 CTLs may recognize cancer-related targets, although their exact targets remain unknown,” Hashimoto says.
The study examined T cells circulating in blood and cannot establish that having more CD4 CTLs protects against cancer or causes exceptional longevity. Hashimoto says the researchers now plan to investigate how these cells behave within 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.”
Reference: “CD4 CTLs in supercentenarians: Signs of adaptive expansion in healthy aging” by Kosuke Hashimoto, Miki Kojima-Ishiyama, Hajime Inokuchi, Michihira Tagami, Takashi Sasaki, Kenji Mizuguchi, Yasushi Okazaki, Ichiro Taniuchi, Kazuyoshi Ishigaki, Nobuyoshi Hirose, Piero Carninci and Yasumichi Arai, 19 August 2026, Cell Reports.
DOI: 10.1016/j.celrep.2026.117728
This work was supported by JSPS KAKENHI grant nos. JP21K06135 and JP24K09423, the Promotion Program for Frontier Protein Research from the Institute for Protein Research, The University of Osaka, 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 MEXT to the RIKEN Center for Integrative Medical Sciences.
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