Aging is accompanied by an increased risk of certain diseases, alongside weakened immunity to illnesses that younger individuals might easily overcome. This has raised an important question for researchers, which is why do some people live to a very old age while avoiding major diseases?
The results of research by a team at Osaka University studying Japanese supercentenarians aged 110 years and older, now suggest that a rare type of immune cell known as CD4 cytotoxic T lymphocytes, or CD4 CTLs, becomes increasingly abundant with extreme age. These rare cells have the ability to both recognize threats and destroy dangerous cells.
“Immune aging is not simply a process of decline,” said Kosuke Hashimoto, PhD, 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 an atypical and relatively rare T cell population. So their marked increase in supercentenarians may provide important clues as to how the immune system is maintained in extreme old age.”
Hashimoto is first author of the researchers’ published paper in Cell Reports, titled “CD4 CTLs in supercentenarians: Signs of adaptive expansion in healthy aging,” in which they say that their collective findings “… suggest that CD4 CTLs expand and diversify as an adaptation to persistent antigens, potentially contributing to longevity through cancer suppression.”
While maintaining good health as we age is important, it is also difficult, considering that the risk of certain diseases increases with age, alongside weakened immunity to some illnesses. “Aging is an inevitable biological process, characterized by gradual declines in physical and cognitive functions. This process is driven by the accumulation of molecular and cellular alterations, including DNA mutations, mitochondrial dysfunction, and cellular senescence,” the authors wrote.
Among the various changes that occur at the cellular and molecular level, the team continued, “… aging of the immune system compromises its ability to defend against external pathogens and eliminate internal abnormal cells such as precancerous or senescent cells, increasing the risk of various diseases.”
This has raised an important question for researchers: why do some people live to a very old age while avoiding major diseases? Aging itself is not a disease, they commented, nor does it necessarily lead to the failure of essential physiological systems.
“Supercentenarians—individuals who live to or beyond 110 years—provide a model of healthy aging, achieving longevity while avoiding or delaying major age-related diseases such as cardiovascular disorders and cancer,” the investigators commented. “They maintain immune, cardiovascular, and epigenomic profiles that appear younger than expected for their chronological age.”
One class of immune cells, T cells, is 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. “Our previous study identified CD4 cytotoxic T lymphocytes (CD4 CTLs) as a hallmark of supercentenarians,” the team stated. These rare cells have the ability to both recognize threats and destroy dangerous cells. “CD4 CTLs are an atypical and relatively rare T cell population,” Hashimoto said. “So, their marked increase in supercentenarians may provide important clues as to how the immune system is maintained in extreme old age.”
To understand exactly how rare these hybrid cells are, the scientists analyzed blood samples of 28 adults who had been divided into three age groups: 70–99 years, 100–109 years, and 110 years and older. “In this study, we conducted integrated single-cell profiling of T cells, combining transcriptome, surface protein, and TCR sequence data across different age groups, including rare cohorts of centenarians and supercentenarians,” the investigators explained.
They found that the proportion of CD4 CTLs increased with age, with median percentages of 4%, 9.6%, and 17.6%, respectively. The hybrid cells remained uncommon throughout most of life, but were found to expand dramatically around the age of 100. In supercentenarians, these cells made up nearly one-fifth of all T cells in the blood, whereas they only comprised 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,” said Hashimoto. “Rather than showing signs of exhaustion, they remain highly active and may help the body cope with persistent threats that increase with age.”
While the study findings 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. The newly reported study found that the most prominent clone accounted for an average of 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 said. “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. 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 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. 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.
“Our results revealed that CD4 CTLs expand with age and exhibit plasticity in cytokine production,” the team wrote in summary. “This suggests that CD4 CTLs may contribute to cancer suppression and longevity through adaptive responses to persistent antigens, emphasizing their role in immune resilience and healthy aging.”
Hashimoto noted that 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 stated. “Our findings suggest that immune adaptation to these changes may contribute to exceptional longevity.”
