Supercentenarians’ Immune System May Explain Their Longevity

Aging is an inevitable part of life, but some remarkable individuals remain healthy well into extreme old age, living to 110 years or older. Known as supercentenarians, these individuals are incredibly rare, prompting researchers to investigate what may contribute to their longevity. Could the secret lie in their diet, genetics, physical activity, or another factor?

One area of particular interest is the immune system, which defends the body against infections and disease. This motivated researchers at the University of Osaka to investigate the immune commonalities among older populations. They first identified a set of specialized immune cells called CD4+ cytotoxic T lymphocytes (CD4+ CTLs) as a hallmark of supercentenarians. These cells are effective cellular bruisers, fending off infection and killing cancer cells.

Now, in a new study, published in Cell Reports, they found that CD4+ CTLs expand into diverse clones around age 100, suggesting that these cells continue to adapt to combat persistent antigens.¹ “CD4+ CTLs are an atypical and relatively rare T cell population,” explained coauthor Kosuke Hashimoto, a bioinformatician at the University of Osaka, in a statement. “So, their marked increase in supercentenarians may provide important clues as to how the immune system is maintained in extreme old age.”

First, the researchers assessed blood samples to generate single-cell immune profiles among three groups: those in their 70s–90s, centenarians (ages 100–109), and supercentenarians (ages 110 and older). Of the T cell populations, they observed that CD4+ CTLs increased with age; notably, the findings suggest that multiplication of these cells begins around age 100.

Next, the researchers sought to further characterize the CD4+ CTLs, such as the types of clonal cells generated and their T cell receptors. They found that these cells were all clonally expanded, which occurs when the immune system is under attack. Of these, the most prominent clone accounted for an average of 33.3 percent of CD4+ CTLs: One centenarian had a single clone that accounted for nearly 54 percent of their CD4+ CTLs. “Immune aging is not simply a process of decline,” explained Hashimoto in the statement. “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.”

But what were these clones mounting a response against? To find out, the researchers matched the receptor sequences of the top CD4+ CTL clones to a comprehensive T cell receptor database. They found nearly three dozen matches for people with lung, breast, and liver cancers. Because none of the study participants had been diagnosed with these cancers, the findings suggest that the expansion of CD4+ CTLs may reflect an early immune response to cancer.

The researchers also investigated the function of these CD4+ CTL clones under unstimulated and stimulated conditions. When exposed to the stimulant ionomycin, the T cells produced a diverse range of cytokines, including multiple cytokines within individual clones, suggesting these cells may be primed to enhance their cytotoxic activity when faced with a threat.

While the researchers emphasized that having an abundance of CD4+ CTLs does not necessarily prevent cancer or lead to longer survival, the findings offer clues about how these cells may contribute to the immune response. Because the study focused on circulating T cells in the blood, the researchers say the next step is to better understand how these cells function within specific tissues.