Mumbai: Why do some people make it past 100 and even 110, while avoiding or delaying diseases that become increasingly common with age? Part of the answer may lie in the way their immune system adapts over a lifetime.
A new study by Japanese scientists has found that people who reach extreme old age have unusually high numbers of CD4 cytotoxic T lymphocytes, or CD4 CTLs. T cells are white blood cells that help the immune system recognise and fight threats. CD4 CTLs are an unusual type of cells that can directly kill infected, damaged or abnormal cells. ‘Cytotoxic’ simply means cell-killing.
The study was led by Kosuke Hashimoto of the Institute for Protein Research at the University of Osaka, along with eleven researchers from RIKEN, Keio University’s Centre for Supercentenarian Medical Research and Human Technopole in Milan.
Researchers found that these cells become markedly more common around the age of 100 and remain active without showing strong signs of T-cell exhaustion, a state in which immune cells repeatedly exposed to a threat gradually become less effective.
Normally, many CD4 T cells act like coordinators, helping organise an immune response rather than killing cells themselves. CD4 CTLs are unusual because they can also behave like frontline fighters.
Researchers examined 43,584 T cells from 28 Japanese participants: eight aged 70-99, 10 centenarians, or people aged 100 or above, and 10 supercentenarians, people who have reached at least 110.
CD4 CTLs accounted for a median of 4 per cent of T cells in the youngest group, rising to 9.6 per cent among centenarians and 17.6 per cent among supercentenarians.
The researchers believe these cells may be responding to persistent antigens, molecular signs of a threat that remain in, or repeatedly appear in, the body and can be recognised by the immune system.
“These findings suggest that CD4 CTLs expand and diversify as an adaptation to persistent antigens,” the researchers write. In simpler terms, the immune system of some exceptionally old people may keep producing and modifying these killer cells in response to long-lasting threats.
What earlier studies found
The cells themselves are not a discovery.
In 2019, Hashimoto and colleagues used single-cell analysis, studying individual cells rather than averaging thousands together, to show that supercentenarians had unusually large populations of cytotoxic CD4 T cells.
In 2023, T. Hasegawa and eight other researchers found that CD4 killer T cells could eliminate senescent cells, which are old or damaged cells that have stopped dividing but remain in the body. The cells recognised signs of cytomegalovirus, a common virus that can remain dormant in the body for years.
In 2024, Takashi Sasaki and colleagues identified genetic factors associated with centenarian longevity and lower risks of several age-related diseases in research that included 964 centenarians, of which 173 were supercentenarians.
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What has the new study added?
The latest study found that CD4 CTLs undergo substantial clonal expansion, which means that certain cells multiply into large groups with the same T-cell receptor. The largest clone accounted for an average 33.3 per cent of CD4 CTLs, which the researchers concluded was consistent with repeated stimulation by persistent antigens.
When the researchers compared the receptors of the most expanded cells with a large T-cell database, 32 of 36 matching expanded sequences were found in cancer samples, including lung, breast and liver cancers. None of the centenarians or supercentenarians studied had a known history of these cancers.
The study does not establish that CD4 CTLs prevent cancer or cause longevity. It concludes that their expansion may represent an adaptive immune response to persistent antigens in extreme old age, while noting that their precise targets and role in healthy ageing are not confirmed.
“Thus, CD4 CTLs likely act as a double-edged sword during aging, mediating either beneficial immunosurveillance or pathogenic tissue damage depending on the degree of inflammatory control,” the study found.
(Edited by Ratan Priya)