Scientists have proposed a hypothesis that immune aging might be necessary to shield people from autoimmune effects, as the repertoire of autoantigens expands with age [1].
A double-edged sword?
The decline of the immune system is a major driver of aging, making us more susceptible to infections and cancer. Autoimmunity, on the other hand, is rarely mentioned in the context of aging, despite recent epidemiological data suggesting that many autoimmune diseases emerge primarily in later life, with type 1 diabetes being a notable exception.
A research team at Mayo Clinic, led by Cornelia Weyand, M.D., Ph.D., has been studying one such disease: giant cell arteritis (GCA), an autoimmune disorder that affects the arteries, and discovered an intriguing connection to aging. Having studied more than 100 older patients, the researchers saw that their immune systems were often surprisingly youthful.
In a new perspective paper published in Nature Aging, the scientists report that a special population of stem-like T cells persists in the bodies of GCA patients at youthful levels. Residing in protected niches within the blood vessel walls, these cells constantly supply fresh, aggressive effector T cells that attack the vessel tissue. Normally, this factory of stem-like T cells is supposed to slow down with age, but in these patients, it keeps running at full capacity.
“We are studying why some individuals have a ‘fountain of youth’ in their immune systems. We want to learn from them,” says Weyand. “We observed that these patients have very young immune systems despite being in their 60s and 70s, but the price they pay for that is autoimmunity.”
Young and aggressive
A healthy immune system has built-in safety brakes. When T cells are activated for too long, like in a chronic disease, antigen-presenting cells (APCs) produce inhibitory signals that cause T cell exhaustion. In GCA patients, APCs fail to display the proper “stop” signals on their surface. As a result, the aggressive T cells never get the message to stand down. They remain relentlessly active, causing continuous inflammation and damage.
While this and other safety mechanisms prevent collateral damage from immune responses, they might also be contributing to the age-related decline in immune function. The researchers hypothesize that the gradual weakening of the immune system with age may be a beneficial adaptation.
At a young age, the immune system is still learning, both to fight pathogens and to not harm the body it protects. This process of creating self-tolerance occurs as T cells and B cells develop in the thymus and bone marrow, respectively. There, they are tested against the body’s own antigens. If a cell is self-reactive, it is either destroyed or rendered harmless, ensuring that it cannot cause autoimmune disease.
However, aging causes an increase in the repertoire of self-antigens, as many more molecules arise that the immune system is not trained to recognize. The researchers discuss various ways in which this happens: for instance, proteins in the extracellular matrix undergo chemical changes such as glycation and carbamylation. Other processes might include DNA mutations, proteostasis failures, chronic tissue-damaging infections, and pollutant exposure, all of which expand the pool of potential targets.
The paper suggests that the age-related decline in immune function, while increasing our vulnerability to infections and cancer, might also be helpful for calming auto-immune responses. Conversely, late-life autoimmunity can arise when selected components of the immune system remain “too youthful” and interact with aged tissues that generate new self-like targets, similarly to what the researchers found in GCA patients.
“Contrary to what one may think, there are benefits to having an immune system that ages in tandem with the body,” says Jörg Goronzy, M.D., Ph.D., a Mayo Clinic researcher on aging and a co-lead author of the paper. “We need to consider the price to pay for immune youthfulness. That price can be autoimmune disease.”
Rethinking immune system rejuvenation
If this hypothesis holds true, its implications can be profound. It suggests that simplistic attempts to rejuvenate the immune systems of older adults could have the unintended consequence of unleashing autoimmune diseases that a properly “aged” immune system would naturally hold in check.
Some anti-cancer therapies are already associated with autoimmune effects [3]. Future interventions may therefore need to be more nuanced, perhaps by promoting tolerance to new self-antigens or dismantling the specific cellular niches that allow for this “age-inappropriate” immunity.
Interestingly, according to previous research, centenarians and supercentenarians are often endowed with youthful immune systems. Perhaps some mechanism, or even pure luck, allows them to enjoy the benefits of a young immune system without this autoimmunity tradeoff.
Literature
[1] Weyand, C. M., & Goronzy, J. J. (2025). Sustained immune youth risks autoimmune disease in the aging host. Nature Aging, 5(8), 1404-1414.
[2] Conrad, N., Misra, S., Verbakel, J. Y., Verbeke, G., Molenberghs, G., Taylor, P. N., … & Cambridge, G. (2023). Incidence, prevalence, and co-occurrence of autoimmune disorders over time and by age, sex, and socioeconomic status: a population-based cohort study of 22 million individuals in the UK. The Lancet, 401(10391), 1878-1890.
[3] Wang, S. J., Dougan, S. K., & Dougan, M. (2023). Immune mechanisms of toxicity from checkpoint inhibitors. Trends in cancer, 9(7), 543-553.
