An Active Immune System: The Genetic Secret of Healthy Centenarians

For decades, we told ourselves one story about centenarians: they got there because they simply managed to avoid things. Less smoking, less bad luck, less accumulated damage. According to this view, longevity is primarily about absence, absence of disease, absence of inflammation, absence of heart attacks. But a new wave of research, including work that made headlines under the name Mayo Clinic, tells a completely opposite story.

It turns out that the secret of healthy long-lived individuals is not what is missing in them, but what is still switched on. While in most of us immune genes gradually turn off with age, in healthy centenarians they remain active, sometimes more active than in 70-year-olds. In other words, centenarians are not those who conquered aging by stopping it, but those who continued to fight. Their immune system has what scientists are beginning to call an active immune system, an active resilience that provides real protection against cancer and infections even in the tenth decade of life.

What Does an Active Immune System Mean?

To understand the finding, one must first understand what happens to most of us. The normal aging of the immune system is called Immunosenescence, and it looks roughly like this:

• Decline in naive T cells: The young cells that are supposed to learn to recognize new threats become depleted. Without them, the body struggles to deal with a virus it has never encountered before.
• Accumulation of exhausted memory cells: Old cells that are no longer effective, but take up space and resources.
• Chronic low-grade inflammation: The phenomenon known as Inflammaging, a persistent low-level inflammatory noise that paralyzes the sharp response when it is truly needed.
• Weak NK cells: The cells responsible for eliminating tumors in their early stages and viral infections lose their potency.

An active immune system is precisely the opposite picture: a balance is maintained between the fast arm (innate immunity) and the focused arm (adaptive immunity), background inflammation remains low and controlled, and killer cells remain sharp. This does not mean the system is identical to that of a 20-year-old, but that it has undergone an adaptive transformation, a smart reorganization instead of a collapse.

The Connection to Longevity: A Surprising Mechanism

The most intriguing finding concerns T cells. A groundbreaking study published in the journal PNAS in 2019 by the team of Kosuke Hashimoto from the RIKEN Center in Japan analyzed at single-cell resolution more than 61,000 blood cells from seven individuals aged 110 and over (supercentenarians) compared to five younger control individuals.

What they found was an almost unprecedented phenomenon: a massive expansion of cytotoxic CD4 T cells. Normally, CD4 cells are helper cells, managers that direct other cells but do not kill themselves. In the 110-year-olds, a large portion of CD4 cells had converted into killer cells capable of eliminating infected and cancerous cells on their own. TCR sequencing revealed that these cells had undergone massive clonal expansion, with the most common clone constituting between 15% and 35% of the total CD4 T cell population. This is a huge number, a signature of an immune system that has been recruited and specialized to continue protecting.

The researchers estimated this is an adaptation to the late stage of aging, a way for the body to compensate for the weakening of other immune arms by turning helper cells into fighters. And that is precisely the point: it is not about passive genetic luck, but an active process in which immune genes are turned on and remain switched on.

Current Evidence

Study 1: Single-Cell Atlas of Centenarians from 2025

The most recent study, published in September 2025 in the journal eBioMedicine of the Lancet group, built a comprehensive single-cell atlas from three groups of centenarians. The team analyzed blood cells from 31 centenarians, 17 of their offspring, and 26 control individuals, combining single-cell RNA sequencing, mass cytometry, and flow cytometry.

The findings: Centenarians showed an increased percentage of NK cells in peripheral blood compared to the control group, along with a lower percentage of B cells and regular CD4 cells. But most importantly was the quality of the NK cells: they had a young protein expression profile and preserved immune function. Additionally, the researchers documented enhanced intercellular communication, a richer signaling network between different immune cells, in contrast to the destructive inflammatory signals that characterize normal aging.

Study 2: The Shared Immune Transformation of Centenarians and Their Offspring

A study published in the journal Aging Cell examined the transcriptome (gene expression) of centenarians and their offspring. The main finding: both groups shared the same pattern of immune transformation, depletion of naive T cells and expansion of cytotoxic T cells, mainly CD8 cells with high expression of the proteins GZMB and CMC1.

The fact that the offspring, people aged 60-70 who are still far from age 100, already carry the same signature, suggests this is a true hereditary tendency and not just a product of long life. In other words, the active immune profile is likely a cause of longevity, not just a result of it.

Study 3: Offspring of Centenarians and Reduced Signs of Immune Aging

An earlier study published in the Journals of Gerontology compared the immune system of centenarians' offspring to that of their age-matched peers in the general population. The result: the offspring had reduced signs of immunosenescence in T cells, healthier proportions of young T cells versus late-differentiated T cells, and fewer CD8 cells that appeared senescent. The adaptive arm of their immune system simply looked younger.

Study 4: Balance of Inflammatory vs. Regulatory Cells

Another study showed that centenarians restrain inflammaging by altering the ratio between Th17 (pro-inflammatory) and regulatory T cells (Treg, anti-inflammatory), and changing the secretory profile of these cells. That is, even when their system is active and fighting, it knows how to turn off unnecessary inflammation and focus energy only where needed.

What About the Connection to Cancer and Infections?

This story is not merely academic. Centenarians are characterized by relatively low rates of tumors and severe infections, and these are precisely the areas where an aging immune system fails. Strong NK cells and preserved cytotoxic T cells are the first line of defense against cells that have become cancerous and against recurring viruses.

This also explains why vaccines work less well in ordinary elderly people: an immune system that has lost its young cells struggles to mount a sharp response to a new vaccine. Centenarians with an active immune system maintain a better response capacity, and this is one reason they survive pandemic waves that fell people decades younger than them.

Is It Only Genetics, or Can We Influence It?

Here we need to stop and be honest. A significant part of this advantage is genetic. The fact that centenarians' offspring already carry the young immune signature indicates a substantial hereditary component that most of us simply were not born with. We must not promise that diet or a supplement will turn you into a 110-year-old; it does not work that way.

But the picture is not entirely deterministic. The same studies on the biological immune clock show that lifestyle factors accelerate or slow immune aging by tens of percent. Genetics determines the starting point, but behavior determines how fast you slide from it. Among the factors identified as accelerators of immune aging:

• Chronic inflammation from visceral obesity, diabetes, and ultra-processed food.
• Chronic stress and poor sleep, both of which suppress NK cell and T cell function.
• Physical inactivity, which accelerates the depletion of young cells.
• Chronic CMV infection, which consumes immune resources managing one dormant virus.

What to Take from the Research?

1. Support your NK cells and T cells through regular physical activity. Studies from 2025 showed that exercise rebalances the immune profile and restores young characteristics. A combination of aerobic and strength training is the most available and powerful immune lever.
2. Lower background inflammation. A Mediterranean diet rich in fiber, healthy fats, and plants helps restrain inflammaging. Reducing ultra-processed food and sugar decreases the inflammatory noise that paralyzes the sharp response.
3. Maintain quality sleep. Sleep is the time when immune cells renew and reorganize. Chronic sleep of less than 6 hours is associated with accelerated immune aging.
4. Manage stress and social connections. Chronic stress directly suppresses killer cells, and strong social connections have been repeatedly linked to better immune function and longevity.
5. If you are older, check your neutrophil-to-lymphocyte ratio in a routine blood test. A ratio above 3 is an accessible marker of immune aging, and a conversation with your doctor can guide early intervention.

The Broader Perspective

The story of centenarians changes the definition of what healthy aging is. For years, we sought the secret of longevity in avoiding damage: fewer toxins, less oxidative stress, fewer DNA errors. Now it turns out that a central part of the story is precisely the opposite, maintaining activity, a system that continues to fight, renew, and adapt even in the tenth decade of life.

The profound lesson is that healthy longevity is not a passive state of absence of disease, but an active process of resilience. Centenarians are not those whose aging stopped, but those whose defense system simply refused to turn off. And if there is one thing to take from all these studies, it is this: the best way to stay young is to stay active, even at the cellular level.

References:
eBioMedicine 2025 - Single-cell atlas of three centenarian cohorts
PNAS 2019 - Cytotoxic CD4 T cells in supercentenarians (Hashimoto et al.)