In a new study, researchers have reconceptualized the way we think about aging.

The study reveals that immune resilience, a measure of a person’s ability to bounce back to good health when faced with inflammation and disease, counters key features of aging.

“When we think about the aging process, we generally think in terms of disease,” said Sunil Ahuja, the study’s senior author. Ahuja is a medical doctor at the Veterans Affairs Center for Personalized Medicine and a professor at the University of Texas Health Science Center, both in San Antonio, Texas, USA. “But aging and developing an age-related disease, such as Alzheimer’s, are not the same thing,” he emphasized. “There are some centenarians who grow old without developing age-related diseases, but they die.”

This is where the concept of salutogenesis—named after the Latin word “salus” for health—comes in. Salutogenesis, the process of generating health, happens concurrently with biological aging. Along our journey “from womb to tomb”, salutogenesis and disease development, called pathogenesis, are in a constant push–pull with each other.  

A yin-yang framework of aging

The salutogenic force, which is related to immune resilience, counters three key aging processes: immune aging (decline in immunity), inflammation, and cellular senescence (the permanent arrest of cell growth). Ahuja calls this “the pathogenic triad.”

Keeping this pathogenic triad at bay is key to longevity, but repeated exposure to pathogens and other internal or external threats, such as environmental stressors, erodes this capacity.

“You’ve always had to encounter infections. They are the strongest evolutionary force that has shaped our human genome,” Ahuja said.

“We have lived in some sort of harmony with infections for eons. In fact, many viruses have captured human genes, changed those around, and incorporated them in their genome, permitting their propagation without necessarily killing us,” he added.

Unlike most other species, humans have a post-reproductive window, allowing us to live well into our 70s and beyond. The “grandmother hypothesis”, which suggests that grandmothers live longer to help rear their grandchildren, could explain this evolutionary adaptation, at least in women. Universally, women tend to live longer than men, which Ahuja says is conceivably due to their better immune resilience.

This ideal window for having and raising children has been coined the “biological warranty period” by longevity expert S. Jay Olshansky. Ahuja defines it as “the lifespan window which facilitates both the reproductive phase as well as the post-reproductive phase.”

This biological window is also crucial to swinging the odds of living longer in our favor. “People who manage to preserve their optimal immune resilience have a longevity advantage that extends them through this particular biological warranty period,” Ahuja stated.

Specific biomarker linked to greater likelihood of survival

To measure immune resilience, the researchers developed two kinds of laboratory metrics, including gene-expression signatures. They also examined the gene-expression signatures driving the aging process. With these tools, they analyzed 17,500 people of all ages and varied health backgrounds.

The populations studied ranged from children with infections to adults with Covid-19 and individuals older than 90 years. They found an important relationship between immune resilience and a particular transcription factor, the name for proteins that switch a particular gene “on” or “off”. People with higher levels of the immune transcription factor TCF7 were the most immune resilient.

“TCF7 plays a very, very important role in maintaining T-cell immunity and T-cell stemness – ‘stemness’ meaning naivety,  keeping youth,” said Ahuja.

Ahuja and his team found that the probability of making it though the biological warranty period is highly correlated with high TCF7 levels, along with metrics of immune resilience and several other transcription factors. “A 40-year-old person, if they had an extremely poor immune resilience status according to the metrics that we studied, they had a 15.5-year survival disadvantage,” he explained. In other words, a person of the same age with optimal immune resilience can be expected to live 15.5 years longer than the poorly resilient person.

However, after the biological warranty period (which ends around age 70), the protective effect of immune resilience linked to TCF7 collapses, but other protective biological signatures may be at work.  

“We think there are other biomarkers or other programs that will provide individuals with a greater protective effect for a longer period of time,” Ahuja commented. “We suspect there are other resilience programs that could extend survival a little longer, and, hopefully, we’ll describe that soon,” he added.

Common survival signatures in Covid-19 and HIV patients

Ahuja says their study, which involved profiling participants in the Veterans Affairs Covid-19 Longitudinal Cohort in San Antonio, Texas, as well as the Framington Heart Study, has been years in the making, beginning with his earlier work on HIV.

“When Covid began, I realized that there were some features of patients with Covid that looked like what I would see in my practice and research with HIV. We applied those markers, [what we call] immune health grades, to all our patients who had Covid at our Veterans Administration Hospital,” he explained.

Ahuja and his colleagues found that people who had the best immune health grade (1, on a scale of 1 to 4), determined in a blood test, were more likely to have mild Covid or recover from Covid, regardless of age.

“We then examined the gene-expression patterns of people with Covid, and asked if any of the gene signatures that were protective for Covid—or associated with mortality with Covid—had correspondingly similar survival or mortality effects in the Framingham Heart study, a very large study conducted in America.”

“To our surprise, we found this to be the case,” he said.

Ahuja calls these shared signatures of survival “immune resilience signatures”. High TCF7 levels, along with features associated with superior immune resilience, protect against the pathogenic triad, premature mortality, age-related diseases such as Alzheimer’s, and vaccine unresponsiveness.

Although Ahuja believes that we can take actions to enhance salutogenesis and counteract pathogenesis, he’s skeptical that we can actually change the rate at which we age. When asked if we could slow human aging, he responded with “I don’t think so.” This view is in line with Olshansky’s, who, in a statistical study, found that overall life expectancy has been decelerating since 1990. According to Olshansky, “radical human life extension is implausible in this century.”

Future work and possible ways to enhance TCF7

Although Ahuja and his team analyzed data from the Veterans Affairs Covid-19 Longitudinal Cohort, participants of the Framingham Heart Study and other aging cohorts, he says they would like to study additional cohorts, ideally monitoring people more frequently and throughout their lives, which is difficult due to the high costs involved.

“To create such large studies where you can follow people serially, sample them serially from childhood, is very challenging,” Ahuja stated.

As for the effects of diet and exercise, more studies need to be done, but Ahuja has some initial insights.

“We have studied some very small exercise cohorts, where, if you do, say, a 24-week exercise intervention, you have benefits (better immune resilience profile), but then, when you stop and examine after a two-week washout period, you go back to your baseline,” he shared.

He suspects diet and perhaps medications might also influence TCF7 levels, but the researchers haven’t looked at these aspects yet.  

Ahuja also says the power of meditation and intentionality should not be underestimated. “Based on some of the other work we’re doing, I think there’s a very strong mind–body synergy. We kind of forget that that is a very important component. We should not neglect the very powerful influence of a bidirectional forces of mind and body,” he said.

Reference: Muthu Saravanan Manoharan et al. The 15-Year Survival Advantage: Immune Resilience as a Salutogenic Force in Healthy Aging, Aging Cell (2025). DOI: 10.1111/acel.70063

Editor’s note: This article has been changed since its original publication. An incorrect version of the article was published, and has now been replaced with the correct version. We sincerely apologise for this error.

Feature image credit: Unsplash