In a new study, researchers found that certain gene signatures make people more likely to bounce back from disease and live longer. The finding fits into a new framework that reconceptualizes the way we think about aging.
The researchers analyzed the gene signatures of 17,500 people of all ages and health backgrounds and found that high levels of one transcription factor, the name for proteins that switch a particular gene “on” or “off”, kept popping up in the most immune-resilient individuals.
“TCF7 plays a very, very important role in maintaining T-cell immunity and T-cell stemness –– ‘stemness’ meaning naivety, keeping youth,” said Sunil Ahuja, one of the study’s lead investigators. Ahuja is a medical doctor at the Veterans Affairs Center for Personalized Medicine in San Antonio, Texas, and a professor at the University of Texas Health Science Center at San Antonio.
“When we think about the aging process, we generally think in terms of disease,” Ahuja said.
“But aging and getting 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.”
The framework proposed by Ahuja and his team views the aging process as independent from health generation and disease development, which can be thought of as opposing forces that are in a constant push–pull with each other.
A yin-yang framework of aging
According to Ahuja, along our journey “from womb to tomb,” we encounter three forces: salutogenesis, pathogenesis, and aging.
The salutogenic force, or health-promoting force, counters immune aging, 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 exposure to pathogenic threats along one’s lifetime is also necessary to build immune resilience.
“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. In fact, many viruses have captured human genes, changed those around, and incorporated them in their genome, so they could continue their longevity or propagation without killing us,” he added.
Unlike most other species, humans have a post-reproductive window, allowing us to live well into our 70s, 80s, and even older. The “grandmother hypothesis”, which suggests that grandmothers stayed alive 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 partially 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
In their study, Ahuja and his team found that the probability of making it past the biological warranty period is highly correlated with high TCF7 levels, along with several other biological signatures.
“A 40-year-old person, if they had an extreme 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.
After the biological warranty period, which ends around age 70, the protective effect of the biological signatures the researchers identified, which they call the “immune resilience program”, collapses, but other protective signatures may be at work.
“We think there are other biomarkers or other programs that will provide you with a greater protective effect for a longer period of time,” Ahuja commented.
“We suspect there’s another resilience program that could extend someone 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 genetically profiling participants in the Veterans Affairs Covid-19 Longitudinal Cohort as well as the Framington Heart Study, has been years in the making, beginning with 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 with HIV in my prior research. 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 recover from Covid, regardless of age.
“We then sequenced the genome for gene expression of people with Covid, and we asked if the genes or gene signatures that were protective for Covid––or associated with mortality with Covid––overlapped with the gene signatures, if they had an effect on mortality or survival, in the Framingham Heart study, a very large study conducted in America.”
“We studied about 3,000 of them and found that some of the signatures protected people from dying from Covid,” he went on. “They were also associated with survival in the Framingham Heart study. That was very interesting to us.”
Ahuja calls these shared signatures of survival “immune resilience signatures”. High TCF7 levels, along with low levels of other gene signatures that degrade 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 only analyzed data from the Veterans Affairs Covid-19 Longitudinal Cohort and participants of the Framingham Heart Study, 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, is very challenging,” Ahuja stated.
“HIV is a very interesting model system, for example, because there is this unusual paradox. People living with HIV develop age-related diseases at a younger age. There’s a divergence in their biological age and chronological age, so some of our patients will die of a heart attack at a young age, when they should have died at a much later age relative to their HIV negative counterparts.”
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 study window, you have benefits, but then, when you stop 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 mindfulness 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
Feature image credit: Unsplash
