SAN ANTONIO, April 23, 2025 – If you have poor immune resilience in midlife, then 40 might be the new 55, and you might have a 69% greater chance of death by age 70.
But by focusing on factors sustaining health that improve immunity to disease rather than solely on those driving disease, new research led by The University of Texas Health Science Center at San Antonio (UT Health San Antonio) and San Antonio Veterans Affairs Hospital shows that persons in midlife can gain as much as a 15.5-year survival advantage.
That's not to say they'll necessarily extend their lives by that many years, as the benefits of immune resilience, which refers to mechanisms that counter disease drivers, tend to dissipate after age 70.
Still, after analyzing data from 17,500 individuals across various life stages, scientists discovered the importance of immune resilience involving T-cell factor 7 (TCF7), a gene essential for maintaining immune cell regeneration potential, in fostering healthy aging and longevity.
That places importance on salutogenesis, or the active process of promoting health and well-being, from birth to approximately age 70, modifiable with lifestyle changes, medications or future immunotherapies that could delay age-related diseases and extend health span. In the future, immune resilience might even be routinely assessed, much like cholesterol is today.
"Individuals with TCF7-linked immune resilience appear better equipped to resist inflammatory stressors and maintain a low-inflammatory immune profile promoting survival and better health," said Sunil K. Ahuja, MD, professor of medicine at UT Health San Antonio and director of the Veterans Affairs Center for Personalized Medicine with the South Texas Veterans Health Care System in San Antonio.
Ahuja led the multi-year, multi-disciplinary study titled, "The 15-Year Survival Advantage: Immune Resilience as a Salutogenic Force in Healthy Aging," published April 23 in the journal Aging Cell. Other authors also are with UT Health San Antonio and the South Texas Veterans Health Care System, as well as the College of Pharmacy at The University of Texas at Austin; the Foundation for Advancing Veterans' Health Research in San Antonio; New York University Grossman School of Medicine, NYU Langone Health; and Gilead Sciences of Foster City, California.
People always have encountered inflammatory challenges, such as infections. Appropriately regulated inflammation is essential for protection against threats and supporting survival. However, inflammation is also linked to many diseases and mortality.
This may have contributed to the emergence of health-promoting salutogenic forces, including immune resilience, which could help mitigate the harmful effects of inflammation. The new study reveals that immune resilience is not fixed, but measurable and adaptable.
Ahuja's team identified the expression TCF7 as a key component of immune resilience. Higher TCF7 levels and related markers correlated with better health outcomes, improved resistance to disease and durable vaccine responses.
The "pathogenic triad": A balancing act
"Our work shows that immune resilience is associated with TCF7, a central master regulator that maintains T-cell health," said Muthu Manoharan, MS, co-first author and senior research scientist at UT Health San Antonio.
The study proposes that TCF7-linked immune resilience may counterbalance what the authors term a "pathogenic triad" – inflammaging (chronic inflammation with aging), immune system aging and cell death or senescence.
Immune resilience can diminish over time due to environmental threats (like infections or trauma) or internal stressors (such as myocardial ischemia). Analogous to a dam protecting a city from floods, immune resilience may act as a biological barrier, reducing the risk of the triad overwhelming the body.
"When salutogenesis declines and pathogenesis emerges, this may create a state of inflammation and immune aging that promotes disease," Ahuja said.
Three immune resilience trajectories
By analyzing data from the 17,500 individuals, the team identified three immune resilience paths during inflammatory stress:
- Immune resilience preservers: Maintain high resilience, potentially countering the triad.
- Immune resilience reconstitutors: Experience temporary resilience declines with restoration during recovery.
- Immune resilience degraders: Show persistent resilience loss and sustained increases in the burden of the pathogenic triad.
"Throughout life, inflammatory insults like infections may gradually reduce immune resilience," said Grace Lee, PharmD, PhD, co-first author and associate professor at The University of Texas at Austin. "Some individuals can preserve resilience longer than others."
Aging and immune resilience's "warranty period"
The study highlights three lifelong processes affecting health: salutogenesis, pathogenesis (drivers of disease) and senescence (aging). Declining immune resilience, potentially exacerbated by the triad, may raise susceptibility to age-related illnesses.
"Disease vulnerability differs from a vulnerability to lose health, which allows disease processes to emerge," said Nathan Harper, MS, senior bioinformatician in the Veterans Health Center of Personalized Medicine. "Aging and age-related diseases are distinct."
However, even robust immune resilience has limits. Around age 70, the protective effects begin to wane – a threshold Manoharan terms "failed salutogenesis."
The study found that participants in a large U.S. population with strong immune resilience at age 40 had a 15.5-year survival advantage over those with low resilience. Midlife (ages 40-70) is a pivotal window for longevity, with immune resilience reducing mortality by 69% during this period.
By age 70, however, longevity trajectories converged, eliminating this advantage.
"There's a biologically modifiable window of opportunity for interventions like diet, exercise or drugs," Lee said. "Beyond this window, improving health span becomes more challenging."
Toward proactive health management
Justin Meunier, BS, a bioinformatician at the Center for Personalized Medicine, raises the possibility of routine immune resilience assessments someday. "Optimal immune resilience is associated with a unique blood biomarker profile that reflects higher levels of growth and immune factors, along with lower levels of inflammation," he said.
And Lee said that personalized plans based on immune resilience status could help prevent disease proactively.
TCF7-linked immune resilience represents a novel, modifiable trait in aging research. Unlike traditional biomarkers tied to disease and inflammation, this immune program may enable personalized salutogenic interventions.
Essentially, the Ahuja team's work shifts the focus from inevitable decline to optimizable resilience. Future strategies to recalibrate immune resilience could move health care more toward sustaining health than treating disease.
The 15-Year Survival Advantage: Immune Resilience as a Salutogenic Force in Healthy Aging
Muthu Saravanan Manoharan, Grace C. Lee, Nathan Harper, Justin A. Meunier, Marcos I. Restrepo, Fabio Jimenez, Sreenath Karekatt, Anne P. Branum, Alvaro A. Gaitan, Kian Andampour, Alisha M. Smith, Michael Mader, Michelle Noronha, Devjit Tripathy, Nu Zhang, Alvaro G. Moreira, Lavanya Pandranki, South Texas Veterans Health Care System (STVHCS) COVID-19 clinical team, STVHCS COVID-19 vaccine team, STVHCS COVID-19 convalescent care team, STVHCS Center for Personalized Medicine, Sandra Sanchez Reilly, Hanh Trinh, Clea Barnett, Luis Angel, Leopoldo N. Segal, Susannah Nicholson, Robert A. Clark, Weijing He, Jason F. Okulicz, Sunil K. Ahuja
First published: April 23, 2025, in the journal Aging Cell
Link to full study: https://onlinelibrary.wiley.com/doi/10.1111/acel.70063
The University of Texas Health Science Center at San Antonio (UT Health San Antonio), a primary driver of San Antonio's $44.1 billion health care and biosciences sector, is the largest academic research institution in South Texas with an annual research portfolio of more than $436 million. Driving substantial economic impact with its six professional schools, a diverse workforce of more than 9,400, an annual expense budget of $1.67 billion and clinical practices that provide 2.5 million patient visits each year, UT Health San Antonio plans continued growth over the next five years and anticipates adding more than 1,500 higher-wage jobs to serve San Antonio, Bexar County and the South Texas region. To learn about the many ways "We make lives better®," visit UTHealthSA.org .
Stay connected with The University of Texas Health Science Center at San Antonio on Facebook , Twitter , LinkedIn , Instagram and YouTube .
