by Claire Kowalick, University of Texas Health Science Center at San Antonio

Salutegenic traits, like immune resilience, provide protection against pathogenic factors. Credit: UT Health San Antonio

What if, rather than focusing solely on the drivers of disease (pathogenesis), we also explored the factors sustaining our health—the concept of salutogenesis (derived from Salus (health) in Roman mythology)?

The idea of salutogenesis through immune resilience, which refers to mechanisms by which the body counters disease drivers, could play a role in disease prevention and may influence lifespan. This concept is explored in a recent study led by Sunil K. Ahuja, MD, professor in the department of medicine at the Joe R. and Teresa Lozano Long School of Medicine at The University of Texas Health Science Center at San Antonio (UT Health San Antonio) and director of the Veterans Affairs Center for Personalized Medicine, South Texas Veterans Health Care System, San Antonio.

Since the dawn of civilization, humans 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.

Ahuja and his team's multi-year, multi-disciplinary study published April 23, 2025, in Aging Cell, investigates this biological mechanism and its potential implications for healthspan and longevity.

The study, "The 15-Year Survival Advantage: Immune Resilience as a Salutogenic Force in Healthy Aging, " reveals that immune resilience is not fixed, but measurable and adaptable. The team identified the expression of T-cell factor 7 (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 as a "pathogenic triad"— inflammaging (chronic inflammation with aging), immune aging and cell senescence. Immune resilience can diminish over time due to environmental threats (e.g., infections, trauma) or internal stressors (e.g., 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 explained. "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."

Three immune resilience trajectories

By analyzing data from over 17, 500 individuals, the team identified three immune resilience paths during inflammatory stress:

"Throughout life, inflammatory insults like infections may gradually reduce immune resilience. Some individuals can preserve resilience longer than others, " said Grace Lee, PharmD, Ph.D., co-first author and associate professor at The University of Texas at Austin.

People with the highest immune resilience show an up to 15.5-year survival advantage over those with the lowest immune resilience. Credit: UT Health San Antonio

Aging and immune resilience's 'warranty period'

The study highlights three lifelong processes affecting health: salutogenesis, pathogenesis 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. Aging and age-related diseases are distinct, " noted Nathan Harper, MS, senior bioinformatician in the Veterans Health Center of Personalized Medicine.

However, even robust immune resilience has limits. Around age 70, the protective effects begin to wane—a threshold Manoharan terms "failed salutogenesis."

Window of opportunity for potential intervention

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. By age 70, longevity trajectories converged, eliminating this advantage.

The findings imply immune resilience might be modifiable from birth to approximately 70 years. Lifestyle changes, medications or future immunotherapies could delay age-related diseases and extend healthspan.

"There's a biologically modifiable window of opportunity for interventions like diet, exercise or drugs. Beyond this window, improving healthspan becomes more challenging, " Lee said.

Toward proactive health management

"We envision a future in which immune resilience is routinely assessed, much like cholesterol testing, " said Justin Meunier, BS, a bioinformatician at the Center for Personalized Medicine. "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."

Lee added that personalized plans based on immune resilience status could help prevent disease proactively.

A new perspective on aging

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.

Ahuja's team work shifts the focus from inevitable decline to optimizable resilience. Future strategies to recalibrate immune resilience could transition health care from disease treatment to sustaining health.

More information: 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  Journal information: Aging Cell