The consensus on the immune system and aging is that dysfunction in immune function is an important contribution age-related degeneration and disease. Firstly increased, constant inflammatory signaling drives harmful changes in cell and tissue function; all of the major age-related diseases are characterized by inflammation. Secondly, loss of immune capacity allows senescent cells, cancerous cells, and infectious pathogens to slip through the net and prosper. Senescent cell burden increases with age, cancer risk scales up with age, and infectious disease is far more a threat to older people than to younger people.
The two aspects of immune aging, chronic inflammation and a growing ineffectiveness, are aggregated under the single heading of loss of immune resilience. Immune resilience is defined as maintaining both an effective immune response to challenges while also controlling inflammation, though different researchers may use different ways of coming to a specific set of measures and numbers that represent immune resilience.
In this context, the authors of today's open access paper mount an interesting argument. They agree that loss of immune resilience to be an important aspect of aging, but, for the span of human age from the 40s to the 70s, suggest that it is only loosely coupled to what we might think of as the rest of aging, whether we think of that more as the accumulation of damage and dysfunction in non-immune cells and tissues after the SENS model, or in terms of the non-immune hallmarks of aging. Thus interventions specifically focused on immune aging may go a long way to reducing mortality in this age range, even if other aspects of aging are not addressed. In practice, whether this is in fact the case will only be established in certainty by developing and widely deploying therapies to restore lost immune function - which should be an important goal regardless!
The 15-Year Survival Advantage: Immune Resilience as a Salutogenic Force in Healthy Aging
Environmental factors, particularly infections, have fundamentally shaped human evolution by selecting for protective inflammatory response mechanisms that enhance survival. This evolutionary pressure has created a core biological paradox: inflammation is indispensable for host defense, yet its dysregulation significantly heightens disease and mortality risk. This fundamental tension raises three fundamental questions about human aging and immunity: (1) How have selective pressures driven the evolution of mechanisms to balance inflammation's protective benefits against its harmful consequences? (2) Why does substantial variability in healthspan persist despite historically stable rates of aging? (3) Does evolutionary prioritization of reproductive fitness inherently limit longevity?
To address these questions, we developed an integrated evolutionary framework comprising four interconnected dimensions. At its foundation lies immune robustness - the ability to neutralize pathogenic threats while minimizing collateral tissue damage. This capability represents a critical evolutionary adaptation balancing protection against immediate threats with long-term tissue integrity. The remaining dimensions include (1) inflammatory stressors (environmental challenges that activate immune responses), (2) salutogenesis (health-promoting processes derived from Latin roots meaning "the origin of health" - "salus" meaning "health"), and (3) immune resilience (the dynamic capacity to respond to and recover from immunological challenges).
When immune robustness fails, it triggers what we term the "pathogenic triad" - three interconnected processes that accelerate biological aging: (1) inflammaging (sterile, chronic low-grade inflammation), (2) immune senescence (progressive impairment of innate and adaptive immunity), and (2) accumulation of senescent cells through Senescence-Associated Secretory Phenotype-driven damage. Importantly, these processes do not simply correlate with aging-they actively accelerate age-related morbidity independent of chronological age and mirror the established molecular hallmarks of organismal aging. Environmental triggers can initiate this triad, thereby elevating the risk of infection, multimorbidity, and mortality.
Our framework posits that immune robustness - shaped by evolutionarily optimized strategies - provides the foundation for salutogenesis, supporting systemic resilience by counteracting the aging hallmarks encompassed in the pathogenic triad. These salutogenic mechanisms mitigate age-related pathologies and extend lifespan through what is conceptualized as a "biological warranty period" encompassing both reproductive and post-reproductive phases. This warranty period closely aligns with the 2024 global average life expectancy of 73.4 years. We propose that premature mortality (before approximately 70 years) likely reflects a failure to sustain salutogenic adaptations rather than representing inherent biological constraints of aging.
To empirically investigate these concepts, we conducted longitudinal multi-omics profiling in approximately 17,500 participants exposed to diverse inflammatory challenges across the lifespan, from birth to over 90 years of age. We specifically mapped immune resilience (IR) trajectories and the emergence of the pathogenic triad across health-to-disease transitions. Our findings demonstrate that maintaining optimal IR with elevated transcription factor 7 (TCF7) levels establishes a clinically actionable salutogenic trait. This TCF7-associated trait significantly reduces the emergence of the pathogenic triad. Mechanistically, TCF7 encodes TCF1, an evolutionarily conserved master regulator of T-cell immunity and stemness. Through genome-wide screening of 1380 transcription factors, we identified a TCF7-centered regulatory network governing IR mechanisms, alongside six co-regulated factors. This finding helps explain the substantial variability in healthspan despite stable aging rates by identifying specific biological mechanisms that can vary between individuals.
View the full article at FightAging
