Manoharan Muthu Saravanan, Lee Grace C, Harper Nathan, Meunier Justin A, Restrepo Marcos I, Jimenez Fabio, Karekatt Sreenath, Branum Anne P, Gaitan Alvaro A, Andampour Kian, Smith Alisha M, Mader Michael, Noronha Michelle, Tripathy Devjit, Zhang Nu, Moreira Alvaro G, Pandranki Lavanya, Sanchez-Reilly Sandra, Trinh Hanh D, Barnett Clea, Angel Luis, Segal Leopoldo N, Nicholson Susannah, Clark Robert A, He Weijing, Okulicz Jason F, Ahuja Sunil K
Veterans Affairs Center for Personalized Medicine, South Texas Veterans Health Care System, San Antonio, Texas, USA.
Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
Aging Cell. 2025 Apr 23:e70063. doi: 10.1111/acel.70063.
Human aging presents an evolutionary paradox: while aging rates remain constant, healthspan and lifespan vary widely. We address this conundrum via salutogenesis-the active production of health-through immune resilience (IR), the capacity to resist disease despite aging and inflammation. Analyzing ~17,500 individuals across lifespan stages and inflammatory challenges, we identified a core salutogenic mechanism: IR centered on TCF7, a conserved transcription factor maintaining T-cell stemness and regenerative potential. IR integrates innate and adaptive immunity to counter three aging and mortality drivers: chronic inflammation (inflammaging), immune aging, and cellular senescence. By mitigating these aging mechanisms, IR confers survival advantages: At age 40, individuals with poor IR face a 9.7-fold higher mortality rate-a risk equivalent to that of 55.5-year-olds with optimal IR-resulting in a 15.5-year gap in survival. Optimal IR preserves youthful immune profiles at any age, enhances vaccine responses, and reduces burdens of cardiovascular disease, Alzheimer's, and serious infections. Two key salutogenic evolutionary themes emerge: first, female-predominant IR, including TCF7, likely reflects evolutionary pressures favoring reproductive success and caregiving; second, midlife (40-70 years) is a critical window where optimal IR reduces mortality by 69%. After age 70, mortality rates converge between resilient and non-resilient groups, reflecting biological limits on longevity extension. TNFα-blockers restore salutogenesis pathways, indicating IR delays aging-related processes rather than altering aging rates. By reframing aging as a salutogenic-pathogenic balance, we establish TCF7-centered IR as central to healthy longevity. Targeted midlife interventions to enhance IR offer actionable strategies to maximize healthspan before biological constraints limit benefits.
虽然衰老速率保持恒定，但健康寿命和寿命却差异很大。我们通过健康生成学——通过免疫弹性（IR）积极产生健康，即尽管衰老和炎症仍能抵抗疾病的能力——来解决这个难题。分析了跨越寿命阶段和炎症挑战的约17500个人，我们确定了一个核心健康生成机制：以TCF7为中心的IR，TCF7是一种保守的转录因子，维持T细胞干性和再生潜力。IR整合先天免疫和适应性免疫以对抗三个衰老和死亡驱动因素：慢性炎症（炎症衰老）、免疫衰老和细胞衰老。通过减轻这些衰老机制，IR赋予生存优势：在40岁时，IR较差的个体死亡率高出9.7倍——这一风险相当于IR最佳的55.5岁个体——导致生存差距达15.5年。最佳IR在任何年龄都能保持年轻的免疫特征，增强疫苗反应，并减轻心血管疾病、阿尔茨海默病和严重感染的负担。出现了两个关键的健康生成进化主题：第一，包括TCF7在内的女性主导的IR可能反映了有利于生殖成功和照顾行为中的进化压力；第二，中年（40 - 70岁）是一个关键窗口，最佳IR可将死亡率降低69%。70岁以后，有弹性和无弹性群体的死亡率趋于一致，这反映了延长寿命的生物学限制。肿瘤坏死因子α阻滞剂恢复健康生成途径，表明IR延缓与衰老相关的过程而非改变衰老速率。通过将衰老重新定义为健康生成 - 致病平衡，我们确立了以TCF7为中心的IR是健康长寿的核心。有针对性的中年干预措施以增强IR提供了可行的策略，以便在生物学限制限制益处之前最大化健康寿命。
