This review discusses how inherited variation in cytokine-regulatory pathways may influence IL-6, TNF-α, interferon, and TGF-β signaling, thereby contributing to inflammatory set points that favor chronic immune activation and inflammaging.
Aging is increasingly recognized as a heterogeneous biological process rather than a uniform chronological phenomenon. Immunosenescence has emerged as a central hallmark of biological aging, profoundly shaping susceptibility to infection, malignancy, autoimmunity, and poor vaccine responses. This progressive decline encompasses both innate and adaptive immunity and is marked by impaired antigen presentation, thymic involution, reduced lymphopoiesis, repertoire contraction, and the establishment of chronic low-grade inflammation. Importantly, immunosenescence does not occur solely as a consequence of chronological time but is accelerated by chronic conditions such as human immunodeficiency virus (HIV) infection, autoimmune disease, metabolic syndrome, chronic kidney disease, and cancer therapy, underscoring the dissociation between chronological and biological immune age. At the molecular level, aged lymphocytes accumulate DNA damage, mitochondrial dysfunction, and metabolic stress that drive canonical senescence pathways. Classical markers, including p16 inhibitor of cyclin-dependent kinase 4a (p16INK4a), p21 cyclin-dependent kinase–interacting protein 1 (p21CIP1), gamma-H2A histone family member X (γH2AX), and senescence-associated β-galactosidase (SA-β-gal), are now complemented by novel signatures such as immune-specific DNA methylation clocks, histone modifications, noncoding RNA networks, telomeric repeat-containing RNAs, mitochondrial dysfunction metrics, and profiles of the senescence-associated secretory phenotype. These biomarkers provide quantitative measures of immune biological age that surpass chronological metrics in predicting health outcomes. This review synthesizes emerging molecular and epigenetic frameworks that redefine immunosenescence as a quantifiable and disease-modifiable dimension of biological aging rather than a passive consequence of chronological time. By integrating immune-specific epigenetic clocks, mitochondrial and telomeric stress signatures, and senescence-associated secretory phenotypes, we highlight actionable biomarkers that enable precise stratification of immune biological age. These insights provide a translational roadmap for targeting immune aging through senotherapeutics, metabolic and epigenetic interventions, and optimized vaccine strategies, advancing immunosenescence toward precision geromedicine. Future advances will arise from longitudinal studies employing single-cell multi-omics, repertoire sequencing, and artificial intelligence–driven modeling to refine predictive aging clocks. Translational strategies targeting immune aging, including senolytics, senomorphics, metabolic modulators, epigenetic reprogramming, and next-generation vaccine adjuvants, hold promise for restoring immune resilience. Integrating these insights into precision medicine frameworks may transform immunosenescence from an inevitable feature of aging into a modifiable determinant of healthspan.
Immune senescence has emerged as one of the principal biological mechanisms linking aging with the development and progression of autoimmune rheumatic diseases. Rather than representing a simple decline in immune function, aging induces profound remodeling of both innate and adaptive immunity, characterized by chronic low-grade inflammation, loss of immune tolerance, impaired cellular regeneration, mitochondrial dysfunction, telomere shortening, epigenetic alterations, and expansion of senescent immune-cell populations. The objective of this review was to analyze current evidence regarding the mechanisms through which immune senescence reshapes autoimmune rheumatic diseases and to examine its clinical implications, biomarkers, and emerging therapeutic strategies. A narrative literature review was conducted using the scientific method and included publications retrieved from PubMed/MEDLINE, Scopus, Web of Science, ScienceDirect, SpringerLink, Nature, Frontiers, and Wiley. The evidence consistently demonstrated that inflammaging, adaptive immune remodeling, and cellular senescence contribute to disease progression, increased susceptibility to infections, reduced vaccine responsiveness, cardiovascular complications, frailty, osteoporosis, sarcopenia, and diminished functional capacity. Conventional inflammatory biomarkers remain widely used; however, increasing attention has been directed toward multi-omics technologies, epigenetic clocks, mitochondrial biomarkers, proteomics, metabolomics, and immune-cell phenotyping for more accurate assessment of biological immune aging. Current therapeutic approaches continue to rely on disease-modifying antirheumatic drugs and biologic agents, while emerging interventions—including JAK inhibitors, mTOR modulation, senolytic therapies, microbiome-targeted strategies, and precision medicine—offer promising opportunities for future individualized management. Overall, immune senescence should be recognized as a fundamental component of autoimmune rheumatic diseases, providing important opportunities for improving diagnosis, risk stratification, therapeutic decision-making, and long-term clinical outcomes in aging populations.
Immunosenescence, characterized by functional decline and altered phenotypes of immune cells with age, can disturb immune tolerance and promote autoreactive responses. Type 1 diabetes (T1D) has traditionally been viewed as a disease of immune dysregulation that leads to the autoimmune destruction of pancreatic β-cells. Emerging evidence suggests that senescence contributes to both the onset and progression of T1D. Autoreactive T cells are associated not only with β-cell death but also with the induction of β-cell senescence. In parallel, senescent β-cells acquire a senescence-associated secretory phenotype that amplifies local inflammation and increases β-cell vulnerability. These interlinked processes position senescence as a mechanistic bridge between aging, immune dysfunction, and autoimmunity. Importantly, a bidirectional loop appears to exist, in which T1D accelerates immune aging while immunosenescence further exacerbates autoimmunity. Recognizing this interplay highlights senescence as a promising and underexplored therapeutic target. Here, we synthesize current knowledge on immunosenescence and cellular senescence, examine their convergence in T1D pathogenesis, and outline future directions where interventions against senescent pathways could open new opportunities for treatment and prevention.
ARTICLE HIGHLIGHTS
The relationship between type 1 diabetes (T1D) and immunosenescence has not been deeply investigated. T1D is characterized by immune activation, metabolic stress, and hyperglycemia, which induce chronic low-grade inflammation. These factors are well-established drivers of immunosenescence. We propose that T1D may induce a state of premature immunosenescence, even in relatively young individuals. Immunosenescence is associated with an impaired immune response, reduced tolerance, and production of proinflammatory mediators. These may further exacerbate autoimmunity, creating a self-reinforcing cycle between autoimmunity and immune aging mechanisms. Integrating these perspectives could expand our understanding of disease mechanisms and lead to novel treatment approaches for T1D.
D. Saavedra, Rahul Mittal, C. Blaschke et al.· Diabetes· 0 citations
Regulation of the endocrine and immune system is pivotal for bodily homeostasis and healthy physiology, and these processes deteriorate as life progresses from adulthood to senescence. Aging, progressively weakening the structural and functional efficacies of the hypothalamic-pituitary-thyroid-adrenal-gonadal autoregulating axis, results in endocrino-immuno-senescence (EIS) that modulates a variety of complications and diseases. Both endocrine and immune responses are compromised during aging, along with impaired tissue regeneration, weakened pathogen detection, and decreased immune surveillance, and these events increase the susceptibility to infection, autoimmunity, cancers, and chronic disorders. Nonetheless, while immunosenescence modulates systemic inflammation and overall host defense, inflammaging accelerates tissue deterioration and intensifies diverse pathologies. Dysregulation of hormonal, genetic, and epigenetic machineries dampens the immune system, elevates pro-inflammatory activity, and fails to defend an organism against foreign pathogens, representing a link between cellular dysfunction and EIS. To mitigate these events, immunomodulation is an important therapeutic strategy that helps renew endocrine and immune dysregulation and simultaneously diminish age health disparities. Moreover, preservation of hormonal stability, involving immune response, emerges as a central determinant and could serve as a preventive medicine for the health and well-being of aged populations. This review provides a comprehensive understanding of the mechanisms by which EIS is coordinately associated with a variety of pathological processes and delineates new insights into immunomodulatory strategies ameliorating age-related diseases for healthy aging and quality living.
P. Manna, Shengping Yang, Chayan Manna et al.· Aging and Disease· 0 citations
Accumulating evidence suggests that outcomes are shaped not only by age and comorbidities, but also by preexisting biological states. A key determinant is immune resilience-the capacity to restore immune function and organ homeostasis. Aging-or accelerated biological aging-promotes accumulation of senescent cells and the senescence-associated secretory phenotype (SASP), driving chronic low-grade inflammation ("inflammaging"), impairing immune function, and reducing host resilience. SASP may also prime the immune system for exaggerated inflammatory responses in sepsis, contributing to cytokine storm. Notably, hyperinflammatory and immunosuppressive responses often emerge concurrently rather than sequentially. Immune cell death pathways help explain this apparent contradiction, as highlighted in the review featured in this issue of the Journal. These pathways provide a mechanistic bridge between these seemingly opposing states. They are not merely consequences of sepsis but active determinants of immune trajectory. Loss of SCFA- producing microbiota may impair immune regulation and promote dysregulated cell death, sustaining both hyperinflammatory and immunosuppressive states. This framework provides a testable model and supports interventional studies to determine whether restoration of SCFA signaling-such as through early administration of butyrate-producing microbes or tributyrin (a stable butyrate triglyceride)-can favorably alter immune trajectories and improve clinical outcomes.
Yu-Yeung Yip, Kwok M. Ho· Journal of critical care· 0 citations
Prostate cancer is a typical age-associated malignancy, and increasing evidence suggests that age-related immune alterations play an important role in its initiation, progression, and therapeutic response. Immunosenescence, characterized by impaired immune surveillance, reduced effector-cell function, contraction of the naïve T-cell repertoire, and persistent low-grade inflammation, may contribute to the establishment of a tumor-permissive microenvironment in older patients. In prostate cancer, these changes are particularly relevant because the disease often develops in an immunologically “cold” and suppressive tumor milieu. In addition to systemic immune aging, cellular senescence and the senescence-associated secretory phenotype (SASP) further reshape the local microenvironment by promoting chronic inflammation, stromal remodeling, and immune dysfunction. Together, immunosenescence, inflammaging, and senescence-related signaling may facilitate tumor persistence, immune escape, and resistance to therapy. Emerging therapeutic strategies therefore extend beyond tumor-intrinsic targets and include optimization of immunotherapy, reprogramming of the tumor microenvironment, and targeting of senescent cells or SASP-related pathways. A deeper understanding of how aging-related immune dysfunction interacts with prostate cancer biology may help improve patient stratification and support the development of more individualized treatment strategies for older prostate cancer patients.
Juntao Guo, Ke Wu, Zheng Ma et al.· Frontiers in Immunology· 0 citations
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