Jul 2026· International Journal of Molecular Sciences· Vol 27, pp. 6037· 0 citations· 189 references
Medicine
TL;DR
Age-related alterations in the function of primary and secondary lymphoid organs, including the bone marrow, thymus, spleen, and lymph nodes are summarized, which include a decline in naïve cell populations, an accumulation of memory and exhausted cells, and a reduction in the diversity of antigen receptors.
Abstract
Aging is accompanied by complex structural and functional immune system changes driven by genomic instability, epigenetic alterations, mitochondrial dysfunction, telomere attrition, loss of proteostasis, deregulated nutrient sensing, and the accumulation of senescent cells exhibiting a senescence-associated secretory phenotype, which altogether lead to severe consequences including altered antimicrobial defense, the overproduction of autoantibodies, and chronic, low-grade inflammation (inflammaging). In this article, we summarize age-related alterations in the function of primary and secondary lymphoid organs, including the bone marrow, thymus, spleen, and lymph nodes. The involution of these organs leads to impaired hematopoiesis, reduced production of naïve lymphocytes, and immune microenvironment disruption. We also describe aging-related impairment of the activity of neutrophils, macrophages, dendritic cells and natural killer cells, as well as dysregulation of T and B lymphocyte responses. Specifically, these alterations include a decline in naïve cell populations, an accumulation of memory and exhausted cells, and a reduction in the diversity of antigen receptors. Consequently, older individuals exhibit increased susceptibility to infections, cancer, and autoimmune diseases, along with diminished vaccine efficacy. Understanding the mechanisms underlying immune aging could lay the foundation for developing therapeutic strategies and lifestyle interventions to mitigate the adverse effects of this unfavorable process.
Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease characterized by loss of immune tolerance and multi-organ inflammation. Although its pathogenesis involves multiple factors, the peak incidence of SLE in individuals over 48 years of age points to immunosenescence as a key driver of the disease.Even in younger patients, SLE frequently often presents as premature aging of the immune system. This review synthesizes recent advances in understanding how immunosenescence drives pathogenesis through immune dysregulation across major lymphocyte and myeloid subsets. Within the chronic inflammatory microenvironment, replicative exhaustion of T cells leads to accelerated telomere attrition, persistent activation of the DNA damage response, and telomerase dysfunction. This cascade culminates in the accumulation of senescent T cells displaying a characteristic CD28-CD57+KLRG1+ phenotype, accompanied by a pro-inflammatory state defined by enhanced cytotoxicity and impaired regulatory function. These characteristics correlated directly with disease activity and cumulative organ damage. The process arises from the interplay of metabolic reprogramming and epigenetic remodeling. In parallel, age-associated B cells (ABCs) accumulate, producing high-affinity anti-dsDNA and other autoantibodies, and potentiating inflammation via enhanced antigen presentation. Meanwhile, an aged bone-marrow microenvironment together with clonal hematopoiesis skews monocyte and macrophage polarization toward a pro-inflammatory (M1) profile. These cells show reduced phagocytic capacity and heightened secretion of senescence-associated secretory phenotype (SASP)-like mediators, further driving inflammaging. This review synthesizes current insights into the relationship between SLE risk and immunosenescence. We discuss the mechanisms through which immune aging instigates autoimmunity and explore emerging therapeutic strategies aimed at mitigating immunosenescence.
Immune system undergo profound age-associated changes underlying impaired immune function in response to infections, malignancies, and vaccines. While cell-intrinsic changes in lymphocyte are well recognized, emerging evidence indicates that degenerative changes in secondary lymphoid organs (SLO) microenvironment decisively contribute to immune decline.
To define the molecular basis of these changes, we performed transcriptomic profiling and functional validation of non-hematopoietic lymph node stromal cells (LNSCs), which regulate lymphocyte homeostasis and orchestrate immune responses.
Aging induces coordinated metabolic defects in fibroblastic reticular cells, a major stromal cell subtype, characterized by reduced expression of amino acid transporters and mitochondrial phosphate and ATP/ADP carriers. These alterations coincided with a metabolic shift from oxidative phosphorylation (OXPHOS) to glycolysis, accompanied by mitochondrial dysfunction and a reduction in their ability to maintain T cells. Functionally, aged LNSCs exhibited impaired proliferation and expansion of the reticular network during West Nile virus and herpes simplex virus type 1 infections, resulting in diminished and hypofunctional antigen-specific CD8+ T cell responses. Restoring mitochondrial quality through mitophagy induction enhanced the ability of aged LNSCs to support naïve T cells in vitro. Ongoing studies aim to identify upstream cues driving these stromal metabolic defects and to leverage FRC-specific genetic models to dissect their role in functional immune decline with age.
Together, these results suggest that age-related mitochondrial and metabolic changes in the lymph node stromal microenvironment contribute to T cell immune function.
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Lymphocyte Differentiation and Peripheral Maintenance (LYM)
S. Sonar, Ruchika Bhat, J. Nikolich· Journal of Immunology· 0 citations
Aging is characterized by progressive physiological decline and accumulation of senescent cells that drive chronic "inflammaging" through the senescence-associated secretory phenotype (SASP). The complement system, traditionally viewed as a systemic extracellular defense mechanism, is now recognized as an essential intracellular network (the complosome). This review synthesizes current research on how intracellular C3 (intC3), and intracellular C5 (intC5) in certain contexts engage in extensive crosstalk with the mTOR, NF-κB, and AMPK pathways to modulate core cellular processes. We detail how intC3 intersects with multiple canonical hallmarks of aging-including cellular senescence, mitochondrial dysfunction, proteostasis loss, genomic instability, epigenetic alterations, altered intercellular communication, stem cell exhaustion, and deregulated nutrient sensing. Furthermore, we examine organ-specific consequences of intC3 dysregulation across the aging brain, liver, eye, kidney, vasculature, lung, and immune system, as well as cancer. Finally, we discuss therapeutic strategies-including complement inhibitors, senolytics, senomorphics, RNA interference, proteolysis targeting chimeras (PROTACs), and nanotechnology-enabled delivery-and outline critical gaps in compartment-specific tools, conditional knockouts, and longitudinal models. Precision strategies that preserve systemic complement function while selectively modulating intracellular pools will be essential to translate complosome biology into durable interventions for age-related diseases.
Naheemat Modupeola Gold, M. N. Okeke, Samuel Ewhea Ajoronor et al.· Ageing Research Reviews· 0 citations
Aging affects lung function, predisposing older adults to respiratory diseases; however, the cellular and molecular mechanisms of lung aging are not fully understood. Leveraging single-cell and spatial transcriptomics data from 184 and 70 lung parenchyma samples, respectively, we present an analytical platform to dissect the cell composition, gene expression modules, and regulatory changes linked to multiple hallmarks of lung aging. Our findings show cell type-specific age-association of senescence markers and a decline in alveolar cell proliferation, autocrine WNT signaling, and stemness indicators with advancing age. Analysis of myeloid cells reveals a global reduction in macrophage subsets and a surge in mitochondrial dysfunction and inflammatory signaling. In contrast, lung parenchyma T cells expand with age and exhibit heightened interferon gamma expression, cytotoxic activity, and exhaustion in older lung and blood samples, indicative of age-related immune dysfunction. Cell interaction and spatial analysis demonstrate aberrant myeloid-T cell cross-talk, leading to an increase in T cell chemotaxis and activation. Lastly, we use machine learning to predict lung biological age and identify putative biomarkers of lung aging and disease risk. In this study, Tsankov and colleagues uncover multiple cellular hallmarks of lung aging in human tissue at single-cell and spatial resolution, including altered alveolar stemness, immune signaling, and macrophage respiration pathways, that may help assess lung biological age and disease risk.
Ke Xu, Grace S Kim, A. Bhagwat et al.· Nature Communications· 0 citations
Cellular senescence is a stress-induced cell-cycle arrest program accompanied by the senescence-associated secretory phenotype (SASP). While senescent cells are typically eliminated through immune surveillance under normal physiological conditions, they tend to accumulate progressively during aging and in chronic diseases. This review summarizes current evidence suggesting that such persistence is attributable not only to immune system decline but also to active, cell-intrinsic mechanisms of immune evasion. We discuss how senescent cells escape clearance by weakening immune recognition, suppressing phagocytic removal, resisting apoptosis, remodeling the inflammatory and structural microenvironment through SASP, and activating inhibitory checkpoint pathways in aged tissues. Furthermore, we investigate the contribution of these mechanisms to representative age-related diseases across multiple organs. Finally, we highlight emerging therapeutic strategies aimed at targeting the immune evasion of senescent cells, including checkpoint modulation, chimeric antigen receptor (CAR)-based cell therapies, vaccination approaches, and other immune-bypass strategies. Collectively, these insights underscore immune evasion as a critical determinant of senescent cell persistence and a promising target for interventions in aging and age-related diseases.
Qikun Ou, Jinran Zhao, Yuanlong Ge et al.· Ageing and Cancer Research &...· 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