Immunosenescence: signaling pathways, diseases and therapeutic targets

Abstract

Immunosenescence refers to the abnormal activation or dysfunction of the immune system as people age. Inflammaging is a typical pathological inflammatory state associated with immunosenescence and is characterized by excessive expression of proinflammatory cytokines in aged immune cells. Chronic inflammation contributes to a variety of age-related diseases, such as neurodegenerative disease, cancer, infectious disease, and autoimmune diseases. Although not fully understood, recent studies contribute greatly to uncovering the underlying mechanisms of immunosenescence at the molecular and cellular levels. Immunosenescence is associated with dysregulated signaling pathways (e.g., overactivation of the NF-κB signaling pathway and downregulation of the melatonin signaling pathway) and abnormal immune cell responses with functional alterations and phenotypic shifts. These advances remarkably promote the development of countermeasures against immunosenescence for the treatment of age-related diseases. Some anti-immunosenescence treatments have already shown promising results in clinical trials. In this review, we discuss the molecular and cellular mechanisms of immunosenescence and summarize the critical role of immunosenescence in the pathogenesis of age-related diseases. Potential interventions to mitigate immunosenescence, including reshaping immune organs, targeting different immune cells or signaling pathways, and nutritional and lifestyle interventions, are summarized. Some treatment strategies have already launched into clinical trials. This study aims to provide a systematic and comprehensive introduction to the basic and clinical research progress of immunosenescence, thus accelerating research on immunosenescence in related diseases and promoting the development of targeted therapy.

Fig. 1

Signaling pathways associated with immunosenescence. Immunosenescence is associated with aberrant activation of various signaling pathways, such as upregulation of the NF-κB, mTOR, JAK-STAT, and cGAS-STING signaling pathways and downregulation of the AMPK, melatonin, and sirtuin pathways. a Accumulation of endogenous DNA damage and oxidative stress cause overactivation of NF-κB signaling, which transcriptionally activates the mechanistic target of mTOR and upregulates antiapoptotic proteins, thus impairing the induction of autophagy and apoptotic clearance of SnCs. b mTOR functions through two distinct complexes: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). mTORC1 integrates signals from nutrients and growth factors to regulate various anabolic processes while inhibiting catabolic processes by phosphorylating ULK1/2 and sequestering lysosomal enzymes. mTORC2 regulates cytoskeletal organization and cell survival pathways through the activation of the AKT and SGK1-Foxo1 axes and the inhibition of GSK3β. c Overactivation of the JAK-STAT signaling pathway during aging contributes to immunosenescence by driving persistent inflammation and altering immune cell function and survival, including T cells and HSCs. d Accumulation of damaged DNA in aging cells activates the cGAS/STING pathway, which further induces NF-κB-dependent expression of inflammatory cytokines with impaired IFN-I production. e AMPK plays a crucial role in the regulation of cellular energy metabolism. It extends lifespan by promoting autophagy via mTOR inhibition and ULK1 activation. The activation of AMPK broadly suppresses proinflammatory signaling pathways, which inhibits the expansion and function of MDSCs and promotes the survival and memory formation of T cells. f Melatonin suppresses proinflammatory cytokines and enhances anti-inflammatory cytokines by inhibiting the NF-κB pathway. It directly scavenges ROS and upregulates the expression of antioxidant enzymes such as superoxide dismutase (SOD) and glutathione peroxidase (GPX), reducing oxidative damage and SASP accumulation in immune cells. Melatonin also mediates SIRT1 pathway activation, which optimizes mitochondrial function and autophagy. g Sirtuin family proteins play crucial roles in immune aging by regulating mitochondrial function, oxidative stress, and NF-κB signaling

Fig. 2

Cellular mechanisms of immunosenescence. Aging-induced alterations in various immune cell populations are depicted with young cells in the top row and aged cells in the bottom row. (1) HSC: Aging increases the number of HSCs but weakens their function. SNS degeneration decreases ADRβ3 signaling, generating an inflammatory niche. Myeloid-biased differentiation reduces lymphoid output, weakening adaptive immunity. (2) Neutrophils: Aged neutrophils exhibit prolonged lifespan, hypersegmentation, and impaired chemotaxis but enhanced CXCL1-driven recruitment. Elevated NET formation, ROS, and TNF-α production promote chronic inflammation. (3) Macrophages and Monocytes: Aging increases the proportion of CD14⁺CD16⁺ monocytes, which exhibit a proinflammatory phenotype with increased TNF-α and IL-6 production. Reduced phagocytosis causes debris accumulation and chronic inflammation. Elevated ROS, NO, and β2M contribute to metabolic diseases and cognitive decline. (4) T cells: Aging reduces the levels of IL-7 and chemokines, impairing naïve T cell survival, proliferation, and lymph node entry and limiting renewal. Aging decreases CD8⁺ T cell diversity and number. CD160 and CD244 expression increases, resembling an exhausted phenotype. Aged CD8⁺ T cells show reduced cytotoxicity and produce less IFN-γ, granzyme B, and perforin. CD4⁺ T cell activation decreases in part due to elevated PD-1 expression. (5) Aged DCs have weaker antigen presentation (MHC/CD40 downregulation), resulting in weaker CD4⁺ T cell responses. (6) NK cells: Aging reduces the number of CD56^bright NK cells and their activating receptors while increasing the number of inhibitory receptors (KIRs), impairing cytotoxicity. Degranulation and perforin secretion decline. NK cells shift toward a CD56^dim subset, where they secrete more proinflammatory cytokines, contributing to chronic inflammation. (7) B cells: In elderly individuals, antibody production and class switching decline due to CD40 downregulation and weakened BCR signaling. ABC expansion disrupts immune balance, weakening humoral immunity

Fig. 3

Immunosenescence in neurodegenerative diseases. In AD, immunosenescence and inflammaging drive chronic neuroinflammation, fostering neuronal damage and impairing Aβ clearance via dysfunctional microglia. Aβ deposition triggers the uncontrolled activation of microglia and astrocytes. Increased BBB permeability allows Th1/Th17 infiltration and the secretion of proinflammatory cytokines, exacerbating neurodegeneration, whereas Tregs help suppress inflammation and clear Aβ. In PD, misfolded α-synuclein aggregates into Lewy bodies, causing dopaminergic neuron loss in the substantia nigra. Peripheral CD4⁺ T cell infiltration and IL-17 signaling drive neuroinflammation and neuronal apoptosis. Activated microglia amplify this process by fostering a proinflammatory environment, whereas reduced Tregs fail to suppress excessive immune activation

Fig. 4

Immunosenescence in cancer. In the left part of the figure, the SASP enhances tumor growth, invasion, and immune evasion, exacerbating immune suppression. Aging-related T cell exhaustion and an impaired TCR repertoire weaken immune surveillance. Additionally, reduced vaccine efficacy and diminished immune checkpoint blockade (ICB) responses are observed in the senescent TME. In the right part of the figure, therapy-induced senescence (TIS) reprograms tumor cells toward stem-like phenotypes and suppresses CD8⁺ T cell activation. This suppression of CD8⁺ T cell activity subsequently contributes to the development of an immunosuppressive environment. A similar effect is observed with the accumulation of senescent T cells, which also suppress CD8⁺ T cell activation and thereby promote immune suppression. Moreover, senescent T cells can recruit MDSCs and Tregs and further induce senescence in neighboring effector T cells, thereby reinforcing immune suppression and impeding effective antitumor responses within the immunosuppressive milieu. Furthermore, CAR-T cell immunotherapy itself can induce SASP-related cytokines. This adverse environment, together with the presence of senescent T cells, synergistically undermines the efficacy of CAR-T cell therapy

Fig. 5

Other immunosenescence-related diseases. (1) Infectious diseases: Immunosenescence increases susceptibility to infections (e.g., SARS-CoV-2, CMV) due to PD-1/Tim-3 overexpression in T cells. Chronic inflammation impairs lung function, contributing to COPD and IPF. Weakened vaccine responses reduce protection in older adults. (2) Autoimmune diseases: Senescent CD28⁻ T cells disrupt immune tolerance, exacerbating RA. Telomere attrition and epigenetic changes sustain chronic inflammation and systemic complications. (3) CVD: Aging-induced inflammation and oxidative stress drive CVD. DAMPs activate PRRs, triggering cytokine and ROS production. Senescent T cells worsen vascular dysfunction. (4) AMD: Dysregulated immune responses and chronic inflammation damage the retina. Dysregulated microglia and NK, T, and B cells drive inflammation, whereas mast cells and monocyte/macrophage activation exacerbate retinal damage through proinflammatory cytokine release. Neutrophil NET formation and complement activation further impair the blood‒retinal barrier, accelerating AMD progression. (5) Metabolic disorders: Immunosenescence promotes inflammation in T2D and obesity. Increased memory CD4⁺ T cells and senescent T cells enhance cytokine production, whereas double-negative B cells expand, leading to enhanced proinflammatory responses and autoantibody secretion. Reduced PBMC function weakens immune defense, exacerbating metabolic dysfunction

Fig. 6

Therapeutic strategies related to immunosenescence. The three types of therapeutic measures mentioned in the review are as follows: (1) Immune intervention, which is mainly divided into interventions targeting immune organs and immune cells. (2) Targeting signaling pathways related to aging; slowing the immune aging process by downregulating NF-κB, mTOR, and JAK-STAT; and upregulating AMPK, SIRT1 and other signaling pathways. (3) Nutritional and lifestyle intervention strategies

Fig. 7

Targeting T cell senescence. a At the genetic level, modifying T cell functionality or engineering chimeric antigen receptor (CAR)-T cells with CD28 may prolong the duration of adoptive cell therapy by mitigating T cell senescence. b Thymic rejuvenation through thymic remodeling supports T cell development and maturation. c By directly targeting senescence-associated molecules in aged T cells, this approach can reverse T cell senescence. d Regulating signaling pathways associated with T cell senescence