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Review
. 2023 May 13;8(1):200.
doi: 10.1038/s41392-023-01451-2.

Immunosenescence: molecular mechanisms and diseases

Zaoqu Liu #  1   2   3 , Qimeng Liang #  4 , Yuqing Ren #  5 , Chunguang Guo  6 , Xiaoyong Ge  1 , Libo Wang  7 , Quan Cheng  8 , Peng Luo  9 , Yi Zhang  10 , Xinwei Han  11   12   13
Affiliations
Review

Immunosenescence: molecular mechanisms and diseases

Zaoqu Liu et al. Signal Transduct Target Ther. .

Abstract

Infection susceptibility, poor vaccination efficacy, age-related disease onset, and neoplasms are linked to innate and adaptive immune dysfunction that accompanies aging (known as immunosenescence). During aging, organisms tend to develop a characteristic inflammatory state that expresses high levels of pro-inflammatory markers, termed inflammaging. This chronic inflammation is a typical phenomenon linked to immunosenescence and it is considered the major risk factor for age-related diseases. Thymic involution, naïve/memory cell ratio imbalance, dysregulated metabolism, and epigenetic alterations are striking features of immunosenescence. Disturbed T-cell pools and chronic antigen stimulation mediate premature senescence of immune cells, and senescent immune cells develop a proinflammatory senescence-associated secretory phenotype that exacerbates inflammaging. Although the underlying molecular mechanisms remain to be addressed, it is well documented that senescent T cells and inflammaging might be major driving forces in immunosenescence. Potential counteractive measures will be discussed, including intervention of cellular senescence and metabolic-epigenetic axes to mitigate immunosenescence. In recent years, immunosenescence has attracted increasing attention for its role in tumor development. As a result of the limited participation of elderly patients, the impact of immunosenescence on cancer immunotherapy is unclear. Despite some surprising results from clinical trials and drugs, it is necessary to investigate the role of immunosenescence in cancer and other age-related diseases.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
A timeline of events in the research history of immunosenescence. In this figure, we summarize the concept regarding immunosenescence, the breakthrough discovery of molecular mechanisms and biomarkers, and draw a timeline of research history
Fig. 2
Fig. 2
Hallmarks of immunosenescence and related diseases. Various immune cell subsets changed during immunosenescence. There were significant changes in T-cell subpopulations, including a decline in T-cell production associated with age due to thymic degeneration, abnormal T-cell metabolism, changes in the proportion of T subpopulations, and an SASP-mediated chronic low-grade inflammatory environment. IFN-γ interferon-γ, IL-6 interleukin-6, IL-8 interleukin-8, IL-18 interleukin-18, IL-29 interleukin-29, MDSC myeloid-derived suppressor cells, NK cells natural killer cells, ROS reactive oxygen species, SASP senescence-associated secretory phenotype, TCR T-cell receptor, TNF tumor necrosis factor
Fig. 3
Fig. 3
Multiple pathways are involved in T-cell senescence. Cellular senescence can be initiated by genomic or epigenomic damage that is induced by persistent antigens and competition for scarce nutrients in the tumor microenvironment. These stimuli lead to the activation of p38, ultimately triggering a DNA damage response, cell proliferation arrest, and inhibition of autophagy. Existing evidence suggests a potential metabolism-epigenetic axis that regulates T-cell senescence, in which mitochondrial function plays an important mediating role. AKT protein kinase B, AMPK adenosine 5′monophosphate-activated protein kinase, ERK extracellular-signal-regulated protein kinase, GLUT glucose transporters, IFN-γ interferon-γ, LCK lymphocyte-specific protein tyrosine kinase, MAPK mitogen-activated protein kinase, mTOR mechanism target of rapamycin, PI3K phosphatidylinositol 3-kinase, ROS reactive oxygen species, SAHFs senescence-associated heterochromatic focis, SAM S-adenosylmethionine, STAT1/3 signal transducer and activator of transcription 1/3, TAB1 transforming growth factor-activated kinase binding protein 1, TCA cycle tricarboxylic acid cycle, TERT telomerase reverse transcriptase, TNF-α tumor necrosis factor α, Treg regulatory T cells, ZAP70 zeta-chain-associated protein kinase 70
Fig. 4
Fig. 4
Metabolic and epigenetic modifications for the fate of T cells. Naïve T cells primarily use FAO and OXPHOS to derive their energy. Upon stimulation by antigens, activated mTOR signaling pathways lead to the release of a series of cytokines such as HIF-1α. The effector T cells then exhibit a general increase in glycolytic metabolism and mitochondrial mass with epigenetic reprogramming. Simultaneously, some intermediate metabolites also coordinate with epigenetic remodeling. For example, SAM produced by one-carbon metabolism subsequently promotes nucleotide synthesis. After clearance of the antigen, memory CD8+ T cells exhibit a metabolic switch to depressed metabolic activity that utilizes FAO and OXPHOS to meet energy demands. A distinct epigenetic landscape with open chromatin architectures is also displayed on particular loci to maintain longevity. With persistent pathological stimulation, T cells engage in exhausted differentiation with abnormal signals and specific cell cycle-related gene expression, inducing metabolic reprogramming such as decreased aerobic glycolysis, low cytotoxic activity, downregulation of mitochondrial biogenesis, and cell cycle arrest. Finally, aging or stress signals drive all types of T cells to turn into aged/senescent cells. Emerging evidence suggests that aged/senescent T cells also exhibit abnormal metabolic regulation such as mitochondrial dysfunction and a unique epigenetic landscape. APC antigen-presenting cells, CTLA-4 cytotoxic T lymphocyte-associated antigen-4, FAO fatty acid oxidation, GZMK granzyme K, HIF-1α hypoxia-inducible factor-1α, KLRG-1 killer cell lectin-like receptor subfamily G member 1, LAG-3 lymphocyte activation gene 3, MEK mitogen-activated protein kinase kinase, OXPHOS oxidative phosphorylation, PD-1 programmed cell death protein 1
Fig. 5
Fig. 5
The circuit between cellular senescence and inflammaging promotes immunosenescence and tumorigenesis. Senescent cells gradually accumulate in vivo. Consequently, the increased SASP of senescent cells aggravates the inflammatory state, which activates counteracting immunosuppression. Subsequently, suppressive Treg cells secrete inhibitory cytokines, such as IL-10 and TGF-β, to prevent CD8 + T cells from surveilling and clearing senescent cells. In addition, senescent cells can enable sustained activation of the NKG2D receptor by releasing soluble NKG2D ligands from their cell surface or by increasing the expression of specific inhibitory proteins. Sustained activation of NKG2D receptor function is inhibited, thereby impairing immune system function and enhancing the expansion of senescent cells in the TME. ECM extracellular matrix, MMPs matrix metalloproteinases, NKG2D natural killer Group 2 member D
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