Aging is a complex phenomenon characterized by a progressive decline in physiological function and the ability to maintain tissue homeostasis, leading to an increased incidence of degenerative diseases and mortality. Numerous theories exist regarding aging, including genetics, cell mutation, free radicals, and neuroendocrine theory. In recent years, many scholars have noted the relationship between immunity and aging and proposed the immunological theory of aging.
Aging manifests itself in significant changes at the cellular and systemic levels of the body. Cellular aging is characterized by cell cycle arrest in dividing cells, and various forms of cell damage or stress can induce cellular senescence. Furthermore, senescent cells often downregulate proliferation-related genes and overexpress inflammatory factors and other molecules that regulate the immune response. The most obvious manifestation of aging is immune system dysregulation, including immune decline and chronic inflammation. Immune decline reduces immune protection against tumor cells and pathogens, while chronic inflammation increases the risk of autoimmune diseases. Consequently, human aging manifests itself in an increased incidence of age-related diseases, such as cancer, metabolic syndrome, autoimmune diseases, infections, cardiovascular and cerebrovascular diseases, and neurodegeneration. Some have therefore called aging an epidemic of immune diseases.
Some characteristics of the aging immune system
- Thymic involution
Decreased thymocyte proliferation and increased apoptosis lead to reduced output of naive T cells. For example, studies have shown that thymic medullary epithelial cells in aged mice exhibit SASP characteristics and decreased expression of the forkhead box N1 (FOXN1) transcription factor, impairing thymocyte development and selection. Furthermore, the perivascular space in the thymus expands and fills with adipocytes, leading to structural changes in the thymus, including reduced volume, loss of functional tissue, and fat replacement. These changes can be clearly observed using imaging techniques such as CT, MRI, and PET.
- Inflammatory aging
With aging, chronic inflammation gradually increases, with elevated levels of inflammatory markers such as tumor necrosis factor-α (TNF-α), C-reactive protein (CRP), and interleukins. This is not directly caused by infection but rather driven by factors such as free radical-induced cellular damage, imbalanced inflammatory cytokines, and cellular senescence. Chronic inflammation plays a key role in the development and progression of cardiovascular disease. 3. Cellular Metabolic Adaptations
Aging T cells undergo metabolic reprogramming, shifting from oxidative phosphorylation to glycolysis. This leads to reduced ATP production efficiency, impairing immune functions such as cell proliferation and cytokine production. Aging also affects the quality and quantity of mitochondrial DNA. Inhibiting the p38 MAPK signaling pathway can promote mitochondrial biogenesis and autophagy, providing a potential therapeutic strategy.
- Hematopoietic Changes
Aging affects the hematopoietic system, particularly hematopoietic stem cells (HSCs). HSCs undergo an increased shift toward myeloid differentiation, leading to altered immune cell composition and function. Concurrently, the diversity and differentiation potential of HSCs are impaired, with a decrease in the number of CD62L+ HSCs. Specific transcription factors are involved in this aging-associated myeloid bias.
Aging has a multifaceted impact on various immune cell types, including macrophages, T cells, B cells, neutrophils, natural killer (NK) cells, and dendritic cells, leading to decreased immune function and increased susceptibility to disease in the elderly.
- Macrophages
Aging reduces macrophage production of the pro-inflammatory cytokine pro-IL-1β, impairing inflammation control and anti-infection capabilities. Abnormal regulation of genes involved in the interferon-γ (IFNγ) response leads to a reduced inflammatory response during muscle regeneration, hindering healing. Telomere loss triggers oxidative stress, mitochondrial abnormalities, and overactivation of the NLRP3 inflammasome, reducing proliferation and DNA repair capacity. This impairs wound healing mechanisms, leading to increased tissue damage and delayed resolution of inflammation.
- T Cells
With aging, the number of CD8+ T cells and CD45RA naive T cells decreases, while the number of CD4+ T cells remains unchanged. This weakens the immune system's ability to respond to new antigens. CD28 expression on CD8+ T cells decreases, impairing T cell survival and activation; the diversity of the T cell receptor repertoire decreases, particularly on CD8+ T cells. Furthermore, CD8+ T cells express high levels of CD57, indicating that they have undergone multiple divisions, have short telomeres, and have poor proliferation capacity. Elevated p53β expression increases the risk of autoimmune diseases. Long-term stimulation causes T cell telomeres to erode, leading highly differentiated CD8+CD28-CD27- T cells to enter the terminal replication stage after activation. Increasing telomerase activity may improve T cell function.
- B Cells
Aging affects selection during B cell affinity maturation, reducing B cell repertoire diversity, decreasing the number of naive B cells, increasing the number of memory B cells, and impairing the immune system's ability to respond to new antigens. Some aged B cells experience increased mitochondrial mass and mitochondrial reactive oxygen species, affecting mitochondrial energy production and one-carbon metabolism, thereby impairing antibody secretion and B cell activation. Although in vitro experiments show no fundamental abnormalities in the proliferation and differentiation of elderly B cells into antibody-secreting cells, germinal center reactions are delayed, the percentage of B-1 cells and the ability to spontaneously secrete IgM decrease, the expression of related transcription factors is altered, and the diversity of the antibody repertoire decreases, leading to reduced antibody production.
- Neutrophils
Aging causes structural changes in neutrophils, reduced plasma membrane viscosity, and weakened adhesion capacity, impacting their role in immune responses. Decreased expression of the chemokine receptor CXCR2 impairs neutrophil chemotaxis to sites of inflammation, impairing the inflammatory response. This impairs their ability to migrate and infiltrate infected sites, reducing their ability to eliminate pathogens like E. coli and producing neutrophil extracellular traps (NETs), leading to a weakened immune response and an increased infection rate in the elderly.
- Natural Killer (NK) Cells
Aging increases expression of killer immunoglobulin-like receptors (KIRs) and decreases expression of the inhibitory receptor NKG2A on NK cells, potentially leading to increased lysis of healthy cells and the initiation of autoimmunity. When stimulated by cytokines, NK cells in the elderly secrete less IL-8 than in younger individuals. The distribution of NK cell subsets is altered, with an increase in the CD56 dim subset and a decrease in the CD56 bright subset. This impairs proliferation and weakens the immune response.
- Dendritic Cells
Aging impairs dendritic cell development, cytokine production, and antigen presentation. Elderly individuals experience a decrease in the number of myeloid dendritic cells (mDCs) in their blood, and a decline in the ability of plasmacytoid dendritic cells (pDCs) to stimulate IFN-γ secretion and CD4+ and CD8+ T cell proliferation, leading to a weakened immune response to viral infections. Dysbiosis in the intestinal flora can affect the tolerance of dendritic cells, preventing them from effectively regulating excessive CD4+ T cell activation and stimulating the production of regulatory T cells (Tregs), thereby weakening the immune system.