Immunology and Antiaging Medicine: Aging Immune Cells and Antiaging

The immune system recognizes self-tissues and foreign factors such as microbes, and is a biological defense mechanism that eliminates non-self. The immune system consists of innate immunity and acquired immunity, the former non-specifically targets foreign factors, while the latter recognizes and efficiently eliminates specific targets through immune memory by T cells and B cells antigen-specific receptors. Changes in immune function with aging are called immune aging, and both innate and acquired immunity change, but the decline in the latter’s function is particularly noticeable. Under the conditions of immune aging, autoimmune risk and inflammatory factors increase. Clinically, issues such as increased susceptibility in the elderly, onset of autoimmune diseases, carcinogenesis, and decreased vaccine efficacy become problems. Although details will be given in the next section, systemic noninfectious chronic inflammation associated with individual aging is called inflammaging and is attracting attention as one cause of aging diseases such as hypertension, diabetes, and sarcopenia. In recent years, we will outline the cell populations and important factors involved in the onset of immune aging that are particularly noteworthy. With aging, it is known that especially acquired immunity decreases and T cells are more affected by aging than B cells. The thymus, which is the site of T cell differentiation, gradually atrophies with adolescence as the peak in humans, and is replaced by adipose tissue in old age. Therefore, in old age, the supply of naive T cells to the periphery decreases, while homeostatic proliferation of T cells suppresses the decrease. This reaction is regulated by factors such as interleukin-7 (IL-7) and interleukin-15 (IL-15). However, excessive homeostatic proliferation induces T cell aging and causes abnormalities in the immune system and immune aging. The increase in inflammatory traits associated with T cell aging is called senescence-associated secretory phenotype (SASP), characterized by a significant increase in the production of inflammatory cytokines and angiogenesis inducers. Excessive SASP causes chronic inflammation, resulting in irreversible remodeling of tissue structure and decreased biological function. The involvement of regulatory T cells (Treg) has also been reported in the prolongation of inflammation with aging. In addition to becoming apoptosis-resistant with age, the supply of Tregs from the thymus decreases. This decrease in Treg diversity leads to a decrease in the suppression of abnormal activation of effector T cells, which is one of the causes of chronic inflammation. In recent research on immune aging, senescence-associated T cells (senescence-associate T cells) are being studied. Tissues; SA-T) have been identified and are attracting attention. SA-T cells, which are memory-type helper T cells, express the inhibitory receptor PD-1 (programmed cell death 1) and CD30L (CD153), which belongs to the tumor necrosis factor (TNF) superfamily. SA-T cells have distinct characteristics from regular helper T cells, such as high expression of bone marrow cell genes and halted proliferation. Furthermore, while they hardly produce typical cytokines in response to stimulation of the T cell receptor, they secrete large amounts of inflammatory cytokines and chemokines such as IFN-γ (interferon-γ), osteopontin, CCL3, CCL4, contributing to the increase of inflammatory factors. Studies in mice have reported that SA-T cells exist not only in lymphoid organs but also in various peripheral tissues such as the kidneys in systemic lupus erythematosus, and that they increase in visceral adipose tissue due to a high-fat diet, inducing insulin resistance through the activation of osteopontin. So far, we have explained the mechanism of immunosenescence focusing on T cells, but recent reports suggest that changes in B cells with aging may also contribute to immunosenescence. In the elderly, B cell subsets are changing, and an increase in a group of cells called age-associated B cells (ABCs) has been reported. These cells first accumulate in the spleen, then in the bone marrow, and increase significantly with aging. In addition to aging, they increase with various viral infections and vaccinations, and are suggested to be involved in the onset and progression of autoimmune diseases. ABCs are characterized by the expression of CD11b/CD11c and T-bet, unlike other B cells. Studies on the cell cycle in mice have shown that ABCs are in the resting phase and are not a subset of self-replicating cells. Their functional characteristics include strong antigen-presenting ability and the ability to produce inflammatory cytokines and chemokines compared to regular B cells, and their differentiation induction involves TLR7 or TLR9 signals, interleukin-21 (IL-21), and IFN-γ stimulation. Also, in a systemic lupus erythematosus (SLE) mouse model, it has been clarified that interferon-regulatory factor 5 promotes the formation of ABCs through IL-21 stimulation. In the future, it is expected that ABCs will become a new therapeutic target for autoimmune diseases. From these findings, the essence of immunosenescence is largely due to the collective and qualitative changes in immune cells such as T cells and B cells, and these changes are strongly associated with the onset and pathogenesis of age-related diseases. Next, we will introduce the possibility of developing therapies from the perspective of overcoming immunosenescence, including our research findings.