Fight Aging!

The commensal microbiomes of the body, such as that of the gut and the oral cavity, change with age in detrimental ways. In part this is due the progressive age-related failure of the immune system to undertake its duties, such as removing problematic microbial species. Other mechanisms are likely involved, however, many of which are less direct. In today's open access paper, researchers focus on one such mechanism, a reduced production of immunoglobulin A antibodies. In mucous membranes, such as of the gut and the mouth, immunoglobulin A antibodies are produced in large amounts and their presence shapes the distribution of microbial populations via selective interactions with different forms of bacteria. With age, immunoglobulin A production in the gut decreases, and this allows the composition of the gut microbiome to shift in harmful ways.

The researchers provide evidence for this loss of immunogloblin A production to derive in part from the presence of senescent B cells in the lymph nodes of tissue close to the mucous membrane. The researchers extend earlier work on the gut microbiome to show that this mechanism likely operates on the oral microbiome as well. The more mechanisms of degenerative aging that are discovered to involve senescent cells, the more of a drive there should be to as rapidly as possible develop senolytic drugs for widespread use. This is true of both existing first generation senolytics such as the dasatinib and quercetin combination, and the much better approaches presently under development in the longevity industry.

B cell senescence promotes age-related changes in oral microbiota

Among various host-derived factors known to be involved in the regulation of commensal microbiota, immunoglobulin A (IgA), which is abundantly secreted on mucosal surfaces, is thought to play an important role. IgA is known to regulate the balance of the commensal microbiota by binding to bacteria and contributing to the promotion or elimination of bacterial colony formation, depending on the type of bacteria. Notably, dysbiosis of the gut microbiota stemming from IgA deficiency has been observed in both human and murine models, with implications for the development of autoimmune disorders through aberrant immune activation. IgA is secreted not only in the intestinal tract but also in other mucosal sites such as the oral cavity. While there is already evidence suggesting the involvement of IgA in the regulation of oral microbiota, the impact of IgA on age-related changes in oral microbiota and its mechanisms remain unclear.

Senescent cells also cause senescence-associated secretory phenotypes (SASP), in which the cells secrete a variety of pro-inflammatory factors into the extracellular fluid. Therefore, the accumulation of senescence-like cells, which is often seen with aging and/or obesity, ultimately leads to harmful side effects. Moreover, our recent studies have shown that age-associated cellular senescence of ileal germinal center (GC) B cells induced by commensal bacteria reduces IgA production and diversity, leading to gut dysbiosis. Based on these findings, we considered the possibility that similar mechanisms may operate in the oral immune system, contributing to abnormalities in the oral microbiota with aging.

Examination of p16-luc mice, wherein the expression of the senescent cell marker p16INK4a can be visualized, raised under specific pathogen-free (SPF) or germ-free (GF) conditions, indicated that, unlike ileal germinal center (GC) B cells, the accumulation of senescent cells in GC B cells of cervical lymph nodes increases with age regardless of the presence of commensal bacteria. Furthermore, longitudinal studies utilizing the same individual mice throughout their lifespan revealed concurrent age-related alterations in the composition of the oral microbiota and a decline in salivary IgA secretion. Further investigation unveiled that B cell senescence leads to reduced IgA secretion and alteration of the oral microbiota. These findings advance our understanding of the mechanism of age-associated changes in the oral microbiota and open up possibilities of their control.