Flagellin Immunization Modestly Extends Life Span After Late-Life Administration in Mice – Fight Aging!

The immune system recognizes flagellin as foreign. Flagellin is the protein found in flagellae, the whip-like structures that bacteria use to move around. Attacking and destroying these bacteria is very much a part of the immune system’s portfolio of normal activities. Thus immunization with flagellin provokes the immune system into greater activity and responsiveness in the short term, and it has been tested in humans as a vaccine adjuvant, intended to make the immune system respond more effectively to the vaccine delivered alongside flagellin. Interestingly, flagellin immunization also makes the immune system clear out harmful microbes from the gut microbiome, improving the function of the gut microbiome by, for example, reducing its contribution to systemic inflammation. This effect has been demonstrated in mice, and in human self-experimentation, but has yet to be the subject of more rigorous research.

In that context, it is interesting to read today’s open access paper, in which researchers demonstrate a modest extension of life span in mice to result from repeated flagellin immunization starting in late life. The researchers used a fusion protein made up of flagellin and another bacterial protein, presumably because one can patent such a novel formulation where one can’t patent the use of flagellin. An observer might wager that the effect on life span is derived from changes in the gut microbiome, given other studies in mice demonstrating improved long-term health to result from improving the gut microbiome. The authors of this paper see it as more a matter of immunomodulation, however. The use of vaccines and immunization can produce a phenomenon called trained immunity, dampening age-related chronic inflammation spurred by the innate immune system.

Mucosal TLR5 activation controls healthspan and longevity

In advanced aging, innate immune activation has been viewed as an inducer of chronic inflammation, which promotes different signs of aging and age-related diseases. At the same time, numerous examples indicate that the innate immune system contributes to tissue homeostasis and repair. Toll-like receptors (TLRs) are crucial for the innate immune system’s response to threats, primarily by regulating inflammation and activating immune responses. The reduction in TLR activity induced by aging leads to a decreased efficiency in immune responses, potentially lowering the body’s resistance to infections.

TLR5 is a remarkably versatile receptor found on both epithelial and immune cells, and its functions are distributed throughout the body. One of its critical roles emerges in the respiratory tract, where TLR5 assumes a pivotal position in initiating protective immune responses, particularly when combating infections like Pseudomonas aeruginosa. It is well known that the reduction in TLR activity induced by aging leads to a decreased efficiency in immune responses, potentially lowering the body’s resistance to infections. However, in our previous study, we discovered that TLR5 expression and signaling were relatively well-preserved in aged mice and older individuals compared to other TLRs. We also demonstrated that TLR5 effectively enhances vaccine efficacy against pneumonia, leading to increased survival rates from pneumococcal infection in old mice. Unlike other TLRs, TLR5 has been reported not only to induce pro-inflammatory signals essential for vaccine efficacy boosting but also to suppress inflammation in lesions, induce tissue regeneration in major disease models, and strengthen the barrier. This unique functionality underscores the diverse applicability and therapeutic potential of TLR5 in addressing age-related health issues and promoting longevity.

In our study, we show that stimulating toll-like receptor 5 (TLR5) via mucosal delivery of a flagellin-containing fusion protein effectively extends the lifespan and enhances the healthspan of aged mice of both sexes. This enhancement in healthspan is evidenced by diminished hair loss and ocular lens opacity, increased bone mineral density, improved stem cell activity, delayed thymic involution, heightened cognitive capacity, and the prevention of pulmonary fibrosis. Additionally, this fusion protein boosts intestinal mucosal integrity by augmenting the surface expression of TLR5 in a certain subset of dendritic cells and increasing interleukin-22 (IL-22) secretion. In this work, we present observations that underscore the benefits of TLR5-dependent stimulation in the mucosal compartment, suggesting a viable strategy for enhancing longevity and healthspan.