TLR5 Activation Improves Health and Lifespan in Aged Mice

The lifespan increase was substantial.


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By activating toll-like receptor 5, an important element of the innate immune system, scientists have increased lifespan and improved multiple health measurements in old mice, despite having started the treatment late in life [1].

TLRs and aging

The immune system gets dysregulated with age, driving multiple age-related conditions [2]. It is manifested in higher tumor prevalence, weaker response to vaccines and infections, and organism-wide sterile inflammation (inflammaging). Immunosenescence also contributes to metabolic and cardiovascular diseases, and frailty. This gradual process is complex, and numerous research teams are working on its various aspects.

One of those aspects is reduced activity of pathogen recognition receptors (PRR). As their name suggests, PRRs’ role is to recognize pathogens and mount an immune response. While PRRs are part of the innate immune system, their dysfunction also affects adaptive immunity, such as in less efficient presentation of antigens to T cells. This might be one of the reasons why older adults show less pronounced response to COVID vaccines. Various PRR-targeting adjuvants (complementing drugs) for vaccines have been explored.

Toll-like receptors (TLRs) are probably the most important PRRs, as they recognize pathogen-associated molecular patterns (PAMPs). TLRs’ activity is blunted by aging, causing diminished vaccine response [3]. In this new study published in Nature Communications, a group of scientists attempted to stimulate a subset of those receptors called TLR5 to alleviate age-related immunosenescence in mice.

Various TLRs are stimulated by different compounds. For TLR5, it’s flagellin, which is the principal protein in bacterial flagella, the tail-like filaments that bacteria use to move around. In their study, the researchers used flagellin fused with pneumococcal surface protein A. This combination, which they called FP, has already been used to improve immune response in mice, which unexpectedly led to some rejuvenation-like phenotypical changes. In this new study, the researchers’ intent was to explore this intriguing effect further.


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Rapamycin-like lifespan extension

The scientists used 21-month-old mice, which is roughly when age-related immunosenescence occurs in these animals. The mice were treated with FP intranasally for eight cycles. This increased lifespan in a sex-dependent manner, with female mice benefiting more. The results were remarkable, given how late in life the treatment began.

TLR Lifespan

Several aging-associated phenotypes were improved as well. The treatment led to an increase in bone density along with a decrease in hair loss and ocular opacity. The weight of the thymus increased too. This organ produces T cells and degenerates with age, which is thought to be an important cause of immunosenescence [4].

Marked improvements were also observed in brain glucose uptake and several behavioral tests. Treated mice showed increased scores in locomotor activity, nest building, novel object recognition, and passive avoidance tasks. The researchers contend that “the degree of health span and lifespan extension by FPNI is comparable to that of rapamycin, when administered starting at 600 days of age” [5].

Both pro- and anti-inflammatory

The researchers also tested FP versus a specific aging-associated disease: pulmonary fibrosis. In a mouse model of this disease caused by the antibiotic bleomycin, a single intranasal administration of FP greatly increased survival and decreased several inflammation markers.

TLR Fibrosis

FP treatment also seemed to preserve intestinal integrity, which is compromised in aged mice and humans. Treated animals consumed more calories than controls without gaining weight, which, according to the researchers, excludes caloric restriction as a possible cause of rejuvenation in treated mice. Both in the intestine and in several other organs, a significant decrease in several inflammation and senescence markers was observed.


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Interestingly, TLR5 activation seems to simultaneously boost immune response, which is needed to combat pathogens, and alleviate chronic age-related inflammation. “These findings”, the researchers note, “highlight the unique and diversified roles of TLR5, setting it apart from its proinflammatory counterparts and underscoring its potential in age-modulation interventions.”

This study illuminates the potential of TLR5 as a modulator of aging, necessitating extensive further research. It is imperative to validate the effects observed across diverse strains and elucidate the underlying mechanisms. … Understanding the detailed mechanisms by which TLR5 contributes to aging and age-related diseases can further aid in the identification of potential therapeutic targets. Our findings unveil the promising horizon of TLR5-centric interventions, setting the stage for future endeavors aiming at the development of novel therapeutic strategies and a deeper comprehension of aging mechanisms through the lens of immune modulation. The revelation of TLR5’s potential in this study underscores the necessity for continued exploration and refinement, ultimately contributing to the betterment of age-related health outcomes.

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[1] Lim, J.S., Jeon, E.J., Go, H.S. et al. (2024). Mucosal TLR5 activation controls healthspan and longevity. Nat Commun 15, 46.

[2] Wang, Y., Dong, C., Han, Y., Gu, Z., & Sun, C. (2022). Immunosenescence, aging and successful aging. Frontiers in immunology, 13, 942796.

[3] Panda, A., Qian, F., Mohanty, S., Van Duin, D., Newman, F. K., Zhang, L., … & Shaw, A. C. (2010). Age-associated decrease in TLR function in primary human dendritic cells predicts influenza vaccine response. The Journal of Immunology, 184(5), 2518-2527.

[4] Liang, Z., Dong, X., Zhang, Z., Zhang, Q., & Zhao, Y. (2022). Age-related thymic involution: Mechanisms and functional impact. Aging Cell, 21(8), e13671.


[5] Harrison, D. E., Strong, R., Sharp, Z. D., Nelson, J. F., Astle, C. M., Flurkey, K., … & Miller, R. A. (2009). Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. nature, 460(7253), 392-395.

About the author
Arkadi Mazin

Arkadi Mazin

Arkadi is a seasoned journalist and op-ed author with a passion for learning and exploration. His interests span from politics to science and philosophy. Having studied economics and international relations, he is particularly interested in the social aspects of longevity and life extension. He strongly believes that life extension is an achievable and noble goal that has yet to take its rightful place on the very top of our civilization’s agenda – a situation he is eager to change.