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A Relationship Between Senescence and Respiratory Infections

Old and young animals' immune reactions to respiratory illness are different.

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A study published in Aging Cell has shown that senescent cells impact the way that CD4 T cells differentiate into types and that senolytics can restore this differentiation to a more youthful one.

Not all T cells are the same

CD4 T cells, often known as helper T cells due to their recruitment and signaling functions [1], perform multiple functions in fighting infection. Age-related depletion of these cells has been linked to delayed recruitment of CD8 T cells [2] along with B cells and other immune cells in influenza [3].

These cells differentiate into other subtypes. CD4 T cells that become T helper 1 (Th1) cells secrete inflammatory factors such as TNF-alpha and IFN-gamma, encouraging the proliferation of CD8 cells that fight infection [4]. T helper 2 (Th2) cells secrete factors that bring immune cells to damaged sites and encourage healing [5]. Regulatory T cells (Treg) secrete IL-10 and IGF-beta, which modulate the immune response to protect against immune overactivation [6].

These normal processes, however, are stymied by senescent cells. Prior research has shown that chemokines and cytokines change with age, harming the way that CD4 T cells differentiate [7]. While prior research has shown that senescent cells sometimes prevent the normal process of clearance by secreting IL6 and IL8 [8] as part of the senescence-associated secretory phenotype (SASP), the full effects of these cells on the immune system have not yet been eludicated.

In this study, the researchers sought to determine the existence of a causal relationship between this altered intercellular communication and the effects of cellular senescence, linking together two of the hallmarks of aging.

Influenza as a tool

The researchers used a mouse model of influenza infection and examined the CD4 cells present at 5, 7, and 9 days after the infection. The results were significantly different between young (2-3 months) and aged (19-22 months) mice, particularly on day 7. On that day, aged mice had substantially greater amounts of Treg cells, as measured by the biomarker FoxP3.

On the other hand, biomarkers of T helper 2 cells were substantially greater in younger mice. The researchers note that these cells are significant in immune resolution and a return to homeostasis after infection.

The relationship to senescence

This study has found that the cytokine TGF-beta is the driver of the increased Treg differentiation, and the researchers confirmed its effects by administering antibodies against it. Surprisingly, the researchers also found that albumin in the lungs, a marker of damage, is also decreased with anti-TGF-beta antibodies, suggesting that these excessive numbers of Tregs are themselves causing damage.

Old mice express substantially more of this cytokine than young mice in the lungs during infection, and the researchers hypothesized that this is due to excessive numbers of senescent cells. They tested this hypothesis by administering the well-known senolytic combination of dasatinib and quercetin (D+Q) to aged mice at approximately 20 days and 6 days prior to influenza infection.

The results were clear. Mice treated with D+Q had nearly no TGF-beta, and they had far fewer Treg cells than the control group. The treatment group also enjoyed substantially higher numbers of Th2 cells, similar to those of young mice.

The researchers even found this to be true when cells were taken from young mice and administered to older animals, thus exposing them to the SASP. Whether the cells’ origin was young or old, they differentiated more into Th2 cells and less into Treg cells when their older recipient was given senolytics.

Conclusion

The researchers conclude their study with the usual caveats about correlation. Given that D+Q are generally cleared within five days, it is unlikely that they were having direct, off-target effects on the T cells themselves. They also were unable to measure senescent cells and the effects of the SASP in lung tissue. Therefore, they were unable to conclusively prove the biochemical link between senolytics, the SASP, and T cell differentiation in any given mouse.

However, with that in mind, these results are certainly strongly suggestive of a causal relationship, and the researchers look forward to the answers to many additional, related questions as progress in this field continues.

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Literature

[1] Luckheeram, R. V., Zhou, R., Verma, A. D., & Xia, B. (2012). CD4+ T cells: differentiation and functions. Clinical and developmental immunology, 2012.

[2] Riberdy, J. M., Christensen, J. P., Branum, K., & Doherty, P. C. (2000). Diminished primary and secondary influenza virus-specific CD8+ T-cell responses in CD4-depleted Ig-/- mice. Journal of virology, 74(20), 9762-9765.

[3] Lefebvre, J. S., Masters, A. R., Hopkins, J. W., & Haynes, L. (2016). Age-related impairment of humoral response to influenza is associated with changes in antigen specific T follicular helper cell responses. Scientific reports, 6(1), 1-14.

[4] Strutt, T. M., McKinstry, K. K., Marshall, N. B., Vong, A. M., Dutton, R. W., & Swain, S. L. (2013). Multipronged CD 4+ T-cell effector and memory responses cooperate to provide potent immunity against respiratory virus. Immunological reviews, 255(1), 149-164.

[5] Gieseck, R. L., Wilson, M. S., & Wynn, T. A. (2018). Type 2 immunity in tissue repair and fibrosis. Nature Reviews Immunology, 18(1), 62-76.

[6] Okeke, E. B., & Uzonna, J. E. (2019). The pivotal role of regulatory T cells in the regulation of innate immune cells. Frontiers in immunology, 10, 680.

[7] Lefebvre, J. S., Lorenzo, E. C., Masters, A. R., Hopkins, J. W., Eaton, S. M., Smiley, S. T., & Haynes, L. (2016). Vaccine efficacy and T helper cell differentiation change with aging. Oncotarget, 7(23), 33581.

[8] Rodier, J. C. C. P. F., & Goldstein, Y. S. D. M. J. (2008). Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol, 6(12), 2853-2868.

About the author
Josh Conway

Josh Conway

Josh is a professional editor and is responsible for editing our articles before they become available to the public as well as moderating our Discord server. He is also a programmer, long-time supporter of anti-aging medicine, and avid player of the strange game called “real life.” Living in the center of the northern prairie, Josh enjoys long bike rides before the blizzards hit.
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