We wanted to draw your attention to a new publication by James Kirkland and his team. Kirkland is one of the pioneers of senolytics, as he demonstrated that a combination of compounds could remove senescent cells and improve healthspan in mice back in 2015 [1].

The contribution of senescent cells to aging has been the subject of intense research in the last year or two, as researchers have focused on ways to remove these problem cells using therapies known as senolytics.

Senescent cells are bad news for healthy tissue

Here, the researchers demonstrate just how harmful senescent cells are and that it only requires a small amount of them to be present in tissue to cause other healthy cells to also become senescent. This is sometimes called the ‘bystander effect’ and shows the result of the harmful proinflammatory cocktail known as the senescence-associated secretory phenotype (SASP), which is formed by signals from senescent cells.

In the study, the research team transplanted small numbers of senescent cells into young mice, which led to harmful changes to the healthy tissue and to physical dysfunction. They observed that once transplanted, the bystander effect took place and caused otherwise healthy cells in the tissue to also become senescent.







They did the same with older mice, transplanting even fewer senescent cells and observing a similar level of harmful changes. The researchers observed that the mice had lower survival rates and that senescent cells shortened both healthspan and lifespan when transplanted into mice.

Finally, they showed that removing these senescent cells using a combination of dasatinib and quercetin was able to reduce the number of senescent cells present in tissue via their selective elimination. This worked for mice with transplanted senescent cells as well as naturally aged mice. The SASP present in the mice was reduced, thus relieving the physical dysfunction that the mice experienced due to these senescent cells. Survival also increased by 36% following treatment and reduced mortality risk by a significant amount.

Abstract Physical function declines in old age, portending disability, increased health expenditures, and mortality. Cellular senescence, leading to tissue dysfunction, may contribute to these consequences of aging, but whether senescence can directly drive age-related pathology and be therapeutically targeted is still unclear. Here we demonstrate that transplanting relatively small numbers of senescent cells into young mice is sufficient to cause persistent physical dysfunction, as well as to spread cellular senescence to host tissues. Transplanting even fewer senescent cells had the same effect in older recipients and was accompanied by reduced survival, indicating the potency of senescent cells in shortening health- and lifespan. The senolytic cocktail, dasatinib plus quercetin, which causes selective elimination of senescent cells, decreased the number of naturally occurring senescent cells and their secretion of frailty-related proinflammatory cytokines in explants of human adipose tissue. Moreover, intermittent oral administration of senolytics to both senescent cell–transplanted young mice and naturally aged mice alleviated physical dysfunction and increased post-treatment survival by 36% while reducing mortality hazard to 65%. Our study provides proof-of-concept evidence that senescent cells can cause physical dysfunction and decreased survival even in young mice, while senolytics can enhance remaining health- and lifespan in old mice.

Conclusion

This is yet more support for the approach of removing senescent cells to improve healthspan and potentially lifespan. While this is only demonstrated here in mice, the good news is that senolytic therapies are now poised to enter human trials any day now via UNITY Biotechnology, and there are a number of other companies and therapies close behind. The field of senolytics is set to be a place of fierce competition, and that can only be a good thing to drive prices down and improve access in the coming years.

Literature







[1] Zhu, Y., Tchkonia, T., Pirtskhalava, T., Gower, A. C., Ding, H., Giorgadze, N., … & O’hara, S. P. (2015). The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging cell, 14(4), 644-658.

[2] Senolytics improve physical function and increase lifespan in old age, Nature Medicine (2018). DOI: 10.1038/s41591-018-0092-9