Clearing ‘zombie’ senescent cells

Interview with Paul Robbins

Aging is arguably the leading risk factor for chronic diseases in the modern world. We have historically thought of aging as an inexorable decline of function, driven by the passage of time – something that we simply have to accept, and that cannot be changed.

But what if aging were actually a modifiable risk factor?

Your chronological age, meaning the length of time that you have been alive, obviously cannot be changed. But we know that biological aging can vary significantly, even among individuals who are of similar chronological age. If we can better understand the fundamental mechanisms that underlie biological aging, we might be able to devise interventions that could prevent or delay age-related diseases.

One of the relevant processes is cellular senescence. Cellular senescence is a phenomenon through which normal cells irreversibly cease to divide in response to genomic damage. Senescent cells accumulate in the body as we get older, and they actually do a lot of bad stuff in the body. Senescent cells secrete pro-inflammatory factors, like cytokines, which induces a state of chronic low-grade inflammation. But it gets even worse. These senescent cells can also drive other healthy neighboring cells into senescence. So senescent cells are basically microscopic zombies!

This has driven interest in identifying senolytics – compounds that can selectively kill senescent cells (while leaving normal cells alone).

In this episode of humanOS Radio, Dan talks to Paul Robbins. Paul is the principal investigator at the Robbins Lab at Scripps Research Institute. Notably, his lab has been screening for drugs that can safely and effectively clear out senescent cells.

This research has produced some remarkable results in animal models. For example, he and colleagues found that older mice that were given senolytics became faster and stronger, and experienced a 36% increased median post-treatment lifespan, compared to a control group.


Senotherapeutics for healthy ageing

Excerpt

One current tactic to provide evidence that a compound has senolytic activity is the ‘hit-and-run’ approach, for example, the one-time treatment of mice with dasatinib and quercetin following hind-leg irradiation3. Here, a single administration of dasatinib plus quercetin yielded a therapeutic benefit that endured for months in terms of treadmill performance, consistent with a senolytic mechanism in which disease-causing cells are killed.

In general, if a short course of treatment yields a sustained reduction in senescence, it is likely acting in a senolytic manner. In contrast, if chronic treatment is needed to suppress senescence markers or prevent secondary senescence, this is more consistent with senomorphic activity.

However, more refined approaches are needed to rapidly demonstrate senolytic activity in vivo. Likely combinations of approaches may be necessary. For example, if a drug kills senescent endothelial cells, it could yield a health dividend, but it will be very difficult to document a reduction in the expression of senescence markers specifically in the endothelium without sophisticated reporter systems.