My Turn: Unlocking the senolytics puzzle

For the Monitor
Published: 8/11/2021 6:00:08 AM

In the back of the telomere lab cell-culture room, in the oldest incubator, I had a pet dish of senescent cells for years.

I was never able to teach them any tricks (well, they would stain blue for P16, but they can only do that trick once), but they did have the advantage of being really easy to care for, since they never divide, never outgrow their dish and don’t have to be re-plated. Just give them 10 ml of new media every week and talk to them (they need high CO2 levels).

Cells go senescent for several reasons. My little slacker BJ fibroblasts had gone senescent from telomere shortening, divided too many times in the ruthless quest for grad students to publish their papers. When a telomere becomes too short to protect its chromosome end from fusing with others, the cell detects the impending disaster and goes senescent. It stops dividing, swells to several times its normal size, and in many cell types, starts secreting a pro-inflammation toxic mix that can drive the neighboring cells into senescence as well.

This apparently self-destructive behavior is actually a useful anti-cancer mechanism for us, at first. But as life goes on, the senescent cells accumulate and eventually these pro-inflammatory secretions raise the whole body’s inflammation level, exacerbating arthritis and other autoimmune diseases.

The senescent cells also take up space and don’t perform their cell types’ normal functions, so over time they become a health hazard in themselves. This could be why recent experiments in extending rodent lifespans by diluting old blood with inert albumin work. They are removing the senescent secretions.

Just a few years ago, it was discovered that it is possible to selectively remove these deadweight cells. The first successful senolytic mix was a combo of Dasatinib (a cancer drug) and Quercetin, a common flavonoid in fruits. Further experiments revealed less toxic chemicals work even better.

One of the most effective is Fisetin, a flavonoid found in strawberries. A lifetime’s accumulation of senescent cells can be removed by a few two-day Fisetin doses. Unfortunately, you would need to eat about 20 pounds of strawberries in one sitting to reach the needed 20 mg/kg. Probably best not to try that even at a pick-your-own farm.

Removing senescent cells from mice resulted in an average lifespan increase of 36%, according to a 2018 paper. These results replicated in other labs using other senolytics. Human trials quickly followed.

According to Mayo’s Dr. Kirkland, as of 2020, there were clinical trials starting up on senolytics for diabetes, idiopathic pulmonary fibrosis, Alzheimer’s disease, COVID‐19, osteoarthritis, osteoporosis, eye diseases, bone marrow transplant and childhood cancer survivors. Recently coronavirus was added to that list, as it is expected that reducing overall excess inflammation of old age will protect against the Cytokine storm that kills many coronavirus patients.

If senolytics work as well on humans as they do on Pinky and the Brain, then medicine and society are in for a happy upheaval. Most autoimmune suffering would be reduced, healthspan, in general, would be extended for a decade or two, and coronaviruses would be less lethal. And all from an inexpensive molecule from strawberries that only has to be taken occasionally to wipe out a lifetime of accumulated dysfunctional cells.

The history of research has quite thoroughly demonstrated that medical results in mice don’t always translate into humans, of course. Mice don’t even turn off their telomerase in their somatic cells, making them a terrible model organism for a lot of human diseases. Killing all the senescent cells in a 90-year-old human at the same time might be too much of a good thing. Different cell types may need different senolytics. And there are always the “unknown unknowns.”

However, senolytic trials are inherently short. If a senolytic works, it clears out the accumulated cells quickly and the senescence-protein markers in the blood should drop abruptly. We should have the results from some of the Mayo Fisetin trials soon (one of them completed in July 2021). Anyone with an aging-related disease (i.e., everyone) should be following this field closely.

(Bill Walker recently retired from medical-imaging database company M2S to spend his time following advances in science and regressions in political economy. He lives in Plainfield.)




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