Kill Senescent Cells Before They Kill You

cells aging

Several readers have asked me to comment on the press release and preprint that came out of the Mayo Clinic this week.  Researchers searched for ways to eliminate cells in the body that have become senescent and destructive.  Their tests in cell cultures and in genetically-modified mice turned up two substances, one natural and cheap, the other patented and dear.  I think theirs is a promising approach, and will soon offer substantial life extension in humans with minimal side-effects, but my guess is that the particular cocktail they have found will be left in the dust.

Here’s the Theory

Our stem cells divide through a lifetime, renewing our muscles, blood vessels, and especially skin and blood cells that turn over rapidly.  But in the process, chromosomes in those stem cells lose their telomeres.  When its chromosomes have telomeres that are too short, a cell becomes “senescent.”  Senescent cells are not just sluggish and moribund, they actually poison the nearby tissue (creating more senescent cells) and poison the body with chemical signals (cytokines) that fan the flames of inflam-aging.  This is called SASP, for “senescent-associated secretory phenotype”.  A tiny number of senescent cells can do a great deal of damage.

Would we be better off without senescent cells?  It was the insight of the Mayo Clinic’s Jan van Deursen to ask this question with an experiment four years ago.  He genetically modified mice in such a way that senescent cells had a bomb and a trigger attached.  By feeding the mice a molecule that matched the trigger, he could cause the senescent cells to self-destruct, leaving normal cells intact.  He did a controlled experiment, comparing the same genetically-modified mice, with and without pulling the trigger.  The result was eye-popping life extension in the mice that had their senescent cells removed.  20 to 25% increase in life span from a single treatment, fairly late in life [ref].

Just a decade ago, such discoveries would remain languishing in the lab for a maddeningly-long time.  But it is a sign of the times that venture capital and even Big Pharma are investing in longevity science.  Van Deursen’s discovery was quickly seized by half a dozen different labs around the world (including a for-profit spinoff by van Deursen himself).  What they are looking for is a drug that will attack the 0.01% of senescent cells while leaving 99.99% of non-senescent cells unharmed.

 

The Research Strategy

The research group at Mayo/Scripps started with gene expression profiles for senescent cells, comparing them to profiles for non-senescent cells.  This was used to identify targets for the drug.  Van Deursen had used p16 to identify senescent cells.  P16 is a gene that keeps senescent cells alive when they really should be eliminating themselves.  The Mayo/Scripps team identified several other drug targets, but did not use p16.  They used RNA interference to silence these genes, one at a time, to help identify effective strategies for differentially targeting the senescers.  Then they screened 46 compounds to see which would best attack the targets they had identified.

The result was two drugs: quercetin seemed to work best for endothelial cells (in arteries), and dasatinib was best for fat stem cells.  Quercetin is cheap and found in many herbs and berries; dasanatib is a patented chemotherapy agent, sold for a scandalously high price by Bristol Myers Squib.  The team tested the combination Q+D for short-term health effects in mice, and found encouraging results.

Q + D

Quercetin is a common flavonoid, polycyclic, found in black currents, cilanthro, red onion, watercress, cranberries, and smaller amounts in many fruits and herbs.  It is an anti-oxidant, but you know I’m not much impressed by that. Though it is natural, it is a mutagen, which means it breaks DNA. Substances like this would never be approved by the FDA, if they had to be approved by the FDA, but they don’t because they escape regulation as GRAS — “generally recognized as safe”.  This is not to damn the stuff–many toxins have a beneficial effect in small doses.  This is hormesis, a paradoxical but common and well-documented fact of longevity science.

But in the case of quercetin, it has been tried in longevity tests with mammals, and the results are not promising.  In 1982, the first published study showed no life extension, and perhaps a slight shortening of life span in male mice. Stephen Spindler, our reality check for life extension claims, found that quercetin had zero effect on mouse life span in a 2013 study.

Dasatinib is a chemotherapy agent, sold by Bristol-Myers Squibb as Sprycel at thousands of dollars per dose for treatment of leukemia.   Dasaitinib has been tested for toxicity but never for life extension.

 

To put this in perspective…

The gold standard for a life extension drug is that it works to extend life span in rodents.  That’s because it’s too easy to extend life span in simpler lab models like worms and flies, but tests in humans overtax our patience.  Even for mice, the test requires three years and hundreds of thousands of dollars, so researchers are motivated to screen different compounds with tests that can be done in a petri dish, or with short-term studies of physiological changes in live mice.  This is exactly what the Mayo/Scripps team did, and it should have yielded good candidates for life extension drugs.  But the result was a “good candidate” that had already been tried, and didn’t do so well.

The reason that short-term benefits to the metabolism are not a good indicator of what might increase longevity is that body chemistry is complicated.  Life span is tightly regulated, with a mind of its own.  Some substances have short-term benefits, and the body over-compensates with a shorter life span.  Anti-oxidants are a good example.  Other substances do short-term damage, and again the body over-compensates and the result is a longer life span.  Look at the way paraquat affects life span in worms!

 

The Bottom Line

I’m betting that the search for strategies that differentially kill senescent cells will soon lead to better drugs than quercetin or dasatinib.

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This article originally appeared here, republished with permission.