Kill Senescent Cells Before They Kill You

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.

 

31 thoughts on “Kill Senescent Cells Before They Kill You

  1. Okay, I know there are people who’ve been using quercetin for years – are they better off than the public at large? It would be a wonderful thing if we could establish something like Consumer’s Report (does it still exist?) for supplements.
    I have to disagree on one point that I don’t know is minor or not – but p16INK4a which you refer to as preventing a cell from apoptosis doesn’t do that. It is a tumor suppressor gene that interacts with the cyclin system to slow down or halt cell division. A cell which has left the cell cycle is not a senescent cell – at least by the criteria of producing SASP (Senescence Associated Secretory Phenomenon- the production of inflammatory cytokines and chemokines, matrix disrupting enzymes) – it does not do so. It must be co-opted by NF-kB a transcription factor which directs SASP. NF-kB is induced by inflammatory factors- so we see loops arising here – as it is suspected (according to Judith
    Campisis) that senescent cells heavily contribute to the chronic systemic inflammation often found in the elderly – and is apparently a product of that environment as well.

    • I’ve been using EMIQ a few months….if someone would spring for the expense of sampling I’d be pleased to contribute blood specimens for the cause.

      Got research bucks?, spend ’em here in Canada! Our dollar could use the support (your Yankee dollar buys ~$1.40 Canadiac.)

      I’m ex-RN, I can hold to nearly any usual experimental protocol required. there are local data-hunter/gatherer outfits. Malatest, for one. They’ll do the paper work and arrange the needle pushes.

      I’m cool.

      Joe Hogan

  2. Hi Josh. You reversed the effects of the two drugs. Quercetin is the one that kills senescent cells in endothelial lining. The chemo drug is the one that works on fat cells. To me that is pretty exciting since we probably have a shot at figuring out a way to effectuate a Quercetin treatment in humans in a short timeframe, and endothelial and other body tissues are probably the most desirable targets.

  3. Senescent cells are probably just the crappiest 0.1% of the cells spectrum. Good that you can kill them, but the not so crappy, but slowly aging 99.9% still keep on killing you…

  4. According to the article they used 10Gy radiation to induce senescence. So they practically might have found the cure for radiation sickness, not aging.
    I guess isolating real aged senescence cells in large enough quantities to perform expression profiling could have been to expensive. Would be nice to see that study.

    • Though they seemed unaware of the senolytic potential, if any, of their therapies at the St. Petersburg Institute for Bioregulation and Geroprotectors, their #1 research topic was radiation poisoning.

      To protect submariners in leaky ass Soviet era ‘atomic’ subs., missile carriers/launchers all. Sailors died at 3x normal rate after a tour of duty. Not gonna’ get any volunteers with these sorry examples viewable in veterans hospitals.

      Sooo, chromatin damage is chromatin damage, regardless of source. different inputs, same output… rad damage, carcinogenesis, cross-linkage/alkylosing disorders. Shit, I should have started alphabetically. ‘Nuf said.

      Trying to rehab or otherwise protect the continued existence and poss. reproduction of these misfit cells is asking for trouble.

      If onion juice will kill ’em, drink it down! (eyes will water, but gosh is it good drinking! Mix with tequila, lime, chili powder and salt on the rim. I’m cool.

      But Isuras (Japan) product, EMIQ serves very well. Up to 40 better absorption than plain Q, 15-time greater AUC, and hits nice quick serum peak value in ~15 after swallowing the dose. One capsule about every 10 days.
      That therapuetic schedule is my own spawn: do it which ever way you wish (or not at all).

      My rationale is elsewhere, on _Greatest Anti-Aging News since Bottled Beer_, or something like that, by Doctor Mittledorf. two three days back.

      Catchya’lll later. Happy hunting, take no prisoners, all senescent cells must die. Soon.

      JHogan

  5. Spindler probably tested quercetin in a continous fashion and in a hormetic dosage (I don’t have full access to the mentioned article).
    However, this approach is NOT likely to result in killing senescent cells.

    For successfull life extension, SASP clearance should be done in a periodic high dose treatment, in alteration with telomere elongation!

    • Yessiree, Prometheus, my strategy exactly.

      I use periodic doses of EMIQ, by Isura Japan, a relatively inexpensive preparation of iso-quercetin along with a hand full of other senescent cell removal promoters.

      EMIQ (enzymaticly modified ISO-quercetin) provides a number of improvements in quercetins’ bioavailability. I trust single capsules taken about each 10 days for a year, then a dose or two or epithalon peptide to lengthen telomeres on the remaining non-senescent population will serve my purposes.

      And who knows what new therapies will emerge in the meantime? I’m watching!

      • Where have you found a safe source of epithalon peptide that is not strictly for research. What dose do you use? Is that injected subcutaneous or intravenously?

    • It certainly does not help that ALA transforms in the body to a two-thiol heavy metal chelator that crosses the blood brain barrier and goes deep intracellular. It might well be that they drained these poor mice of critical minerals like copper by chelating them intracellularly.

      Josh, your “Leave a Reply” feature doesn’t work well under Google Chrome. Most of the time it doesn’t recognize password, and your name email and website field tags are overlaying on top of the field values so you cannot read them.

  6. The study indicated they dosed the mice once with quercetin and they had many months of benefit from that single dose.

    What is your substance of choice for telomerase activation?

    • epithalon peptide.

      I have no experience to report but have obtained a supply for use after I’ve done thirty or so cycles of SASP clearance with EMIQ.

      I expect I’ll be all cleaned up and ready for telomere lengthening in about a year.

  7. In vitro studies, consistently demonstrated quercetin-related mutagenicity. So, the approach to the use of quercetin in the clinic must be extremely cautious. http://nutritionreviews.oxfordjournals.org/content/72/11/720.abstract
    A very promising is gene therapy using an extra copy of the gene “azot” (ahuizotl) – a gene that destroys unhealthy cells. By inserting a third copy of this gene into genom of Drosophila melanogaster, the researchers were able to select better cells more efficiently. The consequences of this improved cell quality control mechanism were, “very exciting” – the flies appeared to maintain tissue health better, aged slower and had longer lifespans (50 – 60 % longer than normal flies). However, this research is still some way from being tested in mammals.
    http://www.cell.com/cell/abstract/S0092-8674(14)01587-6

  8. Research shows that 8 supplements that enhance apoptosis, each increase maximum lifespan by significant amounts.
    They are EGCG, quercetin, tumeric, lycopene, pomegranate extract, fisetin, genistein, and lupeol. Whatever other effects that each of these supplements have, the fact that they all have in common the enhancing of apoptosis suggest that removal of senescent cells is of great importance in slowing ageing.

    • Hi, Tom –
      I’m eager to learn more, but so far as I know the research isn’t so far along. I don’t know what EGCG is, but I know that quercetin has been found to shorten life span in mice. I believe that turmeric and lycopene have not been found to lengthen life span.
      The situation may be different for flies and worms. I’m not so quick to adopt medicines that don’t work in rodents, because there are so many that lengthen life span in flies and worms but that fail in mammals.
      – Josh

    • Tom wrote: “…8 supplements that enhance apoptosis, each increase maximum lifespan by significant amounts. They are EGCG, quercetin, tumeric (sp?-though this is a common mispelling resulting from labelling of turmeric by Baltimore-based McCormick & Company) , lycopene, pomegranate extract, fisetin, genistein, and lupeol.

      these compounds are among the agents I use ~q10days along with EMIQ. Good synergy, I hope!

  9. Pingback: Instapundit » Blog Archive » FASTER, PLEASE: In New Anti-Aging Strategy, Clearing Out Old Cells Increases Lifespan Of Mice By 25…

  10. Josh, our veteran formed , metformin research continues for the 4 volunteers here
    in the Ventura County . We have been testing Ptero-Pure, the synthetic vesion of
    pterostilbene, developed & human tested by the USDA at the U. of Mississippi, the
    same fabricator, in Irvine CA, makes the NAD+ precursor Niagen, we are all on that, as well. In recent weeks we have added quercetin to the caps cocktail mix. All feel well and have lost serious obesity poundage. In 5 months I dropped 45 lbs. My waist has slimmed down by 8 inches, mostly inside the visceral area. My A1C is now 5. ,having been 7.9 a year ago. We will gradually increase the intake of quercetin from the present 500 mg to 1000 by the year’s end. We are on VA blood
    panel periodc testing, all records are legit, and everything seems to be better for each of us. We do 2 fasting finger-sticks daily one at 8 hours and a second at 11 hours during the morning fast period. This gives us a little CR effect, as well. Our calorie regimen vary between the members. I’m trying for a 172 to 175 weight range, the others are trying for about 190. All of us were over 220 just 5 months ago.

    • It’s going to be so valuable to have actual lab results regarding blood values following quercetin use! I hope you can share these values as they clock in, or all at the end of the trial.
      I take no substances specifically for glucose control, but have noticed a marked lack of appetite since starting mitochondria active agents.
      Best of luck, O warrior patients!
      Thank you for your ongoing benefit to the wider society!

      Joe/USMC “brat”-
      Pendleton, Kaneohe, Quantico, Fallbrook NWS

      Canadian since 1972

    • Mr. Silliphant, your work was with the legend of the ‘code talkers’?
      Oh, do I have a tale of Chosin to tell. My father was Osage, adopted into Keetoowah band (me, no blood quantum but adopted into the Delaware).

      • Jeez, Allan, I hope I’m not swamping you with requests for info… but this is for just an opinion:
        Do you think the smarmy character in SCTV, Guy Caballero may be a reference to Caballero Home Video?
        I was too young to get into a theatre to see _The Stewardess’_ way back in the day, but I sure do remember the splash 3-D movies made, pioneered by your work!
        Thanks again, dude!

        J.

  11. Life Extension Foundation believes that Vit. E (tocotrienals especially) will help clear senescent cells but are vague on dosages. However, LEF gives specific dosages for quercetin.

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