May 28, 2019

The Best New Senolytic Isn't a Drug...or New For That Matter.

Some of the hundreds of anti-aging treatments I've tried.
In the last 20 years I've spent an ungodly sum of money on the most promising anti-aging treatments available.  From visits to Ray Kurzweil and Dr. Terry Grossman's Colorado longevity clinic, consults with leading longevity experts, and dozens of different supplements, pharmaceuticals, therapies, and treatments; I've tried them all.  However promising, I continue to take only a handful of the hundreds of longevity remedies I've tested.

In the past I've been really enthusiastic about a few developments (and I continue to be confident in metformin, rapamycin, and telomerase activators), but never once have I written about any of them.  That is, until now.

I'm writing today because I've found an anti-aging treatment that may not only slow, but in some ways reverse the effects aging.  What's more incredible: this treatment is already available, cheap, and likely very safe (probably side effect free).

The treatment?  It's a flavonoid called fisetin.

If you're like me, you're immediately prejudice to the idea that a food derivative (derived from fruit, like strawberries) could do anything to actually move the line in slowing or reversing some of aging's deleterious effects.  You probably figure, as you should, that if it was effective, we'd have figured it out long ago.

That sort of thinking is almost always right.  In this instance, however, it looks like most everyone (of the very few who've taken fisetin with any discipline) were taking far too small a dose to experience any of its anti-aging benefits.

I'll come back to that.

For those interested, fisetin works as a "senolytic", meaning it works to induce death in senescent cells.

A senescent cell is one that's stopped dividing but hasn't undergone apoptosis (programmed cell death).  These zombie-like cells accumulate throughout our body as we age, and secrete toxic, proinflammatory signals that kill nearby cells.  More senescent cells create more senescent cells; a vicious cycle that's believed to contribute significantly to aging.

The understanding of how senescent cells contribute to aging is still relatively new, but it's already mobilized an enormous amount of capital and effort in the pharmaceutical space among those who wish to be the first to discover an effective senotherapeutic compound.

More intriguing is the recently discovered possibility that nature may have beaten pharma to it.  By that I mean, until just a handful of months ago, the most promising senolytic candidates were drugs (with the leading candidate being a combination of the chemotherapeutic drug dasatinib and the supplement quercetin (D+Q).  Then, around early 2019, two significant discoveries were published.  One was a landmark study that trialed many different potential senolytics in animals and found them to meaningfully increase both lifespan and healthspan.  The other was the first ever drug trial of senolytics on humans.  In the human trial, the University of Texas tested D+Q and found it to work substantially better than the best available treatments for the deadly age-related disease idiopathic pulmonary fibrosis.

Even more intriguing was this study which trialed a number of senolytic candidates against D+Q.

The study in animals confirmed that senotherapeutics increased health and lifespan, but, more significantly, that the flavonoid fisetin was better than the most promising senolytic dasatinib + quercetin, but at (human equivalent) doses roughly 10X higher than the standard doses available for fisetin.

I'm pressed for time but have been meaning to get this information out there.  I'll circle back soon to fill in more detail around dosage and frequency (the prevailing belief is that a high-dose cycle of fisetin need not be daily, but instead should be ~5-day short-course therapies once every 3-5 months or so.  Until then, feel free to share any thoughts or questions you may have below.

Christian Hunter

2 comments :

  1. https://www.christianhunter.com/2019/05/best-new-senolytic.html

    Hi, Christian. You may by now have heard of the clinical trials of fisetin presently underway at the Mayo Clinic.

    https://clinicaltrials.gov/ct2/show/NCT03675724?term=fisetin&rank=1

    https://clinicaltrials.gov/ct2/show/NCT03430037?term=fisetin&rank=2

    Interestingly, these trials are using a significantly higher dose (20mg/kg) than would be implied by simply adjusting the mouse study below

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6197652/

    to a Human Equivalent Dose. And they only employ that higher dose for two consecutive days, not for five consecutive days, as in the mouse study.

    The mice in that study were fed 100mg/kg of fisetin daily for five days. Dividing by the usual 13.2 factor to get the human equivalent dose from the mouse dose, we would have about 7.6 mg/kg for humans. So, for a 70kg person, you would need about 500mg per day. Whereas, the Mayo clinical trials will be using 20mg/kg, which would be 1400mg per day of fisetin for that same person.

    I have not been able to ascertain exactly why they do not use the adjusted murine study dosing. But I'm *guessing* that the two day interval is based on the in vitro testing in which they found that senescent cells were killed off in 48 hours. And I'm *guessing* that the higher dose is what they estimate would be required to reach tissue levels in vivo that match those attained in the in vitro experiments.

    This blog post provides some interesting background information:

    https://scienceofparkinsons.com/2018/11/10/senolytics/

    ReplyDelete
  2. Tell everyone how you accepted $20 that was sent by mistake and your bastard ass wouldn't send it back. You rat bastard

    ReplyDelete

I check posts frequently and appreciate your input.

Christian Hunter
Santa Barbara, California

Christian Hunter's Twitter Latest