Results from a Pilot Human Trial of Senolytics versus Idiopathic Pulmonary Fibrosis

Researchers here report on results from an initial pilot trial of the use of a senolytic therapy to treat idiopathic pulmonary fibrosis. The data is perhaps much as expected for a first pass at removing senescent cells associated with a specific condition, using the tools available today: a starting point, benefits observed, but definitely room for improvement. The particular senolytic combination used here is cheap and readily available and can remove as much as half of senescent cells in some tissues in mice, but the degree of clearance varies widely by tissue type, and the optimal human dose is yet to be determined. Typically the next trial following an initial feasibility study will test a range of doses.

The past few years of animal data have indicated that the inflammatory signaling of senescent cells, the senescence-associated secretory phenotype (SASP), plays an important role in producing and maintaining age-related fibrosis in multiple tissues, but may not be the only process involved. Fibrosis is an outcome of disarray in regenerative and tissue maintenance, in which scar-like connective tissue is laid down in place of correctly formed tissue. Organ function is degraded as a result. In the case of idiopathic pulmonary fibrosis death follows within a few years of diagnosis, as the lungs fail.

Cellular senescence is a key mechanism that drives age-related diseases, but has yet to be targeted therapeutically in humans. Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal cellular senescence-associated disease. Selectively ablating senescent cells using dasatinib plus quercetin (DQ) alleviates IPF-related dysfunction in bleomycin-administered mice.

A two-center, open-label study of intermittent DQ (D:100 mg/day, Q:1250 mg/day, three-days/week over three-weeks) was conducted in 14 participants with IPF to evaluate feasibility of implementing a senolytic intervention. The primary endpoints were retention rates and completion rates for planned clinical assessments. Secondary endpoints were safety and change in functional and reported health measures. Associations with the senescence-associated secretory phenotype (SASP) were explored.

The retention rate was 100% with no DQ discontinuation; planned clinical assessments were complete in 13 of the 14 participants. One serious adverse event was reported. Non-serious events were primarily mild-moderate, with respiratory symptoms (16 events), skin irritation/bruising (14 events), and gastrointestinal discomfort (12 events) being most frequent. Physical function evaluated as 6-minute walk distance, 4-minute gait speed, and chair-stands time was significantly and clinically-meaningfully improved. Pulmonary function, clinical chemistries, frailty index (FI-LAB), and reported health were unchanged. DQ effects on circulating SASP factors were inconclusive, but correlations were observed between change in function and change in SASP-related matrix-remodeling proteins, microRNAs, and pro-inflammatory cytokines.

IPF appears to be relentlessly progressive: in large IPF drug trials, no improvements in 6-minute walk distance have been observed in the placebo-control arms. Pulmonary function in this IPF patient population did not change during the course of this preliminary study. It is likely that in this pilot exploration, the follow-up period is too short and the sample size too modest to assess effects on long-term trajectories, especially in a complex chronic disease such as IPF. If resolution of pulmonary scarring and fibrosis does indeed occur, it may take considerable time after clearance of senescent cells from the lung.

Link: https://doi.org/10.1016/j.ebiom.2018.12.052

Comments

This study is a small step in the right direction. I am not sure that D+Q work well for the lungs , though. At least if taken orally. Dasatinib tends to be broken down by the liver, so the concentration going to the lungs might be too low. Of course it is a very preliminary step

Posted by: cuberat at January 7th, 2019 11:13 AM

Good enough for me. This month, I'll be contacting a number of oncologists that specialize in leukemia to see if any of them have the good will to give me an off-label Sprycel prescription. No luck calling around, even with the so-called Princeton Longevity Center.

Posted by: Tom Schaefer at January 7th, 2019 11:33 AM

I'm pinnig my hopes on fisetin as a current senolytic therapy. getting an off label prescription is like trying to win the lottery.

Posted by: scott emptage at January 7th, 2019 12:33 PM

I wouldn't take any strawberry-derived substance until the Health Ranger or someone else properly equipped did a mass spec look for pesticides and metals. Strawberries have been the most polluted crop in the USA. https://www.cnn.com/2017/03/08/health/dirty-dozen-2017/index.html

Never the less, when a clean option arrives at BulkSuppliments, I'll join you.

Posted by: Tom Schaefer at January 7th, 2019 12:59 PM

@Tom Schaefer drs best do a good source

Posted by: scott emptage at January 7th, 2019 1:28 PM

CD, Scott Emptage: You guys are the best!

Posted by: Tom Schaefer at January 7th, 2019 3:03 PM

@Tom Schaefer :))

Posted by: scott emptage at January 7th, 2019 4:07 PM

@scott emptage, come to Russia -- you can get almost everything without any prescription! ;-)

Posted by: Ariel at January 7th, 2019 5:14 PM

@Ariel sounds good. I have never known why you need a prescription in the first place. the reason for it? seems silly if you ask me. metformin is a prime example. I cant get that because I would have to badger a doctor to prescribe it for me just so I can obtain it legaly

Posted by: scott emptage at January 7th, 2019 6:41 PM

@scott emptage - You may have trouble getting off-label prescriptions, but not everyone does - For example, physician assistants, MDs and their friends and families, many lab workers, wealthy persons, … either can get prescriptions, or just buy whatever they need. Unfortunately, other are stuck with a parent-child relationship with their health care providers.

Posted by: L Pagnucco at January 8th, 2019 1:17 AM

@scott emptage the reason we have prescriptions is to stop people who don't know what they are doing taking drugs and harming themselves. Also if you want Metformin just important it, it isn't illegal to import for personal use in the UK.

Posted by: Steve Hill at January 8th, 2019 7:11 AM

From: Tom Schaefer
Sent: Monday, January 7, 2019 2:49 PM
To: CommissionerFDA@fda.hhs.gov
Cc: carol.torgan@nih.gov
Subject: Approve Dasatinib for Off-Label Treatment of Senescent Cells
Mon 1/7/2019, 2:49 PM
Dear Commissioner Gotlieb,

For the past 8 months, I have been undertaking 4-day water fasts to trigger autophagy and release stem cells. There is little doubt that Dasatinib (brand name Sprycel) combines with quercetin (a readily available herbal) to attack malfunctioning "senescent" cells, with the longevity research community now referring to the combination as "DQ". Do you know how hard, in fact nearly impossible your rules make it to get a doctor to prescribe Dasatinib off-label?

I sincerely request that the FDA put out an announcement stating that an exception is being made to your off-label rules in the case of Dasatinib. It is particularly outrageous that doctors in the research community can give prescriptions to themselves and their friends to rejuvenate themselves, but those of us without such connections must find far more expensive alternatives. As for me, I will be traveling to Russia this summer to obtain and use Dasatinib (over the counter) combined with quercetin during a 4-day fast. It is unfair to the "little people" like me, who you should support, that I have to pursue "medical tourism" to get state-of-the-art rejuvenation therapies.

Thank you,
Tom Schaefer

Posted by: Tom Schaefer at January 8th, 2019 7:27 AM

@Steve Hill thanks for explaining that, when it comes to trying to obtain medications it seems to be a very gray area

Posted by: scott emptage at January 8th, 2019 8:23 AM

@Tom Schaefer good work. I hope it goes down well

Posted by: scott emptage at January 8th, 2019 8:24 AM

@Tom,

My wife is from Russia (Siberia). Yes, it is amazing how easy you can get drugs there that is difficult to get here w/o a prescription. We are treated as ignorant citizens not able to make decisions for ourselves. What city do you plan to go to?

Posted by: Robert at January 8th, 2019 11:57 AM

@Tom Schaefer
how often do you do water fasts. What are the effects you experience (I did an 8 days fast in December, and apart of losing some weight, didn't feel much of a difference. )

As for fine your letter. You are not talking the same language as FDA. Their raison d'être is to keep the uninformed and gullible people from using over marketed treatments with unproven benefits and questionable safety. And since they have very a little tolerance for failures, they will tend to err on the forbidding side.
So let's see what dasatinib self-medication implies from their POV:
1) unproven benefit - (no finished doubleblind, randomized, yaddaydayda, human trials ) - checked
2) toxicity and dangerous side effects - checked
3) lawsuit liability - checked,

On top of that for the expensive medicine there might be some hidden financial implications like having special arrangement between the patent holder and the health provider.

sincerely yours,
Party Pooper

On another note, to have a critical mass of grassroot demand we need some minor but immediate cosmetic effect like reversing graying hair, skin wrinkles, or something like that. Even if such effects are present only in 20 % of the treated people then all the beaty practitioners will start using and abusing it FDA regulations be damned. For example sterodis in some states are quite illegal for sale and yet it is not that difficult to obtain them. (alas, probably still harder than meth).

Posted by: cuberat at January 8th, 2019 5:24 PM

@cuberat I use the Dr. Group 4 day water fast plan monthly. You can look him up on the web, where he advertises oxypowder pills to clean out the first couple of days. I'm sorry that I don't allow myself the luxury of feeling well very often, so I wouldn't know how these fasts make me feel. I'm constantly in recovery from workouts and at night am hungry and/or sore. I can't believe how inexpensive Planet Fitness is, and the manager & staff treat me like a friend. All this is penance for many years of bad habits, as I drop from 235 a year ago, 215 now, and on to 190 by the end of the year. LEV offers me the opportunity to have more kids, and if you knew how baby crazy I am, for a whole bunch of reasons including the survival of Western Civilization, you'd understand how much I'm ready to suffer to get there. I watch FightAging.org like a hawk for announcements that will up my odds of getting there.

Posted by: Tom Schaefer at January 9th, 2019 8:12 AM

Fisetin quite rapidly (ten times faster than TA65) removes wrinkles and smooths skin.

Posted by: SilverSeeker at April 29th, 2019 10:43 AM

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