#274

I am not a believer in senolytics.

If you listen to the most recent Attia AMA, there’s a roundtable with Prof Miller (from ITP) and he summarizes nicely. He points out that senolytic drugs failed the ITP, at two different dosing methods (Astaxanthin and meclizine extend lifespan in UM-HET3 male mice; fisetin, SG1002 (hydrogen sulfide donor), dimethyl fumarate, mycophenolic acid, and 4-phenylbutyrate do not significantly affect lifespan in either sex at the doses and schedules used - PubMed).

Worse yet, when they sent tissue samples to the investigators who recommended fisetin, blinded, there was no difference in p16, SA-B-GAL, or any of the markers, in liver, brain etc. So it’s questionable whether they really work in the real world.

Additionally, “senescence” as a whole is insanely complicated, and seems to be a word like “cancer” where it encompasses hundreds of different phenotypes. In the lab, we sometimes induce senescence by treating cells with H2O2, or stressing them with UV. But I’m not exactly sure what that phenotype represents in human aging… IMO, not much.

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#275

Here are 2 studies in humans. Both of which had interesting results.

Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease.

https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(19)30591-2/fulltext

Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study

https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(18)30629-7/fulltext

And some news from the Mayo Clinic.
https://newsnetwork.mayoclinic.org/discussion/senolytic-drugs-boost-key-protective-protein/

Orally-active, clinically-translatable senolytics restore α-Klotho in mice and humans

https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(22)00096-2/fulltext

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#276

They’re definitely interesting, but both are pretty flawed studies to my eyes.

The first is open-label, no proper control group (i.e. it’s a before/after). And no mention of blinding the investigators. Counting positive cells in tissue slices is very subjective, and easily affected by bias, selecting whichever areas to count etc. I note that the only truly quantitative data (gene expression and plasma factors) is kinda hidden by using a heatmap and ranking things into percentiles. IME, that usually means when they simply plotted the numbers, there was no difference. Combine that with the conflicts of interest that the authors have patents on Senolytics drugs, and I become even more sceptical.

The pulmonary fibrosis paper is also very preliminary and again the results are kinda “buried”. 23/50 measured cytokines had correlations. Improvement on physical tests is quite interesting, but again the before/after nature of the experiment means there are many explanations. For example, at the “after” test, the subjects had a much better idea of what was expected, as they’ve done it before. This is common in sports literature, where placebo groups gain strength simple due to familiarity with the tests. A proper trial design can account for that, but obviously requires more resources.

I just have to come back to the ITP, if those mice were given senolytics for their entire life and the blinded samples from multiple organs were indistinguishable… I have to stay sceptical that a few weeks of these compounds would move the needle in humans. However, I will love to be proven wrong by a “proper” trial or a senolytic passing the ITP.

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#277

And that “for entire life” thing is going to prevent any measurable difference in any study. Why? if senescent cells are constantly eliminated, there is no change to measure. That is the basis of the Threshold Theory of Aging.

threshold_theory_of_senescence

The “problem” with senescence is that it does not apply to the young. It’s when you hit 60+ that it’s going to present as a contributor to a wide variety of conditions.

When one looks up various conditions with the word “senescence” added to the search string there are quite a few interesting results. > heart disease senescence <> dementia senescence <> cancer senescence <> just pick your favourite condition… :slight_smile:

If so many human conditions were not affected by senescence, I’d agree with you.

There is more to research than the ITP… as if that program was all that mattered in human science… sure mice are an interesting species but many things that work in mice do not work in humans and vice versa. So I’ll keep an open mind on senescence and the overall science that indicates it is harmful as we humans age.

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#278

Hi Steve, thanks for the thoughtful response. I don’t quite understand this comment. In the ITP there is a control group of mice - thus, if the old mice without drug and the old mice with drug have the same amount of P16+ cells, it implies the drug didn’t work. (Note that old mice in both groups had higher P16 and SA-B-GAL than young mice).

I do agree with you that this is just one drug (Iresin, in this case). SO there are two possibilities, I think:

  1. This specific drug didn’t actually kill senescence cells, and that’s why no lifespan extension. Maybe other drugs would work.

  2. The whole approach just doesn’t work, and/or doesn’t translate to lifespan

I absolutely agree that interesting findings come up when looking at certain organs. My own lab has done some of that research ourselves, on senescence and cardiovascular diseases. I believe there is something going on. As you say, this phenomenon does appear to be involved in many disease; but as I mentioned before, to me, “senescence” is a word a bit like “cancer” where it’s very challenging to define, let alone target.

For example, in the heart, cardiomyocytes in older mice have higher P16 expression, and knocking this down does seem to lower inflammation and result in better cardiac function after injury. A potential good drug is this one: Navitoclax - Wikipedia

However, that’s an acute injury setting, and I’m not sure about prophylactic use for longevity.

I agree that there’s more to research than the ITP, but it’s a damn good model using heterozygous mice, multiple sites etc. The problem is that most small studies are rife with bias. James Kirkland is the author of the two D+Q papers you mentioned, and he’s the one who suggested Iresin to the ITP. But his whole reputation, financial future etc is staked on showing that senolytics work. I’m not picking on him specifically, because this is a very human thing, but that’s why I value the ITP and the total unbiased approach it takes. I absolutely hope they test more senolytic drugs, and if they can actually show reduction of signature (P16, SA-B-GAL etc) cells, and extension of lifespan, I’ll be delighted to be wrong, and I’ll get on board with taking them!

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#279

When it comes to mice, I get that they are a decent screening process but how many times have mice and rats passed the test (what ever test that may be) and the ensuing human trials failed miserably?? Not only that but they are a poor reference system for toxicity.

Even here on this forum we often see “BUT this is in mice, lets see what it does in humans”
99% failure in AD research
Typically 80% or worse in other areas.
https://journals.sagepub.com/doi/10.1177/02611929231157756

When I reference “senescence” I’m more specifically talking about senescent cells, not the entire process of “aging” that is often referred to as “senescence” For me, it’s not like the generic “cancer” but more specifically the cells that become senescent and hang around past their due date :slight_smile:

I appreciate your position and commentary on this topic.

I also get Kirklands commitment to this area of research. One thing about committed researchers, quite often that is what it takes for breakthroughs. Dogged determination against the headwinds, Katalin Karikó, PhD is one recent example of that.

I’ll keep doing my zombie killing processes as there does not seem to be a downside. So far :slight_smile: Unlike our fav intervention here with respect to Rapamycin, which appears to have more risk and yet I continue to take 6mg every 2 weeks :slight_smile:

#280

Hedging my bets by taking rapamycin, which is already senomorphic. But otherwise, I’ve become more and more skeptical of the current crop of senolytics, especially after listening to the Attia roundtable.

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#281

Mice die primarily from cancer - 85-95%. Humans die primarily from heart disease.

I think you have to ponder the question “How much do senescent cells impact cancer?” If the answer is “A lot” then senolytics (as shown by the ITP) probably are not very useful. If the answer is “Not much” but very useful for cardiovascular health or maintaining healthspan in old age, then senolytics may be very useful to humans who do not die primarily from cancer.

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#282

Yours too. Thanks for the civil discussion. And absolutely, I support guys like Kirkland pursuing things, and hopefully we can have bigger, better, longer studies to really answer these things.

Honestly, a lot of this could be answered if we had a better method to measure whether the treatment is actually working. For example, I see your protocol mentioned earlier. If there was something you could track or measure that would be super exciting, even in the absence of lifespan data.

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#283

There is supposed to be a new test that is only available to health care practitioners.

As you noted, we did use a DNAm test from Trudignositc in an attempt to validate our little eval. Plus it is an easy to do at home test. My hope was those markers might be a proxy for overall SASP reduction, but I can’t prove that. Of the 4 that completed the program (not counting myself and my wife, we both improved over a 4 year span) all showed an improvement. What does that mean/indicate? who knows for sure…

Once I saw it “work” for strangers with no skin in the game, that was enough to give me a bit of hope :slight_smile: regardless of what was actually happening LoL! I’d really love to know;

  1. is it actually clearing senescent cells
  2. are the improvements due to this clearance

There are so many mouse studies on this that indicate a benefit but those are mice and I don’t always trust rodents :slight_smile: although they do “naturally” experience cellular senescence as opposed to the need to be genetically manipulated as is the case with AD research.

And then if a level of healthy senescence can be determined, and then maintained/iterated with judicious use of senolytics and testing to evaluate levels, my guess is probably not easily maintained as we age, due to the varied types and locations of SNC’s

The D+Q combo with our addition of Fisetin is limited in “reach”. That combo only appears to reduce senescent cells in adipose and endothelial tissues. One of those limitations.

Which is why we started doing cycles of FOX04-DRI in Dec.

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#284

senescence_affects

Something that has system wide effects on a wide variety of cells and process is probably not inconsequential. Regardless of what lifespan results in mice says…

Targeting senescence or delaying aging is emerging as a critical health strategy for solving age-related diseases, especially in the old population. In the current review, we will delineate the mechanisms of organ crosstalk in systemic aging and age-related diseases to provide therapeutic targets for delaying aging.

https://faseb.onlinelibrary.wiley.com/doi/abs/10.1096/fj.202402479RRR

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#285

Based on the following paper, an SGLT2I should be a part of senolytic therapies.

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#286

I’m using FOX04-DRI, highly diluted because it has a sting. Taking it with MOTS-c, as advised by Alek Kikel.

I pulled a muscle today, but I expect peptide therapy to minimize the damage. I’ve recently added epitalon spray, which does promote extended sleep, to my repertoire.

#287

I didn’t find that for me, and a friend who added Epitalon found the opposite effect.

I think the majority of people using this one do find the sleep benefit.

What dose are you using for Epit?

And what dose and schedule are you using for FOX04-DRI if you don’t mind me asking :slight_smile: I’m going to up my dose for our next cycle April 1.

April is when we will also do our next Trudiagnostic test. Too many people getting ahead of us on the Rejuvenation Olympics leader board LoL! Over 5700 participants there. Joan is just barely in top 10 and at 50 and I’m out of the top 200 at 206. Still pretty good out of 5700 :slight_smile: I think I may hook up with a Longevity Doc :slight_smile:

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#288

The spray provides 10 iu per nostril, which is in the microgram range. Whether it increases telomerse length or not, it is said to retard the aging process. Maybe we’re all regressing, and that’s why we sleep like a baby. Or maybe, as somebody else once said, we have one thought less each year.

I take the FOX04 on an EOD schedule. I started with an 18-g vial, which I first diluted with 3 ml of bac water. It wasn’t enough to mitigate the sharp, persistent pain. I gradually upped the diluent to 9 ml, which gives me 2 mg/ml, more or less.

I know you suggest a saline solution for your spray. Any reason you couldn’t use bac water?

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#289

No reason at all. From what I know about nasal sprays you could also use distilled water, I get that from Walmart, it’s dirt cheap :slight_smile: I use that in our skin care products so I don’t need to use a chelator.

I do prefer a bit of “bacteriostatic” property in a nasal spray though.

That may reduce the risk of contamination, possibly? I also wipe the nozzle before and after use. Ya never know what’s lurking up there and I don’t want it growing in my spray bottle of a month LoL!

The one big BUT with nasal sprays is test the pH. I’ve had a bad experience when I made our NAC+Bromelain nasal spray.

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#290

Bac water has alcohol in it so I imagine it would irritate your nose cavity VS the saline

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#291

That is a good point. In my Selank and Oxytocin spray use Saline 0.9% Bacteriostatic 10ml Vial- With Preservative and dilute it with 10ml distilled water and no issues. I have not tried to use it full strength.

I use a BAC version as 1 full spray bottle will last about 1 month for 2 people and I’m just a bit concerned about stability.

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#292

Yes, a little, but not bad.

#293

Somewhere in this thread there is a study on old mice that when treated with senolytics had a positive effect on their testosterone output.

I started FOX04-DRI the end of Dec 26, 2024 and did one 6 day cycle of 3mg per day.

I’ve had 2 recent testosterone tests Dec 6 2024 and Mar 21, 2025 and one back in May 31, 2021.

had a good increase before starting FOX04-DRI and another little bump up after.

No TRT, just peptides. The only confounding factor would be that I also started Gonadorelin early in December.

I would say that made a difference and that quite possibly the FOX04-DRI is helping as well to enable the “boys” to function better with the addition of Gonadorelin.

We will be doing another cycle of FOX04-DRI next week and upping the dose from 3mg per day x 6 days to 4mg per day x 6 days.

Overall I’m pretty happy with these results considering it’s my boys doing the work. I will be getting another Test - test done in 3 months :slight_smile:

Screenshot 2025-03-31 at 13-51-09 Dynacare Plus - My Lab Test Results
Screenshot 2025-03-31 at 13-51-09 Dynacare Plus - My Lab Test Results713×704 30.4 KB

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