Senolytics ⇒ Paper questions senolytic use due to telomeres

[rhett]

http://www.lidsen.com/journals/geriatri ... -03-01-034

Histological considerations suggest that senolytics will accelerate age-related disease in affected tissues. In a sense, this would be parallel to the known effects of radiation, which can induce cell senescence and reduce stem cell availability [49]. In the case of senolytics, the removal of senescent cells would accelerate stem cell division and consequent cell senescence, inducing premature cell and tissue aging, with subsequent acceleration of age-related clinical disease.

Basically, this paper suggests that senolytics on their own clear the damaged cells, then cause increased cell division to replace those cells. But in aged individuals or those with chronic disease, these new cells telomeres may be so short that the new cells will become senescent quicker than they would have if they hadn’t divided early, causing an acceleration of senescent cells.

I have no idea about the validity of this but thought it was important to bring up for discussion.

[NewLifeScience]

Thank you for posting this Rhett.

It bears some thinking. For example, I wonder if senolytics in combination with NAD+ precursors will behave differently or more selectively.

Also i wonder if some senolytics like Fisetin, or more selective.

The senolytics they list seem to be very targeted types: AP20187 [27], ABT263 [31], INK-ATTAC [29], ABT-263 [32], FOXO4 peptide [33], UBX0101 and UBX1967 [34],

I wonder if anyone has any deeper insight.

[jessicaP]

I read an interview with a Dr. Michael Fossel about this topic. He is also the author of the cited work in the original post.

I try to follow his arguments.. and he mentions citations - but (and I would like to see what Fred has to say) his agenda is obvious and i think he is muddying the waters. It's almost like he is trying to imply his research on telomere trumps any benefit Senolytics confer, and implies that their elimination of senescent cells does more harm than good.

When presented with studies to the contrary, he uses analogies (orchestras, factory workers) or he claims that the damaging consequences later in time.

In this interview, he is trying to obliterate any senolytic therapies as a good idea. That's pretty heavy duty.

I wonder what studies can be cited to either support his contentions or rebuff them.

https://www.lifespan.io/news/are-senoly ... longevity/

[jessicaP]

This guy is definitely going after senolytics. I think his article is disingenuine.

Actually, there are 2 things. He is going after senolytics, and promoting Telomerase gene therapy, which is his baby.

He cites studies that are general positive toward senolytics, then presents his criticism of them with analogies and diagrams, but i don't see citations for several of his statements.

Am I missing something here?

I hope we can really look into this, this merits an investigation.

[smokinjoe]

I have read both articles... one is laid out like an interview, but with all those citations, it looks like it was an interview done on paper over time.

I think Dr. Fossel has made statements that he does not match with citations when he makes a claim about what can happen in the longer term with patients who have been treated with some success, i.e. that they may suffer further harm later on from senolytic therapy.

The study in question was states to show promising results:

...dasatinib and quercetin pilot study with 14 idiopathic pulmonary fibrosis (IPF) patients, a prelude to phase 1 clinical trials. Their team is already testing the same treatment on 15 lung cancer patients and planning a similar study on 20 kidney disease patients.

https://www.lifespan.io/human-pilot-stu ... 34bac59914

[jocko6889]

Dasatinib is a chemotherapy drug, so I wouldn't be surprised if it caused some methylation on the epigenome, like smoking or x-rays. Fisetin however is a natural substance that is a senolytic shown to be extremely safe. All of these are still in human trials, so it's too soon to know for sure the positive/negative benefits.

[jessicaP]

Dasatinib is a chemotherapy drug, so I wouldn't be surprised if it caused some methylation on the epigenome, like smoking or x-rays. Fisetin however is a natural substance that is a senolytic shown to be extremely safe. All of these are still in human trials, so it's too soon to know for sure the positive/negative benefits.

I hear you, but this Dr. Fossel (originator of both articles) seems to be going after all Senolytics and implies they accelerate aging and are dangerous.

Then he touts Telomerase gene therapy as the proper approach.

I wish i had the head to really trace the citations and sources.. but he really doesn't pack his work with citations with strong evidence that senolytics are dangerous OR that Telomerase gene therapy is so great for the body.

I would love to be corrected, one way or the other, but this article irks me.

[jocko6889]

Those that seemed excited by Quercetin + Dasatnib, looks like it's not all it seems...

"Based on the current state of evidence, the beneficial effects of D+Q seem to be extremely limited in humans."

"Therefore, until there are more published results showing benefits in humans, a clearer picture of the senolytic-use specific risk profile, and a consensus on the treatment protocol, we will avoid the use of D+Q senolytic therapy."

[https://brain.forever-healthy.org/displ ... ic+Therapy](https://brain.forever-healthy.org/displ ... ic+Therapy)

[canadahealthy]

Those that seemed excited by Quercetin + Dasatnib, looks like it's not all it seems...

"Based on the current state of evidence, the beneficial effects of D+Q seem to be extremely limited in humans."

"Therefore, until there are more published results showing benefits in humans, a clearer picture of the senolytic-use specific risk profile, and a consensus on the treatment protocol, we will avoid the use of D+Q senolytic therapy."

[https://brain.forever-healthy.org/displ ... ic+Therapy](https://brain.forever-healthy.org/displ ... ic+Therapy)

The issue (for some commenters) is the dismissal of ALL SENOLYTICS and the advocacy of Telomere Gene Therapy in a manner that does not appear to stand up to scrutiny.

I guess we have lost Fred, that is too bad, I would guess he would have had some unique insight about this topic, or perhaps even this Dr. Fossel and his therapy.

[drkris69]

Has Fred left the group?