4 replies to this topic

[Researchgrounded]

You may recall Michael's caution re: D&Q therapy @ thread https://www.longecit...red-supplement/ : 

 

 

Additionally, the results of a senescent cell ablation study by Dmitry Bulavin at Undoing Aging (I hope video will be up soon) scared the snot out of me; I am awaiting to read the paper and understand more before adopting any senolytic protocol (though fisetin, specifically, seems to be less hepatotoxic than other senolytics, and liver damage was the site of the horror in the Bulavin study).

 

 

Dr. Balavin's presentation @ Undoing Aging 2019 is now available online:

 

https://youtu.be/_JZNnmuczxA

 

 

Massive senolysis of LSEC's with replacement with collagen ( ie, fibrosis ) on a massive scale, and commensurate morbidity need to be reconciled with other D&Q protocols consistent with improvement in healthspan. 

 

Following the talk, Dr. Balavin suggested that apparent absence of these horrible consequences in the other D&Q protocols may not be differences in protocols, but that such concerning liver injury may have been overlooked.

 

Yet those other D&Q models have suggested overall less morbidity rather than vice-versa.

 

And on the flipside, liver pathology was reviewed here, https://www.nature.c...les/ncomms15691 "The grade of steatosis (0–3), disease activity, including semi-quantification of lobular inflammation and hepatocyte ballooning, and stage of fibrosis (0–4) were assessed [....and...] calculated for each biopsy," - somewhat but not entirely reassuring given the different model. 

 

Most concerning was that the pathology with periodic lifelong, early-onset senolysis was reproduced in his second model, utilizing a mid-life, hit-and-run senolytic approach.   

 

Looking forward to reviewing his forthcoming publication.

Edited by researchgrounded, 23 May 2020 - 12:50 AM.

[Florin]

The elimination of LSEC and endothelial senescent cells seemed to increase fibrosis in the liver and in endothelial tissue (which led to leaky tissues). There are a few possibilities that might help explain these results.

• Other senolytic protocols might not have eliminated the LSEC SCs. Bulavin claimed that INK-ATTAC probably didn't but he wasn't aware of the efficacy of any other senolytic protocol.
• Bulavin seemed to suggest that killing SCs released LDLs which then led to a vicious cycle of cellular senescence. So, perhaps the SCs of other mouse models lacked the quantity of LDLs needed to kickstart this cycle.
• Some healthy cells might need to be killed off along with the SCs to get the right kind regeneration going and avoid fibrosis.
• Balavin's experiment or that of the other senolytic researchers is fatally flawed in some way.

[kurt9]

It is known that the SASP from senescent cells is necessary feedback to your stem cells to make replacement cells. This we knew from over a year ago. This led me to believe that a mild or partial senolytic, like Fisetin, may be useful in certain cases. But a more effective senolytic like the D&Q may be overkill with deleterious effects. If you remove too many of the senescent cells, or too many in too short of time period, the stem cells do not get the feedback they need and the collagen fills in instead, thus causing the fibrosis as observed in this experiment.

 

What has become clear over the past few months is that senescent cell build up is part of the larger process. The elimination of such must also be done as part of a larger process.

[Florin]

It is known that the SASP from senescent cells is necessary feedback to your stem cells to make replacement cells. This we knew from over a year ago. This led me to believe that a mild or partial senolytic, like Fisetin, may be useful in certain cases. But a more effective senolytic like the D&Q may be overkill with deleterious effects. If you remove too many of the senescent cells, or too many in too short of time period, the stem cells do not get the feedback they need and the collagen fills in instead, thus causing the fibrosis as observed in this experiment.

According to Bulavin, whether a few or many SCs are killed makes no difference.
 

What has become clear over the past few months is that senescent cell build up is part of the larger process. The elimination of such must also be done as part of a larger process.

Most senolytic experiments have produced positive results just by killing off SCs and doing nothing else. As far as I know, only Bulavin has shown that bad stuff can happen.

Edited by Florin, 23 May 2020 - 07:02 PM.

[Researchgrounded]

Here we are:

https://www.scienced...550413120302412