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Most effective senolytics for vascular system senescence

senolytics senescence vascular enothelial

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#1 timedilation

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Posted 04 October 2021 - 03:59 PM


In my opinion, one of the most important factors in aging is the decline of the vascular/circulatory system over time.  The body has to sustain a huge but fragile network of large and small blood vessels to ensure the brain and other vital organs receive enough oxygen and nutrients to function.  This effort requires frequent angiogenesis, which involves the division of vascular endothelial cells, as well as supportive cells like pericytes, fibroblasts, MSCs, etc.  Over time, it seems unavoidable that these cells would start to hit Hayflick limits and enter senescence, which will worsen the vascular system and create a feedback loop of damage, division, and senescence.  This problem is probably even worse for biohackers, who experiment with many substances that upregulate angiogenesis.

 

If the above is correct, it means a vascular-targeted senolytic would be extremely useful/important.  So how much do we know about vascular senolytics?  Do any of the typical players like fisetin, quercetin, dasatnib, FOXO4-DRI, Navitoclax, etc., have strong effects on endothelial cells (or pericytes/fibroblasts/whatever)?



#2 Kentavr

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Posted 04 October 2021 - 06:22 PM

Senolytics have many limitations:

 

1. Quercetin is not a senolytic without dasatinib. Quercetin is a BCL-2 inhibitor, dasatinib is a Bcr-Abl inhibitor. To destroy a cell, you must use two ways at the same time. Read this article:

https://www.oncotarg...cle/28049/text/

 

2. If you have a lot of aging cells (for example, you are over 70 years old), then senolytics can harm you very much. Destroying too many senescent cells can irreversibly impair body function. Some visitors to this forum reported a deterioration in their health after taking senolytics (in particular, fisetin).

 

3. Some of the senescent cells are still needed, since senescent cells can inhibit fibrosis:

https://nestarenie.ru/senolitiki.html (article in Russian)

 

4. If you think that senolytics will prolong your life, then I hasten to upset you. Not a single senolytic has prolonged the life of long-lived mice more than diet (I emphasize, long-lived!). Man is a long-lived animal.

 

I conclude that senolytics are just quality-of-life supplements. They have nothing to do with life extension.

 

If we talk ONLY about extending life, but not about improving its quality, if you lead a healthy lifestyle, senolytics are able to extend life by a maximum of 3-4 years. And then, if you're lucky.

 


Edited by Kentavr, 04 October 2021 - 06:26 PM.

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#3 timedilation

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Posted 04 October 2021 - 07:26 PM

I don't disagree with any of that per se.  It is certainly true that killing too many senescent cells too quickly can lead to disaster and that senescent cells do still serve some necessary roles in the body.  It is probably also true that senolytics alone will not get you very far. 

 

However, I do still think that senolysis is an important piece of the puzzle, one which becomes more effective when combined with other aging therapies simultaneously.  In particular, senescent cell removal must be accompanied by fresh cell replacement in order to have a positive effect on aging.  This can only happen if the body's stem cell supply is large and functional.  Therefore, imo the combination of stem cell rejuvenation and senolysis will be a major therapy in the future.  Turnbuckle's C60 + senolytics protocol is already one big step in that direction. 

 

I am interested in applying that line of thinking to the vascular system in particular, hence this post.



#4 Kentavr

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Posted 04 October 2021 - 07:48 PM

If you want to improve the condition of the cardiovascular system, it is probably better for you not to use senolytics, but to use polyphenols as activators of SIRT 1 to increase the length of telomeres.
 
The cardiovascular system is particularly dependent on the length of the telomeres. This is due to the fact that the cells of the cardiovascular wall do not live as little as the cells of the intestine (they are renewed on average once every 3 days, and telomerase in them is quite active), but also not as long as the cells of neurons (neuron lives for a very long time, and, in fact, the length of telomeres does not play any role there).
 
The cells of the cardiovascular wall have an average rate of renewal, which makes them critically dependent on telomere length. It is for this reason that telomere lengthening has a pronounced effect on the state of the cardiovascular system.
 
If you want to quickly help vascular function, eat right, do exercise, eat walnuts (there are a lot of polyphenols), dark chocolate, take taxifolin and liposomal quercetin, as well as other SIRT 1 activators, as well as follow other usual rules (monitor blood pressure, and etc.). Nothing complicated.

Edited by Kentavr, 04 October 2021 - 07:52 PM.


#5 Florin

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Posted 04 October 2021 - 07:55 PM

2. If you have a lot of aging cells (for example, you are over 70 years old), then senolytics can harm you very much. Destroying too many senescent cells can irreversibly impair body function. Some visitors to this forum reported a deterioration in their health after taking senolytics (in particular, fisetin).


I haven't heard of anyone reporting deteriorating health (beyond what can be considered side effects) after taking senolytics on this forum. Can you link to these posts?
 

3. Some of the senescent cells are still needed, since senescent cells can inhibit fibrosis:
https://nestarenie.ru/senolitiki.html (article in Russian)


SnCs can be beneficial for acute injury (that's what the study mentioned on the page you linked seems to be about) before they're eliminated by the immune system, but the vast majority of the evidence suggests that they only do bad stuff if you keep them around forever.


Edited by Florin, 04 October 2021 - 08:07 PM.

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#6 Kentavr

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Posted 04 October 2021 - 07:59 PM

I don't disagree with any of that per se.  It is certainly true that killing too many senescent cells too quickly can lead to disaster and that senescent cells do still serve some necessary roles in the body.  It is probably also true that senolytics alone will not get you very far. 

 

However, I do still think that senolysis is an important piece of the puzzle, one which becomes more effective when combined with other aging therapies simultaneously.  In particular, senescent cell removal must be accompanied by fresh cell replacement in order to have a positive effect on aging.  This can only happen if the body's stem cell supply is large and functional.  Therefore, imo the combination of stem cell rejuvenation and senolysis will be a major therapy in the future.  Turnbuckle's C60 + senolytics protocol is already one big step in that direction. 

 

I am interested in applying that line of thinking to the vascular system in particular, hence this post.

 

Turnbuckle's Stem Cell Expansion Protocol is not a senolytic protocol. Senolytics in this protocol are just a small addition (to replace the old cell with a young stem cell).
 
This protocol cannot be compared with senolytic therapy. It has other features (and I really appreciate the contributions Turnbuckle has made for the people on this forum).
 
 

Edited by Kentavr, 04 October 2021 - 08:00 PM.


#7 timedilation

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Posted 04 October 2021 - 08:30 PM

 

If you want to improve the condition of the cardiovascular system, it is probably better for you not to use senolytics, but to use polyphenols as activators of SIRT 1 to increase the length of telomeres.
 
The cardiovascular system is particularly dependent on the length of the telomeres. This is due to the fact that the cells of the cardiovascular wall do not live as little as the cells of the intestine (they are renewed on average once every 3 days, and telomerase in them is quite active), but also not as long as the cells of neurons (neuron lives for a very long time, and, in fact, the length of telomeres does not play any role there).
 
The cells of the cardiovascular wall have an average rate of renewal, which makes them critically dependent on telomere length. It is for this reason that telomere lengthening has a pronounced effect on the state of the cardiovascular system.

 

Do you have any sources for this?  Also, that is useful information, but telomere/telomerase therapies will only get you so far.  Telomere length is not the only factor in the age (and epigenetic age) of a cell, and afaik you can't just keep increasing it to divide endlessly.  Out of curiosity, how have telomerase therapies fared at "prolonging the life of long-lived mice"?

 

 

 

Turnbuckle's Stem Cell Expansion Protocol is not a senolytic protocol. Senolytics in this protocol are just a small addition (to replace the old cell with a young stem cell).
 
This protocol cannot be compared with senolytic therapy. It has other features (and I really appreciate the contributions Turnbuckle has made for the people on this forum).

 

 

I never said the Stem Cell Expansion Protocol was a "senolytic protocol."  I said Turnbuckle had a stem cell/age reversal protocol with a senolytic component to it, and that the combination of stem cell rejuvenation and senolytics is a promising avenue of life extension.  Even if you think the stem cell part is much more useful (which I would agree with), the senolytics are still playing an important role.

 

I appreciate this discussion, but I should say that you probably are not going to convince me that the original question isn't worth answering.
 



#8 Kentavr

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Posted 05 October 2021 - 07:08 AM

I haven't heard of anyone reporting deteriorating health (beyond what can be considered side effects) after taking senolytics on this forum. Can you link to these posts?
 

 

For example, here:

 

https://www.longecit...ndpost&p=864115

 

I also saw a message for a long time when one of the members of the longecity forum, after taking fizetin, had incessant ringing in the ear, which did not go away with time. He was of a very great age. The forum participants concluded that he could damage his auditory nerve due to senolytics.
 
Unfortunately, I can't find this message, and I also don't know if he managed to get rid of the ringing in his ear.

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#9 Kentavr

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Posted 05 October 2021 - 08:35 AM

Do you have any sources for this?  Also, that is useful information, but telomere/telomerase therapies will only get you so far.  Telomere length is not the only factor in the age (and epigenetic age) of a cell, and afaik you can't just keep increasing it to divide endlessly.  Out of curiosity, how have telomerase therapies fared at "prolonging the life of long-lived mice"?

 

 

 

I never said the Stem Cell Expansion Protocol was a "senolytic protocol."  I said Turnbuckle had a stem cell/age reversal protocol with a senolytic component to it, and that the combination of stem cell rejuvenation and senolytics is a promising avenue of life extension.  Even if you think the stem cell part is much more useful (which I would agree with), the senolytics are still playing an important role.

 

I appreciate this discussion, but I should say that you probably are not going to convince me that the original question isn't worth answering.
 

 

Your message definitely deserves a reply.

 

However, I want to tell you about several ways that may help your cardiovascular system without using senolytics.
 
Method 1:
 
It was recently discovered that senescent cells of the immune system are potentially some of the most damaging of all senescent cells, as they spread tissue damage and rapid aging to other organs and systems in the body:
 
Further:
an increase in SASP
an increase in CD38 on macrophages M1
degradation of NAD +,
a decrease in SIRT 1-7 activity,
acceleration of telomere shortening due to a decrease in SIRT 1 activity (namely, the RATE OF SHORTING OF telomeres correlates with mortality, not their length),
etc.
 
Now it becomes clear to me why people who have completed several courses of epitalon become outwardly younger over time. Apparently, Epitalon activates the immune system, which returns to a younger state. Perhaps it stops harming the body and again removes only aging cells from the body.
 
I believe that this is the more correct way, since a correctly functioning immune system removes only aging cells without affecting healthy ones. Additionally, a healthier immune system can better protect against cancer, which is also a definite plus.
 
After this news, many scientists are probably shocked. Because this is a more correct way to destroy aging cells.
 
I take the drug Endoluten, which, according to the manufacturer of the drug, has an efficiency of about 80% of the effectiveness of an injection of Epitalon. I have no evidence for this statement, but the drug is really powerful, I can feel it.
 
My wife says that in appearance I look 34 years old, although I am 39 years old (everything can change for the worse even tomorrow, I'm talking about the impression of my wife as of today).
 
Method 2:
 

You Can Take Coenzyme Q10 + Selenium:

https://www.nutraing...rsist-for-years

 

And for this it is not necessary to remove senescent cells.  Which coenzyme to choose so that it works, I wrote in this thread (so that later it would not be excruciatingly painful from the thought that you wasted money):

 

https://www.longecit...mn-in-20212022/

 

This thread also explains why I am not currently using NMN.

 

Method 3:

 

Reduce the thickness of intimate media (taking statins + sartans + diet + exercise):

https://nestarenie.r...st-sosudov.html

https://nestarenie.r...tima-media.html

https://nestarenie.r...yi-molozhe.html

 

 

Method 4:

 

Turnbucle Mitochondrial Dynamics Protocol (especially its February 17, 2021 protocol):

https://www.longecit...ndpost&p=903440

 

Method 5:

 

You can increase NAD + with liposomal quercetin, which will also improve endothelial function without resorting to senolytics. Quercetin alone will not be able to kill senescent cells, as it needs help in the form of dasatinib. I wrote from this thread:

https://www.longecit...mn-in-20212022/

 

 

Etc. There are many of these ways, and it is not necessary to take such risky means as senolytics.  :)


Edited by Kentavr, 05 October 2021 - 08:43 AM.

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#10 FlorianReicht

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Posted 05 October 2021 - 12:00 PM

I'm like more into letting the body clean up senescent cells via autophagy - adding some ceylon cinnamon to deepen the state of autophagy even more, but that's it.

 

I'd rather look that you vascular system is running without hick-ups. Do some 0,3% H2O2 IV's with some Mg, DMSO and Quinton Hypertonic added. This will clean your entire system out, really good - even the tiniest bloodpaths doctors can't handle with state-of-the-art bypass-surgery, are scrubed with tiny Oxygen bubbles (reaction from H2O2 with an enzyme called Catalase) read more in the book "H2O2 medical miracle, by William Campbell MD"

 

Adding some peptide complexes 2x/year (alternative is eating everyting nose to tail, raw year round)

 

https://e-peptide.co...omplexes-vitual


Edited by FlorianReicht, 05 October 2021 - 12:02 PM.


#11 Kentavr

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Posted 05 October 2021 - 01:47 PM

Я больше люблю позволять телу очищать дряхлые клетки с помощью аутофагии - добавляю немного цейлонской корицы, чтобы еще больше углубить состояние аутофагии, но это все.

 

Лучше я посмотрю, что у вас сосудистая система работает без задержек. Сделайте немного 0,3% H2O2 IV с добавлением Mg, DMSO и Quinton Hypertonic. Это очистит всю вашу систему, действительно хорошо - даже самые крошечные кровеносные пути, с которыми врачи не справятся с помощью современной хирургии шунтирования, очищаются крошечными пузырьками кислорода (реакция H2O2 с ферментом под названием каталаза). в книге «Медицинское чудо H2O2, доктор медицины Уильяма Кэмпбелла»

 

Добавление некоторых пептидных комплексов 2 раза в год (альтернатива - есть все от носа до хвоста, сырые круглый год)

 

https://e-peptide.co...omplexes-vitual

 

I know Khavinson's peptides, I use Endoluten and Vesugen. These are two of my favorite peptides. In the previous post I wrote about one of them.
 
Do you have scientific evidence for the benefits of hydrogen peroxide in cardiovascular health?  :)


#12 Florin

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Posted 05 October 2021 - 06:21 PM

 

For example, here:

 

https://www.longecit...ndpost&p=864115

 

I also saw a message for a long time when one of the members of the longecity forum, after taking fizetin, had incessant ringing in the ear, which did not go away with time. He was of a very great age. The forum participants concluded that he could damage his auditory nerve due to senolytics.
 
Unfortunately, I can't find this message, and I also don't know if he managed to get rid of the ringing in his ear.

 

 

Post #291 claims that knee pain got worse after taking fisetin but then the knee became stronger and was more pain-free compared to before using fisetin. There was a net gain in health and any health deterioration was temporary. Whether this positive effect was due to fisetin and/or the NMN and stem cell therapy that the poster also mentioned is anyone's guess.

 

I couldn't locate the claim about auditory damage.


Edited by Florin, 05 October 2021 - 06:22 PM.

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#13 Kentavr

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Posted 05 October 2021 - 07:05 PM

Post #291 claims that knee pain got worse after taking fisetin but then the knee became stronger and was more pain-free compared to before using fisetin. There was a net gain in health and any health deterioration was temporary. Whether this positive effect was due to fisetin and/or the NMN and stem cell therapy that the poster also mentioned is anyone's guess.

I couldn't locate the claim about auditory damage.


Thanks. I sometimes do not translate English well. This is rare, but it does happen.

#14 FlorianReicht

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Posted 06 October 2021 - 12:33 PM

 

I know Khavinson's peptides, I use Endoluten and Vesugen. These are two of my favorite peptides. In the previous post I wrote about one of them.
 
Do you have scientific evidence for the benefits of hydrogen peroxide in cardiovascular health?  :)

 

 

I see you are Russian, so I will repeat it clearly. Have a look in this video what happens when H2O2 is reacting with Catalase (an enzyme in your blood)

 

 

those millions of bubbles are being pushed through your entire vascular system while you are doing an intravenous session (see recipe with 0,3% H2O2 and more ingredients, above) and clean it's path out really good.

 

If you want to know more have a look at the book of William Campbell called "H2O2 medical miracle"

 

https://www.educate-...ll-Douglass.pdf

 

he goes more into detail, recites a colleague who stopped a onsetting stroke with an H2O2 intravenous application - so paint your picture.



#15 timedilation

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Posted 16 October 2021 - 03:56 PM

Regarding the original post, I came across this study recently, which has some useful information on vascular senescence in the lungs.  A few interesting quotes:

 

 

In vitro, we showed that human pulmonary endothelial cells of patients with pulmonary arterial hypertension (PAH) are more vulnerable to senescence than controls in response to shear stress and confirmed that the senolytic ABT263 induces apoptosis in senescent, but not in normal, endothelial cells.

 

ABT263 = Navitoclax

 

 

By targeting senescence using the senolytic ABT263, we reversed MCT+shunt-induced PAH that was refractory to HU

 

 

Moreover, senolytics such as ABT263 or the forkhead box protein O4 peptide Foxo4-DRI have shown to promote tissue regeneration after clearance of senescent cells. The increased expression of BMPR2, Klotho, and MMP2 after ABT263 treatment in this study suggests that regeneration of lung vasculature occurs after clearance of senescent cells.

 

 







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