18 replies to this topic

[Ovidus]

Previously I had a thread where I asked about combining several drugs as well as behavioral interventions for a multi-pronged approach to getting rid of senescent cells

https://www.longecit...ore-i-am-ready/

 

One of the questions was: "Shall we combine fasting with Senolytic drugs?". This is the only question I would love to focus on in this thread. Please do not assume that I am essentially reposting the same question. I wanted to post this thread because I have collected anecdotal -but IMO very valuable- observations over the last few months about fasting. By brainstorming about what I have observed and thinking what that could mean, perhaps we can make more educated guesses about whether it makes sense to combine fasting with Senolytics and if it does, how to do that.

 

My Fasting Experiences
I have not even been able to  fast very long anyways; I did 2 fasts of 4 days and 4.5 days respectively. However, the results were very impressive. Following the second fast, I had a marked improvement in cardiovascular performance. 
I get on the treadmill and do a protocol (100% standard protocol, as far as speed and elevation of the machine and I always use the exact same machine). At the end of this protocol, my heart rate goes to between 165 - 167 and will take anywhere from 90 to 150 seconds to go down to 150 when I stop.
Following my second fast, during the same exercise my heart rate goes up to 159 - 160 and takes 50 - 60 seconds to decline back to 150. This 50 second decline to 150 bpm is very impressive and is a figure I have never seen before. This is certainly not something that IMO can be explained away by the placebo effect.
I also had a very very strange sensation during my first fast, which was getting mucus in the nose on day 3. This wasn't just any type of nasal congestion; rather it was the EXACT same sensation as getting the cold -you know how you walk around with a box of tissues, because you have to blow your nose and a lot of bad stuff comes out... I had that sensation but no other symptoms whatsoever of getting a cold. I was feeling strong, no fever, joints rock solid (as opposed to achy when getting sick). Again, I find it impossible to attribute this to placebo. Is this macrophages clearing after they mop up the bad cells? 

Finally, following my second fast, my injured shoulder was hurting far less.

 

A Lady Friend's Experience

She did a 4 day fast and loved it. But here is the one amazing thing she said. She used to develop mouthsores on a regular basis (had been for years and was often asking me for a cure). Following the fast, which she completed like 6 months ago, she said she had one very mild episode, whereas she'd have at least 3 or 4 during that period of time and they'd be far heavier. Now this is very interesting and immediately makes one think of "elimination of problematic cells".

 

Peter Attia's Experience

Peter is an awesome MD and does longevity related high quality work. He puts his money where his mouth is and practices what he preaches. He did a week-long fast and put out an extremely detailed analysis of the results
https://peterattiamd.com/ama02/

Definitely listen to it.
One thing he too says is that his elbow (or maybe knee... not sure, one or he other) that was previously injured was healed after the fast. 

Now the above are not controlled studies, yes. But they do make you think that a far higher rate of apoptosis / immune cell mediated clearance of problematic tissues occurs during a fast and that fasting may contribute to senescent cell removal.Please critique my thinking if this fails to make sense.

 

With the above in mind, how would you guys combine a senolytic stack (Dasatanib + Quercetin) with fasting? 
 

 

Thanks a lot

 

 

 

 

 

 

 

 

 

[Andey]

You should read @Michael post about it. He made pretty sound arguments that there is no synergy between fasting and senolytics. https://www.longecit...ndpost&p=869671

[MankindRising]

Interesting and thanks for your post.

Ive been wanting to try proper fasting for quite a while now but I will have to do it on a holiday or something as I cant imagine myself doing it during a working week. Also incase I do get sick (I have immune problems - autoimmunity I think) I will need quite a while to recover.

 

Very interesting regarding the mouth sores, Ive been getting systematic low grade inflammation in my mucous membranes (worst in winter when PGE2 and il-6 skyrockets).

Im sure you are aware that 72hour fasts are hypothesized to 'reset' the immune system and I actually made a post about this not too long ago asking who here has done it, but it seems this forum has made a fair transition between discussing longevity related stuff to random crap.

 

Either way once again thanks for your report, this makes me want to try it all the more.

[Ovidus]

You should read @Michael post about it. He made pretty sound arguments that there is no synergy between fasting and senolytics. https://www.longecit...ndpost&p=869671

Just read it and of course I am in no position to argue against the data that Michael put forth; I just don't have the knowledge for that...
I am just curious how one explains the observations I am sharing above. What do you all think may be going on? I am merely curious, I am not presenting the above anecdotal info as evidence...

 

Interesting and thanks for your post.

Ive been wanting to try proper fasting for quite a while now but I will have to do it on a holiday or something as I cant imagine myself doing it during a working week. Also incase I do get sick (I have immune problems - autoimmunity I think) I will need quite a while to recover.

 

Very interesting regarding the mouth sores, Ive been getting systematic low grade inflammation in my mucous membranes (worst in winter when PGE2 and il-6 skyrockets).

Im sure you are aware that 72hour fasts are hypothesized to 'reset' the immune system and I actually made a post about this not too long ago asking who here has done it, but it seems this forum has made a fair transition between discussing longevity related stuff to random crap.

 

Either way once again thanks for your report, this makes me want to try it all the more.

 

Thanks a lot for the kind words and to hell with whoever downvoted your post.

I am not sure that a true fast will have the detrimental effect on your immune system that you suspect. It may not. Read into it

Also, why not during a workweek? I know it is hard and I know that until you get used to it, you will feel hungry and have a hard time focusing on work. But for me, as well as many other people, it is far easier to do it when you are busy with work. Having less to do makes it harder to forget about food. Though of course that also depends on your job...

[MankindRising]

Just read it and of course I am in no position to argue against the data that Michael put forth; I just don't have the knowledge for that...
I am just curious how one explains the observations I am sharing above. What do you all think may be going on? I am merely curious, I am not presenting the above anecdotal info as evidence...

 

 

Thanks a lot for the kind words and to hell with whoever downvoted your post.

I am not sure that a true fast will have the detrimental effect on your immune system that you suspect. It may not. Read into it

Also, why not during a workweek? I know it is hard and I know that until you get used to it, you will feel hungry and have a hard time focusing on work. But for me, as well as many other people, it is far easier to do it when you are busy with work. Having less to do makes it harder to forget about food. Though of course that also depends on your job...

You got a point there regarding working will move the mind away from thinking about food, however Im currently in the process of getting extra work on top of my parttime hours that I have. I do have some anticipatory anxiety of screwing the extra work im about to start (end of this week) up. Also I look like an absolute trainwreck if I go without food for a while and I live in a very large city and the prejudice from people towards looking like a crackhead can bring stress on its own.

Thats why I was thinking of doing it when I have a week off, spend some time with my dog and go to the forest and all that during the fast.

 

I hope to do my first fast somewhere just before summer. Thank you for putting in your perspective of what could work for fasting. Often its better when an outsider makes a judgement than a family member or such.

[ambivalent]

Hello,

 

Sounds as though you've had a great experience fasting, though I'm not sure these benefits are enhanced with senolytics from your account - have you fasted these lengths before?Repairing of old injuries is commonplace fasters, lost of aches and pains come and go, occasionally they last for weeks.

 

These accounts are anecdotal but considerable and offer substantial evidence. We also have this study on injury recovery in fasted rats. One of Longo's studies showed white blood cells dipped during fasting and then were not only repleted post fasting but raised above pre-fasting levels. Is it likely these effects occur without clearing out of senescent cells? 

 

I've done a fair amount of fasting but not much for year or two, at some point I will give a four or five days comparison post fisetin

 

As for Michael's arguments on autophagy - there are somewhat paradoxical behaviours with autophagy. When I read years that risk of dementia was lower with those overweight, I recalled a study which showed that and IGF pathway stimulated autophagy, (which of course fasting does too) so it made sense. I will look for that study, but here is one demonstrating the surprising effect of inhibiting IGF on autophagy:

 

https://www.ncbi.nlm...les/PMC3889807/

 

 

 

Edited by ambivalent, 05 March 2019 - 11:38 PM.

[Andey]

Just read it and of course I am in no position to argue against the data that Michael put forth; I just don't have the knowledge for that...
I am just curious how one explains the observations I am sharing above. What do you all think may be going on? I am merely curious, I am not presenting the above anecdotal info as evidence...

 

 

 

 TBH Your post is not much different from numerous from r/fasting. Fasting heals, an I also practice it. Fasting experience is unique for every individual but yours are not extraordinary in that respect.

The major difference is that your linked it with senolytics which is unwarranted as you didn't even try it in that configuration. BTW I tried D+Q+fasting and found no difference to fasting alone.

[Ovidus]

 TBH Your post is not much different from numerous from r/fasting. Fasting heals, an I also practice it. Fasting experience is unique for every individual but yours are not extraordinary in that respect.

The major difference is that your linked it with senolytics which is unwarranted as you didn't even try it in that configuration. BTW I tried D+Q+fasting and found no difference to fasting alone.

 

OK, all points taken

 

Just share some opinions on how fasting heals injuries? What is the mechanism at work here?
I am not saying it has to be removal of senescent cells... just curious what exactly might be at work if it is not that (if it not removal of senescent tissues).

 

Thanks

[Andey]

OK, all points taken

 

Just share some opinions on how fasting heals injuries? What is the mechanism at work here?
I am not saying it has to be removal of senescent cells... just curious what exactly might be at work if it is not that (if it not removal of senescent tissues).

 

Thanks

 

 I was too harsh, sorry.

 

Probably a lot of things going on with fasting

1. Decrease of mTor

2. Micro and macro autophagy

3. A decrease of SASP(sterile inflammation) signaling from senescent cells (I believe it's shown in work of D Campisi)

4. Stimulating regeneration phenotype on refeed (V.Longo study on pancreatic cells)

5. The decrease of Th17 overreactive-autoimmune T cells, an increase of Treg cells (V Longo work on multiple sclerosis)

6 and probably more )

 

One could probably mimic some of those with mTor inhibition as points 1,2(at least micro part),3,5 are all linked with mTor but fasting would be still more effective and free

[Ovidus]

 I was too harsh, sorry.

 

Probably a lot of things going on with fasting

1. Decrease of mTor

2. Micro and macro autophagy

3. A decrease of SASP(sterile inflammation) signaling from senescent cells (I believe it's shown in work of D Campisi)

4. Stimulating regeneration phenotype on refeed (V.Longo study on pancreatic cells)

5. The decrease of Th17 overreactive-autoimmune T cells, an increase of Treg cells (V Longo work on multiple sclerosis)

6 and probably more )

 

One could probably mimic some of those with mTor inhibition as points 1,2(at least micro part),3,5 are all linked with mTor but fasting would be still more effective and free

 

Really appreciate it; very iluminating

 

"2. Micro and macro autophagy"

Am I correct in thinking that if it is autophagy at work, we do not consider it "clearance of senescent cells".... for something to be senolytic, would it have to force the cell into apoptosis?

[Andey]

Really appreciate it; very iluminating

 

"2. Micro and macro autophagy"

Am I correct in thinking that if it is autophagy at work, we do not consider it "clearance of senescent cells".... for something to be senolytic, would it have to force the cell into apoptosis?

 

  Nope, Michael addressed it explicitly

"In fact, a prominent feature of senescent cells is exactly that they have high, not low, activation of the autophagy-lysosomal system. This is exactly the basis for the widely-used sanescence-associated beta-galactosidase (SA-β-gal) assay for SEN: senescent cells have far more active lysosomes than nonsenescent cells do, with the result that while SA-β-gal — which is a lysosomal enzyme — is undetectable in non-senescent cells under the standard assay conditions, it is prominent in senescent cells. In fact, activation of autophagy is necessary for the conversion of cells to senescence (PMID 19279323, and rapamycin — whose principle mechanism of action is to suppress mTOR and thereby activate autophagy  — reduces the rate at which cells under stress become senescent and inhibits the SASP, but has no effect on SEN survival once they're formed (eg. PMIDs 21715679, 28371119, 19471117 ). (This is fully consistent with the fact that animals on CR per se accumulate fewer senescent cells as they age (PMIDs 26983960, 20844316, 29575469) — including, apparently, CR humans (PMID 29575469 ).

By contrast, inhibiting autophagy has been shown to trigger the death of in senescent cells with exceptionally high SASP engagement (PMID 23945590)."

[xEva]

  Nope, Michael addressed it explicitly

"In fact, a prominent feature of senescent cells is exactly that they have high, not low, activation of the autophagy-lysosomal system. This is exactly the basis for the widely-used sanescence-associated beta-galactosidase (SA-β-gal) assay for SEN: senescent cells have far more active lysosomes than nonsenescent cells do, with the result that while SA-β-gal — which is a lysosomal enzyme — is undetectable in non-senescent cells under the standard assay conditions, it is prominent in senescent cells. In fact, activation of autophagy is necessary for the conversion of cells to senescence (PMID 19279323, and rapamycin — whose principle mechanism of action is to suppress mTOR and thereby activate autophagy  — reduces the rate at which cells under stress become senescent and inhibits the SASP, but has no effect on SEN survival once they're formed (eg. PMIDs 21715679, 28371119, 19471117 ). (This is fully consistent with the fact that animals on CR per se accumulate fewer senescent cells as they age (PMIDs 26983960, 20844316, 29575469) — including, apparently, CR humans (PMID 29575469 ).

By contrast, inhibiting autophagy has been shown to trigger the death of in senescent cells with exceptionally high SASP engagement (PMID 23945590)."

 

It's been a while since I wanted to point out a problem with this post by Michael, first in the original thread, then this one, but still don't have time to supply the refs.  Here he hastily drew a wrong conclusion based on the  fact that senescence-associated beta-galactosidase (SA-β-gal) is a lysosomal enzyme.

 

What's missing in his view is the well-known fact that autophagy is stalled in the senescent cells -- i.e. it is initiated but is not followed through. That's what makes them look bloated with all sorts of junk cluttering their cytoplasm while healthy cells remain small and tidy.

 

And while there is plenty of refs about this (that autophagy is stalled in senescent cells which makes them look bloated), there is not that many refs that fasting allows for this stalled process of autophagy to carry through to completion.  But I believe this may be the case, to an extent, depending on the length of a fast.

 

I'll look for refs and post them later.

Edited by xEva, 14 March 2019 - 01:10 PM.

[xEva]

This well-cited paper from 1970 describes the changes in morphology that accompany senescence: MORPHOLOGIC CHANGES ACCOMPANYING SENESCENCE OF CULTURED HUMAN DIPLOID CELLS. Here they cultured human fibroblasts and observed that, with senescence approaching, the number of lysosomes continued to increase:
 

By ~30-40 cell doublings, the cells "contained a markedly increased number of lysosomes, which had now expropriated much of the cytoplasmic space. (Fig. 3). While many of these lysosomes had transformed into residual bodies, one could usually still find occasional unaltered multivesicular bodies (arrows), suggesting that although turnover of lysosomes and their contents appear impaired, nascent lysosomes continue to be formed. The result is a gradual and eventually overwhelming accumulation of these organelles."  In the end, "most cells resembled that depicted in Fig. 4, with the cytoplasm largely occupied by degenerating residual bodies".

 

['residual bodies' == undigested material, such as lipofuscin, in deteriorating vesicles of ex-lysosomes]

 
The authors stress though, that such striking alterations in morphology are obvious only in in vitro cultures -- and not in biopsies from old individuals. IOW, in vivo, when cells become senescent, it's hard to tell them apart from healthy cells when viewing under a microscope  (again, coz  they don't show such striking degeneration as senescent cells in culture). However, as Michael pointed out, the presence of senescence cells, both in biopsies and in culture, can be revealed by SA-β-gal (senescence-associated-β-galactosidase, which is a stain for this lysosomal enzyme at pH 6.0).
 
But this stain does not mean that "senescent cells have far more active lysosomes than nonsenescent cells do". Rather, it reflects a greater number of lysosomes in the senescent cells, and by all accounts, they accumulate because their function becomes impaired (presumably they fail to clear whatever they are supposed to and so there is no feedback signal to stop their formation).
 
 
This covers the part about the growing number of functionally impaired lysosomes in the senescent cells. Whether fasting can help  this somehow is another matter for another day. 

[xEva]

But this stain does not mean that "senescent cells have far more active lysosomes than nonsenescent cells do". Rather, it reflects a greater number of lysosomes in the senescent cells

 

lol I guess I was skewed by "far more active" and thus did not notice that otherwise  the two statements were identical.

[Ovidus]

Whether fasting can help  this somehow is another matter for another day. 

 

xEva,

 

Thank you so much for your very valued input.

 

There is of course so much unknown about every aspect of this whole field. What exactly fasting does, we are only now uncovering. 
Senescence too, is way too complex a process and we may even come to the conclusion that we shall stop using the term "senescent cell" as that is too broad a term and that the universe of what we call senescent cells should be divided into various categories. 

Despite all these uncertainties, if one were to try and combine a senolytic regimen (of Dasatinib + Quercetin) with fasting, what may be one way of doing so?
You cannot give exact directions perhaps, but how about we brainstorm some...
Would one fast for a number of days and introduce the senolytic compounds at the end; or start with the senolytics and then begin a fast...?
What other actions can be taken to enhance / optimize the effects of the  Dasatinib + Quercetin combo?

Thanks so much again

[Engadin]

lol I guess I was skewed by "far more active" and thus did not notice that otherwise  the two statements were identical.

 

 as the song claims, in the " ... heat of the moment ...".

[xEva]

Senescence too, is way too complex a process and we may even come to the conclusion that we shall stop using the term "senescent cell" as that is too broad a term and that the universe of what we call senescent cells should be divided into various categories.

This is so true! For those of us who may not be quite so up to date, here are some key points from Nature Reviews Forging a signature of in vivo senescence, 2015:
 

Although the term 'cellular senescence' was originally used to define the state of irreversible proliferative arrest by cultured cells that had reached their replicative limit, it is now widely used to describe states of cell cycle arrest in different in vivo biological settings, including age-associated loss of regenerative capacity, tumour suppression, inflammation, wound healing and embryogenesis.

A central problem in the senescence field is the lack of a uniform definition of cellular senescence, coupled with inconsistent application of biomarkers to identify and enumerate senescent cells in vivo.

Although frequently used in various combinations to denote putatively senescent cells in vivo, senescence-associated biomarkers — such as robust expression of lysosomal β-galactosidase and the cyclin D-dependent kinase inhibitor p16INK4A, activation of the DNA-damage response, alterations in paracrine secretion and changes in heterochromatin — are individually nonspecific. There is no consensus on which amalgamation of these biomarkers describes the senescent state.

 

We advocate that 'cellular senescence' should be strictly defined as stress-induced proliferative arrest accompanied by the failure to re-enter the cell division cycle in response to mitogenic and oncogenic stimuli. More-specific descriptors could then be applied to characterize many of the diverse phenotypes that define complex and possibly distinct cellular states currently aggregated under the umbrella term 'senescence'.

 

[xEva]

There is of course so much unknown about every aspect of this whole field. What exactly fasting does, we are only now uncovering. 
Senescence too, is way too complex a process and we may even come to the conclusion that we shall stop using the term "senescent cell" as that is too broad a term and that the universe of what we call senescent cells should be divided into various categories. 

Despite all these uncertainties, if one were to try and combine a senolytic regimen (of Dasatinib + Quercetin) with fasting, what may be one way of doing so?
You cannot give exact directions perhaps, but how about we brainstorm some...
Would one fast for a number of days and introduce the senolytic compounds at the end; or start with the senolytics and then begin a fast...?

 

In regard to fasting I know of one type of 'senescent cells' for which fasting works and that's the infected cells. There was a paper posted here recently that pointed out what I have long maintained, which is that infected cells have all the hallmarks of the senescent cells. To begin with, they are flooded with lysosomes which fail to merge with the phagasomes, in which the bacteria are hiding (and so these cells would definitely come up on the SA-β-gal assay). Their metabolites act as wrenches in the autophagic machinery which otherwise would destroy them. Some also inhibit apoptosis. The infected cells emit all sorts of  inflammatory cytokines meant to summon the immune cells to take them out.

 

Fasting alone will clear these cells. There is no direct refs for this afaik but I believe that, to begin with, nutrient depletion results in lower levels of bacterial metabolites (which interfere with the autophagic machinery), and then ever increasing acidity activates lysosomes and other factors, which together overcome bacterial blocking signals, allowing autophagy to go through. Would it necessarily kill the cell? Prob. not and it's a good thing. I imagine these cells get rid of their uninvited tenants and resume their healthy functioning.

 

Again, there is no refs for this, except indirect ones. I studied this years ago, when I wanted to understand how fasting alone can cure certain chronic infections (which was apparent through old Russian fasting research). We also know that fasting gets rid of the old immune cells and repeated bouts of fasting reboots the immune sys.

 

But of course here we are mostly interested in killing the cells that entered cell cycle arrest due to some form of damage or just severe telomere attrition. To my knowledge there is no refs about fasting and specifically cells with short telomeres. There is only indirect evidence that fasting clears all sorts of damaged cells, even though the 'proof' is mostly limited to reasonable assertions that, starved for nutrients, the body will start consuming old and damaged tissues first (and leave the prime cuts for dessert). Hey, even Longo says something like this in his fasting and cancer papers!

 

And so, to answer your question of when is better to take senolytics, in the beginning or the end of a fast, I'd guess, toward the end. That's what Longo determined in his cancer and fasting studies. Fasting for a couple of days allows  the healthy cells to enter a protective mode when they sorta close the shop (which means that they will uptake less of a drug than the target cells), while at the same time it stresses the damaged cells. Then introduction of a senolytic such as dasatinib, which, appropriately, is a cancer drug, should preferentially do them in.

 

Edited by xEva, 18 March 2019 - 05:59 PM.

[Ovidus]

You are awesome Sir

You taking the time to answer it all in such great detail means a lot to me and your tone is so gentlemanly and kind. Thanks a million.

 

I have actually spent the last few days listening to Longo's interview and presentations on YouTube and have come to the same conclusion myself. Wish fasting was a little easier, especially for people like me who already have a hard time falling asleep. But indeed, you'd need a few days with little or no food for the various mechanisms to kick in and both protect the good cells and (possibly) make the bad guys more vulnerable to attack by the immune system as well as the internal cleaning mechanism.

 

Once again, thank you so much