LONGECITY

Hi Alpharius,

 

Thanks for the link. They also discuss FISETIN but are not clear in the abstract whether it was studied together with the two selective BCL-XL inhibotors A1331852 and A1155463, or independently? One would need to read the full article to establish that naturally occurring fruit flavone FISETIN would possibly be a relatively safe senolytic substance? 

 

 

They tested all 3 substances independently. A1331852 and A1155463 are selective inhibitors of Bcl-XL.

 

They did not explain how Fisetin kills senescent cells, but there are some cancer cell studies with Fisetin which suggest BCL-2 inhibition:

https://www.ncbi.nlm...pubmed/25840992

 

Fisetin binds directly to Bcl-2: https://www.ncbi.nlm...pubmed/28264627
But it seems to hit other Bcl-2 family members like Mcl-1, Bcl-xL and Bcl-w (other name Bcl2L2), either by lowering the protein level or by binding to the antiapoptotic proteins. 
https://www.ncbi.nlm...pubmed/20510331

 

Ok so to me it seems Fisetin inhibits probably not selectively the Bcl-2 antiapoptotic proteins.

 

Thats maybe a problem. Why? Please stay with me here.

Because Navitoclax does the same it binds not selective but strong to Bcl-2, Bcl-XL and Bcl-w.

 

But do we need the Bcl-2 inhibition really or is it just causing side effects like neutrophils toxicity? It seems that the selective Bcl-2 inhibitor TW-37 is not senolytic.

On the other side the selective Bcl-XL inhibitors  A1331852 and A1155463  are senolytic. They do not bind to Bcl-2.

 

So it seems Bcl-2 is not so important in senescent cells but its inhibition could kill other healthy cells.

So from the proteins discussed here, it would be interesting to know if Bcl-w or Mcl-1 inhibition is needed to kill senescent cells. Or maybe even the Bcl-2 inhibition could be needed in some cells or maybe we just need a little bit supression, who knows. We are experimenting here.

 

Fisetin is probably like a natural version of Navitoclax and inhibits all Bcl-2 family members not selectively.
Is it better or worse then Navitoclax, I can`t tell.

 

Maybe it does not even matter because we would just use Navitoclax 1 time in 2-3 months and the positive effects would outweigh the negatives, but this is also speculation.

Hi Alpharus,

 

Thanks for your interesting analysis.

 

However, in anti-aging experimentation conclusions are often hasty on either side of the fence. What matters to me - unlike others here who want every guarantee of effectiveness and safety - is to avoid known or predictable unrecoverable consequences on my health.

 

We know our body continuously regenerates, and we can usually recover and heal from whatever goes amiss, except for serious chronic and mutational degenerations that are irreversible. These it is obviously best to avoid unless on one's deathbed already.

 

Some of those on the "bleeding edge" of discovery are willing to take a step back in order to go two steps forward. Today's experimental treatments are that at best, experimental. New scientific theorems are often only validated by peripheral studies aimed towards other ailments in vivo when not limited to in vitro reactions.  As pioneers we are testing in real life what their new potentialities might bring, and what pitfalls may accompany them.

 

Surely it is better to have teams of seasoned scientists with multimillion dollar laboratories verify every issue and also run human studies with control groups and research vetting. However, this can't happen when their objectives are primarily commercial and their funding is tied to Big Pharma.

 

Discomfort, unpleasantness and even serious but temporary side effects may be what the frontrunners will have to endure until a clear, safe and cost-effective solution is borne of our efforts. As long as whatever hardships one must endure to reverse aging are recoverable, I'm willing to walk the bridge cross the fence. Youth is no longer an evanescent dream or a delusional fallacy. Agelessness has almost come to age, and within our grasp.

 

So it is logical at this most exceptional time in the history of humanity, to try whatever holds promise, within the cautious reasoning of calculated risks. Hence I plan to experiment Navitoclax as well as Fisetin, and maybe A1331852 and A1155463 before they are even given a real name?

 

Cheers,

 

DD

Edited by DareDevil, 19 March 2017 - 07:52 PM.

We could attempt some citizen science here by combining the safe, widely available suspected senolytic supplements (quercetin, fisetin, e.g.) and then chart before and after blood work or blood glucose or blood pressure or weight or subjective (exercise) feelings.

How would we devise a way to learn something useful?

Assuming we reached some idea of how much of what to take for whom, when and why, another question remains: did we do anything like what we'd like to do (e.g., clear the gd senescent cells)?

Rough citizen science (just randomly testing crap on ourselves) has been loosely done all over this site with many, many pills and concoctions and then these written testimonies ("...my weightlifting is improved..." or "...my sleep is better..." and "...my skin is awesome...") and of course it's all ignored anecdotal and called useless until someone gets hurt.

Even so, intelligently targeted self trials are a staple in historically pushing the envelope on potential improvements (look at Fahy's thymus regeneration work, for example). But we don't want to hurt ourselves, and then we want to be able to objectively show that what we did was meaningful (even if it's showing meaningfulness to ourselves only -- if no one else gives a crap because our citizen science projects aren't real science).

How do we assess if what we did was useful?

...snip

 

HUMster's greatest marker is the blood pressure, which showed dramatic reduction

within few weeks after dosing with D+Q+F and holding stable at youthful level of around

120/72 since then, for last half a year.

Here is the historical perspective: The HUMster's blood pressure had been raising

steadily for last 5 years. About 2 years ago it reached levels which became seriously

worrysome.HUMster could see levels of over 150/80 more and more often since then

and HUMster seriously considered starting beta blockers.....but never went so far.

4 doses of D+Q (100 ,6) , each dose week apart , with fasting 2 days before each dosing

did the job ....Also importantly , HUMster had been preloading 3g of Q a day for 2 weeks

before starting D+Q experiment.

 

HUMster's physician  is speechless, wondering what happened.......

 

 

I notice that clearing senescent cells improves blood pressure parameters by reducing calcification from this latest newsletter:

 

Evidence for Senescent Cells to Promote Vascular Calcification
https://www.fightagi...-calcification/

        The progressive stiffening of blood vessels is an important proximate cause of age-related hypertension and cardiovascular disease. One cause of this stiffening is a process of calcification, deposition of calcium into the tissues of blood vessel walls. Recent evidence shows that this process is caused by changes in cellular behavior, which opens up a range of potential targets for therapy and prevention. Here, researchers further demonstrate that the activities of senescent cells are probably involved in this picture. This is good news if validated, as targeted clearance of senescent cells as an approach to the treatment of aging is already heading towards the clinic, under active development at a number of companies.

...snip

HUMster's greatest marker is the blood pressure, which showed dramatic reduction within few weeks after dosing with D+Q+F and holding stable at youthful level of around 120/72 since then, for last half a year.

Fasting by itself (water-only, no food, >48/hrs) reliably drops blood pressure for nearly everyone. So it's good to hear that HUMster's BP sustained normal levels for awhile after the D+Q+F experiment.

Does HUMster attribute BP normalization to the D+Q, or does he think fasting alone (without the senolytics) might also drop it?
Edited by sthira, 19 March 2017 - 11:49 PM.

Hence I plan to experiment Navitoclax as well as Fisetin, and maybe A1331852 and A1155463 before they are even given a real name?

 

I can understand your arguments and I have a simular attitude as I say it could be more dangerous for some people to not take Rapamycin then using it. I go some kind of a middle way. I look for clinically proven pharmaceutical substances where I can approximately estimate the side effects and the net risk/reward ratio. 

 

So far I think Rapamycin, Metformin, Dasatinib+Quercetin, maybe Fisetin are good to go. Especially Rapamycin+Metformin is for me right now the golden standard of anti-aging interventions, others have to proof to be at least as efficient as the Rapamycin+Metformin combination which showed to be more effective then Rapamycin alone: https://www.ncbi.nlm...pubmed/27312235

 

Regarding A1331852 and A1155463: There is no pharmacokinetic data in humans. This substances could be ineffective in vivo at best, toxic at worst.

Hence I plan to experiment Navitoclax as well as Fisetin, and maybe A1331852 and A1155463 before they are even given a real name?

I can understand your arguments and I have a simular attitude as I say it could be more dangerous for some people to not take Rapamycin then using it. I go some kind of a middle way. I look for clinically proven pharmaceutical substances where I can approximately estimate the side effects and the net risk/reward ratio.

So far I think Rapamycin, Metformin, Dasatinib+Quercetin, maybe Fisetin are good to go. Especially Rapamycin+Metformin is for me right now the golden standard of anti-aging interventions, others have to proof to be at least as efficient as the Rapamycin+Metformin combination which showed to be more effective then Rapamycin alone: https://www.ncbi.nlm...pubmed/27312235

Regarding A1331852 and A1155463: There is no pharmacokinetic data in humans. This substances could be ineffective in vivo at best, toxic at worst.

Are there any human studies or even anecdotal evidence that R and M slow human aging? My father in law has been on Metformin for a long time and his health has steadily been getting worse and worse. Does it do anything for mitochondrial health? Lipofuscin? Glycation? Telomeres? Autophagy? How exactly does M (and R) slow human aging? Where are studies and stories of its users?

This thread is going way off topic... D + Q has given me results I've documented.

Are there any human studies or even anecdotal evidence that R and M slow human aging? My father in law has been on Metformin for a long time and his health has steadily been getting worse and worse. Does it do anything for mitochondrial health? Lipofuscin? Glycation? Telomeres? Autophagy? How exactly does M (and R) slow human aging? Where are studies and stories of its users?
This thread is going way off topic... D + Q has given me results I've documented.

 

There is already one small human study on Rapamycin and aging or senescence markers: https://www.ncbi.nlm...pubmed/27883166

Senescence markers went down, as also some inflammation markers by 0.5-2 mg Rapamycin daily in old patients.

 

The mTOR is a highly conserved pathway, AMPK too.
The amount of studies in animal model on autophagy and aging/lifespan with Rapamycin has not been replicated with any other substance. Even with a lack of clinical studies on aging Rapamycin is right now the only medication which comes near to be highly probably a geroprotector.

 

I don`t think we are offtopic here, if I suggest at least to stay away from highly experimental senolytics and give the appropriate pathways why some senolytics should be more or less harmful. I never said anything against Dasatinib which is clinically established as a medication for an existing disease.

 

Edited by Alpharius, 20 March 2017 - 03:03 AM.

 

...snip

 

HUMster's greatest marker is the blood pressure, which showed dramatic reduction

within few weeks after dosing with D+Q+F and holding stable at youthful level of around

120/72 since then, for last half a year.

Here is the historical perspective: The HUMster's blood pressure had been raising

steadily for last 5 years. About 2 years ago it reached levels which became seriously

worrysome.HUMster could see levels of over 150/80 more and more often since then

and HUMster seriously considered starting beta blockers.....but never went so far.

4 doses of D+Q (100 ,6) , each dose week apart , with fasting 2 days before each dosing

did the job ....Also importantly , HUMster had been preloading 3g of Q a day for 2 weeks

before starting D+Q experiment.

 

HUMster's physician  is speechless, wondering what happened.......

 

 

I notice that clearing senescent cells improves blood pressure parameters by reducing calcification from this latest newsletter:

 

Evidence for Senescent Cells to Promote Vascular Calcification
https://www.fightagi...-calcification/

        The progressive stiffening of blood vessels is an important proximate cause of age-related hypertension and cardiovascular disease. One cause of this stiffening is a process of calcification, deposition of calcium into the tissues of blood vessel walls. Recent evidence shows that this process is caused by changes in cellular behavior, which opens up a range of potential targets for therapy and prevention. Here, researchers further demonstrate that the activities of senescent cells are probably involved in this picture. This is good news if validated, as targeted clearance of senescent cells as an approach to the treatment of aging is already heading towards the clinic, under active development at a number of companies.

 

 

The article cites that calcification in blood vessels occurs in part by SASP,( the senescent associated secretory phenotype of senescent cells).  The interesting point is that Humster experienced a -long-lived- drop in blood pressure, which indicates that not only did the SASP diminish, but some of the calcified blook vessels must have been cleaned by some mechanism...

 

Edited by TaiChiKid, 20 March 2017 - 04:37 AM.

Shtira Wrote;

Fasting by itself (water-only, no food, >48/hrs) reliably drops blood pressure for nearly

everyone.

 

In general , for people who do not normally fast , especially when obese, fasting may

indeed often cause the improvement.

I wish it was true in my case. Fasting is a normal state for me and i am pretty lean.

If fastiing had any positive effect on hypertension by itself I would have had noticed

it long time ago. I have not seen any corellation.  We would have to go deeply into the

possible source of the hypertension in the first place. I have some ideas but this is

beyond scope of discussion here. I would rather hear from other people if D+Q+F

worked for them (or not), and then we could get better picture.Mine is only one

isolated case we know about .....we need more numbers to confirm whether it works

the same as in mice or not.

 

cheers

 

 

If endothelial senescent cells are releasing microvesicles into the blood as toxic byproducts, then measuring those microvesicles through (future-designed) blood tests might be an indicator if D+Q is working to clear senescent cells.

Here's a blood test in development (for possibly identifying cancer): https://www.purdue.e...ing-cancer.html

Probably I'm oversimplifying (e.g., which phosphoproteins are detrimental and which are beneficial?); but if we're hunting for ways to know if what D+Q experiment we're doing to ourselves is potentially good, then identifying phosphoproteins (measuring microvesicles numbers) might be on future paths.

A more accessible indicator, as the HUMster suggests, is to just see how D+Q might affect blood pressure numbers over time.

sthira'

 

Even with the senolytic action targeting the same type of cells (eg endothelial) ,

it is not that all the senescent cells will be removed with the same efficiency in

different individuals.

I will give you the example of cancer/senescent cells ablation in smokers vs. nonsmokers.

Below is the article which indicates that nicotine impairs removal of cancer cells

by the  NK cell.......

"Nicotine exposure impairs the ability of NK cells to kill target cells and release

cytokines, a process that is largely abrogated by nAChR β2 deficiency. Further,

nicotinic suppression of NF-κB-induced transcriptional activity in NK cells is

dependent on nAChR β2."

http://journals.plos...al.pone.0057495

 

And there are many other factors which can affect the efficiency of D+Q .....

smoking is only one of them (suppression of NK cells is probably major reason

why smoking increases lung cancer rates, but also increases COPD -which

is caused by senescent cells accumulation).

There are a number of other senolytics being studied however most seem to get discussed in this Group Buy thread mainly because it regroups most Longecity members interested in the latest and greatest potential candidate substances for jevunenation through the death of senescent cells. Maybe the OP can rename the thread adding "and other Senolytics" ??

 

In this vein, the Major Mouse Testing Program is looking at other potential drugs than D+Q or Navitoclax which may help replace aged cells with brand new young ones, such as Venetoclax and ABT-737:

 

http://majormouse.org/?q=research

 

We may help orient their major mouse research, offering informal feedback from human testing? Such reverse-engineered biomedical science would be funny, if the irony of random citizens taking a lead role in substance experimentation wasn't prompted by pharmacological research shortcomings.

 

DareDevil

I would appreciate if a few more knowledgeable members would comment on the validity of this post by Michael Fossel:

 

http://www.michaelfo...com/blog/?p=208

 

Obviously, not a peer-reviewed paper, but on the other hand. it is not written by just 'some-guy-on-the-internet'.

Michael Fossel arguments against a simplicistic view but then uses simplicistic arguments to proof his opinion. Resetting senecent cells sounds more complicated and dangerous then destroying them. Also there is not "the senescent cell" prototype but different phenotypes.

Senescent cells also promote stemness, dedifferentiation and regenerative potential for surrounding cells and support tissue regeneration. But too much of these stimulating and potentially oncogenic factors triggers senescence in the surrounding cells. A vicious circle.

So what Michael Fossel in saying is that we shouldn't use senolytics at all, or not on their own without attending to the health and longevity of the remaining cells?

 

Am I therefore incorrect in assuming that lengthening Telomeres with Epitalon and healing remaining cells with various other supplements will make his warnings useless? I think also that he is a staunch believer that the Hayflick limit of the number of cell divisions is permanently fixed and cannot be affected, in which case we must add to his factory scenario the possibility of hiring fresh new workers in perfect condition.

 

DareDevil

Ladies....and (mostly) Gents"

 

 

I think I found method to protect the Sertolli Cells from untimely demise.

The ,method involves  "COOLING"  the GOODS after dosing with Navitoclax.

The temperature mentioned is 10C.

Cooling causes upregulation of the antiapoptotic Bcl-2, which normally

would be downregulated by Nav. Sort of SUCKING&BLOWING ....but ,this

time , actually would do the job. The article deals with porcine brain .....

but I am sure there is plenty of other research dealing with other tissues.

https://www.ncbi.nlm...pubmed/17382626

 

njurkovi"

 

Just one word about the article written by M. Fossel.

DRIVEL.....

 

You don"t repair something what body already decided its

a garbage and usefulness is none.....The repair resources

would be better utilized when directed at healthy cells .....

eg. stem cells, to keep them youthful and potent.

 

Full rejuvenation of a cell is a very involving and energetically

expensive process, restricted only to progenitor cells and germ line.

 

The rest of the cells (if not removed or mortalized earlier) are supposed

to reach Hayflick limit and die ....(IE Disposable Soma). Tweeking with it,

eg using methods promoted by dr Andrews and associated ppl is a bit

pointless......by extending telomeres you keep lots of sick cells alive

and kicking....

 

 

 

 

Just to keep the conversation flowing:

...this post by Michael Fossel:

http://www.michaelfo...com/blog/?p=208

I think a raised hand of caution here is more than drivel. He has a point, doesn't he, at least conceptually about what happens after the killing? D+Q may indeed kill a few species of senescent cells, then what? Does the body regrow what was killed, how does this magic happen, do healthy cells divide spectacularly to form new baby youth cells, hence speeding their own damage?

When I reread the Longo literature on prolonged fasting his work seems to suggest that fasting sets into motion two biological programs: first, autophagy and apoptosis; then regrowth of new cells. Organs may shrink during a fast, the body tears down damaged cells and proteins, and then recycles and regenerates upon refeeding. It's a good story, anyway: the body does the work. And while I think this is really interesting, the two programs of killing and rebuilding set forth by prolonged fasting do not address Fossel's point:

"In order to replace the cells that you’ve removed, the remaining cells now have to divide, which accelerates their own senescent changes, and hastens the failure of the entire tissue...."

Is this what's going on? Hayflick Limit concerns? Fossel suggests:

"If you want to cure age-related disease, the solution is not to kill senescent cells, but to reset their gene expression to that of young cells." (sic)

Maybe CRISPR advances are making gene expression resets more realistic future advances, maybe the answer will be found in a combination of both killing some cells, and attempting to reset the gene expression of others. Meanwhile, clinical trials are dawning for senolytics, and so the good news is we're likely to learn much more. It's a compelling story -- hopefully it has legs.

So what Michael Fossel in saying is that we shouldn't use senolytics at all, or not on their own without attending to the health and longevity of the remaining cells?

Am I therefore incorrect in assuming that lengthening Telomeres with Epitalon and healing remaining cells with various other supplements will make his warnings useless? I think also that he is a staunch believer that the Hayflick limit of the number of cell divisions is permanently fixed and cannot be affected, in which case we must add to his factory scenario the possibility of hiring fresh new workers in perfect condition.

DareDevil

Kill cells; then rebuild them. Not only are we ahead of the science on the killing part, but we're also ahead of it on regrowing new healthy cells. I'm not sure telomere lengthening compounds have shown much effect yet. One thing I know is that fasting and CR are cheaper and probably safer stop-gap alternatives while we await the turning wheel.

Just to keep the conversation flowing:
Kill cells; then rebuild them. Not only are we ahead of the science on the killing part, but we're also ahead of it on regrowing new healthy cells. I'm not sure telomere lengthening compounds have shown much effect yet. One thing I know is that fasting and CR are cheaper and probably safer stop-gap alternatives while we await the turning wheel.

 

 

In support of sthira's opinion, Longo's fasting mimicking diet leads to remarkable regeneration of beta cells and presumably a wide range of tissues.

 

"Fasting-mimicking diet promotes Ngn3-driven β-cell regeneration to reverse diabetes" (2017) http://www.cell.com/cell/fulltext/S0092-8674(17)30130-7

If anyone in the states has a gram or two they'd be willing to sell, please message me. Thanks!
-Y

Just to keep the conversation flowing:
Kill cells; then rebuild them. Not only are we ahead of the science on the killing part, but we're also ahead of it on regrowing new healthy cells. I'm not sure telomere lengthening compounds have shown much effect yet. One thing I know is that fasting and CR are cheaper and probably safer stop-gap alternatives while we await the turning wheel.

In support of sthira's opinion, Longo's fasting mimicking diet leads to remarkable regeneration of beta cells and presumably a wide range of tissues.
"Fasting-mimicking diet promotes Ngn3-driven β-cell regeneration to reverse diabetes" (2017) )30130-7

Fascinating. I would like to know is happened during fasting too or is it limited to a FMD as a extremely low calories fat based diet.
Are there any information on exact fats that used in FMD ? MCT and LCT oils works quite different on pancreas in regards of oxidative stress.
Any thoughts or insights ?
Edited by Andey, 21 March 2017 - 05:54 PM.

Just to keep the conversation flowing:
Kill cells; then rebuild them. Not only are we ahead of the science on the killing part, but we're also ahead of it on regrowing new healthy cells. I'm not sure telomere lengthening compounds have shown much effect yet. One thing I know is that fasting and CR are cheaper and probably safer stop-gap alternatives while we await the turning wheel.

In support of sthira's opinion, Longo's fasting mimicking diet leads to remarkable regeneration of beta cells and presumably a wide range of tissues.
"Fasting-mimicking diet promotes Ngn3-driven β-cell regeneration to reverse diabetes" (2017) )30130-7

Fascinating. I would like to know is happened during fasting too or is it limited to a FMD as a extremely low calories fat based diet.
Are there any information on exact fats that used in FMD ? MCT and LCT oils works quite different on pancreas in regards of oxidative stress.
Any thoughts or insights ?

The papers coming out of Longo's USC lab regarding prolonged fasting are very exciting. Read up! Senolytic compounds are exciting, too, and combining the experiments -- D+Q+F+N+fisetin.... well, here we are trying stuff for ourselves ahead of the science (yet again haha, long histories here) before we know too much.

To quote maxwatt: hurry up and do it while it still works...
Edited by sthira, 21 March 2017 - 08:34 PM.

The D+Q+F and blood pressure effect is intriguing. I wonder if the possible inaccuracy of home blood pressure testing would invalidate results of somebody trying to recreate the N=1 study outlined above by Longevitarian ? Perhaps measure BP at the same time each day, but multiple readings over a 5 minute period. Or testing multiple times per day spread out? Maybe try with a modified fast. If that fails, the same test could be tried with the original fast outlined by Longevitarian.

I'm still skeptical that fasting is as effective of a synolitic as people would like to believe. If it were I think we'd see more overt evidence of rejuvenation and longevity as people have been fasting religiously for millennia. Maybe I'm biased because of my tough time with it, but there's that to consider.

Edited by Nate-2004, 21 March 2017 - 10:00 PM.

I'm still skeptical that fasting is as effective of a synolitic as people would like to believe. If it were I think we'd see more overt evidence of rejuvenation and longevity as people have been fasting religiously for millennia. Maybe I'm biased because of my tough time with it, but there's that to consider.

Skepticism is encouraged. Fasting isn't for everyone, and it can be dangerous. Longo himself advises against it without physician supervision -- but where you gonna find that? There's Goldhamer and Klapper at True North in Santa Rosa, there's Fung, there are retreats all over the world.

But if you're questioning the health and regeneration powers of prolonged fasting, a quick read of the current literature might undercut some doubt -- at least from the physiological perspective. Fasting does amazing things. But the psychology of fasting is a high hurdle, and in my experienced opinion, the worst aspects are social, not so much physical until very deep into a fast.

Short fasts -- say, under ten days -- are usually available to those interested.

10 Days is *short*? Hahahaahaha. I can barely make 12 hrs.

 

I read about intermittent fasting where you only eat in an 8 or 9 hr period like, from 14:00 to 22:00 every day. I tried it twice, I couldn't even make it to 12:00 without losing myself. My brain was shut down and I couldn't work. I keep wanting to try again but I keep running into that problem. Maybe a retreat like you say is a better option. Where I don't have to work or every day life isn't interfering. 

Definitely don't do it if it doesn't work for you. And I don't mean to sound like fasting for ten days is like some stupid heroic accomplishment. It's a lifestyle choice, and it's a cultivated skill. You don't blindly rush in (unless you're kinda dumb) but rather practice it on your own and explore your limits. But in the end, I'm most living this way -- regularly fasting -- because of the overwhelming amount of great science that's convinced me this is good for health and (maybe) increased lifespan.

Then again, maybe it doesn't do what has been claimed (for free-living, non-caged humans) and maybe the practice of fasting is just another dead end. Actually, I kinda suspect fasting and CR is yet another futile attempt to slow aging, but for now we honestly have nothing else that's even close.

One more point then I'll shut the fuck up about this off topic excursion: when we look out at nature -- creatures living in the natural world -- nearly everyone is hungry nearly all the time. And so too for the majority of humans -- hunger is the natural state -- eating is what's special. Then again, careful, sthira, haha you're falling into to the Naturalist Fallacy (Mother Nature doesn't give a flying fuck).

Meanwhile, dasatinib for the win!

I'm still skeptical that fasting is as effective of a synolitic as people would like to believe. If it were I think we'd see more overt evidence of rejuvenation and longevity as people have been fasting religiously for millennia. Maybe I'm biased because of my tough time with it, but there's that to consider.

Skepticism is encouraged. Fasting isn't for everyone, and it can be dangerous. Longo himself advises against it without physician supervision -- but where you gonna find that? There's Goldhamer and Klapper at True North in Santa Rosa, there's Fung, there are retreats all over the world.

But if you're questioning the health and regeneration powers of prolonged fasting, a quick read of the current literature might undercut some doubt -- at least from the physiological perspective. Fasting does amazing things. But the psychology of fasting is a high hurdle, and in my experienced opinion, the worst aspects are social, not so much physical until very deep into a fast.

Short fasts -- say, under ten days -- are usually available to those interested.

Any guess how much of a weight loss 10 day fast could involve ?
I practice Trf ( time restrictive eating) with occasional 1-2 days fasts and dont really have any spare weight at bmi just barely more then 18. Dont wanna look anorexic ))
Edited by Andey, 22 March 2017 - 07:25 AM.

10 Days is *short*? Hahahaahaha. I can barely make 12 hrs.

 

I read about intermittent fasting where you only eat in an 8 or 9 hr period like, from 14:00 to 22:00 every day. I tried it twice, I couldn't even make it to 12:00 without losing myself. My brain was shut down and I couldn't work. I keep wanting to try again but I keep running into that problem. Maybe a retreat like you say is a better option. Where I don't have to work or every day life isn't interfering. 

 

The stomach is connected to the brain via the vagus nerve and even contains neurons!
In short this means that whichever bacteria (10 for every cell) are dominant in the gut have a direct line to the brain.
They can and do use it to convince you that you...  not them...  are hungry for whatever food they like best.

 

You may want to look at means to influence leptin and ghrelin levels:

https://www.ncbi.nlm...pubmed/17212793

 

But 'Supps to enhance autophagy and macrophagy' is probably a better bet for you:  

http://www.longecity...and-macrophagy/

BCL is mentioned and this is before I knew of its role in senescent cell clearance, so this thread is a good place to looks for leads and adjuncts to D and N etc.

Of note:

The effect of vitamin D which is probably the vitamin I would choose if I could choose only 1...
Inositol/IP3 as found in all? multivitamins blocks autophagy.
 

Bacteria basically eat, digest and excrete the food you eat, so yes; we all live on bacteria shit!
So its good idea to approve of the bacteria who's excrement you are living on and try to feed the good guys while starving and/or killing off the bad.

Butyrate which is produced by a bacteria that likes things like raw potato starch enhances apoptosis of cancerous cells for example.

https://www.ncbi.nlm...pubmed/25500581