27 replies to this topic

[eighthman]

http://www.aging-us....M6QRmQDfFh/text

 

I noticed this on a portal here but not on the main forum, in regard to senolytics.

 

Perhaps this biochemical would be easy to extract.

[RWhigham]

Source for piperlongumine http://www.adooq.com...rlongumine.html  25mg, 50mg, or 10 mM in 1mL DMSO at somewhat affordable prices.

 

In the OP reference 5 uM in vitro killed 25% of the senescent cells and few (or none) non-senescent cells. But increasing the concentration to 10 uM killed 75% of the senescent cells and about 10% of non-senescent cells. 

Edited by RWhigham, 29 December 2016 - 06:37 PM.

[eighthman]

I guess the other relevant question would be - does piperine interfere with piperlongumine ?  One of the studies seemed to say that some antioxidants didn't seem to make any difference as to the senolytic action.

 

My interest is that it might be possible to extract these two substances from pepper roots fairly easily but separating them might be very difficult.  We could have a largely nontoxic supplement here that hits pancreatic cancer and also nails senescent cells - and might be easy to make.

[sthira]

Or just add long pepper to diet? https://www.amazon.c...e bag - 4 Ounce

[eighthman]

We gotta figure out how much to take, how much is in the pepper and whether other stuff in the pepper gets in the way.

[stefan_001]

Hi eighthman, interesting find. So here the data on long peppers:

 

P. longum fruits obtained from Bombay market showed 0.213 ± 0.009% w/w piperine and 0.364 ± 0.014% w/w piperlongumine when analyzed by the proposed method. Similarly, sample fruits obtained from Ahmedabad market had 0.85 ± 0.026% piperine and 2.70 ± 0.065% of piperlongumine.

http://www.akademiai...JPC.27.2014.5.6

 

but before doing the trouble of figuring out how many to eat I am wondering whether anybody has tried to eat these....?

[pamojja]

Pippali or long pepper is commonly used in Ayurveda.

 

 

https://www.toddcald.../herbs/pippali/

 

Dosage:

• Churna: 2-3 g b.i.d.-t.i.d.

 

9 gram would be quite a dose. Taking the average of 1,357% piperlongumine, about 122 mg of it. Personally only took up to 1 gram long pepper.

Edited by pamojja, 31 December 2016 - 12:43 AM.

[Michael]

As I just posted elsewhere:

Folks, acting on this by swallowing large amounts of black pepper or Piper longum is madness ...

First, they haven't even shown that this stuff kills senescent cells in vivo, and we have no idea about a remotely rational dose for doing so. Second, we have no idea yet of the mechanism. Third, while the paper says that "the maximum tolerated dose in mice is very high," this is not remotely like safety data: it's based on the lack of acute toxic effects after 6 days' treatment.

 

And whether or not piperlongumine is safe or effective, swallowing mass amounts of pepper in hopes of getting an undefined minimum amoiunt of piperlongumine is not: piperine inhibits a range of xenobiotic-metabolizing enzymes, including the CYP450s and UDP-glucuronosyltransferase, potentially increasing the absorption of dietary carcinogens and other toxins (particularly in conjunction with the concomitant irritation of the intestinal wall). And while there are studies showing that piperine reduces the toxicity of endotoxin to cultured cells and tissue samples, it's entirely plausible that piperine-mediated increases in instestinal permeability could increase absorption of endotoxin, which increases systemic inflammation and has been implicated in atherosclerosis and a range of chronic diseases.

 

I repeat: they haven't even shown this stuff has senolytic effects in vivo yet, and are very far indeed from showing it's safe. Wait a while, OK? There's senolytic drugs and Oisín's non-integrating genetic senescent cell ablation system coming down the pipe, and they have animal data. There's nothing more embarrassing than dying prematurely from a foolish life extension experiment.

 

[maxwatt]

For those interested in senolytics, I'd like to call your attention to this post  http://www.longecity...ndpost&p=801755    

which links to a crowdfunding site for Cellage, a company seeking to develop molecules more specifically targeted to specific senescent cells, not just those that this happens to reach(or not reach), perhaps with an overly broad sweep.

The write-up about the company on the crowdfunding site is informative.

 

FWIW, long pepper also contains sarmentine, which has been researched as a pesticide.  I was involved in a project to isolate the stuff, but the cost to extract was prohibitive and it never got so far as to test for toxicity to mammals.

 

 

 

[normalizing]

michael, i understand what you are saying but just adding long pepper to a diet, wont do much harm i suppose. piperine is present in higher amounts in black pepper as im aware? and it hasnt caused health problems as of yet even regards to people consuming high amounts of it from diet

[Michael]

michael, i understand what you are saying but just adding long pepper to a diet, wont do much harm i suppose. piperine is present in higher amounts in black pepper as im aware? and it hasnt caused health problems as of yet even regards to people consuming high amounts of it from diet

 
I'm not aware of any data whatsoever showing that high dietary consumption of either black pepper or P. longum doesn't cause cancer or other health problems; can you point to anything? (No, population-level observations like "many Indians eat a lot of it and India doesn't have epidemic cancer" are not a remotely reasonable counterargument, absent prospective data following individual Indian pepper consumers. Until recently there were more smokers per capita in Japan  than in the USA, yet their death rate from lung cancer was lower. To see the effect of smoking you needed individual-level data. 'Sides, in India, the causes of death that outcompete cancer are (after  CVD) "Diarrhea, Lower Respiratory Infections, and Other Infectious," followed by "Chronic Respiratory Disease"; "Neonatal Disorders" still beat out cancer there. And even in the West, only 7% of people with such a standout risk factor for lung cancer as smokers die of the disease).
 
In any case, it would clearly be silly to just add a moderate amount of P. longum to the diet in hopes of getting a senolytic effect. If there is a senolytic effect in vivo (which, again, has not yet been demonstrated, even in rodents), it's going to require very high amounts of fruit to even plausibly deliver the needed amount of PL, and with enormous variability. The in vitro work used 10 µM of the stuff, which is the same concentration found effective in vitro in the rodent cancer study; in the rodent cancer study, they scaled that10 µM up to 2.4 mg /kg; even after allometric scaling, that still means ≈24 mg of the stuff.
 
How are you going to translate that into fruit? The study found by Stefan found 0.364 ± 0.014% PL in P. longum from the Bombay market, and 2.70 ± 0.065% PL in fruits from the Ahmedabad market ; that's a sevenfold difference. Meanwhile, this study found no piperlongumine in P. longum fruit — only in the roots (don't confuse it with piperlonguminine, NB). So are you going to start consuming 889 g (nearly 2 pounds) of Ahmedabad-sourced P. longum every day and hope that it works out? Or 6593 g of the stuff from Bombay? Or are you going to start sourcing and grinding up the root ...?
 
Or are you just going to give up on this silliness until someone at least shows it does something in an actual animal model, and gives you some reason to believe it's not otherwise toxic?

[eighthman]

I believe they've shown effectiveness against cancer in rats in vivo, so I wouldn't dismiss this as silly.  We may need some more info on the means by which the anti-cancer effect took place. Did it trigger apoptosis in a manner that would suggest a similar action against ordinary senescent cells?

[Michael]

I believe they've shown effectiveness against cancer in rats in vivo

Right: I linked the cancer study in my first post, and explicitly used the dose scaling from "the rodent cancer study" in the post to which you're responding.
 

so I wouldn't dismiss this as silly.

See above .
 

We may need some more info on the means by which the anti-cancer effect took place. Did it trigger apoptosis in a manner that would suggest a similar action against ordinary senescent cells?

 
The MoA isn't known: for cancer, it was originally proposed to be a burst of ROS, but there's evidence against this for both cancer and senescent cells (see the paper); however, they didn't link PL's in vitro effect to the specific ROS-independent mechanism proposed in the followup cancer paper.
 

But this is all a sideshow. Even if we knew the MoA, and even if we knew it was effective in isolation in vivo against senescent cells (which, to beat it to death, we do not), I refer you back to my previous points about lack of any evidence on safety, chemical fellow-travelers to PL, and the wildly-varying but enormous doses of P. longum fruit or concentrate that would be required to take a stab at this.

[eighthman]

"PL appears to be safe ; the maximum tolerated dose in mice is very high and it maintains high bioavailability after oral administration"

 

I'm interested in extraction, not consuming the fruit.

[maxwatt]

Well in that case, a 4:1 extract is available.  But Michael's points apply:  we don't know if large amounts over time have undesired side effects - probably but not assuredly not -- and we don't know if it will have the desired senolytic effect in vivo.  Many, many phytochemicals show marvelous effects in vitro (when tested by doctoral candidates who are motivated to get a positive result) but most small molecules never pan out in vivo. 

 

I would be happy to sell you all the Piper Longum extract you want if you are so determined,

[eighthman]

Thanks.  Could you define 4:1 a bit more precisely?  Simply a reduction of weight of fruit down to a quarter of what it was?  Or....

[Michael]

"PL appears to be safe ; the maximum tolerated dose in mice is very high and it maintains high bioavailability after oral administration"
 
I'm interested in extraction, not consuming the fruit.

 
As (again ...) I said in my first post, "while the paper says that "the maximum tolerated dose in mice is very high," this is not remotely like safety data: it's based on the lack of acute toxic effects after 6 days' treatment."

[sthira]

Long pepper is readily available in stores and online, and if nothing else, it does have a different taste than regular ole black pepper. And who knows, small, dietary amounts used to perk up some delicious healthy meal may have mysterious added benefits. You could add it as a spice into raw broccoli sprouts, mustard seed, and tomato sauce, for example, and it'll certainly enlighten the mouth.

[pamojja]

Here an Ayurvedic mongraph for Pippali, as long pepper is called in India:

 

https://www.toddcald.../herbs/pippali/

 

(needs registering)

[eighthman]

I think the danger from senolytics would be heart failure as senescent cells are removed faster than stem cells could theoretically replace.  OTOH, if this is one of only a few things effective against pancreatic cancer, for many, risk is worth considering.

 

 

[pamojja]

(No, population-level observations like "many Indians eat a lot of it and India doesn't have epidemic cancer" are not a remotely reasonable counterargument, absent prospective data following individual Indian pepper consumers. Until recently there were more smokers per capita in Japan  than in the USA, yet their death rate from lung cancer was lower. To see the effect of smoking you needed individual-level data. 'Sides, in India, the causes of death that outcompete cancer are (after  CVD) "Diarrhea, Lower Respiratory Infections, and Other Infectious," followed by "Chronic Respiratory Disease"; "Neonatal Disorders" still beat out cancer there.

 

Here an Ayurvedic mongraph for Pippali, as long pepper is called in India:

 

https://www.toddcald.../herbs/pippali/

 

(needs registering) ..

 

Medical research:
• In vitro: anti-amoebic (Ghoshal et al 1996, Ghoshal & Lakshmi 2002); giardicidal (Tripathi et al 1999); insecticidal (Yang et al 2002)
• In vivo: anti-amoebic (Ghoshal et al 1996, Ghoshal and Lakshmi 2002); giardicidal (Tripathi et al 1999); immunostimulant (Agarwal et al 1994); absorption/bioavailability enhancement (Atal et al 1981, Khajuria et al 2002), anti-ulcerogenic (Agrawal et al 2000), hepatoprotective (Koul and Kapil 1993), antitumor (Pradeep & Kuttan 2002)
• Human trials: a formula comprised of Piper longum and Butea monosperma given to patients suffering from giardiasis completely eliminated the parasite from the stool in 92% of the treatment group, and simultaneously decreased the presence of mucus, pus cells and RBCs (Agarwal et al 1997).

...

 

Probably that's why it's so popular there.

[cesium]

Piperlongumine has a wide range of beneficial effects against almost all cancers it was tested against. It's inhibition of NF-kappaB activity would make it an excellent anti-infammatory,  as well as down regulating the Akt/mammalian target of rapamycin (mTOR) signalling pathway. Researching it on pubmed I've yet to come up with any negatives to give me pause to take it in at least moderate amounts found in long pepper. Not sure of the dosage required but it's decrease of mTORC1 activity like rapamycin does interests me greatly, and I've switched to using long pepper instead of common black pepper on my foods. Not sure I'd want to take 9 grams a day of it though on a regular basis until more is known. 

[Michael]

All:

 

I think the danger from senolytics would be heart failure as senescent cells are removed faster than stem cells could theoretically replace.

 

This seems like a very unlikely risk. In the original "senolytic" report, "treatment of 24-month-old mice with a single dose of [dasatinib and quercetin] significantly improved left ventricular ejection fraction (Fig. 4A) and fractional shortening (Table S3), effects that were mediated by reductions in end-systolic cardiac dimensions (Fig. 4C) but not cardiac preload (Fig. 4B) or alterations in cardiac mass (Table S3). ... Collectively, these data suggest that senescent cells likely exert deleterious effects on cardiovascular function with chronological aging and that acute clearance of senescent cells may be a novel therapeutic approach to improve cardiovascular function and reduce morbidity and mortality from cardiovascular disease in the elderly." Plus, it improves vascular function (and thus likely perfusion), while Campisi and Van Deursen have separately shown that senescent cell clearance prevents early atherosclerosis and reduces the vulnerability of advanced plaque, so the same cardiac structure will likely function better than a non-atherosclerotic mouse model would show.

 

Additionally, there are vanishingly few true stem cells in the heart, and their role in rebuilding new cardiac muscle is extremely limited; on the flips side, the aging heart suffers significant fibrotic infiltration, this being a substantial and early contributor to  hypertrophic cardiomyopathy. So the loss of a very small number of senescent cells is — from first principles — unlikely to make a significant structural impact in the face of other aging changes.
 

Edited by Michael, 14 January 2017 - 10:23 PM.

[eighthman]

Can stem cells be otherwise transported by blood stream and used in the heart?  Can 'the dose make the poison' in removal of senescent cells?  Can removal of such affect rhythm?

 

 

[Michael]

Can stem cells be otherwise transported by blood stream and used in the heart?  Can 'the dose make the poison' in removal of senescent cells?  Can removal of such affect rhythm?

 

Circulating stem cells can't differentiate into cardiomyocytes. They do provide some trophic support during heart attack and stroke which helps the tissue that isn't immediately killed off to recover, but they don't directly contribute to cardiac structure and don't likely contribute to maintenance of the heart against more routine cell loss related to senescence and other aging processes or very minor local trauma or ischaemia. 
 

[Senescentis Salutem]

http://www.longecity...piperlongumine/

[Senescentis Salutem]

 

As I just posted elsewhere:

Folks, acting on this by swallowing large amounts of black pepper or Piper longum is madness ...

First, they haven't even shown that this stuff kills senescent cells in vivo, and we have no idea about a remotely rational dose for doing so. Second, we have no idea yet of the mechanism. Third, while the paper says that "the maximum tolerated dose in mice is very high," this is not remotely like safety data: it's based on the lack of acute toxic effects after 6 days' treatment.

 

And whether or not piperlongumine is safe or effective, swallowing mass amounts of pepper in hopes of getting an undefined minimum amoiunt of piperlongumine..

 

I repeat: they haven't even shown this stuff has senolytic effects in vivo yet, and are very far indeed from showing it's safe.

 

 

I would completely agree. We need to establish it's safety and effectiveness in mice and confirm the same in humans before anyone should consider taking this chemical. 10 days is the longest this has been given to mice [PMID:26649232] which is a very short period of time to determine all the possible side effects.

 

It's noteworthy to mention piper longum fruit toxicity studies have only been done on an ethanolic extract of 100 mg/kg/day for 90 days and while there was no significant mortality it did show an increase in the weight of the lungs and spleen of the treated animals. [PMID: 950084]. To date it is not currently GRAS and there is no human studies I have found. Considering that and the number of pharmacological active chemicals [https://postimg.org/image/msc5uzvrb/] it contains I would not advise anyone consume it.

Edited by Senescentis Salutem, 05 February 2017 - 04:37 AM.

[DJSwarm]

You do know we are talking about black and long pepper?

 

Spices that have been use by humans for millennia and which madras curry aficionados eat in mass quantity and which for most of that time was also used in mass quantity to preserve food before refrigeration. While currently out of favor in the US, long pepper was quit popular here previously and remains very popular in more culinarily adventuresome locals, not to mention being used as a medicine for countless centuries.

 

That seems pretty "GRAS." BTW, rodents are not a good test model here as they find it quite toxic, much like dogs are not good for testing chocolate.

 

The main issue as a possible complication would be that pepper increases the bioavailability of many substances. https://www.ncbi.nlm...les/PMC3458266/

 

That can be good for CoQ10 or turmeric, or even as it is now being used to enhance treatment of tuberculosis. But not so good for drugs with more sensitive dosing profiles.

 

As an effective senolytic it is untested. As a spice it seems easily "GRAS"  for up to a couple grams in curry and it looks like it would be a useful bioenhancer for a wide spectrum of substances. You may notice that lately turmeric comes with pepper added since it boosts its availability about 2000x.