Scientific American article "living to 120" metformin, rapamycin and quercetin

[mikeccolella]

Accolades for metformin in the current issue. Seems research is showing that not only do metformin patients live 18% longer than non diabetics they also live longer than diabetics who have their diabetes controlled by other drugs! This, they claim, strongly suggests an anti aging effect. Also surprisingly Quercetin mentioned as a killer of senescent cells which mouse experiments indicate is a longevity factor.

 

Where do you find quercetin? Capers are loaded with it as well as red onions. Also broccoli, kale, yellow onions, apples with skin, and cranberries. Raw is best because cooking destroys it.

 

So if metformin is really as fantastic as they are suggesting then how the hell do we get it legally?

[Michael R]

All:
 
(Psst: Mike, include the link for goodness' sake! If you only have a print copy and can't find it online, at least give the title, issue number, and page so future readers have some hope of finding it).
 

Accolades for metformin in the current issue. Seems research is showing that not only do metformin patients live 18% longer than non diabetics they also live longer than diabetics who have their diabetes controlled by other drugs!

The latter is what you'd expect, as other diabetes drugs have significant side-effects and many of them either are or elevate levels of insulin, which is a mitogen that stimulates the growth of arterial smooth muscle cells and many cancers. The former is based on a flawed study claiming to show longer lives in metformin users than nondiabetics.
 

This, they claim, strongly suggests an anti aging effect.

It would if it did, but it doesn't so it doesn't ;) . The NIA's ITP just confirmed yet again taht metformin does not extend the lives of healthy, normal mice,(2) confirming previous reports published in one paper from Spindler and separately by in-house work at NIA(3) (the ITP is done at three independent sites at the University of Michigan (by the redoubtable Richard Miller), the Barshop Institute on Aging at the University of Texas, and The Jackson laboratories), and yet another report in normal rats.(4)
 

Also surprisingly Quercetin mentioned as a killer of senescent cells which mouse experiments indicate is a longevity factor.

If this was really a surprise to you, you need to be following FightAging!
 
When you say "mouse experiments indicate is a longevity factor," I assume you mean that mouse experiments indicate that ablation of senescent cells substantially increases median lifespan — as discussed extensively here (pay attention!). (Dean is right to emphasize the caveats on this study, but the result is highly convincing none the less).
 
The former is a real effect, resulting in dramatic benefits in normally-aging mice, and set off a real race for senolytic drugs. However, the in vivo effects have only been documented at high doses, and in combination with the cancer drug dasatinib.(5) Also NB that this study used a very brief intervention to clear senescent cells and then test the animals shortly thereafter: dasatinib is a fairly nasty drug for ongoing use, and chronic high-dose quercetin has been shown to shorten the lives of normally-aging mice.(1)
 
Ablation of senescent cells is one of the many forms of cellular and molecular damage whose removal, repair, or replacement is the key to the damage-repair strategy of SENS. SENS Research Foundation made an early investment in Oisín Biotechnologies, a startup in the field, along with some intellectual property match-making. While their in vivo testing is at an earlier stage of development than the Mayo Clinic compounds or UNITY, Oisín has the decided advantage of going directly after p16, which while imperfect is reasonably specific and selective for senescent cells, whereas existing senolytic agents act by nonspecifically inhibiting pro-survival and anti-apoptotic pathways on which normal, healthy cells also depend to keep themselves alive in order to repair themselves when they are undergoing stress. This leads to the risk of significant GI, renal, haematological, and cardiopulmonary side-effects, some of which have already been observed in animal testing.
 
At Rejuvenation Biotechnology 2016 (full videos now available!), I was privileged to see a private presentation of some of their preliminary in vivo data, which looked pretty damned impressive, and to hear their quite comprehensive strategy to get their therapy to market if demonstrated in proof-of-concept animal studies.
 

Where do you find quercetin? Capers are loaded with it as well as red onions. Also broccoli, kale, yellow onions, apples with skin, and cranberries. Raw is best because cooking destroys it.

You won't get anywhere near the doses used to kill senscent cells (50 mg/kg in mice (5)) from dietary sources.Using the Human Equivalent Dose (HED), which is FDA and EPA's preferred method for adjusting for the effects of species size on metabolic rates andn drug metabolism amongst species and is based on the typical comparative body surface area of the species involved yields 283 mg of quercetin for a 70 kg adult. An alternative method, superior IMO is to use strict allometric scaling based on the weights of the animals in the study vs. the human involved; assuming the mice weighed 40 g (since the gits didn't include this datum) and in this case scaled to the 3/4 power because of extensive metabolism of quercetin (even more than resveratrol: PMID 12554065), yields 541 mg.
 
Are you going to get this from eating more onions and apples? In a Spanish cohort, the mean ± SD intake was 17.1±9.05 mg/d, with the top 20% of diets providing 23.94 mg/d.(6) Similarly, the top quintile of intake in a Finnish cohort was 12 mg.(7)  But intakes in a French cohort were <4 mg, and still <31 mg even if you include its glycosides and complexed compounds that would not likely have the same activity;(8) similarly, intake of all flavonols combined (isorhamnetin, kaempferol, myricetin, and quercetin) was only 15.9 mg/d on average in Americans in NHANES.(9)
 
I'm sure CR diets provide more phenolics generally, and maybe more quercetin in particular, but not by close to thirty times as much as an onion-and-apple-eating Spaniard.
 

So if metformin is really as fantastic as they are suggesting

It's not ...
 

then how the hell do we get it legally?

Go to the doctor, make a good case, and get a prescription.

Or, better yet: don't.

Reference
1: Jones E, Hughes RE. Quercetin, flavonoids and the life-span of mice. Exp Gerontol. 1982;17(3):213-7. PubMed PMID: 7140862.

2: Strong R, Miller RA, Antebi A, Astle CM, Bogue M, Denzel MS, Fernandez E, Flurkey K, Hamilton KL, Lamming DW, Javors MA, de Magalhães JP, Marinez PA, McCord JM, Miller BF, Müller M, Nelson JF, Ndukum J, Rainger GE, Richardson A, Sabatini DM, Salmon AB, Simpkins JW, Steegenga WT, Nadon NL, Harrison DE. Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an α-glucosidase inhibitor or a Nrf2-inducer. Aging Cell. 2016 Jun 16. doi: 10.1111/acel.12496. [Epub ahead of print] PubMed PMID: 27312235.

3. Alejandro Martin-Montalvo, Evi M. Mercken, Sarah J. Mitchell, Hector H. Palacios, Patricia L. Mote, Morten Scheibye-Knudsen, Ana P. Gomes, Theresa M. Ward, Robin K. Minor, Marie-José Blouin, Matthias Schwab, Michael Pollak, Yongqing Zhang, Yinbing Yu, Kevin G. Becker, Vilhelm A. Bohr, Donald K. Ingram, David A. Sinclair, Norman S. Wolf, Stephen R. Spindler, Michel Bernier & Rafael de Cabo Metformin improves healthspan and lifespan in mice Nature Communications 4, Article number: 2192 doi:10.1038/ncomms3192 Published 30 July 2013 PMID 23900241‎

4: Smith DL Jr, Elam CF Jr, Mattison JA, Lane MA, Roth GS, Ingram DK, Allison DB. Metformin supplementation and life span in Fischer-344 rats. J Gerontol A Biol Sci Med Sci. 2010 May;65(5):468-74. doi: 10.1093/gerona/glq033. Epub 2010 Mar 19. PubMed PMID: 20304770; PubMed Central PMCID: PMC2854888.

5: Zhu Y, Tchkonia T, Pirtskhalava T, Gower AC, Ding H, Giorgadze N, Palmer AK, Ikeno Y, Hubbard GB, Lenburg M, O'Hara SP, LaRusso NF, Miller JD, Roos CM, Verzosa GC, LeBrasseur NK, Wren JD, Farr JN, Khosla S, Stout MB, McGowan SJ, Fuhrmann-Stroissnigg H, Gurkar AU, Zhao J, Colangelo D, Dorronsoro A, Ling YY, Barghouthy AS, Navarro DC, Sano T, Robbins PD, Niedernhofer LJ, Kirkland JL. The Achilles' heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell. 2015 Aug;14(4):644-58. doi: 10.1111/acel.12344. Epub 2015 Apr 22. PubMed PMID: 25754370; PubMed Central PMCID: PMC4531078.
 
6: Zamora-Ros R, Andres-Lacueva C, Lamuela-Raventós RM, Berenguer T, Jakszyn P, Barricarte A, Ardanaz E, Amiano P, Dorronsoro M, Larrañaga N, Martínez C, Sánchez MJ, Navarro C, Chirlaque MD, Tormo MJ, Quirós JR, González CA. Estimation of dietary sources and flavonoid intake in a Spanish adult population (EPIC-Spain). J Am Diet Assoc. 2010 Mar;110(3):390-8. doi: 10.1016/j.jada.2009.11.024. PubMed PMID: 20184989.

7: Wright ME, Mayne ST, Stolzenberg-Solomon RZ, Li Z, Pietinen P, Taylor PR, Virtamo J, Albanes D. Development of a comprehensive dietary antioxidant index and application to lung cancer risk in a cohort of male smokers. Am J Epidemiol. 2004 Jul 1;160(1):68-76. PubMed PMID: 15229119.

8: Julia C, Touvier M, Lassale C, Fezeu L, Galan P, Hercberg S, Kesse-Guyot E. Cluster analysis of polyphenol intake in a French middle-aged population (aged 35-64 years). J Nutr Sci. 2016 Jul 7;5:e28. doi: 10.1017/jns.2016.16. eCollection 2016. PubMed PMID: 27547391; PubMed Central PMCID: PMC4976116.

9: Kim K, Vance TM, Chun OK. Estimated intake and major food sources of flavonoids among US adults: changes between 1999-2002 and 2007-2010 in NHANES. Eur J Nutr. 2016 Mar;55(2):833-43. doi: 10.1007/s00394-015-0942-x. Epub 2015 May 31. PubMed PMID: 26026481.

[Sthira]

Every now and then :https://www.amazon.com/gp/aw/d/B0013OULOC/ref=mp_s_a_1_1_a_it?ie=UTF8&qid=1472433984&sr=8-1&keywords=jarrow+quercitin

 

But my understanding is supplementing quercetin isn't too bioavailable? Huh question mark huh

 

And forget the sprycel unless you wanna lose them beautiful dreadlocks to hair loss.

[mikeccolella]

http://www.ncbi.nlm.nih.gov/pubmed/25041462

 

Michael here is the link to the study referenced

 

http://www.immunehealthscience.com/support-files/quercetin_content.pdf

 

Wrt to quercetin this chart indicates that it would be doable to obtain substantial levels with diet.

[Michael R]

http://www.ncbi.nlm.nih.gov/pubmed/25041462

 

Michael here is the link to the study referenced

Right: I linked the full text of the study when I explained why it's flawed in my  reply to you above. Do you read my posts before responding to them? Do you know how to use a hyperlink?

 

http://www.immunehealthscience.com/support-files/quercetin_content.pdf

 

Wrt to quercetin this chart indicates that it would be doable to obtain substantial levels with diet.

Technically, yes. I dare you to eat 200 g of raw capers a day ;) . You could eat a 79 g radish leaf salad, but what are you going to do with all the radishes? I strongly recommend that you do not down almost 2 cups of Elderberry juice concentrate a day. 1.66 kilograms of red onions, maybe ...?

 

After that, your options get pretty limited. And, this assumes that the bioavailability of quercetin in a food matrix is similar to the synthetic supplement in rat chow, which seems unlikely.

[mikeccolella]

mikeccolella, on 28 Aug 2016 - 09:32 AM, said:

So if metformin is really as fantastic as they are suggesting

 

Michael Rae responded

 

"It's not".

 

Michael R u guilty of dogmatism defined here as:

 

"the tendency to lay down principles as incontrovertibly true, without consideration of evidence or the opinions of others."

 

I think sometimes you r????

 

IAC, you MAY be wrong on metformin. There is currently research ongoing that will hopefully shed more light on this subject.

 

 

Metformin, an FDA approved first-line drug for the treatment of type 2 diabetes, has known beneficial effects on glucose metabolism. Evidence from animal models and in vitro studies suggest that in addition to its effects on glucose metabolism, metformin may influence metabolic and cellular processes associated with the development of age-related conditions, such as inflammation, oxidative damage, diminished autophagy, cell senescence and apoptosis. As such, metformin is of particular interest in clinical translational research in aging since it may influence fundamental aging factors that underlie multiple age-related conditions. The investigators therefore propose a pilot study to examine the effect of metformin treatment on the biology of aging in humans. Namely, whether treatment with metformin will restore the gene expression profile of older adults with impaired glucose tolerance (IGT) to that of young healthy subjects.

Metformin in Longevity Study (MILES)

This study is ongoing, but not recruiting participants.

Sponsor:

Albert Einstein College of Medicine of Yeshiva University

Information provided by (Responsible Party):

Albert Einstein College of Medicine of Yeshiva University

 

The investigators hypothesize that treatment with metformin will result in changes in the transcriptome, reverting the expression profile of older adults with IGT to a younger level. The investigators will test this by identifying changes in gene expression in muscle and adipose tissue with RNA Sequencing (RNA-Seq). The investigators will also study expression of specific target genes (using RT-PCR), mitochondrial number and morphology and adipose macrophage content and activation

[Gordo]

While I eagerly await the results of the above mentioned study (which has been discussed elsewhere in these forums) I still tend to think metformin is a bad idea in light of its long list of side effects (including "messing with" the GI tract), when you can achieve the same benefits via other means.  Dean has noted in the cold exposure thread that metformin is a BAT activator, any longevity and blood sugar lowering characteristics might be attributable simply to BAT activation.  To me it makes more sense to focus on BAT activation by other means.  If the general population must have some pill substitute for cold exposure, I'm thinking capsinoids (synthetic or extracts) might have more potential than metformin.  Dean and I are working on a secret project around this right now (haha).