34 replies to this topic

[opales]

http://www.ncbi.nlm....pubmed/24245565

Aging Cell. 2013 Oct 26. doi: 10.1111/acel.12170. [Epub ahead of print]
Acarbose, 17-α-estradiol, and nordihydroguaiaretic acid extend mouse lifespan preferentially in males.

Harrison DE, Strong R, Allison DB, Ames BN, Astle CM, Atamna H, Fernandez E, Flurkey K, Javors MA, Nadon NL, Nelson JF, Pletcher S, Simpkins JW, Smith D, Wilkinson JE, Miller RA.

Source

The Jackson Laboratory, Bar Harbor, ME, 04609, USA.

Abstract


Four agents - acarbose (ACA), 17-α-estradiol (EST), nordihydroguaiaretic acid (NDGA), and methylene blue (MB) - were evaluated for lifespan effects in genetically heterogeneous mice tested at three sites. Acarbose increased male median lifespan by 22% (P < 0.0001), but increased female median lifespan by only 5% (P = 0.01). This sexual dimorphism in ACA lifespan effect could not be explained by differences in effects on weight. Maximum lifespan (90th percentile) increased 11% (P < 0.001) in males and 9% (P = 0.001) in females. EST increased male median lifespan by 12% (P = 0.002), but did not lead to a significant effect on maximum lifespan. The benefits of EST were much stronger at one test site than at the other two and were not explained by effects on body weight. EST did not alter female lifespan. NDGA increased male median lifespan by 8-10% at three different doses, with P-values ranging from 0.04 to 0.005. Females did not show a lifespan benefit from NDGA, even at a dose that produced blood levels similar to those in males, which did show a strong lifespan benefit. MB did not alter median lifespan of males or females, but did produce a small, statistically significant (6%, P = 0.004) increase in female maximum lifespan. These results provide new pharmacological models for exploring processes that regulate the timing of aging and late-life diseases, and in particular for testing hypotheses about sexual dimorphism in aging and health.
© 2013 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

KEYWORDS:

NDGA , acarbose, estradiol, heterogeneous mice, lifespan, methylene blue PMID:
24245565
[PubMed - as supplied by publisher]

[normalizing]

interestingly on a forum about longecity, nobody seems interested in this to reply here...

[Sciencyst]

Very cool. I look forward to researching or reading research on the mechanisms of said substances and the exploring the new pharmalogical models associated with them. Also curious about the different effects per gender

[Darryl]

Looks like acarbose was mostly acting to reduce effective calorie intake. Its unclear why the males received more benefit:

Acarbose reduced body weights considerably more in females than in males: At 6, 12, 18, and 24 months of age, males were 15%, 14%, 11%, and 9% lighter than controls, while females were 15%, 22%, 23%, and 22% lighter, respectively

Nordihydroguaiaretic acid (NGDA, from chapparal / creosote) similarly extended male mice median lifespan in a past trial as well. Female mice never achieved similar plasma concentrations as males, their high dose maximum was lower than male low dose concentrations.

Strong, Randy, et al. "Nordihydroguaiaretic acid and aspirin increase lifespan of genetically heterogeneous male mice." Aging cell 7.5 (2008): 641-650.

NGDA caught my eye in this screen of 2000 compounds for activation of Nrf2, the main transcription factor for endogenous antioxidant responses. NGDA was one of only 3 compounds to potently activate Nrf2 with switch-like kinetics.

Smirnova, Natalya A., et al. "Development of Neh2-luciferase reporter and its application for high throughput screening and real-time monitoring of Nrf2 activators." Chemistry & biology 18.6 (2011): 752-765.

Possibly more important for longevity, NGDA inhibits IGF1-R kinase so its of interest as an anti proliferative agent. Unfortunately, creosote/chapparal is hepatotoxic in humans, with multiple cases of acute fulminant liver failure requiring liver transplant (and there are no purified NGDA supplements).

Arteaga, Silvia, Adolfo Andrade-Cetto, and René Cárdenas. "Larrea tridentata (Creosote bush), an abundant plant of Mexican and US-American deserts and its metabolite nordihydroguaiaretic acid." Journal of ethnopharmacology 98.3 (2005): 231-239.

Edited by Darryl, 13 December 2013 - 07:44 AM.

[opales]

interestingly on a forum about longecity, nobody seems interested in this to reply here...

Hah, I was wondering the same. Perhaps my title is a bit misleading (though it's the name of the study), these are the results of the ITP 2009 cohort, so this is probably the most important lifespan study of the year.

I can't access the full text, could someone tell what were the dosages used?

So if I combine all the published papers of the ITP screening and Spindler lab screening, + DR Spindlers presentation and notes taken from it:
Presentation:


Notes:
http://biogerontolgy...t-spindler.html

Positive effect on maximum and median lifespan:
-Rapamycin (and also everolimus), acarbose

Positive effect on median lifespan:
- β1-blockers (slightly better results with metoprolol than nebivolol), 17-α-estradiol (males only), NDGA (males only, very narrow therapeutic dose), Aspirin (males only), Simvastatin+enalapril (together but not when taken individually)

Positive but only marginally statistically significant effect on median lifespan:
-Oxaloaceate (failed at ITP testing though apparently they used only 25% of the intended dose), metformin

No change:
-Orthocore, ALT-711, blueberry, pomegranate, green and black tea, cinnamon, sesame, and French maritime pine bark (Pycnogenol and taxifolin), curcumin, morin, quercetin, resveratrol (multiple tests with different dosages), Nitroflurbiprofen (NFP), 4-OH-alpha-phenyl-N-tert-butyl nitrone (4-OH-PBN), CAPE, MCT oils

ITP testing:
http://www.nia.nih.g...mpounds-testing

"Neutral to negative" (not statistically significant):
-Carnitines, lovaza and Krill oil, LExtension mix (neutral to negative), biostimus-??, nicotinic acid, nutraceutical combo DIY (detrimental), orthocore+pomegranate+resv+SAMe+sesame oil (toxic! / liver damage), cyperone acetate (bad liver damage)

"Other":
-Methylene blue (positive effect on female max lifespan), green tea extract (positive effect on midlife deaths at ITP testing)

Edited by Michael, 30 December 2013 - 01:26 AM.

[opales]

Metoprolol has been shown to increase human lifespan so it is probably legit:
https://groups.google.com/forum/#!searchin/sci.life-extension/metoprolol/sci.life-extension/mYc7gMZ1yLI/u3rn4XysYegJ

[blood]

orthocore+pomegranate+resv+SAMe+sesame oil (toxic! / liver damage)

This one is a bit worrying.


Are people (other than diabetics) experimenting with acarbose as a life extension (or even weight or fat loss) intervention?

Edited by blood, 13 December 2013 - 10:52 AM.

[Kevnzworld]

" Another low-cost drug that lowers glucose levels is acarbose, which reduces the absorption of ingested carbohydrates by inhibiting the glucosidase and other sugar absorbing-enzymes in the small intestine. A typical dose is 50-100 mg of acarbose taken before each meal. Some people experience intestinal side effects, but otherwise, acarbose is highly efficacious in reducing blood glucose levels and reducing several cardiac risk markers in the blood.9,12,13 "

http://www.lef.org/m...ch&key=acarbose

I take Metformin, which also showed some longevity benefits in the ITP study, and chlorogenic acid, ( green coffee bean extract .

[hav]

Here's another project info link:

http://www-personal....millerr/ITP.htm

Howard

[smithx]

This actually seems interesting, in that it lowers blood sugar and therefore should reduce insulin, which seems to be quite a good thing for longevity.

There are very rarely some bad side-effects, but very little of the compound is actually absorbed. The typical side effects are similar to those found when consuming a lot of sugar alcohols like maltitol.

http://www.drugs.com/ppa/acarbose.html

Edited by smithx, 15 December 2013 - 04:16 AM.

[Hebbeh]

How much of the longevity effect of acarbose can be attributed to the compounds created from fermentation of undigested carbs in the colon much like the health effects of a high fiber diet?

[Kevnzworld]

How much of the longevity effect of acarbose can be attributed to the compounds created from fermentation of undigested carbs in the colon much like the health effects of a high fiber diet?

I may be wrong, but I've always thought the health effects of a high fiber diet were mostly due to its effect on lowering glycemic load, as well as aiding digestion and bowel movement.
The health effect of acarbose is attributed to its effect on the enzyme that facilitates the absorption of simple carbs ( low in fiber ) which are easily converted to glucose causing post prandial sugar spikes. Essentially it's a calorie restriction drug.

Edited by Kevnzworld, 15 December 2013 - 08:54 AM.

[Hebbeh]

How much of the longevity effect of acarbose can be attributed to the compounds created from fermentation of undigested carbs in the colon much like the health effects of a high fiber diet?

I may be wrong, but I've always thought the health effects of a high fiber diet were mostly due to its effect on lowering glycemic load, as well as aiding digestion and bowel movement. The health effect of acarbose is attributed to its effect on the enzyme that facilitates the absorption of simple carbs ( low in fiber ) which are easily converted to glucose causing post prandial sugar spikes. Essentially it's a calorie restriction drug.

Of course acarbose was developed and dispensed to treat diabetes by controlling blood sugar at the source for those unwilling to control their diabetes through careful diet (eat a doughnut and pop an acarbose) and I'm sure that obviously the lowered blood sugar will improve longevity of diabetics but not all of us are struggling with blood sugar issues and that will not be the cause of increased longevity for most of us (or the normal and healthy).

And it's simplistic to believe that all the health benefits of fiber is for the reasons you mentioned (I don't believe those are even the main benefits) as again, those benefits would only be apparent for diabetics and that wouldn't encompass most of us. It has long been discussed of the many beneficial compounds created during the fermentation and digestion of fiber by the gut flora (sodium butyrate and other short chain fatty acids just for starters).

As a side note, I doubt fiber has that great of an effect on glycemic load itself when consumed with a comparable meal of equal digestible and absorbable carbs (sugars and starches). The recommendation of using high fiber meals for blood sugar control is by replacing starches and sugars with high fiber foods (that require to be broken down by the gut flora), not just adding fiber to an already starch and sugar heavy meal.

edit - The point I'm trying to make, is acarbose, by preventing the digestion and absorbtion of carbs in the intestine and allowing them to pass into the colon undigested, feeding the gut flora and amplifying all the beneficial and healthful things (that we know and don't know) attributed to the gut microbiome.

Edited by Hebbeh, 15 December 2013 - 02:12 PM.

[hav]

How much of the longevity effect of acarbose can be attributed to the compounds created from fermentation of undigested carbs in the colon much like the health effects of a high fiber diet?

I may be wrong, but I've always thought the health effects of a high fiber diet were mostly due to its effect on lowering glycemic load, as well as aiding digestion and bowel movement. The health effect of acarbose is attributed to its effect on the enzyme that facilitates the absorption of simple carbs ( low in fiber ) which are easily converted to glucose causing post prandial sugar spikes. Essentially it's a calorie restriction drug.

Another side effect of a high fiber diet is on leukocyte telomere length.

Doesn't high fiber latch onto fats interfering with their digestion, rather than inhibiting digestion of carbs? You'd probably want to be careful combining acarbose with a high fiber supplement for too long. However, cycling them together, maybe every other day or two, might be a safe strategy to achieve caloric restriction.

There also seems to be some selectivity to acarbose's effect on monosaccharide digestion:
EFFECT OF ACARBOSE ON IN VITRO INTESTINAL ABSORPTION OF MONOSACCHARIDES IN DIABETIC RATS

The rate of intestinal absorption of glucose and galactose in the presence of acarbose was significantly reduced in both normal and diabetic rats, while fructose and sucrose absorption was not affected significantly by acarbose in diabetic rats. Mannose absorption was not affected significantly by acarbose.

Howard

[normalizing]

interested in NGDA and how it extends life, but how is it possible to cause liver problems ? could it, adultered plant that was used or chinese supply of tainted plants ? does NGDA by itself cause this or the whole extract of the plant ? im confused, if it can extend life, it shouldnt cause any organ problems.

[blood]

> 17-α-estradiol

Is this the same substance?:

http://en.wikipedia....iki/Alfatradiol

Alfatradiol (INN,^[1] or 17α-estradiol, trade names Ell-Cranell Alpha and Pantostin in Germany) is a 5α-reductase inhibitor used topically for the treatment of androgenic alopecia (hair loss) in men and women.^[2]

Exp Dermatol. 2002 Aug;11(4):376-80.
17alpha-estradiol induces aromatase activity in intact human anagen hair follicles ex vivo.

Hoffmann R, Niiyama S, Huth A, Kissling S, Happle R.

Source

Department of Dermatology, Philipp University, Deutschhausstrasse 9, D-35033 Marburg, Germany.

Abstract


For topical treatment of androgenetic alopecia (AGA) in women, solutions containing either estradiol benzoate, estradiol valerate, 17beta- or 17alpha-estradiol are commercially available in Europe and some studies show an increased anagen and decreased telogen rate after treatment as compared with placebo. At present it is not precisely known how estrogens mediate their beneficial effect on AGA-affected hair follicles. We have shown recently that 17alpha-estradiol is able to diminish the amount of dihydrotestosterone (DHT) formed by human hair follicles after incubation with testosterone, while increasing the concentration of weaker steroids such as estrogens. Because aromatase is involved in the conversion of testosterone to estrogens and because there is some clinical evidence that aromatase activity may be involved in the pathogenesis of AGA, we addressed the question whether aromatase is expressed in human hair follicles and whether 17alpha-estradiol is able to modify the aromatase activity. Herewith we were able to demonstrate that intact, microdissected hair follicles from female donors express considerably more aromatase activity than hair follicles from male donors. Using immunohistochemistry, we detected the aromatase mainly in the epithelial parts of the hair follicle and not in the dermal papilla. Furthermore, we show that in comparison to the controls, we noticed in 17alpha-estradiol-incubated (1 nM) female hair follicles a concentration- and time-dependent increase of aromatase activity (at 24 h: 1 nM = +18%, 100 nM = +25%, 1 micro M = +57%; 24 h: 1 nM = +18%, 48 h: 1 nM = +25%). In conclusion, our ex vivo experiments suggest that under the influence of 17alpha-estradiol an increased conversion of testosterone to 17beta-estradiol and androstendione to estrone takes place, which might explain the beneficial effects of estrogen treatment of AGA.

PMID: 12190948 [PubMed - indexed for MEDLIN

Ann N Y Acad Sci. 2005 Jun;1052:116-35.
Development of 17alpha-estradiol as a neuroprotective therapeutic agent: rationale and results from a phase I clinical study.

Dykens JA, Moos WH, Howell N.

Source

MIGENIX Corporation, 12780 High Bluff Dr., San Diego, CA 92130, USA. jdykens@migenix.com

Abstract


17alpha-estradiol (17alpha-E2) differs from its isomer, the potent feminizing hormone 17beta-estradiol (17beta-E2), only in the stereochemistry at one carbon, but this is sufficient to render it at least 200-fold less active as a transactivating hormone. Despite its meager hormonal activity, 17alpha-E2 is as potent as 17beta-E2 in protecting a wide variety of cell types, including primary neurons, from a diverse array of lethal and etiologically relevant stressors, including amyloid toxicity, serum withdrawal, oxidative stress, excitotoxicity, and mitochondrial inhibition, among others. Moreover, both estradiol isomers have shown efficacy in animal models of stroke, Alzheimer's disease (AD), and Parkinson's disease (PD). Data from many labs have yielded a mechanistic model in which 17alpha-E2 intercalates into cell membranes, where it terminates lipid peroxidation chain reactions, thereby preserving membrane integrity, and where it in turn is redox cycled by glutathione or by NADPH through enzymatic coupling. Maintaining membrane integrity is critical to mitochondrial function, where loss of impermeability of the inner membrane initiates both necrotic and apoptotic pathways. Thus, by serving as a mitoprotectant, 17alpha-E2 forestalls cell death and could correspondingly provide therapeutic benefit in a host of degenerative diseases, including AD, PD, Friedreich's ataxia, and amyotrophic lateral sclerosis, while at the same time circumventing the common adverse effects elicited by more hormonally active analogues. Positive safety and pharmacokinetic data from a successful phase I clinical study with oral 17alpha-E2 (sodium sulfate conjugate) are presented here, and several options for its future clinical assessment are discussed.

PMID: 16024755 [PubMed - indexed for MEDLINE]

I wonder if drugs like letrozole could be life shortening in men by reducing synthesis of this substance? (Does letrozole get into the brain?)

Edited by blood, 16 December 2013 - 08:54 AM.

[smithx]

> 17-α-estradiol

Is this the same substance?:

No.

The article cited in the first post of this thread studied 17-α-estradiol as well as Acarbose. They are completely different types of compounds.

[normalizing]

the one you posted has so many severe side effects that prolonging life or not, seems like a shit substance to take !

[blood]

> 17-α-estradiol

Is this the same substance?:

No.

The article cited in the first post of this thread studied 17-α-estradiol as well as Acarbose. They are completely different types of compounds.

In the abstract in the first post of this thread, it is reported that 17 alpha-estradiol increased male media lifespan by 12%.

I'm wondering if this is the same 17 alpha-estradiol that is used to prevent female pattern baldness etc.

[Jembe]

I wonder if drugs like letrozole could be life shortening in men by reducing synthesis of this substance? (Does letrozole get into the brain?)

I don't know, but taking it improved my joint problems by about 70% and fixed a few other things.

[Kevnzworld]

This recent study, also sponsored by the NIH showed increased lifespan in male mice given Metformin beginning in middle age .
Lowering blood sugar levels ( acarbose, metformin ) do seem to extend lifespan.

" NIH researchers find diabetes drug extends health and lifespan in mice "
" In this study, researchers found male mice on a 0.1 percent metformin treatment had a 5.83 percent increase in lifespan compared to control group mice on a standard diet with no metformin. The 1 percent metformin treatment had the opposite effect. These mice had a 14.4 percent shorter lifespan compared to the control group, likely due to kidney failure. The lower metformin dose did not seem to cause any negative effect on the renal system."
http://www.nia.nih.g...d-lifespan-mice

[smithx]

I considered metformin, but it is systemic and has many potential side-effects.

What seems good about acarbose is that it operates primarily in the gut and isn't absorbed much.

[normalizing]

so why dont you guys concentrate on natural substances which lower blood sugar levels instead of pharmaceuticals ? most likely most of them werent studied for longevity yet hence now popular refered to such. but what about we make a list and propose as lowering blood sugar substance perhaps it has some logevity effect ?

[normalizing]

what about cinnamon. it lowers blood sugar levels very much alike the diebetus drugs posted here and could possible extend lifespan ? of course no longecity study was done on it because it has no profit. but would you guys not think it might extend lifespan just any of the blood sugar lowering drugs mentioned ??

[normalizing]

testing fiber for lowering blood sugar. i had a lot of pizza which is known to cause rapid spike in blood glucose. 1 hour time i feel like shit. i proceeded to consume lots and lots of fiber bulk powder i have had for a while and interestingly enough, i lost the feeling of sickness related to the pizza only to be replaced by extreme gastrointestinal problems to the point, i hurt so bad and my stomach making horrible growling noises that im thinking, wtf did i do!? i substituted one sickness for another. nevertless, this might be lowering blood glucose, it reminds me of the side effects of the antidiebetic drugs mentioned. absolutely same fucking side effects, gastrointestinal problems +50% at least of all cases mentioned.

[opales]

what about cinnamon. it lowers blood sugar levels very much alike the diebetus drugs posted here and could possible extend lifespan ? of course no longecity study was done on it because it has no profit. but would you guys not think it might extend lifespan just any of the blood sugar lowering drugs mentioned ??

As I mentioned in my previous post, Spindler's lab screening effort did test cinnamon and tons of other "natural" blood sugar lowering substances for effect on mouse lifespan. No effect:

Rejuvenation Res. 2013 Apr;16(2):143-51. doi: 10.1089/rej.2012.1386.
Influence on longevity of blueberry, cinnamon, green and black tea, pomegranate, sesame, curcumin, morin, pycnogenol, quercetin, and taxifolin fed iso-calorically to long-lived, F1 hybrid mice.

Spindler SR, Mote PL, Flegal JM, Teter B.

Author information



Abstract


Phytonutrients reportedly extend the life span of Caenorhabditis elegans, Drosophila, and mice. We tested extracts of blueberry, pomegranate, green and black tea, cinnamon, sesame, and French maritime pine bark (Pycnogenol and taxifolin), as well as curcumin, morin, and quercetin for their effects on the life span of mice. While many of these phytonutrients reportedly extend the life span of model organisms, we found no significant effect on the life span of male F1 hybrid mice, even though the dosages used reportedly produce defined therapeutic end points in mice. The compounds were fed beginning at 12 months of age. The control and treatment groups were iso-caloric with respect to one another. A 40% calorically restricted and other groups not reported here did experience life span extension. Body weights were un-changed relative to controls for all but two supplemented groups, indicating most supplements did not change energy absorption or utilization. Tea extracts with morin decreased weight, whereas quercetin, taxifolin, and Pycnogenol together increased weight. These changes may be due to altered locomotion or fatty acid biosynthesis. Published reports of murine life span extension using curcumin or tea components may have resulted from induced caloric restriction. Together, our results do not support the idea that isolated phytonutrient anti-oxidants and anti-inflammatories are potential longevity therapeutics, even though consumption of whole fruits and vegetables is associated with enhanced health span and life span. PMID:
23432089
[PubMed - in process]

http://www.ncbi.nlm....pubmed/23432089

[normalizing]

opales i dont get it. whats so unique about those synthetic blood sugar lowering drugs comparison to natural substances doing the same job ?

[Hebbeh]

Metformin activates AMPK and acarbose very likely provides support for beneficial gut flora. The life extension effects of each are independent of blood sugar and very likely has little to do with blood sugar....especially since the effects can be demonstrated in the preexisting absence of abnormal blood sugar levels.

[normalizing]

hebbeh, i remember i was reading reading that keeping blood sugar in normal range generally is extending life rather than oposite, high blood sugar and quick aging. but maybe those drugs do have other effects which are more important in logevity its just that its not proven which mechanism actually does it.

[Hebbeh]

hebbeh, i remember i was reading reading that keeping blood sugar in normal range generally is extending life rather than oposite, high blood sugar and quick aging. but maybe those drugs do have other effects which are more important in logevity its just that its not proven which mechanism actually does it.

I don't know where this "opposite" is coming from.

Most people that are concerned with health and longevity aren't obese or diabetic. They generally eat a healthy diet, exercise, and maintain a healthy weight thereby controlling blood sugar naturally and maintaining blood sugar in the normal and ideal range (without band-aid pills).

So how are drugs whose only MOA revolve around controlling high out of control blood sugar going to benefit the already healthy? If your blood sugar is out of control, than you are doing everything wrong and need to get the basics (which are what are going to make the biggest difference) in control. Don't plan on having great health and/or longevity by not paying attention to the basics by not eating a healthy diet, not exercising, and not maintaining a healthy BMI and then expect to make up for it all by popping a pill with that extra helping of pie.

If you are doing everything right and your blood sugar is in the ideal range, how can it get any better than that? Rather than depend on a pill, I would put my money on a healthy lifestyle.

Since metformin and acarbose demonstrate longevity effects in healthy mice, it's not due to effects on already healthy blood sugar levels...it's obviously due to other mechanisms...especially since other substances whose only MOA is blood sugar lowering effects don't display the same longevity enhancements. Blood sugar, like all things, has an ideal range and attempting to artificially lower below ideal with pills is not going to improve health...as the studies have shown.

Of course, while metformin and acarbose will improve the health of the obese, diabetic, and the sick, it's simply a band-aid approach and better results would be had by getting their act together and maintain blood sugar through the discipline of a complete healthy lifestyle of proper diet and exercise to maintain a lean healthy BMI and the ideal health markers that come with proper living.

I think it is clear that metformin and acarbose longevity effects are due to other mechanisms (in the healthy) than simple blood sugar control (that's not needed). I've used both in the past (for blood sugar manipulation when I was involved in bodybuilding) but feel the effects are not worthwhile in the healthy. There are better compounds than metformin to activate AMPK (and control SIRT and mTOR) and better compounds than acarbose to promote beneficial gut microbiome.