14 replies to this topic

[Michael]

J Gerontol A Biol Sci Med Sci. 2010 Oct 25. [Epub ahead of print]
Rapamycin, But Not Resveratrol or Simvastatin, Extends Life Span of Genetically Heterogeneous Mice.

Miller RA, Harrison DE, Astle CM, Baur JA, Boyd AR, de Cabo R, Fernandez E, Flurkey K, Javors MA, Nelson JF, Orihuela CJ, Pletcher S, Sharp ZD, Sinclair D, Starnes JW, Wilkinson JE, Nadon NL, Strong R.
Rapamycin was administered in food to genetically heterogeneous mice from the age of 9 months and produced significant increases in life span, including maximum life span, at each of three test sites. Median survival was extended by an average of 10% in males and 18% in females. Rapamycin attenuated age-associated decline in spontaneous activity in males but not in females. Causes of death were similar in control and rapamycin-treated mice.

Resveratrol (at 300 and 1200 ppm food ["doses two- to eightfold higher than the dose studied by Pearson and colleagues"]) and simvastatin (12 and 120 ppm) did not have significant effects on survival in male or female mice.



Further evaluation of rapamycin's effects on mice is likely to help delineate the role of the mammalian target of rapamycin complexes in the regulation of aging rate and age-dependent diseases and may help to guide a search for drugs that retard some or all of the diseases of aging.

PMID: 20974732 [PubMed - as supplied by publisher]

More details on the SENS Research Foundation CSO Team Blog.

 

[Edit: updating broken link].

Edited by Michael, 21 September 2014 - 04:18 PM.

[AgeVivo]

Bump. 3 doses of resveratrol do not extend lifespan in healthy mice.

[Michael]

Bump. 3 doses of resveratrol do not extend lifespan in healthy mice.

Actually, that's now at five doses: the earlier study(1) gave resveratrol at 100, 400, or 2400 mg/kg of food. The diet composition was different, as were the mice, so the concentrations don't quite translate, but the 400 mg/kg dose in the early study (which partly normalized LS in the high-saturated-fat, high-Calorie-diet-induced diabetic-obese animals in (1)) translated to 22 mg/kg mouse body weight, while 300 and 1200 ppm food in the new study correspond to 50 and 200 mg/kg mouse.

Reference
1. Pearson KJ, Baur JA, Lewis KN, Peshkin L, Price NL, Labinskyy N, Swindell WR, Kamara D, Minor RK, Perez E, Jamieson HA, Zhang Y, Dunn SR, Sharma K, Pleshko N, Woollett LA, Csiszar A, Ikeno Y, Le Couteur D, Elliott PJ, Becker KG, Navas P, Ingram DK, Wolf NS, Ungvari Z, Sinclair DA, de Cabo R. Resveratrol Delays Age-Related Deterioration and Mimics Transcriptional Aspects of Dietary Restriction without Extending Life Span. Cell Metab. 2008 Aug;8(2):157-68. PMID: 18599363 [PubMed - as supplied by publisher]

Edited by Michael, 28 October 2010 - 11:17 AM.

[nowayout]

So is anybody on Rapamycin yet?  

[mikeinnaples]

Bump. 3 doses of resveratrol do not extend lifespan in healthy mice.

What about 'healthy' lifespan?

[maxwatt]

Bump. 3 doses of resveratrol do not extend lifespan in healthy mice.

What about 'healthy' lifespan?

Exactly; the resveratrol mice remained physically active to much older ages than the controls. So even without extending lifespan, there is a possible benefit, probably due to the mitochondrial biogenesis that resveratrol has been shown to induce. Also, Sinclair's earlier study showed that EOD fasting plus resveratrol extended lifespan slightly more than EOD fasting alone in mice. Resveratrol apparently protects against some of the insults of aging, but not enough to extend lifespan without some other intervention.

Many polyphenols, flavones and stilbenes have beneficial effects for improving blood lipids profiles and reducing insulin resistance, as well as possible activating SIRT1. Sinclair chose to focus on resveratrol, and it got all the publicity.

I would not suggest taking rapamycin unless you want to live in a sterile bubble. It compromises the immune system. The mice had to be maintained under sterile conditions, or they would have died young of disease.

Edited by Michael, 28 October 2010 - 05:32 PM.
Trimming accidental paste

[medievil]

Since resveratrol inhibits mTOR dont we have to review its effect on aging?

[Michael]

What about 'healthy' lifespan?

Exactly; the resveratrol mice remained physically active to much older ages than the controls.

Only the females, and only at the highest dose.

Sinclair's earlier study showed that EOD fasting plus resveratrol extended lifespan slightly more than EOD fasting alone in mice.

Maybe. The numerical difference was nonsignificant.

Attractive as this 'healthy lifespan' reasoning is intuitively, it does run up against the fact that healthy organisms don't just drop dead. If the animals are more functional on one parameter, but are dying just as quickly, it implies at the least the ongoing progression of a life-limiting pathology, which isn't really 'healthy lifespan,' or alternatively an active acceleration of death from some other cause of death against which the expected benefit of greater health in other areas is counterbalanced.

Since resveratrol inhibits mTOR dont we have to review its effect on aging?

I know of zero evidence that resveratrol inhibits mTOR in vivo in any system, let alone unchallenged mTOR activity in mammals after oral administration.

[Michael]

So is anybody on Rapamycin yet?  

Jesus, I hope not, unless they're a transplant patient, etc; see maxwatt's reply. (Though the effects of rapamycin on the immune system are paradoxical -- especially in aging mice.(1,2))

Also, as noted in the SENS Foundation CSO Blog entry, the survival curves for mice that started rapa at ages 9 vs 20 mo (say, ~27 and ~61 human y) almost completely overlapped, so even if one foolishly assumes perfect human translatability and no complications related to living a free-living human lifestyle instead of spending life in a cage in a specific-pathogen-free lab, there would be no reason to start taking it much before you first sign up for Medicare.

References
1: Chen C, Liu Y, Liu Y, Zheng P. mTOR regulation and therapeutic rejuvenation of
aging hematopoietic stem cells. Sci Signal. 2009 Nov 24;2(98):ra75. PubMed PMID:
19934433.

2: Araki K, Turner AP, Shaffer VO, Gangappa S, Keller SA, Bachmann MF, Larsen CP,
Ahmed R. mTOR regulates memory CD8 T-cell differentiation. Nature. 2009 Jul
2;460(7251):108-12. Epub 2009 Jun 21. PubMed PMID: 19543266; PubMed Central
PMCID: PMC2710807.

 

[Edit: updating expired link]

Edited by Michael, 21 September 2014 - 04:16 PM.

[mikeinnaples]

Attractive as this 'healthy lifespan' reasoning is intuitively, it does run up against the fact that healthy organisms don't just drop dead. If the animals are more functional on one parameter, but are dying just as quickly, it implies at the least the ongoing progression of a life-limiting pathology, which isn't really 'healthy lifespan,' or alternatively an active acceleration of death from some other cause of death against which the expected benefit of greater health in other areas is counterbalanced.

Michael, I think you miss the point. There are two ways to die at age 80 and I will give you a personal example. My uncle died at age 80 in his sleep, living an active, healthy life until he was 78 or so. Regularly fishing with his buddies and still going to the gym and enjoying light jogs on the beach. My grandfather died at 80 as well ...from about 60 onwards he was constantly battling various age related diseases and he ultimately was taken by his third heart attack.

While we prefer no death period, which would be the preferable way to grow old.... healthy or disease ridden? If resveratrol decreases any chance of the latter ...it is a worthy supplement.

[nowayout]

 

Attractive as this 'healthy lifespan' reasoning is intuitively, it does run up against the fact that healthy organisms don't just drop dead.

EXACTLY! 


Why do pretty much all popular articles on life extension commit this fallacy?  It is as if nobody wants to admit that they want to make people life a limitless life, maybe because they are pandering to some elements in society who might find it hubristic and morally repugnant.  

[maxwatt]

Sinclair's earlier study showed that EOD fasting plus resveratrol extended lifespan slightly more than EOD fasting alone in mice.

Maybe. The numerical difference was nonsignificant.

My recollection was the de Cabo* study found statistical significance to the combination, in fact did resveratrol feeding extended both mean and maximal lifespan by 15% over Standard Diet controls.
"our EOD feeding regimen was initiated at 12 months of age, and while average life span was increased, the effect did not reach statistical significance, except in combination with resveratrol (EODLR versus SD)."

So EOD feeding as a stand in for CR did extend life span significantly, except with the addition of resveratrol. And:

"resveratrol-fed elderly mice show a marked reduction in signs of aging, including reduced albuminuria, decreased inflammation, and apoptosis in the vascular endothelium, increased aortic elasticity, greater motor coordination, reduced cataract formation, and preserved bone mineral density. However, mice fed a standard diet did not live longer when treated with resveratrol beginning at 12 months of age ...."

Notably resveratrol with a high calorie diet extend lifespan over the high calorie controls, notably via "a reduction in the number of deaths attributed to cardiopulmonary distress (specifically, fatty changes in the liver combined with severe congestion and edema in the lungs;"

"Notably, EOD [every other day] feeding in combination with the lower dose of resveratrol did extend both mean and maximal life span by 15% compared to SD [standard diet] controls"

IF, and that's a BIG IF, de Cabo's mouse study is extendable to humans, resveratrol would prove life extending for those on a high calorie diet, or those initiating late-life calorie restriction. It would also be expected to ameliorate some of the tribulations of aging. My own experience would argue for it, though I do not suggest anyone follow my example based on my recommendation.

* Pearson KJ, Baur JA, Lewis KN, Peshkin L, Price NL, Labinskyy N, Swindell WR, Kamara D, Minor RK, Perez E, Jamieson HA, Zhang Y, Dunn SR, Sharma K, Pleshko N, Woollett LA, Csiszar A, Ikeno Y, Le Couteur D, Elliott PJ, Becker KG, Navas P, Ingram DK, Wolf NS, Ungvari Z, Sinclair DA, de Cabo R. Resveratrol Delays Age-Related Deterioration and Mimics Transcriptional Aspects of Dietary Restriction without Extending Life Span. Cell Metab. 2008 Aug;8(2):157-68. PMID: 18599363

Edited by Michael, 29 October 2010 - 10:54 AM.
Cleaning quotes

[nowayout]

So is anybody on Rapamycin yet?    

Jesus, I hope not, unless they're a transplant patient, etc; see maxwatt's reply. 

I would not suggest taking rapamycin unless you want to live in a sterile bubble.  It compromises the immune system.  The mice had to be maintained under sterile conditions, or they would have died young of disease.

It might not be so bad.
Some rheumatoid arthritis and psiorasis patients use a similar drug, Ciclosporin, long term, without significant deleterious side effects, and without having to live in a bubble.    For first-hand information, I believe Missminni here is on Cyclosporin. 

What is the supposed mechanism?  Dialing down of chronic inflammation?

Edited by viveutvivas, 28 October 2010 - 11:14 PM.

[maxwatt]

...
Some rheumatoid arthritis and psiorasis patients use a similar drug, Ciclosporin, long term, without significant deleterious side effects, and without having to live in a bubble.    For first-hand information, I believe Missminni here is on Cyclosporin. 

What is the supposed mechanism?  Dialing down of chronic inflammation?

Ciclosporin does not inhibit mTor, which is the mechanism of rapamycin. It acts on the
immune system in a different way.

[Michael]

Sinclair's earlier study showed that EOD fasting plus resveratrol extended lifespan slightly more than EOD fasting alone in mice.

Maybe. The numerical difference was nonsignificant.

My recollection was the de Cabo* study found statistical significance to the combination, in fact resveratrol feeding extended both mean and maximal lifespan by 15% over Standard Diet controls.

our EOD feeding regimen was initiated at 12 months of age, and while average life span was increased, the effect did not reach statistical significance, except in combination with resveratrol (EODLR versus SD).

So EOD feeding as a stand in for CR did extend life span significantly, except with the addition of resveratrol.

Sorry, I put that poorly. Your summary is correct; the question is where the actual differences lie. If you look at the max survival data:



... you see the effect that you describe. And certainly, the survival of the EOD+low-dose Res lived longer (and statistically significantly longer) than SD, while EOD alone did not live significantly longer than SD (anyone who thinks this is a shocking revelation, please read this). But the nominal difference between EOD and SD looks larger than the nominal difference between EOD and EOD + low-dose res, and there's no statistically significant difference between the latter 2. So the question is whether there is or is not a real difference between EOD and EOD + low-res, and also whether there was a real difference between SD and EOD alone.

The "curve-squaring" effect looks more impressive on the graph:


... but (a) as noted, it'd've been more impressive if they'd've had somewhat longer-lived, squarer-curved controls, and (b) the differences are again NS (personal communication, Pearson), so that could be noise, too.

And, there's the awkward fact that high-res made EOD animals live nominally SHORTER lives than EOD alone ...

And:

resveratrol-fed elderly mice show a marked reduction in signs of aging, including reduced albuminuria, decreased inflammation, and apoptosis in the vascular endothelium, increased aortic elasticity, greater motor coordination, reduced cataract formation, and preserved bone mineral density.

Yes. And on that point:

Attractive as this 'healthy lifespan' reasoning is intuitively, it does run up against the fact that healthy organisms don't just drop dead. If the animals are more functional on one parameter, but are dying just as quickly, it implies at the least the ongoing progression of a life-limiting pathology, which isn't really 'healthy lifespan,' or alternatively an active acceleration of death from some other cause of death against which the expected benefit of greater health in other areas is counterbalanced.

Michael, I think you miss the point. There are two ways to die at age 80 [...] While we prefer no death period, which would be the preferable way to grow old.... healthy or disease ridden? If resveratrol decreases any chance of the latter ...it is a worthy supplement.

I agree, of course. The question is whether it actually does that, and whether we can meaningfully take advantage of it. Yes, the headline results from Pearson et al were impressive on that regard, but when you dig down there's a lot of variability in its realization by dose, gender, and feeding regimen; and, we still dont have a clue how to translate the pharmacokinetics. And, it still leaves my concern above unaddressed; please cogitate .

Reference
* Pearson KJ, Baur JA, Lewis KN, Peshkin L, Price NL, Labinskyy N, Swindell WR, Kamara D, Minor RK, Perez E, Jamieson HA, Zhang Y, Dunn SR, Sharma K, Pleshko N, Woollett LA, Csiszar A, Ikeno Y, Le Couteur D, Elliott PJ, Becker KG, Navas P, Ingram DK, Wolf NS, Ungvari Z, Sinclair DA, de Cabo R. Resveratrol Delays Age-Related Deterioration and Mimics Transcriptional Aspects of Dietary Restriction without Extending Life Span. Cell Metab. 2008 Aug;8(2):157-68. PMID: 18599363