121 replies to this topic

[Michael]

All:

> Here [1] we report that longevity of both TGM
> [transgenic overexpressors of GH] and normal mice
> is extended by this supplement. Treated TGM showed
> a 28% increase (p <.00008) in mean longevity. An 11% increase in
> mean longevity was also significant (p <.002093) for treated normal
> mice, compared to untreated normal mice.

This really is a dime-a-dozen result. There was only a MEAN LS "extension" in either strain, and the "extension only constituted a NORMALIZATION of the LS of the strains in question. The control strain was C57Bl/6, which is a relatively longevous spp. A normal, healthy, non-genetically-fucked-up mouse should on average live ~900 d, and ~1200 max (2); the mean LSs & their upper 95% confidence intervals were:


Unsupplemented GH transgenics: 336.27 / 349.51 days
Supplemented GH transgenics: 431.12/444.60 days
Unsupplemented normals: 687.55 / 792.15 days
Supplemented normals: 764.60 /899.57 days

They don't formally report max LS (tenth-decile survivorship), but eyeballing the curves (Fig 1, A & B) show that the last mouse in each group died at the age of roughly:

Unsupplemented GH transgenics: 600 days
Supplemented GH transgenics: 690 days
Unsupplemented normals: 950 days
Supplemented normals: 975 days

It's no surprise that the transgenics were short-lived; the C57Bl/6 result suggests that these folks just don't know how to raise healthy mice. All the supplement did was move the 2 strains closer to -- and in no case fully! -- the average and maximum lifespan expected of mice that aren't genetically disfavored or in poor husbandry conditions.

Of course, a zillion things -- melatonin, cysteine, hydroxylamine, alpha-tocopherol, ethoxyquin, 2-mercaptoethylamine, etc etc -- do this. This tells us something about how antioxidants can counter the abuse of poor animal husbandry or catastrophically bad genes, but it doesn't tell us anything about basically healthy animals -- and even less about aging per se.

> These data support the
> hypothesis that TGM are a model of accelerated aging,

Of course they don't. Almost anything that messes up normal gene function but takes a while to kill one will look like "premature aging;" the question is what if any relationship they bear to "normal" aging.

"Until you show me that you can postpone aging, I don't know that you've done anything," sniffs Michael R. Rose, geneticist at the University of California. "A lot of people can kill things off sooner, by screwing around with various mechanisms, but to me that's like killing mice with hammers -- it doesn't show that hammers are related to aging."((5); see (6-10) for examples).

> and demonstrate that complex
> dietary supplements may be effective in ameliorating aging
> or age-related pathologies where simpler formulations have generally
> failed.

Again, multiple "simpler formulations" have accomplished this much; the trick is to actually demonstrate retarded biological aging, by extending species maximum lifespan, reducing MRDT, and reducing pathology relative to healthy, normal, well-cared-for controls.

-Michael

1: Lemon JA, Boreham DR, Rollo CD.
A complex dietary supplement extends longevity of mice.
J Gerontol A Biol Sci Med Sci. 2005 Mar;60(3):275-9.
PMID: 15860460 [PubMed - in process]
http://biomed.geront...stract/60/3/275

2. Miller RA, Harper JM, Dysko RC, Durkee SJ, Austad SN.
Longer life spans and delayed maturation in wild-derived mice.
Exp Biol Med (Maywood). 2002 Jul;227(7):500-8.
PMID: 12094015

5. http://exn.ca/Storie...98/05/13/66.asp

6: Trifunovic A, Wredenberg A, Falkenberg M, et al. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature. 2004 May 27;429(6990):417-23. PMID: 15164064 [PubMed - indexed for MEDLINE]

7. Nature 1997 Nov 6;390(6655):45-51
Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Kuro-o M, Matsumura Y, Aizawa H, et al.
PMID: 9363890 [PubMed - indexed for MEDLINE]

8. Mol Cell Biol 2000 Jun;20(11):3772-80
Analysis of ku80-mutant mice and cells with deficient levels of p53.
Lim DS, Vogel H, Willerford DM, Sands AT, Platt KA, Hasty P.
PMID: 10805721

9. Takeda T.
[Senescence-accelerated mouse (SAM): with special reference to age-associated pathologies and their modulation]
Nippon Eiseigaku Zasshi. 1996 Jul;51(2):569-78. Review. Japanese.
PMID: 8783874 [PubMed - indexed for MEDLINE]

10: Baker DJ, Jeganathan KB, Cameron JD, et al.
BubR1 insufficiency causes early onset of aging-associated phenotypes and infertility in mice.
Nat Genet. 2004 Jul;36(7):744-9. Epub 2004 Jun 20.
PMID: 15208629 [PubMed - indexed for MEDLINE]

[icyT]

I can understand Rose not liking the results of that... but in actuality, if you can prove something like GH is harmful, then while it doesn't actually help you find what IS longevity-supportive, it eliminates something that doesn't work.

Their ability in raising mice and possibly overdosing them on GH is what I would have used to exclude the argument. They should have used a spectrum of various GH doses, made sure it was the same family of mice, and also released information on the living conditions the different mice specimens all inhabited, yes?

Science is fun...

[Michael Price]

Same formulation later repeated on normal mice and they lived longer and got smarter.

[timar]

Yeah, sure, why not exhume a 9(!!) year old topic, to respond with one single, unreferenced sentence...
 

[Michael Price]

Because I can't post a link yet.

[Michael Price]

Pmid 22120182 if you want to post the link for me.

[niner]

You could have at least referenced the paper.  You don't need a link to do that.
 
Here is Table 1 from the 2013 paper, providing the ingredients in the "Complex Dietary Supplement":
 

Ingredients included in the complex dietary supplement

 

Ingredient    Mouse dose (mg/day/100 mice)
Vitamin B1    30.5
Vitamin B3 (niacin)    30.5
Vitamin B6    60.0
Vitamin B12    0.18
Vitamin C    350.6
Vitamin D    0.02
Acetyl-l-carnitine    146.5
Alpha-lipoic acid    182.9
Acetylsalicylic acid    132.1
Beta-carotene    21.9
Bioflavonoids    792.7
Chromium picolinate    0.30
Folic acid    0.61
Garlic    3.81
Ginger root extract    600.4
Gingko biloba    18.3
Ginseng    631.1
Green tea extract    487.8
l-Glutathione    30.5
Magnesium    45.7
Manganese    19.1
Melatonin    0.73
/N/-Acetyl cysteine    304.9
Potassium    18.1
Rutin    304.9
Selenium    0.05
Vitamin E    326.8
Cod liver oil (omega 3)    1,219.5
Coenzyme Q10    60.0
Flax seed oil    1,219.5

 

 
The paper:
 

Age (Dordr). 2013 Feb;35(1):23-33. doi: 10.1007/s11357-011-9325-2. Epub 2011 Nov 27.
A complex dietary supplement augments spatial learning, brain mass, and mitochondrial electron transport chain activity in aging mice.
Aksenov V1, Long J, Liu J, Szechtman H, Khanna P, Matravadia S, Rollo CD.

We developed a complex dietary supplement designed to offset five key mechanisms of aging and tested its effectiveness in ameliorating age-related cognitive decline using a visually cued Morris water maze test. All younger mice (<1 year old) learned the task well. However, older untreated mice (>1 year) were unable to learn the maze even after 5 days, indicative of strong cognitive decline at older ages. In contrast, no cognitive decline was evident in older supplemented mice, even when ∼2 years old. Supplemented older mice were nearly 50% better at locating the platform than age-matched controls. Brain weights of supplemented mice were significantly greater than controls, even at younger ages. Reversal of cognitive decline in activity of complexes III and IV by supplementation was significantly associated with cognitive improvement, implicating energy supply as one possible mechanism. These results represent proof of principle that complex dietary supplements can provide powerful benefits for cognitive function and brain aging.

PMID: 22120182 PMCID: PMC3543739 Free PMC Article

[Michael Price]

Is that all you guys do here, moan all the time? Talk about the glass half empty. I posted some factually correct and highly relevant information and get blasted. Sure I could have posted more, but I didn't.

[niner]

Is that all you guys do here, moan all the time? Talk about the glass half empty. I posted some factually correct and highly relevant information and get blasted. Sure I could have posted more, but I didn't.

 

Maybe you should pay a little more attention to the culture here.    How is anyone supposed to know if your one-liner is factually correct or not? 

[Michael Price]

I see a lot of unreferenced claims on other threas.

[krillin]

I couldn't find any lifespan data in that paper. Was there another? Spindler tried to duplicate the results and found the complex mixture to be ineffective in mice that aren't metabolically morbid. (It could be another form of incompetent animal husbandry that hurt the McMaster group's control group, but I just love using the term "metabolically morbid".)

[Michael Price]

There're two highly relevant studies on longevity from this supplement mix. Cut and paste from my mobile is difficult, so I'll just give the PMIDs: 15860460 & 24531571. 11% increase in LS from the older study and the more recent study found that longevity was linear with consumptionmof the nutrient mix.....!

[Michael Price]

The Spindler null result is a puzzle, given the success Rollo et al have had. Perhaps the LE Mix isn't comprehensive enough (I certainly take it alongside quite a few side dishes, so to speak), or the amounts were simply too low?

[timar]

I didn't know that new members are not allowed to post links. But, as niner said, you could at least have provided some more information in your initial post. There are too many people here making all sorts of claims.

 

The Spindler null result is a puzzle, given the success Rollo et al have had. Perhaps the LE Mix isn't comprehensive enough (I certainly take it alongside quite a few side dishes, so to speak), or the amounts were simply too low?

 

A puzzle? Not so much, if you consider that Spindler used a healthy strain, whereas the studies you referenced all used some "genetically fucked-up" mice prone to cancer and accelerated aging. Complex supplement mixtures such as the LEF Mix are advertised - more or less explictly - to "extend" the health- or even lifespan of generally healthy people. They are not advertised as a special supplement for people carrying catastrophic genetic mutations similar to those utilized in such mouse models.

 

Spindler's mice, on the other hand, may actually have been a bit too healthy and calorie-controlled to be an appropriate model for a free-living "wild-type" human. If you take all those studies together, it really seems like a wash.

 

Josh Mitteldorf wrote a good article about the Spindler study on his blog and I wrote a comment there.

Edited by timar, 01 October 2014 - 03:50 PM.

[Michael Price]

You are wrong, Rollo's strains were not all fucked up. In fact in the latest experiments they chose a non transgenic hybrid strain, CB57BL/6L_5JLL to avoid such criticism.

[timar]

The title of the 2014 study is: Impact of a complex nutraceutical supplement on primary tumour formation and metastasis in Trp53+/- cancer-prone mice.

[Michael Price]

I stand by my statement, and I trust you read more than study titles. Normal mice were used and reported separately in two of the three studies whose PMIDs I've posted.

[krillin]

I stand by my statement, and I trust you read more than study titles. Normal mice were used and reported separately in two of the three studies whose PMIDs I've posted.

Of those two, only one had lifespan data. And it was torn apart by Michael in post #1 of this thread. These supplements are at best just curve squarers that help keep you healthy until you die right on schedule from aging.

 

[niner]

 

I stand by my statement, and I trust you read more than study titles. Normal mice were used and reported separately in two of the three studies whose PMIDs I've posted.

 
Of those two, only one had lifespan data. And it was torn apart by Michael in post #1 of this thread. These supplements are at best just curve squarers that help keep you healthy until you die right on schedule from aging.

 

 

Well, yeah, but sometimes there's a place for curve squarers...
 

Mutagenesis. 2014 May;29(3):177-87. doi: 10.1093/mutage/geu002. Epub 2014 Feb 15.
Impact of a complex nutraceutical supplement on primary tumour formation and metastasis in Trp53+/- cancer-prone mice.
Aksenov V1, Boreham D, Rollo CD.

A complex dietary supplement designed to impact multiple mechanisms associated with aging and cancer reduced overall tumorigenesis in cancer-prone heterozygous Trp53+/- mice by ~30% (P < 0.018). Carcinomas were reduced by 67% (P < 0.006). Remarkably, metastasis (a leading cause of cancer mortality) was undetectable in treated animals (P < 0.004), and the occurrence of multiple primary tumours was reduced by 74% (P < 0.012). Reduction of pulmonary adenocarcinoma by 62% (P < 0.021) was of particular note given that lung cancer is the second leading cause of death in humans. Tumours showed pronounced age-related expression in untreated animals older than 600 days. Benefits of treatment only emerged in these later ages, suggesting that the supplement acted on mechanisms common to aging and cancer. The supplement was administered daily on bagel bits that were usually eaten within minutes by the mice. Although longevity was not statistically different between treatments, longevity was strongly related to the compliance of mice in eating the supplement. Linear regression revealed a strong positive relationship between the proportion of supplement eaten and the longevity of mice within the treatment group (P < 0.0001).

PMID: 24531571

The thing I don't like about the "complex nutraceutical supplement" is the complexity.  I'm going to guess that the metastasis result was largely from NAC, (on the basis of this and this) but who really knows?

[Hebbeh]

 

These supplements are at best just curve squarers that help keep you healthy until you die right on schedule from aging.

 

 

And what is wrong with that?  Shouldn't that be the goal?  Would you rather spend your final years sick and decrepit (like most) before you die?  It's incredibly unrealistic to expect to be immortal as some would desire....not even considering the immortality of contributing to worsening overcrowding and all the global ills accompanying such a selfish goal.  However, unlike most now, if we could all live a reasonably long, healthy, and productive life....right up to the end....that would be huge...rather than "just at best".  Such a goal would lesson the burden on society rather than increase the burden in either of the other 2 scenarios.  And such a goal would appear in reach here and now...rather than "not in my lifetime".  I'll take heath span over the alternative but suit yourself.

[Michael Price]

Well said Hebbeh.

Niner, I like the complexity, and refuse to attribute the longevity, cognitive and anticancer effects to any particular component. As they say, the whole is greater than the sum. Synergy and all that.

Krillen, Michael Rae's methodology is fundamentally flawed; His approach is to always point to the existence of a longer-lived sub-strain somewhere else in the world and claim this invalidates everything. Of course this is bogus; would the existence of Bowhead whales invalidate sucessful human trials?

[krillin]

Well said Hebbeh.

Niner, I like the complexity, and refuse to attribute the longevity, cognitive and anticancer effects to any particular component. As they say, the whole is greater than the sum. Synergy and all that.

Krillen, Michael Rae's methodology is fundamentally flawed; His approach is to always point to the existence of a longer-lived sub-strain somewhere else in the world and claim this invalidates everything. Of course this is bogus; would the existence of Bowhead whales invalidate sucessful human trials?

 

The McMaster people used one of those longer-lived strains and their supplement couldn't do any better than living a healthy Spindler lab lifestyle. Using short-lived strains does invalidate the results unless you happen to have the same genetic defects. If human lifespan is extended by fixing something that is not broken in bowhead whales, then the trials are indeed invalidated from the perspective of the bowhead whales.

 

I never said I'm opposed to practicing curve squaring, I just don't think we should be using the phrase "increased lifespan" in that context. (It should be reserved for increases in the species maximum lifespan.) And we certainly shouldn't be getting excited about it. We've had all the curve-squarers we need for a long time now and we shouldn't be encouraging people to research them when they could be researching anti-aging instead. The thing that I kept saying to myself while reading Aubrey's book was "Well, there's another chapter that supplements can't do jack about."

[Michael Price]

Krillin,
I disagree with your use of the Bowhead Whale example. Suppose that dietary deficiencies contribute significantly to aging, and that we share these same dietary deficiencies with mice and whales (I happen to believe both these propositions), then correcting those deficiencies would benefit mice, men and bowheads. So human experiments would have relevance for whales, just as mice experiments have relevance to humans.

[krillin]

Mutagenesis. 2014 May;29(3):177-87. doi: 10.1093/mutage/geu002. Epub 2014 Feb 15.
Impact of a complex nutraceutical supplement on primary tumour formation and metastasis in Trp53+/- cancer-prone mice.
Aksenov V1, Boreham D, Rollo CD.

A complex dietary supplement designed to impact multiple mechanisms associated with aging and cancer reduced overall tumorigenesis in cancer-prone heterozygous Trp53+/- mice by ~30% (P < 0.018). Carcinomas were reduced by 67% (P < 0.006). Remarkably, metastasis (a leading cause of cancer mortality) was undetectable in treated animals (P < 0.004), and the occurrence of multiple primary tumours was reduced by 74% (P < 0.012). Reduction of pulmonary adenocarcinoma by 62% (P < 0.021) was of particular note given that lung cancer is the second leading cause of death in humans. Tumours showed pronounced age-related expression in untreated animals older than 600 days. Benefits of treatment only emerged in these later ages, suggesting that the supplement acted on mechanisms common to aging and cancer. The supplement was administered daily on bagel bits that were usually eaten within minutes by the mice. Although longevity was not statistically different between treatments, longevity was strongly related to the compliance of mice in eating the supplement. Linear regression revealed a strong positive relationship between the proportion of supplement eaten and the longevity of mice within the treatment group (P < 0.0001).

PMID: 24531571

The thing I don't like about the "complex nutraceutical supplement" is the complexity.  I'm going to guess that the metastasis result was largely from NAC, (on the basis of this and this) but who really knows?

 

Those mice have had a partial knock-out of p53, so they're less vulnerable to harm from NAC because the damage has already been done. (NAC lowers p53 activation. When p53 is totally knocked out NAC doesn't increase lung cancer cell proliferation anymore, but you're still totally screwed compared to having functional p53.)

 

[krillin]

Krillin,
I disagree with your use of the Bowhead Whale example. Suppose that dietary deficiencies contribute significantly to aging, and that we share these same dietary deficiencies with mice and whales (I happen to believe both these propositions), then correcting those deficiencies would benefit mice, men and bowheads. So human experiments would have relevance for whales, just as mice experiments have relevance to humans.

 

Then how come supplements don't ever work against aging in the longer-lived strains of mice that live healthy lifestyles?
 

[Michael Price]

Rollo et al discuss this. LE results from combinations of supplements. And such studies are quite rare.

[timar]

I wholeheartedly agree with what Hebbeh said. This is why I strongly object against cryonics, which to me seems like the most absurd extension of individual egoism - to waste all those ressources and produce tons of CO2 after your own demise, just out of a vague hope and the fear of death. If one can't accept the fact of death in its definitiveness he or she should turn towards religious ideas, like most people did before, instead of becoming an undead consumer of precious ressources becoming more and more scarce for future generations.

 

Well, enough off-topic rant...

 

Krillin,
I disagree with your use of the Bowhead Whale example. Suppose that dietary deficiencies contribute significantly to aging, and that we share these same dietary deficiencies with mice and whales (I happen to believe both these propositions), then correcting those deficiencies would benefit mice, men and bowheads. So human experiments would have relevance for whales, just as mice experiments have relevance to humans.

 

I basically agree with your first proposition concerning curve squaring by correcting functional deficiencies (I have gone on record here persistently advocating a sensible multivitamin supplementation as well as to eat a diet enriched in polyphenols).

 

I think, however, that it is not only doubtful whether we share the "same dietary deficiencies with mice and whales" and hence question the significance of such studies, but also that "complex dietary supplement" products such as the LEF Mix should be regarded with some degree of skepticism, not only because of their wildly heterogenous formulations (the LEF Mix, for example, contains excessive amounts of some vitamins and trace minerals and negligible amounts of most polyphenolic ingredients) based more on the fancy of the formulator than on solid scientific evicence, but also because there is a lot of money to be made from selling such "premium-grade" supplements - money that many people buying those supplements would get more from if they invested it into a healthy diet instead.

Edited by timar, 02 October 2014 - 08:30 AM.

[niner]

These supplements are at best just curve squarers that help keep you healthy until you die right on schedule from aging.

 
And what is wrong with that?  Shouldn't that be the goal?  Would you rather spend your final years sick and decrepit (like most) before you die?  It's incredibly unrealistic to expect to be immortal as some would desire....not even considering the immortality of contributing to worsening overcrowding and all the global ills accompanying such a selfish goal.  However, unlike most now, if we could all live a reasonably long, healthy, and productive life....right up to the end....that would be huge...rather than "just at best".  Such a goal would lesson the burden on society rather than increase the burden in either of the other 2 scenarios.  And such a goal would appear in reach here and now...rather than "not in my lifetime".  I'll take heath span over the alternative but suit yourself.

 
I agree with most of this, and have never understood the grief that curve-squarers get. I just wanted to point out that we could have much longer lives (say, for the sake of argument, 250 years) without the problems of overpopulation, pollution, etc. It would require that we bring the entire world up to first world educational and economic standards, at which point everyone would probably adopt the reproduction habits of modern developed economies, causing population to slowing drift downward due to fewer births, even if people lived a lot longer on average. People who live longer in perfect health can continue to contribute to society, rather than being a drag on it. Living longer gives more time to amortize the cost of education, training, and bionic modifications.

Niner, I like the complexity, and refuse to attribute the longevity, cognitive and anticancer effects to any particular component. As they say, the whole is greater than the sum. Synergy and all that.

Why would you like complexity? It's not a virtue in itself. I'd prefer to understand what was going on in its entirety. What if some of the components of the mixture are working at cross purposes with others? You might get more life extension and/or better health with some components removed. And why would you "refuse" to attribute any of the desirable effects to a particular component? If that turns out to be the fact of the matter, then you either accept it or you're in denial of reality.

[Michael Price]

Niner,
perhaps I should say I acknowledge the complexity. Biology is complex, which is why solutions have to be complex. Trying to isolate cause and effect in a reductionist manner is the wrong approach. We need to acknowledge the synergy operating here. This, AFAICS, is reality. The hunt for reductionist explanations and comprehensible mechanisms is a great barrier to progress in anti-aging interventions.

Edited by Michael Price, 03 October 2014 - 02:28 AM.