15 replies to this topic

[Alistair]

Dietary lipoic acid supplementation can mimic or block the effect of dietary restriction on life span.

The study:
http://www.ncbi.nlm....ov/sites/entrezhttp://www.ncbi.nlm....Pubmed_RVDocSum

The news:
http://www.independe...ike-887123.htmlhttp://www.independe...ike-887123.html

Our evidence-based assessment:
http://aging-managem...lipoic_acid.phphttp://aging- manage...ipoic_acid. php

Best Regards,

Alistair

[drmz]

nice link management cover up

[cronnie]

cool. So i do CR for 6 months withoutout ALA and then eat the next 140 years as much as i want with ALA xD

[hamishm00]

I just saw this too...

Here's the write up from pubmed:

Dietary lipoic acid supplementation can mimic or block the effect of dietary restriction on life span.Merry BJ, Kirk AJ, Goyns MH.
School of Biological Sciences, University of Liverpool, Liverpool L69 7ZB, UK. bm01@liverpool.ac.uk

Dietary restriction feeding extends survival in a range of species but a detailed understanding of the underlying mechanism is lacking. There is interest therefore in identifying a more targeted approach to replicate this effect on survival. We report that in rats dietary supplementation with alpha-lipoic acid, has markedly differing effects on lifetime survival depending upon the dietary history of the animal. When animals are switched from DR feeding to ad libitum feeding with a diet supplemented with alpha-lipoic acid, the extended survival characteristic of DR feeding is maintained, even though the animals show accelerated growth. Conversely, switching from ad libitum feeding a diet supplemented with alpha-lipoic acid to DR feeding of the non-supplemented diet, blocks the normal effect of DR to extend survival, even after cessation of lipoic acid supplementation. Unlike the dynamic effect of switching between DR and ad libitum feeding with a non-supplemented diet where the subsequent survival trajectory is determined by the new feeding regime, lipoic acid fixes the survival trajectory to that established by the initial feeding regime. Ad libitum feeding a diet supplemented with lipoic acid can therefore act as mimetic of DR to extend survival.

PMID: 18486188 [PubMed - in process]

Edited by hamishm00, 08 August 2008 - 11:29 AM.

[maxwatt]

I just saw this too...

Here's the write up from pubmed:

Dietary lipoic acid supplementation can mimic or block the effect of dietary restriction on life span.Merry BJ, Kirk AJ, Goyns MH.
School of Biological Sciences, University of Liverpool, Liverpool L69 7ZB, UK. bm01@liverpool.ac.uk

Dietary restriction feeding extends survival in a range of species but a detailed understanding of the underlying mechanism is lacking. There is interest therefore in identifying a more targeted approach to replicate this effect on survival. We report that in rats dietary supplementation with alpha-lipoic acid, has markedly differing effects on lifetime survival depending upon the dietary history of the animal. When animals are switched from DR feeding to ad libitum feeding with a diet supplemented with alpha-lipoic acid, the extended survival characteristic of DR feeding is maintained, even though the animals show accelerated growth. Conversely, switching from ad libitum feeding a diet supplemented with alpha-lipoic acid to DR feeding of the non-supplemented diet, blocks the normal effect of DR to extend survival, even after cessation of lipoic acid supplementation. Unlike the dynamic effect of switching between DR and ad libitum feeding with a non-supplemented diet where the subsequent survival trajectory is determined by the new feeding regime, lipoic acid fixes the survival trajectory to that established by the initial feeding regime. Ad libitum feeding a diet supplemented with lipoic acid can therefore act as mimetic of DR to extend survival.

PMID: 18486188 [PubMed - in process]

So those of us who have taken lipoic acid without CR are doomed; CR will not help now.

[JLL]

Strange... does anyone have access to the whole study? How long does it take for the effect to kick in - if I do CR for a week and then start eating normally and taking ALA, what will happen? Or what if I stop taking ALA and start doing CR?

[edward]

This has been discussed extensively in a topic Matt started here http://www.imminst.o...o...c=22205&hl=

Matt sent me the .pdf of the study and I posted it in that thread. But ill post it again here.

Basically what this study says is:

1. Calorie Restricted Rats switched to a normal diet with Alpha Lipoic Acid added, looked from a lifespan perspective like they continued on CR for the rest of their lives only they were able to gain weight like normal rats on a normal diet. That is to say Alpha Lipoic Acid extended the CR effect after CR was stopped

2. Animals on a normal diet with Alpha Lipoic Acid added that were then switched to a CR diet (and their Alpha Lipoic Acid was no longer given) had less extension of life and their lifespans resembled more those of the controls

PROBLEMS

Refer to Table 1 on Page 2 of the study ......(first note they call their calorie restricted animal dietary restricted and use DR instead of CR, note also the rat chow all animals got is called CRM, this can be confusing unless you read carefully)

1. Take a look at groups 9 and 10, these are the groups that were on a Normal Diet + ALA supplementation and then were switched to CR (DR) and no ALA. Note that group 9 was on a normal diet for a total of 10 months or 300 days and this is the only group that showed lifespan similar to controls, group 10 which was on ALA and a normal diet for 120 days showed lifespan similar to the longest lived group. 300 days is a big chunk in a rats life and 300 days of a normal diet is enough time to account for groups 9's lifespans looking more like the controls.

2. Previous CR rat studies with CR starting later in life (past juvenile stage) have failed, 300 days is plenty past the juvenile stage to have this effect. See problem 1.

3. They do not show what would happen if the rats in groups 9 and 10 started CR and continued taking Alpha Lipoic Acid. Perhaps it was the combined stress of stopping ALA and starting CR that was too much and caused problems especially since these groups started ALA as juveniles and arguably their bodies were adapted to having it.

4. There is no straight CR control group. Yes, they didn't have a group on only CR for their whole life, not to mention a CR + ALA group which would have been nice too.

5. The biggest problem of all...... The dose!!! They supplemented with 1.5 grams per kg of bodyweight which is frankly, insane. Using straight g/kg that would be like me taking 111 grams of ALA a day. Using a rat scaling factor would bring my dose down some to 54 grams a ALA a day, still a huge dose, roughly 90 times higher than what I currently take (300 mg twice a day)

edit: spelin n' gramur

Attached Files

•  CR_ALA_etc.pdf   654.59KB   137 downloads

Edited by edward, 08 August 2008 - 09:49 PM.

[Michael]

How long does it take for the effect to kick in - if I do CR for a week and then start eating normally and taking ALA, what will happen? Or what if I stop taking ALA and start doing CR?

cool. So i do CR for 6 months withoutout ALA and then eat the next 140 years as much as i want with ALA xD

So those of us who have taken lipoic acid without CR are doomed; CR will not help now.

It's good to see people asking the right questions ...

First, please read my disclosure here; in particular: while there, it was my initiative that sourced, brought to market, and promoted the first R(+) lipoic acid supplement on the market (ie, the physiological enantiomer, rather than the "alpha-lipoic acid" racemate in most supplements and used as a diabetes drug in Europe). This was rapidly followed up by a lot of companies producing fraudulent and/or poor-quality knock-off products, many of them plagiarizing my writing or nakedly cribbing from it to add literary insult to material injury. The big exception was of course Geronova, who were real pioneers in a way that even my company was not, producing new science and developing a potassium salt whose superior stability & bioavailability they have actually documented, including an human bioavailability study (1). (Altern Med Rev has historically been mostly a disguised infomercial for a supplement company, and IMO certainly should not be MEDLINE-indexed without a great deal of reform, but note Lester Packer's involvement; as well, Geronova's driving force, David Carlson, and am convinced of his sincerity & competence). (FWIW, my old employer, in addition to having the regular stuff, produces a tromethamine salt which (at least when formulated by the former Asta Medica (now part of Swedish pharmaceutical company Meda AB)) has also shown superior bioavailability).

Next, please indulge me in a bit of preamble. As most of you know, Tory Hagen and Bruce Ames did some extremely exciting work around the turn of the century, showing late-life 'rejuvenation' of heart and brain with the R(+) form of lipoic acid, which encouraged a lot of people to think that it might actually slow down biological aging; this was encouraged further by the mechanistic hypothesis that, by lowering electron reduction at Complex I, R(+)-lipoic acid might actually reduce the mitochondrial generation* of free radicals (rather than merely quenching some of them as an antioxidant post facto).

Unfortunately, lipoic acid has consistentently failed to extent lifespan in rodent studies. As part of the LEF LifeSpan Project, Steve Spindler tested the racemate at 600 mg/kilogram of the control diet -- either or with NAC (2000 mg/kg), vitamin E (585 mg/kg), and lycopene (300 mg/kg) and found no effect (2); under the same funding source, racemic lipoic acid (600 mg/kg) also flunked for Weindruch; and even R(+) flunked for Ames (personal communication to me & several others at SENS1 -- he's never published it, alas).

However, several researchers -- Spindler (2), Weindruch, Ames (who offered this as an explanation for the R(+) flunk), and de Grey -- have noted that well-cared-for, longevous mice die so overwhelmingly of cancer (having not fallen prey to anything else first) that an intervention that had strong impacts on multiple mechanisms of aging but that did not directly impact cancer might have no detectable impact on lifespan. CR, in this model, might have at least 2 major effects that combine to delay death: retardation of aging per se, and an antiproliferative effect which (in combination with the reduction of the age-associated increase in vulnerability to mortality) prevents the animals from dying early from cancer. Clearly, CR is not just a cancer therapy -- but such a bimodal effect might help to explain the discordant effects on the survival curve in mice (shift the curve to the right) vs rats (pull out the curve).

Creative genius that he is, de Grey has come up with an experimental design that would help to resolve this question: do the experiment in cancer resistant (albeit short-lived) mutant mice with unusually active p53 (4,5). While still potentially susceptible to confounding from effects of high p53 activity on tissue renewal, this might allow the anti-aging effect of any particular intervention to be isolated from any anticancer effect.

Of course, if this hypothesis is correct, then done and dusted interventions suddenly spring forth from the soil: we open up an enormous panoply of antioxidant and other interventions which suddenly once again become plausible anti-aging therapies. But R(+) strikes me as a particularly promising candidate for a couple of reasons.

First, although many of the antioxidant effects of lipoic acid have been shown to be due to Nrf2 stimulation rather than its intrinsic antioxidant properties or its metabolite, DHLA (6), it's still possible, mechanistically, that by lowering electron reduction at Complex I, lipoic acid actually lowers mtROS generation; if, per MiFRA, mtROS fuel aging, this would fit the above model nicely, as of course mtROS overwhelmingly 'hit' mtDNA & virtually never DIRECTLY 'hit' nuDNA -- & in any case, mutations leading to cancer in the real world overwhelmingly do not come from ROS, but from errors in fidelity of DNA replication.

Second, the effects reported by Hagen and Ames for late-life 'rejuvenation' of heart and brain are pretty darned impressive AFAICS -- in some respects, better than those of CR.

And now comes this recent report by Brian Merry (who is one of my all-time favorite biogerontologists) (7).

CR folk of course have always wished someone would do good studies combining promising-looking antioxidants and other putative anti-aging interventions with CR, which has essentially never been done except in one old study by Weindruch, Walford, and Harris (8) with the synthetic antioxidants ethoxyquin and 2-mercaptoethylamine and ethoxyquin ethoxyquin back in teh 80s; in that study, unfortunately, the CR animals' small livers apparently couldn't handle the stuff (ethoxyquin is hepatotoxic) -- a flop, but not particularly insightful.

Merry's group combined different combinations of age of onset and CR or AL (including switching from CR in early life with AL late, eg) with and without lipoic acid. Without going thru' the results in detail, most of the results of the various switches between CR and AL diets were as you would expect from previous studies in rats (as distinct from what you see in mice). It was principally the inclusion of lipoic acid (racemic, unfortunately) that made it interesting. Also unfortunately, most of the cohorts were somewhat too small (25 animals), which made the results underpowered. From personal correspondence with Merry, this was not just lack of funding (tho' that played into it of course -- sigh ), but also because it was originally designed primarily to test the effects on redox sensitive transcription factors, which would be expected to change with age, CR, and lipoate status.

The results to hand have enough solid data, and enough room for speculation, to make for a very tantalizing read. Now, Merry was most intrigued by an apparent 'memory' effect highlighted in these popular articles: "Animals fed ad libitum alpha-lipoic acid supplemented diet 2–12 months, then switched to DR feeding the [unsupplemented] diet" decidedly did not do as well as animals switched from unsupplemented AL to unsupplemented CR -- they seemed 'fixed' in their old life trajectory.Animals switched earlier (at 6 mo) and thus given more time on CR had an intermediate survival, mostly due to a more AL-like mortality pattern in midlife. Contrariwise, animals initially on CR, but switched to AL + LA at 12 months, seemed to do pretty nearly as well as animals kept on CR throughout life, and those switched a little earlier had survival intermediate between AL and CR. Merry's hypothesis is that the supplement exerts a stable, epigenetic effect on REDOX-sensitive transcription factors, and thus prevents the shift into the alternative metabolic state.

There is one major confounder to this study, which is that they nowhere indicate that the AL --> CR (± LA) @ 12 mo groups were eased into CR. As previously discussed, adult organisms must enter into CR gradually to get the LS benefits. So the 'memory' effect might simply reflect a CR protocol that wouldn't've worked anyway. However, there are several lines of evidence against this in the report. First, surprisingly (granted the equivalent mouse data), the AL ---> unsupplemented CR @12 mo group did enjoy a LS gain that looks like a straight dose-response CR effect. Perhaps this is a species-specific result: the survival curves of rats and mice on CR do have distinct profiles (9), tho' certainly no one has ever made 'shock therapy' work in still older rats (17 mo + -- (eg, (10,11)). IAC, the fact that it worked in Merry's hands in this report shows that the same protocol absent the LA does give a classic anti-aging CR life extension effect, suggesting that the addition of LA really did somehow impair the shift into 'CR mode.' There is also the consistency of the cohort that made the switch at 6 mo (say, 17 human-equivalent years): CR initiated at this time this did extend life without the LA, and this result confirms previous findings that CR still works as 'shock therapy' in rats at this age (eg, 12). Yet, here, adding in LA impaired this benefit as compared to the same protocol without the supplement. It's interesting that this group had an intermediate LS, better than lifelong AL (± LA) but not as good as AL ---> unsupplemented CR at the same, youthful age; note, especially, that that the survival curve shows typical AL mortality during AL and continuing for some months after the switch to the CR + LA diet, but that they did eventually enter into a more CR-like pattern (see Fig 4b), suggesting a memory effect that was overcome with enough time and initial youthful metabolic flexibility. And, finally, there is the corresponding CR ---> AL (± LA) data, which is again consistent with Merry's hypothesis.

IAC, while this is all very intriguing, it has no practical import for most individual life extensionists who gets started as adults:

How long does it take for the effect to kick in - if I do CR for a week and then start eating normally and taking ALA, what will happen? Or what if I stop taking ALA and start doing CR?

cool. So i do CR for 6 months withoutout ALA and then eat the next 140 years as much as i want with ALA xD

No. First, no one can 'do CR for a week': again, to work in adults (and no one is advocating its imposition on children!), you have to ease your way into CR gradually[/url]. The process takes a month in rodents; this could be many months, or credibly even a few years, in humans. Second, these animals started on CR at weaning; it's far from clear that the same reprogramming or epigenetic effects would be observed in adults (more work for the Merry lab!). And third, 6 to 10 months in a rodent is a very long time indeed: the human equivalent of ~16 and ~27 years --not something you can crash in on briefly.

So those of us who have taken lipoic acid without CR are doomed; CR will not help now.

This worry is the converse of the overly-optimistic interpretation above; and yes, if you've been on high-dose LA on an AL diet for many years, I'd say this study definitely is a bummer. I sure hope you're a member of The 300 . Ironically, in this case, many life extensionists will for once have benefitted from the misrepresentations of supplement companies: plenty of people out there life extensionists only take a couple of hundred mg -- far too little of the stuff to exert a meaningful physiological effect anyway or only recently bumped up their dose. In my own case, I started on a mere 50 mg LA back in the early 90s, and while I was still eating AL was rarely over 150 mg until after I'd been on CR for a couple of years.

From my own perspective as an established CR practitioner, I was most interested in "Group 11": the rats that were put on CR, and then had LA added, without switching back to AL eating. In particular, median, mean, and "max LS" (eyeballed single longest-lived animal from the survival curve -- not the proper, 10th decile survivorship operational definition, for which unfortunately they didn't provide numbers) were, in days:

Lifelong AL: 926 - 854 - 1100
Lifelong AL + lipoic: 900 - 858 - 1105
CR --> AL + LA @ 6 mo: 996 - ? - 1210
CR --> AL + LA @ 12 mo: 1041 - ? - 1205
Lifelong CR: 1047 - 1025 - 1210
CR, + Lipoic @ 12 mo: 1125 - 1068 - 1230

I've also attached the relevant survival curves. Again, the study is underpowered, but looks as if there may have been a modest benefit for the combination -- particularly relatively late in life. If such an effect is real, IAC, it's very small. I think this consistent with the idea that CR both retarded 'aging' and inhibited tumors, and the lipoate boosted the former just a little bit, whereas there was no such benefit for AL as per the hypothesis under discussion. Unfortunately, the paper doesn't give any pathology results; I have asked Dr. Merry if he has any data on this, tho' I suspect that the low cohort numbers will make any results extremely uncertain.

Dosage: LA was administered at 0.15% of diet weight; per Merry's email to me, "The DR rats eat between 8.5 and 11.5 g of food per day depending on their age so this would be a consumption of 10-13 mg of LA per animal per 24 hours. So if we average this and say about 11 mg of lipoic acid per animal of about 200g" we get 55 mg/kg body weight. Adjusting for Kleiber's law of metabolic scaling, this is 890 mg/d in what was, prior to the obesity epidemic, an average American adult of 70 kg; this is one of those cases where CR saves you some money . These doses are in the ballpark, at least, of doses used in clinical trials and approved in Europe for use in diabetes, and also of the extrapolated doses from the Hagen/Ames studies.

The benefit, if any, of adding LA to CR is so minimal that I'm not sure it's worth running after; at the very least, it's reassuring that LA clearly didn't hurt the CR animals, or impinge on their benefits. (Nothing stupider than spending 40 yrs weighing your food and being bored to tears by "CR may not make you live longer, but it'll sure feel that way" clichés in the pop press, only to have it undermined by a stupid dietary supplement). OTOH, the Hagen/Ames results, and some people's subjective benefits, might make it worth while for CR people in late middle age to take it up at an appropriate dose.

-Michael
References
1. Carlson DA, Smith AR, Fischer SJ, Young KL, Packer L.
The plasma pharmacokinetics of R-(+)-lipoic acid administered as sodium R-(+)-lipoate to healthy human subjects.
Altern Med Rev. 2007 Dec;12(4):343-51.
PMID: 18069903 [PubMed - indexed for MEDLINE]

2. Spindler SR, Mote PL.
Screening candidate longevity therapeutics using gene-expression arrays.
Gerontology. 2007;53(5):306-21. Epub 2007 Jun 15. Review.
PMID: 17570924 [PubMed - indexed for MEDLINE]

3. Lee CK, Pugh TD, Klopp RG, Edwards J, Allison DB, Weindruch R, Prolla TA.
The impact of alpha-lipoic acid, coenzyme Q10 and caloric restriction on life span and gene expression patterns in mice.
Free Radic Biol Med. 2004 Apr 15;36(8):1043-57.
PMID: 15059645 [PubMed - indexed for MEDLINE]

4. Tyner SD, Venkatachalam S, Choi J, Jones S, Ghebranious N, Igelmann H, Lu X, Soron G, Cooper B, Brayton C, Hee Park S, Thompson T, Karsenty G, Bradley A, Donehower LA.
p53 mutant mice that display early ageing-associated phenotypes.
Nature. 2002 Jan 3;415(6867):45-53.
PMID: 11780111 [PubMed - indexed for MEDLINE]

5. Maier B, Gluba W, Bernier B, Turner T, Mohammad K, Guise T, Sutherland A, Thorner M, Scrable H.
Modulation of mammalian life span by the short isoform of p53.
Genes Dev. 2004 Feb 1;18(3):306-19.
PMID: 14871929 [PubMed - indexed for MEDLINE]

6. Suh JH, Shenvi SV, Dixon BM, Liu H, Jaiswal AK, Liu RM, Hagen TM.
Decline in transcriptional activity of Nrf2 causes age-related loss of glutathione synthesis, which is reversible with lipoic acid.Proc Natl Acad Sci U S A. 2004 Mar 9;101(10):3381-6. Epub 2004 Feb 25.
PMID: 14985508 [PubMed - indexed for MEDLINE]

7. Merry BJ, Kirk AJ, Goyns MH. Dietary lipoic acid supplementation can mimic or block the effect of dietary restriction on life span. Mech Ageing Dev. 2008 Apr 22;129(6):341-348. [Epub ahead of print] PMID: 18486188

8. Harris SB, Weindruch R, Smith GS, Mickey MR, Walford RL.
Dietary restriction alone and in combination with oral ethoxyquin/2-mercaptoethylamine in mice.
J Gerontol. 1990 Sep;45(5):B141-7.
PMID: 2394907 [PubMed - indexed for MEDLINE]

9. Merry BJ.
Dietary restriction in rodents--delayed or retarded ageing?
Mech Ageing Dev. 2005 Sep;126(9):951-9. Review.
PMID: 15893804 [PubMed - indexed for MEDLINE]

10. Lipman RD, Smith DE, Blumberg JB, Bronson RT.
Effects of caloric restriction or augmentation in adult rats: longevity and
lesion biomarkers of aging.
Aging (Milano). 1998 Dec;10(6):463-70.
PMID: 10078316 [PubMed - indexed for MEDLINE]

11. Lipman RD, Smith DE, Bronson RT, Blumberg J.
Is late-life caloric restriction beneficial?
Aging (Milano). 1995 Apr;7(2):136-9.
PMID: 7548264 [PubMed - indexed for MEDLINE]

12. Yu BP, Masoro EJ, McMahan CA.
Nutritional influences on aging of Fischer 344 rats: I. Physical, metabolic, and longevity characteristics.
J Gerontol. 1985 Nov;40(6):657-70.
PMID: 4056321 [PubMed - indexed for MEDLINE]

Attached Files

•  MerryCR_LipoicSurvivCurves.tiff   93.14KB   78 downloads
•  MerryCR_LipoicFigs4_5.tiff   184.6KB   69 downloads

Edited by Michael, 09 August 2008 - 08:19 PM.

[cronnie]

wow, impressive post Michael. Thanks!

[Michael]

PROBLEMS
1. Take a look at groups 9 and 10, these are the groups that were on a Normal Diet + ALA supplementation and then were switched to CR (DR) and no ALA. Note that group 9 was on a normal diet for a total of 10 months or 300 days and this is the only group that showed lifespan similar to controls, group 10 which was on ALA and a normal diet for 120 days showed lifespan similar to the longest lived group. 300 days is a big chunk in a rats life and 300 days of a normal diet is enough time to account for groups 9's lifespans looking more like the controls.
2. Previous CR rat studies with CR starting later in life (past juvenile stage) have failed, 300 days is plenty past the juvenile stage to have this effect.

As I indicated, normally I'd agree with this critique, but in this case (in Merry's hands and in rats), this switch did work without the LA (Groups 5 & 7; Fig 1 (b) & ©).

3. They do not show what would happen if the rats in groups 9 and 10 started CR and continued taking Alpha Lipoic Acid. Perhaps it was the combined stress of stopping ALA and starting CR that was too much and caused problems especially since these groups started ALA as juveniles and arguably their bodies were adapted to having it.

You seem to be describing Group 4: CR fed the unsupplemented diet until 12 months (10 mo after CR initiation), then continuing on CR but with LA. As noted, adding the LA either had no effect, or was modestly beneficial.

4. There is no straight CR control group. Yes, they didn't have a group on only CR for their whole life, not to mention a CR + ALA group which would have been nice too.

I def'ly agree that a group on lifelong CR + LA would've been nice. But note that Group 2 was lifelong unsupplemented CR (starting at 2 mo, which is standard: you have to wait until after weaning!).

5. The biggest problem of all...... The dose!!! They supplemented with 1.5 grams per kg of bodyweight which is frankly, insane.

It would be, and the paper is unfortunately ambiguous, but I am assured by Dr. Merry (personal communication) that the dose was 1.5 g/Kg of diet, not body mass. And, remember to apply Kleiber's law (fortunately, the difference in biotransformation in rats vs humans is much less for LA than for flavonoids, so you don't have the huge uncertainty of eg resveratrol).

-Michael

[Alistair]

Hi Michael,

Thanks very much for the time and effort you put into such a detailed and informative post.

"OTOH, the Hagen/Ames results, and some people's subjective benefits, might make it worth while for CR people in late middle age to take it up at an appropriate dose."

Although the study that kicked this thread off looked at longevity in mice and this has been much of the focus of the discussion so far, shouldn't the main reason for us humans, whether calorie restricted or not, taking R-ALA be due to it's evidence base in two main other aspects of age-related disease rather than the aging process per se or an expectation of increased longevity?

Bearing in mind that heart disease is a major cause of death and diminished quality of life in humans, R-ALA appears to me to have enough evidence to support it's use, although I wish there were more human data.

More significantly, the onset of neurodegenerative disorders and age-related cognitive decline is something I personally am extremely keen to avoid for as long as possible and R-ALA's role in mitigating these complications of aging makes it a supplement 'must have' for me (as you suggest with the Hagen/Ames results).

To me, this puts R-ALA into a quality of life rather than quantity of life perspective. I would be keen to hear whether you think I have this right and would appreciate any opportunity to learn more on this fascinating subject.

Also, I heard that Prof. Ames was half way through a well designed, adequately powered RCT looking at effects in humans, but I can't find anything on this on the web. As you are considerably closer to this than I am, do you have any details or views on this?

Many Thanks in advance,

Alistair

(Whilst I would love to take credit for the work on the references below, but that should go to my brother.)

Heart Disease Refs:

• Kendler, B.S., Supplemental conditionally essential nutrients in cardiovascular disease therapy. J Cardiovasc Nurs, 2006. 21(1): p. 9-16.
• Br J Pharmacol. 2007 Oct 1 Effects of alpha-lipoic acid on endothelial function in aged diabetic and high-fat fed rats. Sena CM, Nunes E, Louro T, Proença T, Fernandes R, Boarder MR, Seiça RM. Institute of Physiology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal [2] 2Center for Neurosciences and Cell Biology of Coimbra, University of Coimbra, Coimbra, Portugal.
• Rev Port Cardiol. 2007 Jun;26(6):609-19. Endothelial dysfunction in type 2 diabetes: effect of antioxidants. Sena CM, Nunes E, Louro T, Proença T, Seiça RM. Instituto de Fisiologia, Faculdade de Medicina, Universidade de Coimbra, Coimbra, Portugal.
• J Altern Complement Med. 2007 Jun;13(5):577-84. Effects of alpha-lipoic acid supplementation in peripheral arterial disease: a pilot study. Vincent HK, Bourguignon CM, Vincent KR, Taylor AG. Center for the Study of Complementary and Alternative Therapies, University of Virginia Health System, Charlottesville, VA, USA. vincehk@ortho.ufl.edu
• J Clin Hypertens (Greenwich). 2007 Apr;9(4):249-55. Effect of combined treatment with alpha-Lipoic acid and acetyl-L-carnitine on vascular function and blood pressure in patients with coronary artery disease. McMackin CJ, Widlansky ME, Hamburg NM, Huang AL, Weller S, Holbrook M, Gokce N, Hagen TM, Keaney JF Jr, Vita JA. Evans Department of Medicine and Whitaker Cardovascular Institute, Boston University School of Medicine, Boston, MA, USA.
• Cheng, P.Y., et al., Heme oxygenase-1 contributes to the cytoprotection of alpha-lipoic acid via activation of p44/42 mitogen-activated protein kinase in vascular smooth muscle cells. Free Radic Biol Med, 2006. 40(8): p. 1313-22.
• Lee, Y., et al., Alpha-lipoic acid prevents lipotoxic cardiomyopathy in acyl CoA-synthase transgenic mice. Biochem Biophys Res Commun, 2006. 344(1): p. 446-52.
• El Midaoui, A., et al., Modulation of cardiac and aortic peroxisome proliferator-activated receptor-gamma expression by oxidative stress in chronically glucose-fed rats. Am J Hypertens, 2006. 19(4): p. 407-12.

Neurodegenerative Disorders Refs:

• J Neural Transm Suppl. 2007;(72):189-93. Alpha-lipoic acid as a new treatment option for Alzheimer's disease--a 48 months follow-up analysis. Hager K, Kenklies M, McAfoose J, Engel J, Münch G. Department of Medical Rehabilitation and Geriatrics, Henriettenstiftung, Hannover, Germany.
• Free Radic Biol Med. 2007 Feb 1;42(3):371-84. Epub 2006 Nov 10. Involvement of PI3K/PKG/ERK1/2 signaling pathways in cortical neurons to trigger protection by cotreatment of acetyl-L-carnitine and alpha-lipoic acid against HNEmediated oxidative stress and neurotoxicity: implications for Alzheimer's disease. Abdul HM, Butterfield DA. Department of Chemistry, Center of Membrane Sciences, University of Kentucky, Lexington, KY 40506-0055, USA.
• Pharmacol Ther. 2007 Jan;113(1):154-64. Epub 2006 Sep 20. Lipoic acid as a novel treatment for Alzheimer's disease and related dementias. Holmquist L, Stuchbury G, Berbaum K, Muscat S, Young S, Hager K, Engel J, Münch G. Department of Biochemistry and Molecular Biology and Comparative Genomics Centre, School of Pharmacy and Molecular Sciences, James Cook University, Townsville, Australia.
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[Wulf]

The benefit, if any, of adding LA to CR is so minimal that I'm not sure it's worth running after; at the very least, it's reassuring that LA clearly didn't hurt the CR animals, or impinge on their benefits. (Nothing stupider than spending 40 yrs weighing your food and being bored to tears by "CR may not make you live longer, but it'll sure feel that way" clichés in the pop press, only to have it undermined by a stupid dietary supplement). OTOH, the Hagen/Ames results, and some people's subjective benefits, might make it worth while for CR people in late middle age to take it up at an appropriate dose.

Thank you so much for the comprehensive analysis and commentary. Based on the application of the studies results to my situation, I've decided to give up ALA. My particular situation reflects Group 9. I'm young (25) and was just about to begin therapeutic doses of ALA (600 mg of Na-RALA). At some point later in my life, I would probably try an institute CR. Specifically, Merry's conclusion:

This suggests a possible explanation for the effects on survival observed in which a-lipoic acid forms stable transcription-regulation complexes that block diet-induced changes in expression of genes central to the DR induced extension in longevity

Unfortunately, this all comes after I recently purchased 100 grams of GeroNova's Na-RALA. Any "CR people in the late middle age" interested in some heavily discounted Na-RALA?

Again, thank you for the discussion.

[tintinet]

Maybe...what qualifies as "late middle age?"

[Blue]

The given table 1 has a very obscure formatting. Cleaning:

Diet Days Group number
AL 926 1
AL + LA 900 3

CR 1047 2
CR (12 months) then CR + LA 1125 4

AL (6 months) then CR 1078 7
AL + LA (6 months) then CR 1086 10

AL (12 months) then CR 1031 5
AL + LA (12 months) then CR 934 9

CR (6 months) then AL 928 8
CR (6 months) then AL + LA 996 12

CR (12 months) then AL 975 6
CR (12 months) then AL + LA 1041 11

All animals on AL only diet until 2 months.

Adding LA generally has a beneficial (4 cases) or only slightly negative effect (1 case). What really stands out as an exception is group 9 where adding LA was associated with a large decrease in survival. Which is what the whole study takes as evidence for making the very startling claim that temporary intake of ALA makes lifelong diet irrelevant. Exceptional claims requires exceptional evidence and should be doubted until replicated. More likely there is a mistake or a confounding factor.

It is strange that group 10 did not show similar decrease. But maybe we can solve this by making the exceptonal claim even more exceptonal by stating that LA only has this effect at a certain age (6-12 months) or that ALA only locks in the diet if the rat is on it for 12 months but not for 6 months.

Instead of this note that except in group 1-3 there were only 25 rats per group. A fluke regarding a few rats can easily upset the results regarding a group. Lets look at graph 4a where we can see the survival curve for group 9. What really stands out is the sudden drop at around day 200. Nothing similar happened in any of the other curves. Most importantly the curve for group 3 which had had the same diet at this point. Did something happen there like a disease, some accident, same mistake in feeding or handling etc? According the Occam's razzor this is a far simpler explanation than hyperexceptional ad hoc theories and thus the preferred explanation.

Edited by Blue, 22 August 2009 - 03:26 PM.

[exigentsky]

I know this is an old thread but a lot of it contained cutting edge information. Have there been any recent updates about any of this?

I'm 23 and was taking R-ALA for its purported health benefits but I want to move towards a CRON diet and I'm thus very uneasy about R-ALA. Plus, I read some dubious but nonetheless scary claims that it may be a bad idea if I have mercury amalgam fillings. There were also some studies that suggest antioxidants may negate the benefit of exercise.

I'm really lost about good longevity supplements and protocols at this point. It seems like the consensus changes every other year.

Edited by exigentsky, 09 June 2011 - 09:51 PM.

[1kgcoffee]

When in doubt, dont' take it.
FYI, there have been some reports of LA causing greying of the hair...