42 replies to this topic

[AgeVivo]

It doesn't make much sense that anti-aging supplements are hyped for years without having been tested on lifespan.
Improve knowledge and reduce risks: ask and answer here which supplements have been tested on lifespan
- of cells, worms, flies, or much better, mammals -

[AgeVivo]

I am using the "perpetual Edit" feature of MF's forum to maintain a post about which interventions extend mammalian lives. Here is the content for now; post here to help me keep it clear, simple, accurate, updated.

digest from lifespan databases and forum threads:

• reports of mammalian lifespan extension:
  • Food low in methionine or in tryptophan: life extension in rat and mice; bigger effects with methionine restriction, plus already practiced in case of cancers and special diseases.
  • 2-MEA( 2-mercaptoethanol) and 2-MEA hydrochloride : +20 or 30% in mice. Warning: combination with ethoxyquin reduced lifespan!
  • PNB (alpha-phenyl-N-t-butyl-nitrone): small extension in normal old mice; 30% in human cells and in short-lived mice; to test: large extension in normal young adult mice? More generally N-hydroxylamines (NtBHA, NMHA, NBHA, PBN) extend human fibroblast lifespan
  • Diphenylhydantoin, Phenformin: different drugs tested by Dilman and Anisimov, 1980, +20 to +30% in female mice; anti-cancer, anti-diabetic, other.
  • Nordihydroguaiaretic acid: small increase in mice (Intervention Testing Program)
  • aspirin: small increase in mice (Intervention Testing Program)
  • Royal Jelly: 25% increase in mice mean lifespan, not maximum
  • weekly DNA and RNA Injection in rats: huge extension based on few rats; Odens, M. 1973. Almost no info so difficult to reproduce...
  • hypothyroidism at birth (Thyroxine injections): +10% in rats
• Very unclear:
  • Methylene Blue: good results against Alzheimer in patient; extends life of human fibroblasts; improves leucomotion in rats; other; well known, toxic at high doses; one mouse survival study (stopped at age 2y!!) implies possible life extensions.
  • SKQ1 (Anisimov): specifically designed mitochondrial antoxidant; extends lifespan of fungus, pollutant-sensitive shrimps, and 2 kinds of short lived mice
  • acetyl-L-carnitine (ALCAR) and/or R-alpha-lipoic acid (LA): many good things reported in rats but not lifespan. To test?
  • Clioquinol: extends life of human fibroblats; has been used for years in Japan; dangerous in rare cases; no mouse survival study?
  • lithium: +45% in c elegans; to test in mice?; have been used against mood disorders for years in humans
  • ethosuximide: +47% in c elegans; to test in mice?; have been used against epilepsy for years in humans
  • L-carnosine: longer fibroblast life; not tested in vivo
  • Retinoic acid: life extension in human keratinocytes; no lifespan reported in vivo
  • D-glucosamine, D-Glucose, D-Glycerol, D-sorbitol, D-Xylitol: extends life in yeast... testable in mice?
  • Deprenyl: first experiments showed life extension in different animal types, later observations showed reduced lifespans in different animal types (including in human!)!
  • Ethoxyquin: extended lifespan in normal mice but reduced lifespan under caloric restriction!
  • fish oil: longer life than corn oil, under CR or not, in short-lived mice
  • Melatonin: very slight extension in mice; opposite findings in flies
  • Selenium: extends life of flies
  • Ginko Biloba (Tamarixetin): extends lifespan of worms by 25%
  • Tea (an extract): extends lifespan of flies by 21%
  • Vitamin C: no increase in worms, increase in human cells, no more info!?
  • cancer resistant granulocyte injection: mice sent from Dr Cui's lab?
• Reduced lifespan although there was much hope:
  • oxygen: 60% as well as 11% and 16% in mice (whereas 3% extends mouse fibroblasts and humans fibroblats' life)
  • Accelerated photoperiodic cycle: monkey
  • antioxydant mix: no effect on lifespan in rats; vitamin E extended lifespan of various animals but not mice; vitamin C questionable as said above
  • Methionine

[AgeVivo]

Improve knowledge and reduce risks: ask and answer here which supplements have been tested on lifespan

Oh, i see why so few people posted: it wasn't clear: please mention supplements, ideally the ones you are taking, and that haven't already been mentioned in this thread. I'll try to find references for corresponding lifespan tests, I will answer unless other people answer before me. And I'll maintain a public list of what has been tested on lifespan

Edited by AgeVivo, 19 May 2009 - 08:18 AM.

[burungnasar]

Improve knowledge and reduce risks: ask and answer here which supplements have been tested on lifespan

Oh, i see why so few people posted: it wasn't clear: please mention supplements, ideally the ones you are taking, and that haven't already been mentioned in this thread. I'll try to find references for corresponding lifespan tests, I will answer unless other people answer before me. And I'll maintain a public list of what has been tested on lifespan

Echinacea (tested on mice):

http://www.springerl...847r02k22714p2/

[JLL]

What is the data on coenzyme-Q10 and lifespan?

[AgeVivo]

Echinacea (tested on mice): http://www.springerl...847r02k22714p2/

Good to know! It seems that it extended mouse lifespan, though in relatively poor conditions:

Some mice were maintained on a regular chow diet to which was added Echinacea purpurea daily (2 mg/mouse) (...) At approximately 13 months of age, mice consuming untreated diet had a 46% survival rate while those consuming Echinacea were 74% alive

Extended lifespan in mice: though both survival curves are a bit low (75% alive at 400 days is 'normal'; 85% is typically reached when a wheel is added so that mice do sport: see for example this graph taken from this list of life extension strategies) and it would have been better to see the experiment until death: it is still a positive point for Echinacea, and it would be good to retest it
Echinacea: it's a common flour. it is among the best-selling herbs in the world. Polysaccharides, alkylamides and cichoric acid are thought to be the active compounds.
Treatment in humans: (Wikipedia Echinacea purpura and Medicinal effects of Echinacea): dried Echinacea angustifolia root has been tested to fight colds, with positive results at the dose of three grams per day; reported side effects are primarily allergic, and hepatotoxicity (so beware of what else you take). It has been tested in many conditions including cancers.

Edited by AgeVivo, 19 May 2009 - 11:14 AM.

[AgeVivo]

This thread is obviously going to be long (which is great, because it is important to know supplement/drugs effects on lifespan) so if you feel like answering for a given drug/supplement please go ahead (you may say it if want, you can typically google "site:imminst.org echinacea" or use pubmed or these lifespan databases or google) and try to be concise (a good answer is a sentence plus a link to an existing review of the effects of echinacea on animal lifespans). If you don't agree to many ways for an answer, create a specific thread. If the thread ever gets very large it may be transformed into a specific website.

...for now there is only one question, about coenzyme Q, i am looking at it.

Edited by AgeVivo, 19 May 2009 - 11:20 AM.

[AgeVivo]

What is the data on coenzyme-Q10 and lifespan?

Dietary coenzyme Q has been tested on lifespan in worms, flies, mice and rats via normal and mutant animals. Partial *restriction* of coenzymes Q (that are needed for mitochondrial ATP production) robustly extended life in mice (2009) by approx 15% and various worms (2002) but not in flies (2003). Coenzyme Q10 *supplementation* did NOT affect lifespan of 'normal' mice nor rats (1998). Coenzyme Q10 supplementation extended life of rats fed a high PUFA diet (2004) by 11%.

To me the current results suggest that coenzyme Q10 supplementation would NOT extend lifespan, unless you suppose that your diet is dangerously rich in polyunsaturated fatty acids (PUFA). But appearently papers are in press that might soon give a global picture. Effects of coenzyme Q10 on lifespan might typically be discussed in this thread.

[mwestbro]

Here's an oldie that doesn't get talked about much these days: aloe vera.

The Effects of Lifelong Aloe Ingestion on Aging and Pathology

By Byung Pal Yu, Jeremiah Herlihy and Yuji Ikeno
Department of Physiology
University of Texas Health Science Center, San Antonio

The use of Aloe vera has crossed the barriers of time and culture in its promise to alleviate a broad range of illnesses. The basis of its reputation resides mainly with the steadfast beliefs in claims of its curative properties, but without hard scientific evidence.

The objective of our study was to initiate a systematic and scientific investigation of the effects of long-term aloe ingestion on laboratory rats. Utilizing well-characterized, inbred male F344 rats, housed under specific pathogen-free barrier conditions, we determined longevity, age-related pathology, and selected physiological and metabolic parameters. A total of 360 rats were divided into four groups: Group 1 (control) was fed a semi-synthetic diet without aloe; Group 2 was fed a diet containing a 1% freeze-dried aloe filet; Group 3 was fed a diet containing a 1% charcoal-processed, freeze-dried aloe filet; and Group 4 was given whole leaf aloe (0.02%) in drinking water.

For the longevity and pathological studies, 60 rats from each group were used. For the physiological and metabolic studies, 30 rats were sacrificed at 4, 8, and 16 months of age.

A summary of results are as follows: Aloe ingestion, both crude and processed, was shown to extend (¬10%) average life span and slow the mortality rate doubling time. Also, several beneficial effects from aloe ingestion on age-related disease were found: Group 2 and 3 showed a lower incidence of atrial thrombosis than Group 1. Furthermore, Group 2 showed a significantly lower incidence of fatal chronic nephropathy and occurrence of multiple causes of death compared to the control group. All groups ingesting aloe showed a slightly lower incidence of fatal leukemia. Moreover, no adverse, toxic effects were found with the ingestion of aloe vera.

Mike again: I took this off an "aloe science association" website. As far as I can see, it doesn't show up in Medline (although a more restrained abstract by this same team does). It would be interesting to know if it was ever published anywhere.

[mwestbro]

Now that I think about it, there are a number of substances that were once very popular in the longevist community but which have since faded from sight. It would be interesting to know if there has been any recent work with activated charcoal, B6 (not necessarily pyridoxamine, but plain ole pyridoxine), pantothenic acid, dmae, centrophenoxine, chromium, or panax ginseng. All of these have at least one old report of lifespan extension. If no one has pursued work with these, why not? Those of us looking in on the scientific community from the outside would like to know if there is an obvious reason why interest in a given compound has declined. I know that there was at least one failure to replicate with dmae, but resveratrol has had its failures as well and it still seems to generate a lot of enthusiasm.

Another one I have wondered about is piracetam. It seems like an obvious candidate for a lifespan study, but as far as I know, one has never been done. Is there a failed lifespan study somewhere that is an open secret among researchers? One wonders how to interpret a lack of interest in these old compounds.

Mike

[AgeVivo]

Aloe Vera

Aloe ingestion, both crude and processed, was shown to extend (...) average life span (...) it doesn't show up in Medline (although a more restrained abstract by this same team does)

There is weak suggestion of extended mean lifespan, in rats

the abstract accepted for publication does NOT say that lifespan was extended:

The influence of long-term Aloe vera ingestion on age-related disease in male Fischer 344 rats Phytotherapy research : PTR 2002 Dec;16(8):712-8.
(...) these findings suggest that life-long Aloe vera ingestion does not cause any obvious harmful and deleterious side effects, and could also be beneficial for the prevention of age-related pathology

The full text says

The survival curves for the rats in Groups A, B, C and D were not significantly different (data not shown).

but a table suggests that there was indeed a trend for extended mean lifespan: (n=60)

Edited by AgeVivo, 19 May 2009 - 09:56 PM.

[mwestbro]

A few in vivo lifespan studies for substances listed above:

Carnosine
PMID: 12447464 (Drosophila)
PMID: 12802415 (senescence-accelerated mice)

Alcar
PMID: 2234279

Plus a few new ones:

Creatine
PMID: 17416441

Mianserin
http://www.scienceda...71121144946.htm

[mwestbro]

Lithium:
PMID: 7843854 (lupus mice)
PMID: 19162061 (a somewhat cryptic abstract in senescence accelerated mice--I can't tell if this is a true lifespan test or not)
PMID: 19176408 (a warning sign? it doesn't seem to do much for humans)

Curcumin and green tea:
PMID: 17516143

And a failed fish oil trial:
19377016

[AgeVivo]

activated charcoal, B6 (not necessarily pyridoxamine, but plain ole pyridoxine), pantothenic acid, dmae, centrophenoxine, chromium, or panax ginseng.

Absolutely great list and great references! I'll take a moment every few days to make digests if needed, and to update the list of things that seem to extend lifespan in mammals. Even if we don't answer instantaneously, everything will be looked at.

[waldemar]

Very nice thread. What about Vitamin C? NAC?

[mwestbro]

I almost forgot metformin!

These aren't in mammals, but they are interesting: PBA and rhodiola.

This is my favorite antioxidant abstract, since it hints at a possible reason for the failure of some other studies. PMID: 9080401

And finally, a strange one. PMID: 3191547 is a lifespan study of fo ti, or polygonum multiflorum. There is no abstract, and the article is in Chinese. A Usenet poster provided the following information from the article here.

"Results: The time of death in 50% quails were respectively 205, 304,
322, and 213 days in control, large dosage Fo-ti, small dosage Fo-ti,
and vitamin E groups. The average survival time in 50% dead quails
(M±SD, days) were respectively 144.2±56.9 and 175.7±107.1 in large
dosage Fo-ti and small dosage Fo-ti groups, which were lengthened
remarkably as compared with the control group (89.9±61.9) (P<0.05 and
P<0.01)."

[waldemar]

Echinacea was mentioned as "shot down repeatedly" here: http://www.imminst.o...mp;hl=echinacea

[2tender]

How about ALA and its various forms? Im taking an Na RALA supplement combined with NAC. Any comments about that?

[mwestbro]

Lipoic Acid, from Towards a Life Prolonging Pill? Small Molecules with Anti-Ageing Properties by: Wagner, Gerd. Current Drug Targets, Nov2006, Vol. 7 Issue 11, p1531-1537

The antioxidant lipoic acid (Fig. (2)) showed activity in an accelerated assay for the identification of lifespan-extending interventions in Drosophila melanogaster [23]. At 0.005%, lipoic acid increased the lifespan of DTT flies in a gender-dependent manner up to 12% (females) and 4% (males) respectively [23]. Virtually identical results were obtained in the wild-type Canton-S strain upon administration of lipoic acid on day 10 after eclosion, while mortality rose dramatically when the compound was fed to flies from the day of eclosion. Also, no beneficial effects on lifespan in the DTT mutants were observed at higher concentrations of lipoic acid (0.05– 0.5%), and other antioxidants (tocopherol, catechin) did not result in increased lifespan in this assay [23]. Therefore, the lifespan extending effect of lipoic acid in this system appears to be independent from its antioxidant properties. The authors suggested further studies to clarify the different effect of lipoic acid on male and female flies [23].

And in mammals, here is the one that has caused a significant amount of confusion:

1: Mech Ageing Dev. 2008 Jun;129(6):341-8. Epub 2008 Apr 22.

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

[mwestbro]

Vitamin C: this is very much a mixed bag. All of the mouse trials, both positive and negative, should be taken with a grain of salt since mice produce their own vitamin C.

1: J Gerontol A Biol Sci Med Sci. 2008 Jan;63(1):35-42.

The effects of vitamin supplementation on Drosophila life span under normoxia and
under oxidative stress.

Bahadorani S, Bahadorani P, Phillips JP, Hilliker AJ.

Department of Biology, York University, Toronto, Ontario, Canada.

Vitamin A (retinol), vitamin C (ascorbic acid), and vitamin E (alpha-tocopherol)
are each thought to play an important role in the aging process. Here, we
investigated the effects of these vitamins on Drosophila melanogaster life span
under different oxidative stress conditions. Among the vitamins tested,
alpha-tocopherol exhibited the strongest antioxidant activity, extending average
and maximum life span for wild-type flies under hyperoxia and for Cu/Zn
superoxide dismutase-deficient (SOD1-deficient) flies under normoxia. Retinol
supplementation extended life span of SOD1-deficient flies under normoxia, and
ascorbic acid supplementation extended life span of wild-type flies under
normoxia. However, both retinol and ascorbic acid exhibited a strong prooxidant
activity under hyperoxia and shortened life span. Furthermore, ascorbic acid
supplementation enhanced the toxic effects of iron, with the iron pool
significantly increased in adult whole-body extracts. Taken together, our results
document antioxidant and prooxidant contributions of vitamins to D. melanogaster
life-span determination under normoxia and under oxidative stress.

Publication Types:
Clinical Trial
Research Support, Non-U.S. Gov't

PMID: 18245758 [PubMed - indexed for MEDLINE]

2: Mech Ageing Dev. 2006 Dec;127(12):897-904. Epub 2006 Nov 7.

Life-long vitamin C supplementation in combination with cold exposure does not
affect oxidative damage or lifespan in mice, but decreases expression of
antioxidant protection genes.

Selman C, McLaren JS, Meyer C, Duncan JS, Redman P, Collins AR, Duthie GG,
Speakman JR.

Aberdeen Centre for Energy Regulation and Obesity (ACERO), School of Biological
Sciences, University of Aberdeen, Aberdeen AB24 2TZ, UK. c.selman@ucl.ac.uk

Oxidative stress is suggested to be central to the ageing process, with
endogenous antioxidant defence and repair mechanisms in place to minimize damage.
Theoretically, supplementation with exogenous antioxidants might support the
endogenous antioxidant system, thereby reducing oxidative damage, ageing-related
functional decline and prolonging life- and health-span. Yet supplementation
trials with antioxidants in animal models have had minimal success. Human
epidemiological data are similarly unimpressive, leading some to question whether
vitamin C, for example, might have pro-oxidant properties in vivo. We
supplemented cold exposed (7+/-2 degrees C) female C57BL/6 mice over their
lifespan with vitamin C (ascorbyl-2-polyphosphate), widely advocated and self
administered to reduce oxidative stress, retard ageing and increase healthy
lifespan. No effect on mean or maximum lifespan following vitamin C treatment or
any significant impact on body mass, or on parameters of energy metabolism was
observed. Moreover, no differences in hepatocyte and lymphocyte DNA oxidative
damage or hepatic lipid peroxidation was seen between supplemented and control
mice. Using a DNA macroarray specific for oxidative stress-related genes, we
found that after 18 months of supplementation, mice exhibited a significantly
reduced expression of several genes in the liver linked to free-radical
scavenging, including Mn-superoxide dismutase. We confirmed these effects by
Northern blotting and found additional down-regulation of glutathione peroxidase
(not present on macroarray) in the vitamin C treated group. We suggest that high
dietary doses of vitamin C are ineffective at prolonging lifespan in mice because
any positive benefits derived as an antioxidant are offset by compensatory
reductions in endogenous protection mechanisms, leading to no net reduction in
accumulated oxidative damage.

Publication Types:
Research Support, Non-U.S. Gov't

PMID: 17092545 [PubMed - indexed for MEDLINE]

3: Gerontology. 1984;30(6):371-5.

Dietary vitamin C improves the survival of mice.

Massie HR, Aiello VR, Doherty TJ.

Feeding C57BL/6J male mice 1% ascorbic acid (1,430 mg/kg body weight) in their
drinking water for life increased the average life span by 8.6% (p less than
0.05) and perhaps by as much as 20.4%. The ascorbic acid group weighed 6-7% less
than the control group up until 800 days of age. The maximum life span for the
control group was 965 days and 993 days for the ascorbic acid group, representing
an increase of only 2.9% in the maximum life span. The copper content of heart,
liver, kidney, and brain was unchanged after feeding 1% ascorbic acid for 48
days. The copper content of heart declined by 20.4% after feeding 2% ascorbic
acid. Liver, kidney, and brain were unchanged.

PMID: 6519438 [PubMed - indexed for MEDLINE]

4: Exp Gerontol. 1991;26(5):487-94.

Ascorbic acid in Drosophila and changes during aging.

Massie HR, Shumway ME, Whitney SJ, Sternick SM, Aiello VR.

Masonic Medical Research Laboratory, Utica, New York 13501.

The ascorbic acid content of Drosophila melanogaster was found to be high in the
absence of a dietary source. The amount of ascorbic acid per fly declined with
aging in both the Oregon R and Swedish C strains. The median life span at 25
degrees C was 45 days for Swedish C and 59 days for Oregon R. The amount of
ascorbic acid in Swedish C flies (0.078 micrograms/fly) was higher than that for
Oregon R (0.058 micrograms/fly) for newly emerged flies but the rate of decline
with aging was greater for Swedish C than Oregon R. The decline in ascorbic acid
content with aging was 70.4% for Swedish C versus 19.9% for Oregon R. A brief
cold shock was found to significantly increase the amount of ascorbic acid in
Oregon R flies. Feeding the precursor of ascorbic acid synthesis,
L-gulonolactone, did not improve the life span. Life-time feeding of ascorbic
acid did not improve the life span of either Swedish C or Oregon R flies.

Publication Types:
Research Support, Non-U.S. Gov't

PMID: 1756780 [PubMed - indexed for MEDLINE]

[mwestbro]

NAC: the first abstract is in lupus mice. I'm not sure how relevant this is to most of us.

1: Lupus. 2001;10(4):258-65.

Antioxidants suppress mortality in the female NZB x NZW F1 mouse model of
systemic lupus erythematosus (SLE).

Suwannaroj S, Lagoo A, Keisler D, McMurray RW.

Division of Rheumatology, Department of Medicine, Faculty of Medicine, Khon Kaen
University, Khon Kaen, Thailand.

Inflammation produces reactive oxygen intermediates (ROI) that cause vascular
damage and activate T lymphocytes. Conversely, antioxidants not only protect
tissue from oxidative damage but also suppress immune reactivity. The objective
of this study was to examine immunomodulatory effects of the non-enzymatic
antioxidants, N-acetylcysteine (NAC) and cysteamine (CYST), on autoimmune
disease, glomerulonephritis, and mortality in the female B/W mouse model of human
systemic lupus erythematosus (SLE). The development of murine lupus was assessed
during the lifespan of female B/W mice given NAC or CYST. Morbidity and mortality
were assessed daily. At 6 week intervals mice were examined for weight change,
albuminuria, serum BUN, antibodies to DNA, and IgG immunoglobulin levels. Serum
prolactin, estrogen and progesterone were measured at 18 weeks of age. In a
parallel study, NAC- and CYST-treated and control B/W mice were examined at 24
weeks of age for interval renal histopathology, lymphocyte adhesion molecule
expression, and antibody titers and in vitro cytokine production in response to
immunization with DNP-KLH. CYST significantly suppressed development of
albuminuria and azotemia at 36 and 42 weeks of age compared to control and
NAC-treated mice. NAC significantly suppressed anti-DNA antibody levels at 24
weeks. In contrast CYST significantly increased anti-DNA antibody levels at 18
weeks of age (P < 0.001 CYST vs control and NAC-treated mice). Kidneys of
CYST-treated mice also had accelerated inflammatory histologic changes despite
their lower incidence of albuminuria and azotemia. Mean (+/- s.e.m.) survival of
control mice was 33 +/- 2 weeks compared to 38 +/- 2 weeks in NAC-treated mice (P
< 0.05 vs control), and 48 +/- 2 weeks in the CYST-treated group (P < 0.01 vs
control mice). The antioxidants, NAC and CYST, significantly improved mortality
in the female B/W mouse model of SLE. NAC suppressed autoantibody formation and
modestly prolonged survival. CYST, despite its augmentation of anti-DNA levels
and renal inflammatory changes, inhibited the development of renal insufficiency
and markedly improved survival. These findings suggest that ROIs play a role in
the pathogenesis of lupus nephritis and that antioxidants reduce the damage
causing renal insufficiency. Antioxidants may be a beneficial adjunctive therapy
in the treatment of human SLE.

PMID: 11341102 [PubMed - indexed for MEDLINE]

2: Cell Mol Life Sci. 1997 Dec;53(11-12):960-6.

N-acetylcysteine slows down ageing and increases the life span of Drosophila
melanogaster.

Brack C, Bechter-Thüring E, Labuhn M.

Laboratory of Molecular Gerontology, University of Basel, Switzerland.
Brack@ubaclu.unibas.ch

Ageing can be defined as the time-dependent decline of physiological functions of
an organism. The molecular causes for the ageing process are multiple, involving
both genetic and environmental factors. It has been proposed that antioxidants
may positively influence the ageing process, protecting the organism against free
radical-induced damage. Here we show that the antioxidant N-acetylcysteine (NAC)
has a life-extending effect on Drosophila melanogaster. Dietary uptake of NAC
results in a dose-dependent increase in median and maximum life span. Flies fed
on 1 mg/ml NAC food live 16.6% longer; at 10 mg/ml, life span increases by 26.6%.
We have examined the effect of NAC treatment on protein and RNA levels: we
observe an NAC-dependent increase in absolute amounts of total RNA and ribosomal
RNA, but no differences in protein levels. The NAC effect on longevity may
involve differential expression of specific mRNA genes, as suggested by RNA
finger-printing experiments.

Publication Types:
Research Support, Non-U.S. Gov't

PMID: 9447249 [PubMed - indexed for MEDLINE]

[mwestbro]

A few additions:

The first is the study that, IIRC, stimulated all the interest in various forms of lipoic acid. Note how artificial the experimental protocol is, and how short-lived the breed of mouse is.

1: Arzneimittelforschung. 1997 Jun;47(6):776-80.

Influence of selegiline and lipoic acid on the life expectancy of
immunosuppressed mice.

Freisleben HJ, Neeb A, Lehr F, Ackermann H.

Gustav-Embden-Zentrum der Biologischen Chemie, Laboratorium für Mikrobiologische
Chemie, Frankfurt/Main Germany.

Ten groups of 14 immunosuppressed NMRI-mice (nu/nu) were raised and kept under
germ-reduced conditions. The control animals were fed a germ-reduced diet, nine
other groups received the same diet with selegiline (CAS 14611-51-9, Deprenyl) or
lipoic acid (thioctic acid, CAS 62-46-4) admixed at various amounts. The 50%
survival rate, the total life span of each group and the areas under the curves
were determined to evaluate life expectancy as compared to the controls. The
racemate of lipoic acid at high dosage (350 mg/kg body weight) reduced the life
span significantly. The S(-)-enantiomer of lipoic acid (75 mg/kg body weight)
increased the 50% survival rate, whereas the physiologic R(+)-enantiomer (9 mg/kg
body weight) expanded the total life span of its group. Alteration of only one
out of three parameters was not considered significant. All other groups except
for one did not differ from controls: only animals which obtained 75 micrograms
selegiline per kg of body weight and per day exerted increased life expectancies
by all three parameters. This group exhibited also in statistical evaluation a
significantly (p < 0.05) prolongated survival time up to about 200% as compared
to the control animals.

PMID: 9239459 [PubMed - indexed for MEDLINE]

Second is a negative vitamin C study summarized by Michael Rae on Usenet several years ago. This study has no abstract in Medline, so he did us a service here. Actually, the whole thread is worth reading for those of us with an interest in lifespan studies. There are several common errors shot down by the big brains at work here.

[mwestbro]

An anecdotal datapoint for aloe (which I don't use--I don't find any of this very convincing):

The Times (London)

July 10, 2001, Tuesday

Nine long lives

SECTION: Home news

LENGTH: 46 words

Spike, listed in The Guinnness Book of Records as the world's oldest cat, has died at his home in Bridport, Dorset, aged 31 -said to be the feline equivalent of 217. Mo Elkington, his owner, an aromatherapist, put Spike's great age down to a daily dose of aloe vera.

[mwestbro]

Vitamin C again:

Olfafur on Usenet provided some detail from one of the "failed" vitamin C studies above here.
"No significance in median lifespan (747 ± 139 days compared with 710 ± 131 days) between the vitamin C supplemented group and the control group, respectively, was observed"
An increase which isn't statistically significant is different from no increase at all, or a decrease.

[AgeVivo]

Of note, the MPrize@home project has just been posted in imminst's project section.
Its goal is to test the effect of compounds on mammalian lifespans. Its force is the number of people involved.
Anyone can contribute by having a few mice at home.

[Michael]

[*]reports of mammalian lifespan extension:
[*]Food low in methionine or in tryptophan: life extension in rat and mice; bigger effects with methionine restriction, plus already practiced in case of cancers and special diseases.

To be clear, the extremely-low levels of Met (+Cys) and of Trp used in these studies cannot be achieved while eating natural foods. "Food low in Met + Cys or Trp" is thus rather misleading.

[*]2-MEA( 2-mercaptoethanol) and 2-MEA hydrochloride : +20 or 30% in mice. Warning: combination with ethoxyquin reduced lifespan!
[*]PNB (alpha-phenyl-N-t-butyl-nitrone): small extension in normal old mice; 30% in human cells and in short-lived mice; to test: large extension in normal young adult mice? More generally N-hydroxylamines (NtBHA, NMHA, NBHA, PBN) extend human fibroblast lifespan
[*]Diphenylhydantoin, Phenformin: different drugs tested by Dilman and Anisimov, 1980, +20 to +30% in female mice; anti-cancer, anti-diabetic, other.
[*]Nordihydroguaiaretic acid: small increase in mice (Intervention Testing Program)
[*]aspirin: small increase in mice (Intervention Testing Program)
[*]Royal Jelly: 25% increase in mice mean lifespan, not maximum
[*]weekly DNA and RNA Injection in rats: huge extension based on few rats; Odens, M. 1973. Almost no info so difficult to reproduce...

I am familiar with the studies underlying each of the claims above. ITP did not report an increase in maximum LS from either NDGA or aspirin (the effect was for median LS), and (without digging up the studies one by one) none of the other listed interventions extended the normal lifespan of healthy, well-cared-for, non-genetically-buggered mammals: ~900 d mean and ~1100-1200 d max, respectively.

Edited by Michael, 03 June 2009 - 12:12 PM.

[AgeVivo]

Michael, thank you as always for being the voice of clarity.
I'll rephrase the positive achievements so that what has been not shown very clearly does not appear as necessarily wrong:

• Severe methionine restriction was reported to extend lifespan in rats and mice, achievable via non natural foods/protein powders
• NDGA and aspirin were reported to globally extend lifespan in mice, not maximum life extension but:
• one can usually not expect to detect *maximum* life extension effects
  because unless they are huge it statistically requires *many* animals
• other reported life-extending compounds [exist, they] need to be confirmed
  in good conditions where the mean lifespan of controls is around 900 days

Edited by AgeVivo, 03 June 2009 - 01:05 PM.

[kismet]

To be clear, the extremely-low levels of Met (+Cys) and of Trp used in these studies cannot be achieved while eating natural foods. "Food low in Met + Cys or Trp" is thus rather misleading.

Maybe there's a work-around, methionine degrading enzymes (rMETase). However, I don't think met-restriction is worth pursuing in the first place if it produces similar effets to CR (i.e. the same growth retardation, which is what we want to get rid off!). We don't need another form of CR, crypto-CR or what you have.

I believe the only worthwhile attempt would be to replicate the Metformin data in some well-cared for mice, but we won't be able to produce meaningful results: as MR stated we need long lived C57BL/6 to produce any new and worthwhile data and we'd need to get hold of the drug Metformin.

From the mfoundation discussion about the ITP, NDGA, Aspirin, etc:
Does anyone know the timelines for completion of the different ITP cohorts?

Maximum lifespan requires MANY animals to be measured reliably so one can not expect usual mouse survival tests to significantly detect effects on maximum lifespan (except if the effect is really huge).

I don't want to be insulting to the whole NIA, but they can't be that stupid; the trial must have been well-powered enough to show the expected effect on max life span (I'm not sure if this applies to max or mean, but they say: "Sample size was sufficient to detect a 10% difference in lifespan in either sex,with 80% power, using data from two of the three sites."). There was merely a very weak trend towards increased max life span NDGA (p = 0.12). Inspection of the mortality graph would tell us more (I did not read the paper as I wasn't particularly impressed, but I may have to do so). Furthermore, lack of an effect in female mice may be a good thing if it's related to absorption and concealed a real, small effect on max life span or very bad if it is in fact a real effect (e.g. male mice show some abnormalities which are fixed by NDGA).
MR did no follow-up post about that cohort, but my interpretation is that it was a failure. Although, I may be wrong.

If they couldn't show an effect we wouldn't be able to do better. Maybe we can perform a meta-analysis afterwards.  I'm not sure if they are doing follow-up studies as they indicated (anyone?): "Further studies are warranted to find whether NDGA or aspirin, over a range of doses, might prove to postpone death and various age-related outcomes reproducibly in mice."
If the NIA deems it worthwhile I'm sure they will do a follow-up. Perhaps we should try something else... but looking at my notes I can't think of anymore interventions that we could easily try and which have a remote chance of success.

We might want try some combinations (which is more realistic anyway): IF+resv; cocoa, green tea, resv(?), etc

Or maybe we could test the Russian compounds in healthy animals for a change. Epitalon, SKQ1. Anisimov et al. never cease to amaze with their short-lived cohorts of short-lived and sick mice.

Edited by kismet, 03 June 2009 - 04:41 PM.

[mwestbro]

I completely agree that if one wants to learn something useful about aging, one should insist on interventions which extend (as Michael puts it above) "the normal lifespan of healthy, well-cared-for, non-genetically-buggered mammals". However, if we also have an interest in not dying, then interventions which don't meet this stringent standard may still have value. Some of us are unhealthy, poorly-cared-for, and genetically-buggered. I would rather see a comprehensive list of lifespan studies, good, bad, and indifferent, than one which excluded studies of lesser quality. What would make sense, it seems to me, would be to make the standard for true anti-aging very clear at the top of the list, and to make it clear when a lifespan study doesn't meet it. And if I could have perfection, I would add a list of common rat and mouse strains and what they typically die of. Some of us might find an anti-lupus effect, or an anti-diabetes effect, very interesting.

Mike

[AgeVivo]

Hi Kismet,

fast answer that may later require deeper answers:

Methionine restriction

To be clear, the extremely-low levels of Met (+Cys) and of Trp used in these studies cannot be achieved while eating natural foods. "Food low in Met + Cys or Trp" is thus rather misleading.

Maybe there's a work-around, methionine degrading enzymes (rMETase).

No need to brainstorm, a solution has already been found and quite extensively tested. Methionine restriction is already a treatment in case of homocysteinuria, cystinuria, and recently being tested in various cancer trials. They use special protein powders that do not contain methionine and take a little of meet or fish from time to time in order to still have some methionine. I haven't tried but it is reported to be well tolerated even in the long term.

However, I don't think met-restriction is worth pursuing in the first place if it produces similar effets to CR (i.e. the same growth retardation, which is what we want to get rid off!). We don't need another form of CR, crypto-CR or what you have.

Yes. Although the advantage of methionine restriction is that mice eat as much as they want. I don't know whether the patients have difficulties in following their methionine restriction diet, it would be nice to ask a relevant doctor about it.

Metformin

I believe the only worthwhile attempt would be to replicate the Metformin data in some well-cared for mice, but we won't be able to produce meaningful results: as MR stated we need long lived C57BL/6 to produce any new and worthwhile data and we'd need to get hold of the drug Metformin.

I'll have a deeper look at that thread that seems interesting. I'm not so sure that we can not do it. Measuring lifespan extension of C57BL/6 mice accross our living environments is in a way more desirable than in one unique SPF lab. As confirmed by the NIA there is a huge effect of site over lifespan...

Max lifespan stories...

From the mfoundation discussion about the ITP, NDGA, Aspirin, etc: (...) the trial must have been well-powered enough to show the expected effect on max life span (...) Inspection of the mortality graph would tell us more

No: well-powered (80%) to globally say if one group lives 10% longer than the other, that's it. Since there is a high site effect, pooling over 3 sites only has only a small improvment. Quite often people draw huge conclusions about maximum lifespan but it is rarely the case that it is meaningful. You could redo the experiment and have quite a different maximum lifespan. If you want i can make a program (or excel sheet; it might take me a little time) that measure/draws that precision?

Resv, epitalon and SKQ1 stories...

We might want try some combinations (...): IF+resv; cocoa, green tea, resv(?), Epitalon, SKQ1

If resv and epitalon were extending lifespan in good conditions i think it would be clear by now. I am less doubtful about SKQ1, but all this is just some guess about people's work who i don't know.

PS: Mike, Michael, indeed the list in the MF thread requires a better distinction of what clearly works and what needs to be confirmed, and even badly proven extensions are good to know

Edited by AgeVivo, 03 June 2009 - 06:02 PM.