42 replies to this topic

[kismet]

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.

Just mentioned it to somewhat counter the point "not possible with a normal diet", if you inject pegylated rMETase it sure sounds possible (and possibly dangerous, impractical, etc).

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?

My statistics suck; but I'm sure you can do the same calculation to find out how likely there were to detect an X% change in max. life span? I think I need to read their paper...

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.

I mentioned resv+IF because it showed a slightly increased max. life span in one study. I'm not sure, if you want to call the Russian gerontologists crazy, but it seems they're already using Epitalon in clinical (gerontological) practise and it seems to be backed up by a similar amount of data like SKQ1 (short lived SHR mice, fruit flies, etc)

[mwestbro]

Here's one more:

1: Br J Nutr. 2008 Dec;100(6):1192-9. Epub 2008 Apr 11.

Effects of lifelong intervention with an oligofructose-enriched inulin in rats on
general health and lifespan.

Rozan P, Nejdi A, Hidalgo S, Bisson JF, Desor D, Messaoudi M.

ETAP - Applied Ethology, 13 rue du Bois de la Champelle, F-54500
Vandoeuvre-lès-Nancy, France. email prozan@etap-lab.com

Ageing is associated with changes in physiology and morphology; nutritional
strategies to decrease morbidity and to prolong life are of high interest. The
aim of the study was to investigate the effects of lifelong supplementation with
an oligofructose-enriched inulin on morphological and biological markers and
lifespan in male and female rats. Male and female rats, age 3 months, were
randomised into two groups to receive either a diet with 10 % of an
oligofructose-enriched inulin (Synergy 1) or a standard diet (control) for 27
months. The rats were weighed every 2 weeks and their food intake was evaluated
on four successive days every 4-6 weeks. Samples were taken at 12, 18 and 24
months of age. During the whole intervention period, male rats receiving Synergy
1 (SYN1-M) displayed lower body weight, cholesterol and plasma
triacylglycerolaemia compared with the controls (Cont-M). The survival rate at 24
months of age of SYN1-M rats was 35.3 % greater than that of Cont-M rats. In
female rats, the Synergy 1 supplementation (SYN1-F) group also reduced body
weight, cholesterol and triacylglycerolaemia levels, but results were less
consistent over the experiment. The survival rate at 24 months of age in SYN1-F
rats was 33.3 % greater compared with that of the control (Cont-F) group. To
conclude, lifelong intervention with Synergy 1 improved biological markers during
ageing and survival rate (lifespan) of rats.


PMID: 18405402 [PubMed - indexed for MEDLINE]

[AgeVivo]

MAXIMUM lifespan effects CAN be detected by usual lifespan studies

I must apologize many times because i said the contrary and was completely wrong:

• one can usually not expect to detect *maximum* life extension effects
  because unless they are huge it statistically requires *many* animals

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 never thought they were stupid) My statement was fully wrong. Here is visual clarifications, as well as basic confirmations because I don't want my wrong statement to perturb what the main results suggests: NDGA and aspirin slightly extend mean but not maximum lifespan in male mice; there is a site effect on lifespans.

Edited by AgeVivo, 09 June 2009 - 03:26 PM.

[Michael]

MAXIMUM lifespan effects CAN be detected by usual lifespan studies

I must apologize many times because i said the contrary and was completely wrong:

[list]
[*]one can usually not expect to detect *maximum* life extension effects
because unless they are huge it statistically requires *many* animals

(I never thought they were stupid) My statement was fully wrong.

Yeah, I should've jumped in on this earlier: Spindler, Weindruch, and others have repeatedly documented statistically significant LS extensions with 50 animals per cohort. Even using a newer, more complicated analytical method,(1) which the authors claim (IANA stats guy!!) reduces type I errors, they still show that they can detect significant differences in cohorts this size.

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

I really don't think that they help us at all. There are such an enormous number of bogus "life extension" studies, and no way (short of repeating the experiment properly) to distinguish the signal from the noise, that you could spend the rest of your part-time career running after them -- and unintentionally get a lot of people excited, and provide fodder for unscrupulous supplement companies etc. We need to focus, laser-like, on things that clearly do work, or for which there is a special, strong basis for expectation that they will.

-Michael

Reference
1: Gao G, Wan W, Zhang S, Redden DT, Allison DB.
Testing for differences in distribution tails to test for differences in 'maximum' lifespan.
BMC Med Res Methodol. 2008 Jul 25;8:49.
PubMed PMID: 18655712; PubMed Central PMCID: PMC2529340.

[VespeneGas]

We need to focus, laser-like, on things that clearly do work, or for which there is a special, strong basis for expectation that they will.

i.e. caloric restriction and SENS?

[AgeVivo]

or products such as methylene blue, metformin, lithium, other?
or methodogic approaches such as SENSE?

Edited by AgeVivo, 05 August 2011 - 05:50 PM.

[AgeVivo]

mwestbro and others: i'm not forgetting this thread and i'll try to keep up readings and digests when i have time. rapamycin is now a great thing to look at

[AgeVivo]

In SENS4 (Cambridge, Thursday Sept 3rd) Stephen Spindler will talk about
Screening potential longevity therapeutics using rodent lifespan assays
http://www.sens.org/...n...ract&ID=163

In this presentation we will describe screening studies of potential longevity therapeutics using mouse longevity assays that avoid these and other artifacts. Among the agents tested alone and together in our 60 treatment groups are compounds that enhance somatostatin, insulin, or dopamine D(2)/D(3) receptor signaling; reduced androgen, thyroid, angiotensin II, or β-adrenergic receptor signaling; inhibit advanced glycation end product, HMG CoA reductase, acetyl CoA reductase, fatty acid synthase, MAO-B, mTOR, dipeptidyl peptidase 4, or α-glucosidase activity; or induce telomerase or SirT1 activity.

He has done MANY lifespan tests in mice, won the MPrize; from pubmed readings he appearently believes in CR and GH insufiiciency and gene expression array - related approaches to first quest for potential life extension drugs:
Comment on: The case for prioritizing research on late-onset life-extension interventions in mammals.
Screening candidate longevity therapeutics using gene-expression arrays.
I'don't currently clearly see his global views and will probably know them thanks to sens4

[AgeVivo]

In SENS4 (Cambridge, Thursday Sept 3rd) Stephen Spindler will talk about
Screening potential longevity therapeutics using rodent lifespan assays
http://www.sens.org/...n...ract&ID=163

In this presentation we will describe screening studies of potential longevity therapeutics using mouse longevity assays that avoid these and other artifacts. Among the agents tested alone and together in our 60 treatment groups are compounds that enhance somatostatin, insulin, or dopamine D(2)/D(3) receptor signaling; reduced androgen, thyroid, angiotensin II, or β-adrenergic receptor signaling; inhibit advanced glycation end product, HMG CoA reductase, acetyl CoA reductase, fatty acid synthase, MAO-B, mTOR, dipeptidyl peptidase 4, or α-glucosidase activity; or induce telomerase or SirT1 activity.

He has done MANY lifespan tests in mice, won the MPrize; from pubmed readings he appearently believes in CR and GH insufiiciency and gene expression array - related approaches to first quest for potential life extension drugs:
Comment on: The case for prioritizing research on late-onset life-extension interventions in mammals.
Screening candidate longevity therapeutics using gene-expression arrays.
The video is here: http://75.126.26.34/...p;g2_itemId=218
(the second half of the video corresponds to this thread) and here is the list of things his lab is currently testing on the lifespan of 1 year old mice, with a particular care to avoid caloric-restriction effects and to link the experiments with diseases and mechanisms:

Controls
- 296 negative control group
- 20% CR positive control group
- 40% CR positive control group
CR/dwarf-like (trying to chemically reproduce the effect of caloric restriction on major signaling systems)
- Sandostatin injection that lowers IGF1 levels, and IGF1 levels are measured: Sandostatin LAR depot (Somatostatin, super-agonist)
- Bromocripine lowers growth hormone levels as well as prolactin levels: (Dopamine D????) receptor agonist
- Cyproterone acetate lowers androgens (Androgen receptor antagonist)
- Iodine free diet with methymazole & perchlorate: makes hyperthyroid
- Bromocriprine, cyproterone, numidazole, potassium perchlorate
- OAA (increase NAD+NAOH)
- resveratrol
Cardioprotection
- Simvastatin (Statin)
- Rampril (ACE inhibitor) & Simvastatin (statin)
- Carderatan I, Angiotensin II receptor antagonist,
Rampril, Simvastatin & aspirin
- Netoprovol (beta1 adrenergic receptor blocker)
- Nethovel (beta adrenergic receptor blocker)
because such blockers extend lifespan
- Lovata (omega-3 fatty acids): "fish oil" in essence
- KHOH
- Niopiric acid (reduces LDL-C, HDL-Cl, liporetdnfi)
Anticancer
- Everolimus (Orally available rapamycin defuntive, mTOR inhibitor)
- Green tea extract (FAS inhibitor)
- Green tea extract, Black tea extract, Morin
(O.O5% in diet) & Tricloman (0.1% in diet) (FAS inhibitors)
Insulin sensitivity
- Metformin (2 doses)
- Resveratrol & 20% CR
- Stagiptin (cypristicylseptidase 4 inhibitor, enhances insulin secretion)
- Vigobone (alpha-glucosidase inhibitor, lowers post-prandial blood glucose)
Inflammation
- NDGA (4 doses)
- Curcumin (microencapsulated, 2 doses)
Miscellaneous
- Rasagiline (Orally available degrol)
- TA-65 (Telomerase induction; 2 doses)
- Creatinine
- Juvenon
- SAMe
- CoQ10 (Coenzyme in Caphom)
- Carnitine (taty acids uptake into mitochondria)
- Glutathione (in liposomes)

note: if someone can explain those choices for laymen, go ahead, that would be great


Also, here is the list of things the NIA is testing in mice, and the dose and mouse-age at start:
http://www.nia.nih.g...dsInTesting.htm

Cohort 1:
Aspirin - 20 ppm - 4 months
NFP - 200 ppm - 4 months
NDGA - 2,500 ppm - 9 months
4-OH-PBN - 315 ppm - 4 months
Cohort 2:
CAPE - 30 ppm - 4 months
CAPE - 300 ppm - 4 months
Enalapril Maleate - 120 ppm - 4 months
Rapamycin - 14 ppm - 20 month
Cohort 3:
Rapamycin - 14 ppm - 9 months
Simvastatin - 12 ppm - 10 months
Simvastatin - 120 ppm - 10 months
Resveratrol - 300 ppm - 12 months
Resveratrol - 1200 ppm - 12 months
Cohort 4:
Resveratrol - 300 ppm - 4 months
Oxaloacetic acid - 2200 ppm - 4 months
Green tea extract - 2000 ppm - 4 months
Curcumin - 2000 ppm - 4 months
Medium Chain Triglyceride Oil - 60000 ppm - 4 months
Cohort 5:
17α-Estradiol - 4.8 ppm - 10 months
Methylene Blue - 28 ppm - 4 months
Acarbose - 1000 ppm - 4 months
Rapamycin_LoPhase II - 4.7 ppm - 9 months
Rapamycin_MidPhase II - 14 ppm - 9 months
Rapamycin_HiPhase II - 42 ppm - 9 months
(Compound - Concentration in food - Age at treatment initiation)

I interpret that:
- schedule: they are done with cohorts 1 and 2, and that they are starting the lifespan tests of cohort 3. Based on when the results with aspirin were published (cohort 1) the results with Methylene blue would be published by mid/late 2012 (Methylene blue is/was the first thing we have/had in mind for MPrize at home)
- rapamycin: the rapamycin tests are done under a quasi-sterile unvironment (SPF)? (a 'normal' environment would be of interest because rapamycin is an immunosuppressant).
If you can confirm/correct me, please go ahead. Also if you can easily explain why those compounds and doses are interesting, that would be great. Note: the ITP is currently asking for new things to test...

note: this post is similar to what I wrote in MF: http://www.mfoundati...read.php?p=8327

Edited by Michael, 25 December 2009 - 02:21 PM.

[mwestbro]

More lifespan study fun!
Calcium
Persimmon oligomeric proanthocyanidins

[Logic]

BHT?

[Logic]

BHT?

Effects of the antioxidant butylated hydroxytoluene (BHT) on mortality in BALB/c mice.
http://www.ncbi.nlm....v/pubmed/448040

Rejuvenescence and extension of an urochordate life span following a single, acute administration of an anti-oxidant, butylated hydroxytoluene
http://www.ncbi.nlm....pubmed/12020943

The " tert-butyl effect " and it`s importance to life extension.
http://ask.lef.org/Topic4644.aspx

Life and Death: Metabolic Rate, Membrane Composition, and Life Span of Animals
http://physrev.physi....expansion.html

[Mind]

A related thread about Spindler's massive study with mice and life extension supplements....almost nothing works, as a stand-alone supplement, in mice.