5 replies to this topic

[maxwatt]

Time to rain on the rapamycin parade:

 

J Clin Invest. 2013 Aug;123(8):3272-91. doi: 10.1172/JCI67674. Epub 2013 Jul 25.

Rapamycin extends murine lifespan but has limited effects on aging.

Neff F¹, Flores-Dominguez D, Ryan DP, Horsch M, Schröder S, Adler T, Afonso LC, Aguilar-Pimentel JA, Becker L, Garrett L, Hans W, Hettich MM, Holtmeier R, Hölter SM, Moreth K, Prehn C, Puk O, Rácz I, Rathkolb B, Rozman J, Naton B, Ordemann R, Adamski J, Beckers J, Bekeredjian R, Busch DH, Ehninger G, Graw J, Höfler H, Klingenspor M, Klopstock T, Ollert M, Stypmann J, Wolf E, Wurst W, Zimmer A, Fuchs H, Gailus-Durner V, Hrabe de Angelis M, Ehninger D.

Author information

Abstract

Aging is a major risk factor for a large number of disorders and functional impairments. Therapeutic targeting of the aging process may therefore represent an innovative strategy in the quest for novel and broadly effective treatments against age-related diseases. The recent report of lifespan extension in mice treated with the FDA-approved mTOR inhibitor rapamycin represented the first demonstration of pharmacological extension of maximal lifespan in mammals. Longevity effects of rapamycin may, however, be due to rapamycin's effects on specific life-limiting pathologies, such as cancers, and it remains unclear if this compound actually slows the rate of aging in mammals. Here, we present results from a comprehensive, large-scale assessment of a wide range of structural and functional aging phenotypes, which we performed to determine whether rapamycin slows the rate of aging in male C57BL/6J mice. While rapamycin did extend lifespan, it ameliorated few studied aging phenotypes. A subset of aging traits appeared to be rescued by rapamycin. Rapamycin, however, had similar effects on many of these traits in young animals, indicating that these effects were not due to a modulation of aging, but rather related to aging-independent drug effects. Therefore, our data largely dissociate rapamycin's longevity effects from effects on aging itself.

Comment in

• Rapamycin, anti-aging, and avoiding the fate of Tithonus. [J Clin Invest. 2013]
• Rapamycin extends life- and health span because it slows aging. [Aging (Albany NY). 2013]

PMID:23863708   PMCID:PMC3726163 DOI:10.1172/JCI67674

 

Full text available HERE

[malbecman]

 Yes, but if you look at Table 1 (phenotypes rescued by Rapamycin), some of those look pretty decent.  Certainly having improved cognition, CV performance and body wt/composition would help one feel

better as they aged (I think so).

[RWhigham]

The mice were fed 14 mg/kg in their daily food as a permanent part of their diet. This is a high chronic dose like those given to transplant patients for immune suppression.  This is not representative of a life extension regimen.

[Hebbeh]

Just to be clear, the rapamycin dose was 14 mg/kg of food... not 14 mg/kg mouse weight or 14 mg/day... I'm not sure how long it would take a mouse to eat a kg of food for the 14 mg dose or how that would compare to the standard scaling factor in extrapolating to equivalent human dose ... as follows:

 

The encapsulated rapamycin was administered at 14 mg/kg food.

 

 

[maxwatt]

A mouse eats 3 to 5 grams of food a day.   Let's assume 5 grams of food, .014g rap/1000 * 5 = .00007 grams of rapamycin a day.

An average adult mouse weighs between 17 and 25 grams.  Assume a 21 gram mouse:  .00007/21 = .000003 grams rapamycin per gram of mouse ....  .003 grams per kg. (inconsistently rounding to significant digits)

 

So a 70 kg mouse would be getting  210 mg.  Consider scaling, humans equivalent dose at a factor of 1/6 .... That would be a human equivalent dose of about 35 mg   

 

That's consistent with the dose for some transplant patients, but is much higher than the 6 mg weekly dose of Dr. Green's protocol.   Inverted U shaped dose/response curve?  Tell your grad student to rerun the experiment with a lower dose.

 

Unless I messed up the arithmetic 

[RWhigham]

An adult mouse weighs about 20 grams and eats about 5g/day of food.  Food rapamycin = (14 mg/kg)x(5g).  Divide by 20 g of mouse weight and we get 3.5mg/kg of rapamycin daily.  HED scaling by 1/12 for a 60kg person is (60/12) x 3.5mg/d = 17.5mg/d which is a high daily dose typical for a 60 kg transplant patient.

 

Note: These were mice (HED = 12), not rats (HED = 6).

Edited by RWhigham, 04 June 2017 - 05:40 AM.