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[Crosspost] How (Not) To Run a Lifespan Study


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#1 Michael

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Posted 27 March 2011 - 01:10 PM


This is a cross-post from the main Bioscience forum; please consolidate all discussion there.

All:

Much of the distraction in the literature of biogerontology, and much more of the tripe that supplement dealers use to push sales of pills, is from the results of badly-run lifespan studies in mice (or occasionally rats). Melatonin, resveratrol, BCAAs, SkQ1, FIRKO mice, RNA, various vitamin mixtures, deprenyl ... a long series of instantiations of the Original Sin of biogerontology: short-lived controls.

A normal, healthy, well-husbanded, non-genetically-fucked-up mouse (which will on av'g live ~900 days at maximum (tenth-decile survivorship) 1100 d, as is routine in the standard control groups in studies run by people who know what they're doing (Spindler, Weindruch, Miller, etc). But in report after report of 'life extension' in mice, NONE of the animals eeven live THIS long (or at best, the INTERVENTION group does).

Whether it's buggered-up mutants that die early of things of purely putative mechanistic or structural significance to 'normal' aging, or (most commonly -- resveratrol and many others) diabetic obesity from overfeeding, or malnourishment, or (as in this case) failing to keep a good lid on pathogens, you raise a colony in which ALL the animals are short-lived, by incompetence or by design; then if your intervention helps to partially normalize their miserably short lives, you proclaim a radical life-extension breakthru'.

Steven Spindler, who has done a great deal of important CR research (including the study definitively establishing that CR continues to be effective in early seniority (19-20 mo old at initiation -- say ~60 y.o.), and one of the few investigators to run genuinely rigorous mouse lifespan studies (and who has thereby debunked multitudes of "anti-aging" supplements -- to cite but a few examples:

Posted Image
Control diet alone (solid black square), or with aminoguanidine (downward pointing triangle; 65 mg/kg body weight), aminoguanidine and alpha-lipoic acid (hollow diamond; 65 and 73 mg/kg), aminoguanidine, alpha-lipoic acid, pregnenolone, and coenzyme-Q 10 (hollow circle 65, 73, 0.2, and 12 mg/kg), melatonin (hollow square, 41 µg/kg body weight/d), or melatonin and pregnenolone (upward pointing triangle, 41 and 200 µg/kg respectively)
Spindler SR, Mote PL. Screening candidate longevity therapeutics using gene-expression arrays. Gerontology. 2007;53(5):306-21. Epub 2007 Jun 15. Review. PubMed PMID: 17570924.


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Thus, we all already owe a debt of gratitude to Spindler for his years of painstaking labor on our behalf in the laboratory.

Now, this same Dr. Spindler has now written an extensive review of all the flaws that litter the litters in the literature (yes, I enjoyed that little turn of phrase ;) ). I haven't yet read the full text, but a significant amount of the contents were previewed in an earlier publication(PMID: 19853062)), and of course in the abstract -- and, happily, not only will I be able to read the new report in full, but so will any of you that want to be informed readers of any future reports, because the full text is available for free online.

I was surprised to see that the situation was even worse than I'd known, as subtle flaws in execution and reporting that I'd've blithely passed over or accepted prove to be important to certainty about the meaning of the results, and bring into question several good-looking studies (tho' in most cases, hyped-up reports with subtle flaws also have larger ones).

I invite everyone out there to gain from Spindler's years of experience, and to become an informed reader of the literature on which they will base future decisions, including often literal bets on their future health and lifespan.

-Michael

Age (Dordr). 2011 Mar 22. [Epub ahead of print]
Review of the literature and suggestions for the design of rodent survival studies for the identification of compounds that increase health and life span.

Spindler SR.


Much of the literature describing the search for agents that increase the life span of rodents was found to suffer from confounds. One-hundred-six studies, absent 20 contradictory melatonin studies, of compounds or combinations of compounds were reviewed.

Only six studies reported both life span extension and food consumption data, thereby excluding the potential effects of caloric restriction. Six other studies reported life span extension without a change in body weight. However, weight can be an unreliable surrogate measure of caloric consumption. Twenty studies reported that food consumption or weight was unchanged, but it was unclear whether these data were anecdotal or systematic.

Twenty-nine reported extended life span likely due to induced caloric restriction. Thirty-six studies reported no effect on life span, and three a decrease. The remaining studies suffer from more serious confounds.

Though still widely cited, studies showing life span extension using short-lived or "enfeebled" rodents have not been shown to predict longevity effects in long-lived animals.

We suggest improvements in experimental design that will enhance the reliability of the rodent life span literature. First, animals should receive measured quantities of food and its consumption monitored, preferably daily, and reported. Weights should be measured regularly and reported. Second, a genetically heterogeneous, long-lived rodent should be utilized. Third, chemically defined diets should be used. Fourth, a positive control (e.g., a calorically restricted group) is highly desirable. Fifth, drug dosages should be chosen based on surrogate endpoints or accepted cross-species scaling factors. These procedures should improve the reliability of the scientific literature and accelerate the identification of longevity and health span-enhancing agents.

PMID: 21424790

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Edited by Michael, 27 March 2011 - 01:15 PM.

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