Freitag, 20. Juni 2014

Miscellaneous Lifespan Studies: Atenolol, Nutraceuticals, n3 fatty acids, SIRT, macronutrients and CR

Recently, I noticed that many study author have the bad habit of not providing full lifespan data, i.e. Kaplan–Meier curve as well as numerical mean and maximum lifespan (90th percentile survival) as well as numerical changes and statistical interpetation. That's just sloppy in my mind.
Another note: I think it's time to stop working with the venerable C57BL/6 ("black 6") strain in favour of more heterogenous and vigorous crosses, e.g. C57BL/6 x DBA/2n (5) or C57BL/6 x C3H (1).


1.a. Many common nutraceuticals / supplements may be harmful, if you take them carelessly, as is suggested by Spindler's recent study.

1.b. Spindler confirms that fish oil - i.e. highly unsaturated fatty acids (HUFA) - may be unhealthy and could promote aging, although, overall the evidence is not totally convincing. High doses of HUFA might as well be killing through frank toxicity rather than a true effect on the rate of aging.

2a. C57BL/6J mice were administered "the SIRT1 activator SRT1720":
"Survival among the SD-fed groups was significantly different as assessed via the non-parametric log-rank (Mantel-Haenszel) test (χ2=4.168, p=0.0412). Mean lifespan was increased 8.8% and we observed a trend towards an increase in median lifespan of 5 weeks (Su and Wei, 1993) with SRT1720 supplementation (χ2=2.77, p=0.096). However, there was no difference in 90th percentile survival (Wang et al., 2004) despite the overall significant effect on lifespan. "
Median LS of ~840 days is acceptable but not outstanding. The lack of an increase in Max LS is elegantly demonstrated by the Kaplan–Meier curve. Single outlier Max LS for the longest-lived animals is ~1100days which is also quite low. Remember, 50 and 90 percentile survival for black 6 mice should be 900/1100 days.
The result is unimpressive at a first glance.

2b. A similar study by the same group using "SRT2104". Mean LS again ~840d, and max LS as above. This time around there is a significant difference in max LS making the paper more interesting. However, the difference is only 5%.
See also: http://arc.crsociety.org/read.php?2,221241

3. The question whether CR works in wild-derived animals or if it is a laboratory artifact remains unanswered, with some evidence favouring either side. Recently, Linda Partridge concluded an experiment in Drosophila and found that CR was quite universal in four wild-derived strains. We still need to repeat the only study performed in wild-derived mice, however, as its result was rather equivocal.

4. On the surface, a study about macronutrient balance. Male and female C57BL/6 were used in this study. Group-size was approx. 34, minus 10 animals that were culled early for further study, fortunately the lack of power should be offset by the existance of a range of similar groups (total n ~ 800).
Main finding: "Median lifespan increased from about 95 to 125 weeks (approximately 30%; Table S2) as the protein-to-carbohydrate ratio decreased."
A median LS of below 700d is completely horrible. And I see no mention of effects on maximum lifespan which matters the most if you want to talk about aging. In any case, estimated 90 percentile survival is in the same ballpark as median LS, it's horrendously low at around <1000d.

Additionally, the authors studied CR achieved through "dietary dilution". Animals were given a diet containing 50% cellulose and eventually consumed 30% fewer calories than controls. This is an unusual protocol, but there is no reason why it should not work. Which is why the null result this study yielded is so shocking. It was unclear to me how many animals were put on this CR diet, but after reading the supplementary material and contacting the authors it seems as if 1/3 of all animals was consistently given this reduced energy density diet, which would make it quite powerful.
Age of onset also wasn't the problem as all treatments were started early at 3 weeks of age.

Let's speculate what could produce an artifact here, except the low study quality we discussed above: cellulose toxicity? Some types of fibre can be toxic (at higher doses). Neuroendocrine feedback? It is possible that the smell and taste of food, the act of eating per se, matters for calorie restriction, but I really don't think this is applicable here.

Currently, I am much more inclined to believe Sohal (6) and many other critics that have postulated, that CR is largely an artifact of studying lab adjusted strains prone to overfeeding, than this paper. However, CR should have worked in the gluttonous "black 6" strain for exactly this reason.
It is also surprising that their result wasn't much discussed by the study authors.

5.
Barja and colleagues finally published their atenolol study, in which they used a long-lived black 6 x DBA/2n (F1) cross (n=86). Their hybrid mouse is unusually long-lived even by literature standards at 32 and 47 months for median and maximum LS.
Broadly, they show that the drug greatly reduces membrane peroxidation index (PI) and improves markers of health, but does not extend lifespan, contradicting the long-held belief - even by Barja himself - that low PI drives higher lifespans.
Some less straight-forward explanations are provided by the authors (effect masking), but to some extent this sounds like post hoc goalpost shifting. Atenolol may lower heart rate and central aortic pressure (and thus cardiac output) endangering the already weakened aged heart and end-organ perfusion. To my knowledge, however, cardiovascular disease is rather uncommon in mice.
Spindler, in a similar study, raised the possibility of liver toxicity: "Both metoprolol and nebivolol approximately doubled the number of liver tumors..."

1.a. Age (Dordr). 2014 Apr;36(2):705-18. doi: 10.1007/s11357-013-9609-9. Epub 2013 Dec 28.
Lifespan effects of simple and complex nutraceutical combinations fed isocalorically to mice.
Spindler SR1, Mote PL, Flegal JM.

1.b. Dietary supplementation with Lovaza and krill oil shortens the life span of long-lived F1 mice.
Spindler SR, Mote PL, Flegal JM.
Age (Dordr). 2014 May 10. [Epub ahead of print]

2a. Cell Rep. 2014 Mar 13;6(5):836-43. doi: 10.1016/j.celrep.2014.01.031. Epub 2014 Feb 27.
The SIRT1 activator SRT1720 extends lifespan and improves health of mice fed a standard diet.
Mitchell ... Bernier M2, de Cabo R7.

2.b. Aging Cell. 2014 Jun 16. doi: 10.1111/acel.12220. [Epub ahead of print]
SRT2104 extends survival of male mice on a standard diet and preserves bone and muscle mass.Mercken EM1, Mitchell SJ, Martin-Montalvo A, Minor RK, Almeida M, Gomes AP, Scheibye-Knudsen M, Palacios HH, Licata JJ, Zhang Y, Becker KG, Khraiwesh H, González-Reyes JA, Villalba JM, Baur JA, Elliott P, Westphal C, Vlasuk GP, Ellis JL, Sinclair DA, Bernier M, de Cabo R.

 3. PLoS One. 2013 Sep 10;8(9):e74681. doi: 10.1371/journal.pone.0074681. eCollection 2013. Dietary restriction extends lifespan in wild-derived populations of Drosophila melanogaster.Metaxakis A1, Partridge L.

4. Cell Metab. 2014 Mar 4;19(3):418-30. doi: 10.1016/j.cmet.2014.02.009.The ratio of macronutrients, not caloric intake, dictates cardiometabolic health, aging, and longevity in ad libitum-fed mice.Solon-Biet...Sinclair et al.

5. Aging Cell. 2014 Jun;13(3):551-60. doi: 10.1111/acel.12205. Epub 2014 Feb 26. Lifelong treatment with atenolol decreases membrane fatty acid unsaturation and oxidative stress in heart and skeletal muscle mitochondria and improves immunity and behavior, without changing mice longevity.Gómez A1, Sánchez-Roman I, Gomez J, Cruces J, Mate I, Lopez-Torres M, Naudi A, Portero-Otin M, Pamplona R, De la Fuente M, Barja G.

6. Caloric restriction and the aging process: a critiqueRajindar S. Sohala, Corresponding author contact information, E-mail the corresponding author, Michael J. Forsterb

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