Freitag, 16. August 2013

Another large screening effort (Spindler et al.)

Gerontologists are ingenious, and consequently the field has never suffered from a lack of theories. (Arking)
The first time I heard of a large ongoing rodent study, which was screening substances for life extension effects, must have been years ago. I did not know how large it was exactly at that time nor if it ever got completed, but finally official data is emerging (1):
[This was a] large[...] study using a total of 2400 mice in which groups of 36 treated mice and 297 control mice were used to maximize the number of treatment groups
That's 58 interventions á n=36. You may have noticed the large control group. According to Spindler this improves power, which means that 36 animals per intervention suffices - normally you would like 40-50. Either way, the study is the largest such screen today or at least in the same ballpark as NIA's ITP. As we speak, Spindler et al. must be preparing more data from his mega-study to be published. So far we got two papers. Keep in mind that he really knows how to carry out mouse studies with mean lifespans of almost 1000d (1, 2), so the data must be taken seriously.

In the first of the two published papers Spindler et al. (1) screened the following substances for life extension in mice: blueberry, cinnamon, green and black tea, pomegranate, sesame, curcumin (two doses), morin and combined [pycnogenol, quercetin, and taxifolin]
While many of these phytonutrients reportedly extend the life span of model organisms, we found no significant effect on the life span of male F1 hybrid mice, even though the dosages used reportedly produce defined therapeutic end points in mice. The compounds were fed beginning at 12 months of age. The control and treatment groups were iso-caloric with respect to one another. A 40% calorically restricted and other groups not reported here [such a tease!] did experience life span extension.
Other interventions fared slightly better (2), but do note that maximum lifespan is the gold standard, but was unchanged:
Chronic treatment with β-adrenergic receptor (βAR) agonists increases mortality and morbidity while βAR antagonists (β-blockers) decrease all-cause mortality for those at risk of cardiac disease. Levels of sympathetic nervous system βAR agonists and βAR activity increase with age, and this increase may hasten the development of age-related mortality. 
Also note that, adenylyl cyclase 5 (AC5) is part of the β-adrenergic receptor pathway and AC5 KO mice live longer.
Here, we show that β-blockers extend the life span of healthy metazoans. The β-blockers metoprolol and nebivolol, administered in food daily beginning at 12 months of age, significantly increase the mean and median [not maximum] life span of isocalorically fed, male C3B6F1 mice, by 10 and 6.4 %, respectively (P < 0.05). Neither drug affected the weight or food intake of the mice, indicating that induced CR is not responsible for these effects, and that energy absorption and utilization are not altered by the drugs. Both β-blockers were investigated to control for their idiosyncratic, off-target effects. Metoprolol [overall slightly superior, although both showed some liver toxicity/carcinogenity!] and nebivolol extended Drosophila life span, without affecting food intake or locomotion.
This result is worth noting in particular, because Pamplona, Barja, Sanchez-Roman and colleagues demonstrated that a similar drug lowers membrane unsaturation (3) and Spindler found highly unsaturated n3 fatty acids to be toxic (unpublished, see below). For some reason the Barja paper did not get cited by Spindler.
The data clearly support the hypothesis that highly unsaturated fatty acids in membranes are involved in aging, but we will need larger and "cleaner" studies to be sure. There are many faults with the current evidence. Simply put, it is easy to kill, maim or poison mice - even accidentally - so we want a study that shows life extension, not shortening from n3 feeding. It is also easy to prevent premature death, so we want a study that shows extension of maximum lifespan. And we want to exclude off-target effects, so in the best case we would only alter membrane long-chain n3 content.
EDIT: Beta-blockers, or at least adenylyl cyclase 5 KO, may work through tumor prevention (PMID: 23957304).

Other interventions tested by Spindler et al.
(Note, I may be misremembering some of the facts, so you should check out the video interview yourself.)

There is also unpublished data (straight from the source) on simvastatin and simvastatin+enalapril, which seem to work in his screening test. In the same talk Spindler says, he "confirmed" the NDGA data using at least 3 different doses - top dose was toxic, however. Everolimus (rapamycin-related) seemed to make the cut too. Oxaloacetate worked somewhat. Something "strange" worked (undisclosed substance). Other drugs already in clinical use also made it. ALT-711 failed (AGE inhibitor). Carnitine was neutral to negative(!) CoQ10 - meh! Rasagiline i.e. a Deprenyl derivative did nothing.

LExtension mix (neutral to negative), orthocore (neutral), "biostimus-??" (neutral to negative), lovaza ("it was death to these mice..actually it was not quite significant, but you decide whether you want to take it[...]..liver damage"), nicotinic acid (bad), nutraceutical combo DIY (detrimental), orthocore+pomegranate+resv+SAMe+sesame oil (toxic! / liver damage), cyperone acetate (bad liver damage)

Conclusions
The susceptibility to liver damage seems to be extraordinarily high in these mice. Spindler's conclusion in his video talk, which I think is justified nonetheless, was that laypeople should not experiment with these unproven substances. In my opinion, there may be rare exceptions to this rule.

In any case, I only counted 9 + 2 published + approx. 21 unpublished interventions in the above studies and Spindler's talk. So stay tuned for more results!

1. Rejuvenation Res. 2013 Apr;16(2):143-51. doi: 10.1089/rej.2012.1386.
Influence on longevity of blueberry, cinnamon, green and black tea, pomegranate, sesame, curcumin, morin, pycnogenol, quercetin, and taxifolin fed iso-calorically to long-lived, F1 hybrid mice.
Spindler SR, Mote PL, Flegal JM, Teter B.

2. Age (Dordr). 2013 Jan 15. [Epub ahead of print]
β1-Adrenergic receptor blockade extends the life span of Drosophila and long-lived mice.
Spindler SR, Mote PL, Li R, Dhahbi JM, Yamakawa A, Flegal JM, Jeske DR, Li R, Lublin AL.

3. Rejuvenation Res. 2010 Dec;13(6):683-93. doi: 10.1089/rej.2010.1062. Epub 2010 Sep 6.
The β-blocker atenolol lowers the longevity-related degree of fatty acid unsaturation, decreases protein oxidative damage, and increases extracellular signal-regulated kinase signaling in the heart of C57BL/6 mice.
Sanchez-Roman I, Gomez J, Naudi A, Ayala V, Portero-Otín M, Lopez-Torres M, Pamplona R, Barja G.

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