Freitag, 26. Juni 2015

How not to run a lifespan study

Every biogerontologist should have a poster on the wall with the following paper:

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

Why do I care about other people's research so much? One could obviously quip: Why does it matter if people run badly designed lifespan studies? Isn't it up to the principal investigator (PI) to decide if they want to screw with taxpayer and grant money? Well, first of all, I don't think that people run these weak studies on purpose, but I do believe they should know better. It's the PI's job to be on top of current research practise. Admittedly, the mouse facility may be out of your control, but if you cannot guarantee high quality, why would you commit to a 4-year lifespan study? The main issue I have with these weak studies is that they waste more than the money of a single research group or a grant. They also lead to unnecessary follow-up research. Let me give a few examples.

Resveratrol research produced a lot of unwarranted hype that was later defused by the NIA's ITP, yet how many research dollars were spent to do so? The initial study by Sinclair fell into a common trap: methodically weak (2), but not terrible enough to rule it out as a waste of a biogerontologist's time. Due to the hype, it produced a lot of unnecessary follow-up work. Soon afterwards, for reasons completely beyond me, Resveratrol was granted three "slots" in the ITP study at varying doses (a slot here is one whole lifespan study, there are 3-5 slots available per year). Instead, we could have studied something more productive, but hype and perhaps politics got in the way.

Another type of "methodically weak, but not terrible" research plagues the fields of autophagy, glycation and aging. These studies are good enough so there is little grant money to repeat what seems like a redundant study, but weak enough to cast doubt on the results (no replication, crypto-CR,  short-lived controls). To quote myself:
Autophagy 
I am not exactly sure what is holding back the field. However, there are 2 promising interventional studies in mice, or perhaps, I should say only two. ATG5 overexpression (7a) in somewhat short-lived strain and hepatic rejuvenation by the Cuervo lab (7b). Unfortunately, Dr. Cuervo has never responded to my inquiries about extending and reproducing her work.
Advanced Glycation Endproducts  
Again, I am not exactly sure what is holding back the field. Since the failure of Alagebrium (around 2013) and some promising studies by Vlassara (around 2007, ref. 9) there has been a dearth of relevant proof of principle studies. I have not kept up with the field, but it seems to have shifted towards diabetes and mechanistic understanding. All in all, I do believe the field may deliver some breakthroughs, but it will take time. Meanwhile reduction of dietary AGEs may provide modest benefits (we don't really know).

Verdict
I really fear that mediocre lifespan studies can stunt the development of whole fields, or as in the case of Resveratrol, completely derail the research. Multiple factors affect mouse lifespan and some are outside of our control (e.g. sporadic infections), but overall husbandry is often inadequate. Researchers need to stay strong and demand better mouse facilities!

References
1. Spindler SR. Review of the literature and suggestions for the design of rodent survival studies for the identification of compounds that increase health and life span. Age (Dordr). 2011 Mar 22. [Epub ahead of print] PubMed PMID: 21424790.

2. Nature. 2006 Nov 16;444(7117):337-42. Epub 2006 Nov 1.
Resveratrol improves health and survival of mice on a high-calorie diet.
Baur JA1, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, Prabhu VV, Allard JS, Lopez-Lluch G, Lewis K, Pistell PJ, Poosala S, Becker KG, Boss O, Gwinn D, Wang M, Ramaswamy S, Fishbein KW, Spencer RG, Lakatta EG, Le Couteur D, Shaw RJ, Navas P, Puigserver P, Ingram DK, de Cabo R, Sinclair DA.
Problems: All mice unhealthy (fed a high-fat diet), no maxLS reported. It is not even so much a weak study; it's simply inadequate as an aging study.

Samstag, 20. Juni 2015

Optimizing resource use by outsourcing of lifespan research

Is it possible to outsource lifespan studies to laypeople (who are supported by professionals)? The idea may seem far-fetched to some of you, but in the end it would amount to a "pragmatic trial"; which is certainly an accepted study design. This type of study is generally less rigorous but considerably more realistic than a classic RCT (3).
It should be easy to get pet-owners to participate since life span testing on animals it at worst ethically neutral and most probably a net positive for the animals. Obviously, drugs and interventions designed to extend the lifespan will be minimally invasive and have a high risk/benefit ratio. Sine qua non. And since all animals age, enrolling them in such a trial would be beneficial for them; like enrolling cancer patients in a cancer trial.

Outsourcing of lifespan studies to pet owners
The idea seems ingenious and abstruse at the same time (1), but these days it has reached the mainstream. As we have discussed, Kaeberlein and others have suggested to test rapamycin for late-life rejuvenation in dogs. The advantage is obvious. As a researcher you can save on housing facilities, animal food, doctor visits and drugs (loving pet owners visit the veterinarian themselves), caretaker costs, taxes, toys, accessories, "environmental enrichment". On the other hand, you still have to pay drug costs, additional vet visits (e.g. specialized tests), recruitment, administrative costs and the salaries of the involved researchers. As it turns out, all the latter costs are quite high. Kaeberlein mentioned costs in the range of 10^5 to 10^6$for his study. Additionally, you have to cope with the added problem of heterogeneity (every pet owner behaves somewhat differently) and lack of training (these people are not trained technicians or health professionals).

Outsourcing of lifespan studies to zoos?
There are more than a thousand zoos world-wide by a conservative estimate (2), perhaps closer to 5000. I see no reason why those places could not conduct lifespan studies, if pet owners can. So far, I think I'm the first person to propose this study design. The idea is simple, one could for instance, mimic a cluster randomized trial (4). The advantages over individual pet-owners are lower heterogeneity in husbandry, availability of primates, better access to trained professionals, improved record-keeping, etc. It's difficult to think of a disadvantage, except that it's harder to recruit Zoos for altruistic reasons than pet-owners.
Edit: I briefly brought the idea up at an aging conference I attended and felt little optimism. I think the concern is that husbandry is worse in practice than one would assume and the aggressive use of euthanasia precludes an aging study. It seems no zoo wants to keep elderly animals that might look unhealthy (even if they are not suffering). This is an important concern, I agree, and it remains to be seen if my idea is feasible.

General ethics of animal keeping
There are concerns that keeping animals is unethical per se. (Some would even argue that all animal research is useless [5b]. They are wrong.) Husbandry is often criticized, especially in Zoos (5). I am sure this can be improved and it is necessary to do so. But is it unethical to keep well-husbanded animals? In the case of many animals the answer is, definitely not. The reason should be self-evident to any loving pet-owners and right now I don't want to delve into the details. Just to mention, an interesting argument for the ethics of keeping lab mice for longevity research is that they live longer, healthier and more peaceful lives in captivity than in the wild (6). At some point, I will probably do a longer post on research ethics in animal studies.

References
1. I became aware of this idea perhaps 5 years ago. It was championed (maybe even invented) by Edouard D. and other people from longecity/imminst.
http://www.longecity.org/

2. http://www.statisticbrain.com/zoo-statistics/

3. Patsopoulos, N. A. (2011). A pragmatic view on pragmatic trials. Dialogues in clinical neuroscience, 13(2), 217.

4. Donner, A., & Klar, N. (2004). Pitfalls of and controversies in cluster randomization trials. American Journal of Public Health, 94(3), 416-422.

5a. http://www.captiveanimals.org/news/2010/03/10-facts-about-zoos
5b. http://www.isthmus.com/archive/isthmus-35/june-4-2004-inside-the-monkey-house/
(not yet read in full)

6. Suckow, M.A., Stevens, K.A., Wilson, R.P., 2012. The Laboratory Rabbit, Guinea Pig, Hamster, and Other Rodents. Academic Press.
Note: The deer mouse (Peromysces), for instance, lives 8 years in captivity but only ~1 year in the wild.
I cannot find the data for M. musculus but it looks very similar from what I recall.

Samstag, 13. Juni 2015

What's hot in Aging Research? (2015 List)

I. Which interventions could produce a life-extension breakthrough in the next decade or so? (Short Term breakthroughs)
II. Which interventions hold promise, but are a little more speculative? (Mid Term breakthroughs)

Starting from now, I would like to review this question annually or every two years. In my analysis I'll include interventions, drugs, diets, etc. that could have a large and meaningful effect on aging or any of the major age-related diseases. From a methodological point, the answer must consider: A. effect sizes and B. plausibility (how advanced is the science?). Aspirin is an example of an intervention with high plausibility, but small effect size, since the effects are limited to cancer prevention. In fact, even if Aspirin reduced cancer incidence by 10-50% this would only result in 1 or 2 years added to the average human lifespan.

The answer to this question is personal opinion to some extent. To be as objective as possible I tried to track down reviews highlighting "important" research (3-6).