Freitag, 18. September 2015

Mitochondrial Deletions Matter in the Heart: another mosaic piece gets us closer to a solution

Here, I will discuss a recent paper by Baris, ..., Wiesner et al. (1). This work is from a Cologne group and the renowned “Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD)”.

In the discussion the authors describe their hypothesis thusly:
Tissues of aged mammals display respiratory mosaicism, i.e., few cells with severe mitochondrial dysfunction embedded into normal tissue. This was shown for heart, skeletal muscle of the limbs and extraocular muscle, substantia nigra, and liver (reviewed in Larsson, 2010). However, it was unclear whether this mosaic phenotype is responsible for causing any of the typical aging-related symptoms of organ dysfunction.

Of course, the interested reader will note that it was not at all "unclear". The evidence is certainly controversial, particularly in humans/Rhesus monkeys, but by no means non-existent. I am not a fan of overselling and plenty of data by Aiken-McKenzie and others supports the idea (c.f. ref. 3 and start from there). One should give credit when it’s due, which is what the editorial by Khrapko et al. does (2). The paper by Baris et al. while interesting is certainly not any more definitive than the data we already have. However, it does clarify some controversy surrounding the TWINKLE KO model of accelerated deletion accumulation.

Dienstag, 21. Juli 2015

Drug approvals - more good news from Pharma

More than two years ago I blogged about an upturn in drug approvals. Although, there were concerns this might be a temporary fluke, so far the trend has continued. Let's just hope that drug prices do not rise all that much in the future, since 2014 has been the year of biologics and orphan drugs, not exactly known to be cheap. (Note: In 2013, 7 out of 10 best-selling drugs were biologics.)

Drug approvals (New Molecular Entity + Biologics, ref. 1, 2) increased from the low 20s from the years past.
2007: <20
2012: 39
2013: 27
2014: 41

What's the link to biogerontology?
First of all, the pace of pharma research indicates whether we are capable of addressing challenging diseases or if they are intractable for some reason. Second, aging is one of the most challenging diseases or disease-causing conditions and the first, primitive drugs to treat it may well be small molecules. Since development of these anti-aging drugs will require the help of pharma at some point, it's good to see the business thriving again.



Dienstag, 14. Juli 2015

Aspirin and Ethics - a brief reflection

When I was reading current literature on Aspirin I found this gem (emphasis mine):

"Once-daily, low-dose aspirin did not significantly reduce the risk of the composite outcome of cardiovascular death, nonfatal stroke, and nonfatal myocardial infarction among Japanese patients 60 years or older with atherosclerotic risk factors...
[Hence] The [JPPP] study was terminated early by the data monitoring committee after a median follow-up of 5.02 years (interquartile range, 4.55–5.33) based on likely futility...We plan to conduct further analyses to establish whether aspirin had beneficial effects in particular subgroups of patients or if there were beneficial effects with respect to cancer prevention."

Is this the ethics committee-equivalent of first shoot, then ask questions? Why would you kill the study for futility before conducting a full analysis including cancer? I know that there are confounding issues if cancer was only a secondary endpoint, but at some point something must have gone ridiculously wrong, be it initial study design or the decision by the ethics committee. Perhaps, we are just dealing with sloppy writing, the monitoring committee knowing that cancer was unchanged, and the authors hoping that a signal will emerge now or in the future. Something isn't quite right here.

Either way, it'd be a travesty if there turns out to be a signal, yet the trial (n~14 000) was stopped precociously.

1. Ikeda, Yasuo, Kazuyuki Shimada, Tamio Teramoto, Shinichiro Uchiyama, Tsutomu Yamazaki, Shinichi Oikawa, Masahiro Sugawara, et al. 2014. “Low-Dose Aspirin for Primary Prevention of Cardiovascular Events in Japanese Patients 60 Years or Older with Atherosclerotic Risk Factors: A Randomized Clinical Trial.” JAMA 312 (23): 2510–20. doi:10.1001/jama.2014.15690.

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:
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).

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!

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.

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.

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.


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.

(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).

Mittwoch, 13. Mai 2015

The oxidative stress theory of aging - concepts and limitations

What do we know about the involvement of oxidative stress in disease?
Definitely not enough. The speakers at MiP-School London reminded us that researchers use the term "ROS" as explanation to hide behind with little explanatory value. Berry Halliwell (3,4) and Mike Murphy (6) gave fascinating talks on this topic. I would like to add a more biogerontologic perspective.

A deep mechanistic understanding of how ROS regulate lifespan might be called for, but I don't think we should over-emphasize detailed understanding in the field of aging as a whole. Gerontology is difficult. There are enough basic questions still unanswered. (Is calorie restriction a universal mechanism? Are current models of mouse lifespan extension redundant/convergent? etc.)

Historically, progress has come from rather crude phenotypic screens. Calorie-restriction was discovered before the Second World War, using mice without fancy molecular biology. To me, the whole Interventions Testing Programme is one big, naive phenotypic screen (readout = dead mice). The rationale for some of the tested compounds is almost cringe-worthy. Guess what? It's the most successful programme in the world, yielding multiple promising leads. Particularly, Rapamycin. To propose a test of rapamycin as a CR-mimetic we do not need to understand the underlying biology in any detail. Unsurprisingly, the first data on the mTOR pathway was generated using simple phenotypic screens in yeast and 6 years after the rapamycin lifespan study in mice, we still do not understand the mTOR pathway very well. The big invention by the ITP, and others like Spindler, were perfect animal husbandry combined with a modicum of understanding.

Given how little we understand about aging, the naive phenotypic screen will remain a worthwhile strategy. Knowing "just enough" is often quite useful. However, the naive approach to the oxidative stress theory of aging has produced conflicting results. Is it time to re-consider some of the basics?