Samstag, 21. November 2015

Resources for biogerontologists

Suggestions for Animal husbandry

List of lifespan extension...
Genetic (1, 2). No good online resource or database available. "Lifespan Observations Database" is outdated
Other interventions

AnAGE database: lists maxLS for different species

(to be continued)

1. Ladiges W, Van Remmen H, Strong R, et al. Lifespan extension in genetically modified mice. Aging Cell. 2009;8(4):346–352

2. Liao, C. Y., & Kennedy, B. K. (2014). Mouse models and aging: longevity and progeria. Mouse Models of the Nuclear Envelopathies and Related Diseases, 109, 249-285.

Donnerstag, 19. November 2015

Cliffnotes: anti-aging effects GHRKO, what is the target tissue?

GHRKO - Growth hormone receptor knpck-out robustly extends lifespan, but how? Is it through lower IGF1, lowere GH, both and which tissue are the targets?

Very briefly, superficially:

Kopchick, Miller and others (1) have been running tests at two different sites to dig into an answer, but so far they haven't really uncovered any answers. So far they looked into liver, muscle and fat tissue.
An increase in survival and in maximal lifespan was detected in male MuGHRKO [muscle specific GHRKO] at UM mice, though not in a parallel experiment at OU and not in females at either test site. [OU, UM are the 2 different test sites/universities]
While removal of GH action in muscle of male mice results in features that are consistent with the hypothesis that blocking the anti-insulin activity of GH improved glucose homeostasis, the hypothesis that improved glucose homeostasis in MuGHRKO mice will improve lifespan remains questionable. However, we do know that removal of GHR in muscle did not shorten lifespan as discussed above. Since MuGHRKO mice were one of three lines simultaneously generated and studied by our laboratories, we can compare the effects of disrupting GHR in three insulin sensitive tissues (muscle, liver, and fat). Our previous work with liver- and fat-specific GHR gene disrupted mice indicates that lifespan does not always positively correlate with glucose homeostasis. For example, liver-specific disruption of the GHR (LiGHRKO) produces mice that have impaired glucose homeostasis [21, 22]. However, these mice have a normal lifespan as determined by two laboratories (OU and UM)[34]. Furthermore, fat-specific disruption of GHR (FaGHRKO) produces mice that have normal glucose homeostasis and these mice are short lived (List, Kopchick and Miller unpublished results at OU and UM). This suggests that other processes related to aging may have been altered (improved in LiGHRKO and impaired in FaGHRKO mice) to counteract the effect of glucose homeostasis on aging.
The authors state:
Collective data regarding muscle from MuGHRKO, global GHR−/−, Ames, and LiGHRKO mouse lines suggests that removing the indirect GH action, i.e. lowering IGF-1, may be more important in protection against musculoskeletal frailty.
Which to me doesn't quite add up (at a first glance). Another paper utilizing large, multi-site testing (2) found that IGF-1 itself has a small (but apprently real) effect on aging. For a few years now, I think, there has been mounting evidence that global GHRKO is somehow "better" than messing with IGF1 only. I recall quite clearly other controversial IGF1R papers (e.g. ref. 3).

I suppose lowered IGF1 could be more important in muscle, but on a whole body level there must be some beneficial effect of lowered GH.


1. Aging (Albany NY). 2015 Jul;7(7):500-12.
Removal of growth hormone receptor (GHR) in muscle of male mice replicates some of the health benefits seen in global GHR-/- mice.
List EO, Berryman DE, Ikeno Y, Hubbard GB, Funk K, Comisford R, Young JA, Stout MB, Tchkonia T, Masternak MM, Bartke A, Kirkland JL, Miller RA, Kopchick JJ.

2. Lorenzini A, Salmon AB, Lerner C, Torres C, Ikeno Y, Motch S, McCarter R, Sell C. Mice producing reduced levels of insulin-like growth factor type 1 display an increase in maximum, but not mean, life span. The journals of gerontology Series, A, Biological sciences and medical sciences. 2014;69:410–419.

3. Aging Cell. 2014 Feb;13(1):19-28. doi: 10.1111/acel.12145. Epub 2013 Sep 11.
Longevity effect of IGF-1R(+/-) mutation depends on genetic background-specific receptor activation.
Xu J1, Gontier G, Chaker Z, Lacube P, Dupont J, Holzenberger M.

Freitag, 30. Oktober 2015

Stress resistance, Proteostasis and Aging reviewed (2015)

Let's start with a brief literature review by Alper, Bronikowski and Harper 2015 (1). I have excerpted some particularly noteworthy passages.

CR does not lead to epigenetically stable programming, hence an ex vivo model of CR has been hard to come by:
Interestingly, cells grown from dietary models of life extension fail to show this correlation. More specifically, dermal fibroblasts from mice subjected to life-long caloric restriction (CR) or provided with a diet low in the essential amino acid methionine, were no more stress resistant to multiple cytotoxins relative to their normal-fed counterparts (Harper et al., 2006b). Caloric restriction is perhaps the most robust life-extending intervention known (Fontana and Partridge, 2015) while diets low in methionine have been repeatedly shown to increase longevity in both rats and mice (Perrone et al., 2013, Sun et al., 2009 and Miller et al., 2005). A clue to this apparent discrepancy comes from studies using conditioned media; or more specifically, cells exposed to media supplemented with serum collected from rodents undergoing CR are more stress resistant than are cells grown in the presence of normal media alone. This suggests the presence of specific circulating factors needed for the life extending effects of dietary restriction that are lost during the derivation and expansion of individual cell lines (de Cabo et al., 2003 and De Cabo et al., 2015).
Multi-stress resistance correlates with long lifespans but there are exceptions to the rule:

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.