Montag, 11. Januar 2016

Cliffnotes: Molecular targets downstream of CR

A very brief list and not a comprehensive one follows. I focus on direct evidence from KO models and lifespan studies, because this is the most robust study design. I don't care for surrogate endpoints, with the exception of pathology. The most common study design can be summarized thusly: When you combine "Factor X" with CR, does this affect the magnitude of LS extension from CR? Where X is either a gain of function (e.g. other LS extension) or loss of function (usually KO) intervention.

A. Direct evidence
B. Indirect evidence
C. Speculative or parallel pathways

A. Direct evidence

GH/IGF1

Montag, 14. Dezember 2015

Optimizing resource use - Chronic toxicity and preclinical studies

This post is related to the idea of "Optimizing resource use by outsourcing of lifespan research" to pet owners and zoos.

What should we study? We're clueless!
We don't understand aging very well. That's the reason why we need to perform both naive screens with novel chemical matter (more on that below) as well as large, high-throughput screens with drugs that target plausible pathways. But what are the plausible pathways if we are clueless?

Well, it's not quite as bad as you may think, since we do have some basic paradigms in aging research. Bluntly put, there's for instance "anti-growth" as well as "mimic CR/dwarfism" (= which usually amounts to an "anti-growth" paradigm). The idea that diminished signalling through a multitude of growth pathways extends longevity has been shown to be true in scores of studies (just recently, ref. 1, 2).

Preclinical studies: how about worms and flies?
Preclinical safety studies presently include cell culture work in human cells as well as rodent models (usually rat) and non-rodent models. The latter often includes dogs and primates (5). From a basic science perspective, we should consider mandating chronic "safety" testing in invertebrates. This would be very useful to biogerontologists, as we can expect to find a reasonable number of life extending drugs by pure chance. On the other hand, it is not clear if such "safety" testing has any meaning for human toxicity. An alternative would be to compel companies to give out the drugs (in a blinded fashion to prevent IP problems) and for the government to perform lifespan testing. This method would work particularly well to test the already available drug libraries. (As of today no free market based incentive exists to develop anti-aging therapies. We won't consider the details here.)

Indeed thousands of failed drug candidates must exist and represent a large untapped source for biogerontology. Modern cancer drugs are particularly promising since they target various growth-related pathways. In 2015 "According to the Pharmaceutical Research and Manufacturers of America (PhRMA), 771 new drugs and vaccines are in development by US companies" just to treat cancer (6). It is difficult to find high quality lists with advanced drugs, but there's one up to date list for lung cancer (7). These lists may come in handy for "smaller" projects like the NIA's ITP. It might also be helpful to think in terms of drug targets and then prioritize the most plausible targets and drugs (8).

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)


References
1. Ladiges W, Van Remmen H, Strong R, et al. Lifespan extension in genetically modified mice. Aging Cell. 2009;8(4):346–352
http://onlinelibrary.wiley.com/doi/10.1111/j.1474-9726.2009.00491.x/full

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.

References

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.

1. http://pharmamkting.blogspot.co.at/2014/12/43-of-new-drug-approvals-in-2014-were.html
2. http://cen.acs.org/articles/93/i5/Year-New-Drugs.html

FDA:
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugInnovation/ucm429247.htm