Samstag, 13. Dezember 2014

Expanded Deletions vs Mutations: an unsolved Mystery

Edit (02-18-2015)
Based on a study I read, or rather skimmed. The problem of aging (stem) cells explained (1):
A significant increase in the frequency of respiratory chain deficient colonic crypts with age correlates with the frequency of mutations detected by [next generation sequencing]
But to this day we do not know why deletions accumulate in muscle and point mutations in the colonic epithelium.

Mechanism of Action (1): Speculation
Mathematical modelling studies have suggested that clonal expansion of mtDNA mutations within an individual cell is likely to be due to random genetic drift and predict that it can take at least 20 years for an mtDNA mutation to clonally expand to high levels sufficient to cause COX deficiency [37]–[39]....Previously we examined colonic epithelial tissue from a similar ageing mouse colony and showed that clonal expansion of mtDNA mutations was a very rare event in these animals compared with aged humans [41]. This may explain the species differences in these data, consistent with modelling studies that emphasise the difficulty of generating clonal expansion through random drift in short-lived animals [39].
The question arises if mutations leading to a COX negative phenotype are additionally selected for, like in muscle? (2) If not, then why? Induction of mitochondrial biogenesis could help to answer this question in a mouse model. If I had to speculate, I guess, the aetiopathogenesis might be completely different between muscle and colonic mitochondrial dysfunction. Perhaps substantia nigra and muscle rely more on OXPHOS (aerobic) whereas stem cells do not (4), thus deletions in muscle would not trigger a vicious cycle as in (2)?

Freitag, 5. Dezember 2014

Parabiosis enabled mouse rejuvenation - will the data transfer to humans?

Two recent papers make you wonder, will the mouse aging data ever translate to humans? So far we have found out that mouse cancer data rarely applies to humans, but anti-aging interventions have never been tested in humans before.

Katsimpardi et al. 2014 (1a) (Wagers and Rubin labs)
GDF-11 leads to "Vascular and neurogenic rejuvenation of the aging mouse brain". Interestingly, the protein, which has been indentified in parabiosis experiments (3), is related to myostatin (!) and a "circulating transforming growth factor–β (TGF-β) family member". It also "reverses cardiac hypertrophy in aged mice" apparently mimicking many effects of actual parabiosis.

And as a side-note: "Systemic factors in old blood can have detrimental effects on hippocampal neurogenesis in young animals..."

Donnerstag, 4. Dezember 2014

The death of a Hypothesis: Cholesterol and Heart Disease (Ezetimibe edition)

Recent events have cast doubt on the well established "lipid hypothesis" of heart disease. In particular, the failure of Vytorin, aka ezetimibe, to lower intima media thickening. Instead the cholesterol absorption inhibitor appeared to worsen thickening, if it had any effect at all, in this rather small study. Of course, the lipid hypothesis is backed by other lines of evidence (1) but the most reliable evidence always comes from interventional studies.

So the key point of this controversy has been that no lipid lowering drug has ever reduced CVD (usually measured as a composite endpoint*) in a large study, with the exception of statins. This means it would be conceivable that some other effect of statins is responsible for their protective effects, the so called pleiotropic effects of statins.

The controversy can be put to rest given the results of the secondary-prevention study IMPROVE-IT with n ~ 18 000. I will spare you the details and just link to two other reviews instead. (Note, that the arseholes from medscape may require you to register before you can read the summary)

Dienstag, 18. November 2014

Short notes: massively parallel in vivo screening; thoughts on senescence and telomeres

Recently, I attended two very useful seminars/talks. There are two kinds of talks. Those seminars that are helpful, but boring. And those that leave you amazed at every step. The boring ones can be useful when they give your mind time to wander, and ponder some minor detail of the talk, or think about your own research. These talks had a little of both worlds:

1. FunSel: Functional in vivo selection using adeno associated viruses [AAV].
AAV lead to efficient infection of post-mitotic tissues. Selection is based on a simple principle: if AAVs express protective proteins, they will be enriched in surviving cells. The main assumption is that there is some selection on the cell level, e.g. some cells die, others survive. If this works, you could imagine applying it to most diseases e.g. neurodegeneration, beta-cell death, muscle cell loss (sarcopenia), etc.
I am still searching for publications on this topic, as it appears that most of the research is still ongoing.

How could we adapt this technique to aging research if it works as promised? For example:
A. Using FunSel with a model of mitochondrial aging (the interested reader can figure out which one I mean)
B. More speculative: Using it for in vivo optimization of amino acid sequence and function, e.g. vector optimization

Montag, 3. November 2014

Age-related calcification: how prevalent is it in the animal kingdom?

It has been some time since I read about calcification. I can't access the below paper, but I find it fascinating just how prevalent this phenomenon seems to be across different species. Unfortunately, the wording of the abstract does not distinguish between idiopathic and age-related calcification. Perhaps I missed these papers, but I don't think age-related calcification has been studied (and shown to occur) in all these species. In fact, judging by the references most refer to the idiopathic type, but I have no time to read it in more depth. Edit: A brief e-mail exchange with the authors more or less confirmed my suspicion, their secondary/tertiary sources mostly deal with "regular" pathologic calcification.

Comp Med. 2014 Jun;64(3):224-9.
Extensive vascular mineralization in the brain of a chimpanzee (Pan troglodytes).
Connor-Stroud et al.

Spontaneous vascular mineralization (deposition of iron or calcium salts) has been observed in marble brain syndrome, mineralizing microangiopathy, hypothyroidism, Fahr syndrome, Sturge-Weber syndrome, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, and calciphylaxis in humans and as an aging or idiopathic lesion in the brains of horses, cats, nonhuman primates, mice, rats, cattle, white-tailed deer, and dogs. Here we present a 27-y-old, adult male chimpanzee (Pan troglodytes) with spontaneous, extensive vascular mineralization localized solely to the brain. The chimpanzee exhibited tremors and weakness of the limbs, which progressed to paralysis before euthanasia. Magnetic resonance brain imaging in 2002 and 2010 (immediately before euthanasia) revealed multiple hypointense foci, suggestive of iron- and calcium-rich deposits. At necropsy, the brain parenchyma had occasional petechial hemorrhage, and microscopically, the cerebral, cerebellar and brain stem, gray and white matter had moderate to severe mural aggregates of a granular, basophilic material (mineral) in the blood vessels. In addition, these regions often had moderate to severe medial to transmural deposition of mature collagen in the blood vessels. We ruled out common causes of brain mineralization in humans and animals, but an etiology for the mineralization could not be determined. To our knowledge, mineralization in brain has been reported only once to occur in a chimpanzee, but its chronicity in our case makes it particularly interesting.

Mittwoch, 15. Oktober 2014

Short Notes: Methionine-mediated lifespan extension solely dependent on GH signalling?

Aging Cell. 2014 Sep 19. doi: 10.1111/acel.12269.
[Epub ahead of print]Growth hormone signaling is necessary for lifespan extension by dietary methionine.
Brown-Borg HM1, Rakoczy SG, Wonderlich JA, Rojanathammanee L, Kopchick JJ, Armstrong V, Raasakka D.

...Methionine intake affects also lifespan, and thus, GH mutant mice and respective wild-type littermates were fed 0.16%, 0.43%, or 1.3% methionine to evaluate the interaction between hormone status and methionine. All wild-type and GH transgenic mice lived longer when fed 0.16% methionine but not when fed higher levels. In contrast, animals without growth hormone signaling due to hormone deficiency or resistance did not respond to altered levels of methionine in terms of lifespan, body weight, or food consumption. Taken together, our results suggest that the presence of growth hormone is necessary to sense dietary methionine changes, thus strongly linking growth and lifespan to amino acid availability.

Methodological note: some of the control mice in this paper are somewhat short-lived, especially dwarf control and some GHRKO controls.

This reminds me of the Bartke papers showing how difficult (almost impossible) it is to further extend the lifespan of GHRKO mice by restricting them. Taken together these papers have the obvious implication that most life extending interventions (CR, MR possibly essential AA restriction) act through suppressed GH signalling or converge on the same effectors.

Overall, this means that we should seek to find interventions that extend LS on top of CR/GHRKO, if we want to identify novel pathwys.

Methionine moderation
Met moderation has been proposed as a feasible strategy to promote health span and lifespan (e.g. by Michael Rae, or Richie JP). In contrast, methionine moderation (0.43%) had no effect whatsoever in this study.

Freitag, 20. Juni 2014

Miscellaneous Lifespan Studies: Atenolol, Nutraceuticals, n3 fatty acids, SIRT, macronutrients and CR

Recently, I noticed that many study author have the bad habit of not providing full lifespan data, i.e. Kaplan–Meier curve as well as numerical mean and maximum lifespan (90th percentile survival) as well as numerical changes and statistical interpetation. That's just sloppy in my mind.
Another note: I think it's time to stop working with the venerable C57BL/6 ("black 6") strain in favour of more heterogenous and vigorous crosses, e.g. C57BL/6 x DBA/2n (5) or C57BL/6 x C3H (1).

Donnerstag, 5. Juni 2014

Noted for May (2014)

Brief summaries of current topics pertinent to health and life-extension. I am trying to cover "hot" topics, those with high impact and a random assortment of topics I find interesting.

1. In Pakistan, Nigeria and Afghanistan endemic Polio rears its ugly head again.

2. Flie researchers also have problems with artificial lifespan extension due to bad husbandry (ref. 2, chapter 5)

3. "Mice fear [the smell of] men", which could introduce artifacts in many life-span, or at least, health-span experiments. I guess. This could be particularly important in behavioral assays.
Exposure to the smell of males apparently leads to anxiety and analgesia.

4. Stem cell exhaustion (exhaustion of proliferative potential, atrophy) is one possible contributor to aging:
"Once the stem cells reach a state of exhaustion that imposes a limit ontheir own lifespan, they themselves gradually die out and steadily diminishthe body's capacity to keep regenerating vital tissues and cells, such asblood."

5. Juicing alters the glycemic profile of fruits/vegetables, but freezing is generally fine. Except with cruciferous vegetables, which, preferably, should not be frozen. (ref. 5, first 3 posts)

6. Cochrane found that Tamiflu may be almost completely ineffective and Roche made a large effort to hide the data.

7. Physical activity, i.e. wheel running, protects black 6 mice from osteoarthritis(OA) if it is initiated before the development of OA. Generally, black 6 develop OA early by 9 months of age and thus are not the best model for this disease.

References
1. http://www.aerzteblatt.de/nachrichten/58541/Polio-Notstand-WHO-fordert-Impfung-von-Erwachsenen (German link)

2. Sell, C., Lorenzini A. and Brown-Borg, H.M (eds): Life-span extension: single-cell organisms to man. Suresh, Rattan. Follow Journal Biogerontology , Volume 11. 2009.

3. Nat Methods. 2014 Apr 28. doi: 10.1038/nmeth.2935. [Epub ahead of print]
Olfactory exposure to males, including men, causes stress and related analgesia in rodents.
Sorge et al.

4. http://arc.crsociety.org/read.php?2,220387

5. http://arc.crsociety.org/read.php?2,220129,220134#msg-220134

6. http://pipeline.corante.com/archives/2014/05/16/the_real_numbers_on_tamiflu.php

7. Int J Rheum Dis. 2014 Mar 18. doi: 10.1111/1756-185X.12291. [Epub ahead of print]
Lifelong physical activity and knee osteoarthritis development in mice.
Hubbard-Turner T1, Guderian S, Turner MJ.

Donnerstag, 29. Mai 2014

Quick Notes: Neuropeptidy Y, calorie restriction and aging (Draft)

Here's a short and unpolished intro to this topic. We're going to discuss the following article:

Sci Rep. 2014 Mar 31;4:4517. doi: 10.1038/srep04517.
A key role for neuropeptide Y in lifespan extension and cancer suppression via dietary restriction.
Chiba et al.

Sample size is this study's major weaknes
sample size WT-AL (n=48), NPY-AL (n=25), WT-CR (n=42), NPY-CR (n=24).
"As suspected from the survival curves, WT and Npy−/− mice seemed to respond differently to the DR diet in terms of lifespan extension (p = 0.0578 [Genotype × Diet])....The small numbers of mice in the longevity study also limit our conclusions."
The rule for a successful study should be 40-50 mice per group. Unfortunately, the most important groups in this study were the smallest.

A second huge problem is the lifespan (LS) of controls:
The strain used was 129S1/SvImJ or closely related. Median lifespan of their mice was ~840d, single outlier maximum LS below 1000d. A good rule is "900/1200" for healthy mice - 900 days mean LS and 1200d for 10%-survivorship. All other studies can be considered as using unhealthy or short-lived (strains of) mice.

In this particular instance, mean lifespan matches or surpasses values reported for the 129S1/SvImJ strain (approx. 820-880) (ref. 1). Maximum lifespan, on the other hand, is unacceptably low both compared to the vigorous black 6 strain as well as 129S1 mice kept by others (2). Mean lifespan of the last 20% surviving mice in a well kept colony of 129S1/SvImJ mice has been reported to be above 1000d (2).

Strain background
"A limitation of this study is the fact that the genetic backgrounds of the Npy/− (Npytm1Rpa/J, approximate to 129S1/SvImJ) and WT (129S6/SvEvTac) mice differed..."

Now, given those limitations, we can discuss the study, but the data is seriously called into question. The NPY hypothesis is sound, as we know from the introduction, but this paper does not make the most convincing case in favour of it.

Donnerstag, 1. Mai 2014

Proteostasis, Proteasomes and Aging

We are pretty sure that insufficient protein catabolism plays a role in aging (1-7). Important age-related pathologies include (extracellular) amyloidoses, inside and outside the brain, like those in Alzheimer's disease or less widely known in transthyretin amyloidosis. Intracellular aggregates include α-synuclein (AS) in the case of Parkinson's disease. In addition, intra-lysosomal protein-containing aggregates accumulate with aging, e.g. lipofuscin, or "A2E" in the retina. The interested reader is referred to reviews by Terman and Brunk (4), Rubinsztein (2), Cuervo (7) as well as the SENS-Foundation blog.

As an example of the proteostasis-aging link, enhanced autophagy is generally beneficial and associated with extended lifespan or rejuvenation (1, 2). Unfortunately, barring a few exceptional studies with specific interventions (1), most data is indirect ("rapamycin extends lifespan and also increases autophagy"), confounded (offtarget effects, generally) or of little translational relevance (lifespan extension in invertebrates).
A credible in vivo test of the "protein homeostasis hypothesis" would require that multiple inducers of autophagy extend lifespan in long-lived mice. The same goes for inducers of the proteasome, unfolded protein response, or chaperone mediated autophagy (CMA). So far, rapamycin, and perhaps calorie restriction, are the only examples of autophagy inducing interventions shown to extend lifespan in healthy rodents. I might be missing some, but there are only few in any case.

Now, a recent study (3) has made me question the importance of the proteasome compared to CMA and general autophagy. Since catabolic pathways are interlinked, evidence against the "proteasome hypothesis" weakens the "autophagy/CMA hypothesis" and is worth investigating, no matter your preferred hypothesis.

Donnerstag, 10. April 2014

ITP: Acarbose (ACA), 17-α-estradiol (EST), NDGA, Methylene Blue (MB)


Another paper from NIA's Interventions Testing Programme has been published a few months ago. Read it, it's free (1).
This study includes data from their "Cohort 5: [treatment started in] C2009"
 and preliminary data from "Cohort 6: C2010". As is obvious from the starting dates, a mouse lives up to about 1200 days. The authors claim that:
"Here, we report strong evidence for lifespan extension by ACA [acarbose], evidence for a possible effect of EST [17a-estrogen], and strong confirmatory evidence for benefits from NDGA."
Although, then they qualify their statement a little: "Surprisingly, each of these three agents extends lifespan either in males only or (for ACA) much more strongly in males than in females."

Later they also mention a problem that might invalidate a lot of their now-published data:
"One possible reason for the larger or exclusive effects of these compounds on males is the short lifespan of the male controls at two of the three sites (medians of 704, 807, and 924 days from male controls at UT, TJL, and UM, respectively, while female control medians are 864, 918, and 887, Table 1)."

However, a robust intervention must work in both genders. Must. No exceptions made. All validated life extension methods do, e.g. Rapamycin, Calorie Restriction (CR), Methionine Restriction (? maybe?), severe lack of GH (GHRHKO, GHRKO, Ames and Snell dwarfism). If it does not work in females, a mechanism must be shown and follow-up studies should alter the protocol so that it does work.
Remember, interventions solely reducing IGF-1 preferably extend LS in females (the opposite of what we see here). That's one of the reasons why these interventions are not considered established.


Acarbose (ACA) extended maximum lifespan by around 10% in both genders and also led to a similar decrease in weight. Max LS +11% in males, +9% in females. This is consistent with the effect being solely or mostly due to ("crypto-")CR, not glucose absorption kinetics or any other pharmacological effect. The data on median lifespan and weight-adjusted maximum LS is better to the compound:
"...we expected that ACA might produce some survival benefits, although not as much as produced by DR, because the weight reductions from ACA (Fig. 4) were much less than those seen in DR mice. In addition, as weight reductions (% body weight) due to ACA were greater in females [depending on time point, on the order of -20% vs -10%] than in males (Fig. 4), we hypothesized that lifespan effects would, similarly, be larger in females. The results were thus surprising: median lifespan was increased 22% in males and only 5% in females (Fig. 1)."

I maintain that crypto-CR is the most likely explanation until this is refuted by a pair-feeding study. I would not rule out some minor beneficial effect on top of crypto-CR, however.
The authors disagree with me or so it would seem at first glance: "...the lengthened survival for ACA-treated males vs. ACA-treated females cannot be explained by changes in body weight or seen simply as the effect of overall caloric restriction."
But this lengthended lifespan is a meagre 2% difference between +9% and +11%, when it comes to the all-important Maximum LS.


17-α-estradiol (EST) did not extend max LS, although, it had a similar effect to acarbose on weight. Again, this somewhat strengthens the ACA data: not all reductions of bodyweight seem to lead to Crypto-CR.
It is still beyond me why EST was chosen in the first place and for two cohorts, this being the first to publish data! Apparently "it might mimic, in male mice, the beneficial effects produced by estrogen in control females".
This is forgetting that mice as a species do not show a consistent sexual dimorphism in longevity (c.f. ref. 2). Their heterogenous cross (UM-HET3) does, but this could be quite easily an idiosyncratic trait if it doesn't apply to the species as a whole.

NDGA does not look all that promising, but this is only an interim analysis. Its effects seem to be limited to changes in median/avg. lifespan of male mice. However, the effect of NDGA does not extend to females even at the same blood levels as in males. That's a red flag. In the first NDGA study published the authors speculated that they'd have to increase the dose for the female mice so that they have the same blood-levels of the drug:
The blood level was indeed increased in females receiving 5000 ppm to a value similar to that in males receiving 2500 ppm NDGA (Fig. S5), but we saw no evidence for an increase in female lifespan with 70% of the survival curve complete...The high dose reduced female body weight about 14%, 22%, and 23% at 12, 18, and 24 months, respectively, while male weight was only reduced 3–6% (Fig. S6B); thus, the lack of effect of NDGA on female lifespan cannot be explained by concentration in the plasma or by effects on body weight. It is possible that NDGA produces beneficial effects in both sexes but produces harmful effects in females that prevent lifespan extension.
Interestingly, as stated abvoe, NDGA causes considerable weight-loss in females (-1x-2x%) but not males, which could be suggestive of toxicity, at least giving a plausible mechanism for the gender disparity.

Methylene Blue (MB) had a tiny positive effect of 6% on female max LS, but not on male LS. This is very little and could be a statistical fluke. I'd study other substances first before continiung with MB. We're desperate, but not that desperate.
Why was MB chosen in the first place? The rationale presented by the authors is not very convincing. It reads kind of like a supplement ad. We're desperate, I get it. But are we that desperate? Perhaps I'll do a follow-up post with better suggestions for treatments. And I'm not saying MB was a bad shot, just that there should be better substances.


Conclusions
Out of the 4 substances tested none merit any hype, but ACA and NDGA should be followed-up.

Pair-feeding of Acarbose, to match weights between control and intervention group, is the most important follow-up. We should investigate ACA as a CR-mimetic, but not so much on its own merits. We'll see if other interventions targetting glucose metabolism can be successful. Some time ago there were a few successes with AGE-restriction.
I am not sure ACA works as a CR-mimetic in humans as I did not find any documentation of "weight-loss" as a side-effect.


Finish the NDGA study and find out why it does not work in females. The compound remains unvalidated, but interesting. Spindler reported toxicity with high dose NDGA, so let's see how the NIA's highest doses look in the end. It must show maximum lifespan extension in both genders to be interesting from a biogerontologic perspective.

On a side-note, gender-related differences seem to be widespread in mice and their responses to "anti-aging" interventions. I am actually a little surprised, although, I shouldn't be.

References

1. Aging Cell. 2014 Apr;13(2):273-82. doi: 10.1111/acel.12170. Epub 2013 Nov 19.Acarbose, 17-α-estradiol, and nordihydroguaiaretic acid extend mouse lifespan preferentially in males. Harrison DE1, Strong R, Allison DB, Ames BN, Astle CM, Atamna H, Fernandez E, Flurkey K, Javors MA, Nadon NL, Nelson JF, Pletcher S,Simpkins JW, Smith D, Wilkinson JE, Miller RA.
http://onlinelibrary.wiley.com/doi/10.1111/acel.12170/full

2. Handbook of the Biology of Aging, Seventh Edition (Handbooks of Aging). Masoro and Austad.

Dienstag, 25. März 2014

Does reduced GH/IGF signalling extend lifespan? A possible answer.

Berryman et al. (Kopchick lab) recently published a paper (1) that I sort of disagree with. I'd like to take the opportunity to discuss a bigger issue: how can we know the true effects of GH-inihibtion, at least in mouse models? Isn't the data conflicting as Sonntag et al. have shown?

Let's start with a brief introduction to long-lived dwarf mice (1):
"[T]here appears to be a preferential accumulation of excess fat in the subcutaneous depots, which is thought to have metabolically beneficial effects in ... long-lived mice and that may contribute to their counterintuitive association between obesity and life span."
Then the authors say that:
"Not all mouse strains with reduced GH or IGF-1 action show improvements in life span. One example is GH receptor antagonist (GHA) transgenic mice, which were generated in our laboratory more than 20 years ago (22–24)...
The GHA expressed in these mice contains a lysine in place of glycine at position 119 (22–24) in the bGH protein. This single substitution results in the production of a protein that competes with endogenous GH for GHR [Growth Hormone Receptor] binding..."
However, I'd like to contest their claim that these mice fail to show lifespan (LS) extension. I don't think their data is able to show one way or another.

Consider the problem of sample size and power. GHA mice weigh more than classical dwarf mice, e.g. GHR -/- mice, which is due to their incomplete inhibition of GH-signalling. Female GHA mice weigh up to 33% less than controls (ref. 1), males are even heavier. GHR -/- weigh closer to 60-70% less compared to controls! But this also implies that the effects on lifespan will be diminished in GHA mice, albeit non-zero. I think the IGF-1 data also highlights this striking difference:
"In the GHA mice, [serum IGF-1] levels were reduced to about 75–80% the level of controls (P 0.05). In the GHR [KO] mice, levels were reduced to about 20% the level of controls (P 0.0001)." (2)

Lorenzini et al. recently showed that subtle differences in LS due to modest changes in GH/IGF signalling may require n ~ 100 per group (3). In contrast: Coschigano et al."only" used n~50 per group. Normally, a very respectable sample size, but Lorenzinin and Co needed a larger sample size even though their mice have lower IGF1-levels, i.e. ~50% of controls.
In fact, in the study by Coschigano (2), numerically, the median, mean and maximum lifespan is higher in both genders.

Secondly, males show a smaller numerical improvement in lifespan (2):
Although there was a tendency for the GHA mice to live longer than their controls, especially for the females, this difference did not reach statistical significance for either gender.
First of all, this is consistent with other studies also showing a gender disparity. In addition, given their new data (1) it seems that some idiosyncratic side-effect of GH-antagonism or GH/gentoype interaction might be harming male mice.
"...male GHA mice had significantly lower body weights than WT males until 52 weeks, but thereafter, no statistical difference was observed. In contrast, female GHA mice had significantly lower body weights (ranging from 66% to 81% of female littermate controls) throughout the study...40% and 33% of the total body weight of male and female GHA mice, respectively, was attributed to fat by 68 weeks of age compared with 17% for both control males and females of the same age...  
male GHA mice became significantly more obese with advancing age...The mass of all adipose depots was higher in male GHA mice than their littermate controls at 82 weeks of age; however, there was only a significant increase in the mass of subcutaneous and retroperitoneal fat pads (p = 1.0 × 10−6 and p = .04, respectively) "
So either excess fat is harming them, or perhaps, GH antagonism is not maintained throughout the whole lifespan. However, I am not very satisfied with either explanation, since Berryman et al. also showed beneficial changes in male mice, i.e. increased adiponectin and subcutaneous adiposity with low-normal liver triacylglycerol content. There was also a slight uptick in late-life insulin levels and an increase of the leptin-adiponectin ratio which is more consistent with harmful effects.

Third, as much as I hate to say it, but their study (2) is not good enough, not rigorous enough. Their controls on the black 6 background have mean and median lifespans below 800d, while 900d would be expected. Maximum lifespans also appear to be well below the ~1200d expected from a healthy lab mouse.
Overall this weakens conclusions we can draw based on this study, though, it should not introduce much systematic bias. In fact, low LS is often seen as contributing to exaggerated lifespan effects. In particular, with interventions that offset some harmful aspect of questionable husbandry.

Fourth, GH-toxicity might be a real thing biasing low-IGF1 models, which often show compensatory increases in GH levels (5). I do wonder if the GHA-model (Kopchick lab) and the IGF1 hypomorphic mice also show these compensatory increases?
Increased GH-levels have been shown for the liver IGF1 deficient mice (5) and apparently for "Liver-specific GH receptor gene disrupted (LiGHRKO) mice" as well (6), also by Kopchick.

The solution
A meta-analysis  - not a narrative review, not a systematic review - could in principle overcome the issues I raised above, especially sample size and power. Husbandry effects and study quality could be considered as well.

Is the data too heterogenous for analysis? Perhaps, but I don't think so. Meta-analyses of the effects of dietary restriction have been performed, some even comparing different taxa (c.f. 4.a to d).

So far I'd side with the idea that almost all healthy, well-husbanded models of low GH/IGF1 signalling will show delayed aging if there's no frank toxicity. Let's not forgot that toxicity (extrinsic mortality) shouldn't be confused with intrinsic aging - which is what we'd like to study. It's quite possible that things like CVD-toxicity ultimately limit the efficacy of GH/IGF1-signalling reduction.

References

1. A Dwarf Mouse Model With Decreased GH/IGF-1 Activity That Does Not Experience Life-Span Extension: Potential Impact of Increased Adiposity, Leptin, and Insulin With Advancing Age. Berryman DE, Lubbers ER, Magon V, List EO, Kopchick JJ.J Gerontol A Biol Sci Med Sci. 2014 Feb;69(2):131-41. doi: 10.1093/gerona/glt069. Epub 2013 May 21

2. Coschigano KT, Holland AN, Riders ME, List EO, Flyvbjerg A, Kopchick JJ.
Deletion, but not antagonism, of the mouse growth hormone receptor results in severely decreased body weights, insulin, and insulin-like growth factor I levels and increased life span. Endocrinology. 2003; 144: 3799–3810.

3. J Gerontol A Biol Sci Med Sci. 2013 Jul 20. [Epub ahead of print]Mice Producing Reduced Levels of Insulin-Like Growth Factor Type 1 Display an Increase in Maximum, but not Mean, Life Span. Lorenzini A, Salmon AB, Lerner C, Torres C, Ikeno Y, Motch S, McCarter R, Sell C.

4.a. Aging Cell. 2013 Jun;12(3):410-4. doi: 10.1111/acel.12061. Epub 2013 Mar 27.Dietary restriction of rodents decreases aging rate without affecting initial mortality rate -- a meta-analysis. Simons MJ1, Koch W, Verhulst S.

4.b. Dietary restriction in rats and mice: a meta-analysis and review of the evidence for genotype-dependent effects on lifespan.Swindell WR.Ageing Res Rev. 2012 Apr;11(2):254-70. doi: 10.1016/j.arr.2011.12.006. Epub 2011 Dec 23. Review.

4.c. Mol Biosyst. 2012 Apr;8(4):1339-49. doi: 10.1039/c2mb05255e. Epub 2012 Feb 10.A meta-analysis of caloric restriction gene expression profiles to infer common signatures and regulatory mechanisms.Plank M1, Wuttke D, van Dam S, Clarke SA, de Magalhães JP.

4.d. Int J Cancer. 2003 Sep 20;106(5):766-70.Energy restriction and the risk of spontaneous mammary tumors in mice: a meta-analysis.Dirx MJ1, Zeegers MP, Dagnelie PC, van den Bogaard T, van den Brandt PA.

5. Reductions in serum IGF-1 during aging impair health span.Gong Z, Kennedy O, Sun H, Wu Y, Williams GA, Klein L, Cardoso L, Matheny RW Jr, Hubbard GB, Ikeno Y, Farrar RP, Schaffler MB, Adamo ML, Muzumdar RH, Yakar S.Aging Cell. 2013 Dec 17. doi: 10.1111/acel.12188. [Epub ahead of print]

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