Montag, 30. Dezember 2013

Vicious Cycle Hypothesis of Mitochondrial Aging - Everything Old is New Again

There is little doubt that the classic vicious circle mitochondrial free radical "theory" of aging has been refuted. However, recent data shows that a different type of vicious circle may act on mitochondria (1) to promote organismal aging and drive sarcopenia.
Mitochondria in certain tissues are known to accumulate high levels of one and the same (= clonal) deletion. Several hypotheses have been postulated that can explain this accumulation - replication advantage, "survival of the slowest"and drift - but empirical evidence for these models has been lacking. Now the Aiken and McKenzie lab has considerably strengthened the replication advantage angle by showing a vicious circle that operates in vivo by promoting mitochondrial DNA replication. On the other hand, modeling by Kirkwood, Kowald and others (2, 3) further confirms that drift and size based replication advantage in and of themselves, and without any vicious feedback loops, operate too slowly to explain aging in short-lived species like mice.

Now, based on these three studies (1-3) we can propose a basic model for deletion accumulation that, as far as I can tell, is consistent with published data: Drift and replication advantage lead to an accumulation of OXPHOS-deficient, deletion-bearing mtDNAs until a critical threshold is reached. Then, the cell tries to compensate. Drift + Replication Advantage + Feedback Loop = fast accumulation of deletions. Aiken et al. call this feedback loop "non-adaptive program of mitochondrial biogenesis" or vicious cycle.

Two compensatory mechanisms could be maladaptive in this situation and a trigger of this vicious cycle:

Mittwoch, 11. Dezember 2013

"Vitamin D: chasing a myth?"

Hereby, I have to weaken my recommendation in favour of vitamin D supplementation, which is partly based on past analyses by Autier et al. (2) and a good risk/benefit ratio. Nowadays vitamin D still seems safe to supplement but useless.
However, the big weakness of recommendations for or against vitamin D is that the interventional studies on this topic are few and those that exist are weak. No matter how often you re-analyze garbage, the result won't improve. After so many years of research, we have not advanced much beyond the basic recommendation that vitamin D may benefit the elderly and there mainly women. Thus we absolutely have to wait for large studies to complete if we want to make strong recommendations, e.g. the VITAL and VIDAL studies.

Low serum concentrations of 25-hydroxyvitamin D (25[OH]D) have been associated with many non-skeletal disorders. However, whether low 25(OH)D is the cause or result of ill health is not known. We did a systematic search of prospective and intervention studies that assessed the effect of 25(OH)D concentrations on non-skeletal health outcomes in individuals aged 18 years or older. We identified 290 prospective cohort studies (279 on disease occurrence or mortality, and 11 on cancer characteristics or survival), and 172 randomised trials of major health outcomes and of physiological parameters related to disease risk or inflammatory status. Investigators of most prospective studies reported moderate to strong inverse associations between 25(OH)D concentrations and cardiovascular diseases, serum lipid concentrations, inflammation, glucose metabolism disorders, weight gain, infectious diseases, multiple sclerosis, mood disorders, declining cognitive function, impaired physical functioning, and all-cause mortality. High 25(OH)D concentrations were not associated with a lower risk of cancer, except colorectal cancer. Results from intervention studies did not show an effect of vitamin D supplementation on disease occurrence, including colorectal cancer. In 34 intervention studies including [only!] 2805 individuals with mean 25(OH)D concentration lower than 50 nmol/L at baseline supplementation with 50 μg per day or more did not show better results. Supplementation in elderly people (mainly women) with 20 μg vitamin D per day seemed to slightly reduce all-cause mortality. The discrepancy between observational and intervention studies suggests that low 25(OH)D is a marker of ill health. Inflammatory processes involved in disease occurrence and clinical course would reduce 25(OH)D, which would explain why low vitamin D status is reported in a wide range of disorders. In elderly people, restoration of vitamin D deficits due to ageing and lifestyle changes induced by ill health could explain why low-dose supplementation leads to slight gains in survival.

*1. Vitamin D status and ill health: a systematic review
Philippe Autier, Mathieu Boniol, Cécile Pizot, Patrick Mullie
The Lancet Diabetes & Endocrinology 1 January 2014 (Volume 2 Issue 1 Pages 76-89 DOI: 10.1016/S2213-8587(13)70165-7)

2. Vitamin D supplementation and total mortality: a meta-analysis of randomized controlled trials.
Autier P, Gandini S.
Arch Intern Med. 2007 Sep 10;167(16):1730-7. Review.

*not read in full

Samstag, 16. November 2013

Coffee and all-cause mortality and morbidity

A few years ago I was reading a lot about coffee and noticed that recent studies were more and more suggestive of health benefits.
These days I still periodically check the literature, but rarely have the time to read the full text of papers. All in all, I do consider recent data to be consistent with beneficial effects at moderate intakes.

Here, I provide current abstracts and added comments.

Eur J Epidemiol. 2013 Jul;28(7):527-39. doi: 10.1007/s10654-013-9834-7. Epub 2013 Aug 11.
A meta-analysis of prospective studies of coffee consumption and mortality for all causes, cancers and cardiovascular diseases.
Malerba S, Turati F, Galeone C, Pelucchi C, Verga F, La Vecchia C, Tavani A.
Several prospective studies considered the relation between coffee consumption and mortality. Most studies, however, were underpowered to detect an association, since they included relatively few deaths. To obtain quantitative overall estimates, we combined all published data from prospective studies on the relation of coffee with mortality for all causes, all cancers, cardiovascular disease (CVD), coronary/ischemic heart disease (CHD/IHD) and stroke. A bibliography search, updated to January 2013, was carried out in PubMed and Embase to identify prospective observational studies providing quantitative estimates on mortality from all causes, cancer, CVD, CHD/IHD or stroke in relation to coffee consumption.
A systematic review and meta-analysis was conducted to estimate overall relative risks (RR) and 95 % confidence intervals (CI) using random-effects models.
The pooled RRs of all cause mortality for the study-specific highest versus low (≤1 cup/day) coffee drinking categories were 0.88 (95 % CI 0.84-0.93) based on all the 23 studies, and 0.87 (95 % CI 0.82-0.93) for the 19 smoking adjusting studies.
The combined RRs for CVD mortality were 0.89 (95 % CI 0.77-1.02, 17 smoking adjusting studies) for the highest versus low drinking and 0.98 (95 % CI 0.95-1.00, 16 studies) for the increment of 1 cup/day. Compared with low drinking, the RRs for the highest consumption of coffee were 0.95 (95 % CI 0.78-1.15, 12 smoking adjusting studies) for CHD/IHD, 0.95 (95 % CI 0.70-1.29, 6 studies) for stroke, and 1.03 (95 % CI 0.97-1.10, 10 studies) for all cancers.
This meta-analysis provides quantitative evidence that coffee intake is inversely related to all cause and, probably, CVD mortality.
Then I would like to highlight contradictory evidence, perhaps suggesting a non-linear dose-response(?), or more worryingly, something else.
In this case, the authors speculate that coffee may benefit the old while harming the young. Interestingly, a similar hypothesis about the effects of alcohol exists. This does not mean that young people cannot benefit from red wine or coffee, however. Presumably, the benefits on cardiovascular disease would accrue over time, because it is a chronic disease that begins ante- or perinatally (at around birth) and worsens throughout life.

Mayo Clin Proc. 2013 Oct;88(10):1066-74. doi: 10.1016/j.mayocp.2013.06.020. Epub 2013 Aug 15.
Association of coffee consumption with all-cause and cardiovascular disease mortality.
Liu J, Sui X, Lavie CJ, Hebert JR, Earnest CP, Zhang J, Blair SN.
During the 17-year median follow-up, 2512 deaths occurred (804 [32%] due to cardiovascular disease). In multivariate analyses, coffee intake was positively associated with all-cause mortality in men. Men who drank more than 28 cups of coffee per week had higher all-cause mortality (hazard ratio [HR], 1.21; 95% CI, 1.04-1.40). However, after stratification based on age, younger (<55 years old) men and women showed a significant association between high coffee consumption (>28 cups per week) and all-cause mortality after adjusting for potential confounders and fitness level (HR, 1.56; 95% CI, 1.30-1.87 for men; and HR, 2.13; 95% CI, 1.26-3.59 for women).
In this large cohort [n=43 727], a positive association between coffee consumption and all-cause mortality was observed in men and in men and women younger than 55 years. On the basis of these findings, it seems appropriate to suggest that younger people avoid heavy coffee consumption (ie, averaging >4 cups per day). However, this finding should be assessed in future studies of other populations.
And a verbal summary:
J Am Coll Cardiol. 2013 Sep 17;62(12):1043-51. doi: 10.1016/j.jacc.2013.06.035. Epub 2013 Jul 17.
Effects of habitual coffee consumption on cardiometabolic disease, cardiovascular health, and all-cause mortality.
O'Keefe JH, Bhatti SK, Patil HR, DiNicolantonio JJ, Lucan SC, Lavie CJ.
Coffee, after water, is the most widely consumed beverage in the United States, and is the principal source of caffeine intake among adults. The biological effects of coffee may be substantial and are not limited to the actions of caffeine. Coffee is a complex beverage containing hundreds of biologically active compounds, and the health effects of chronic coffee intake are wide ranging. 
From a cardiovascular (CV) standpoint, coffee consumption may reduce the risk of type 2 diabetes mellitus and hypertension, as well as other conditions associated with CV risk such as obesity and depression,
but it may adversely affect lipid profiles depending on [preparation technique]
Regardless, a growing body of data suggests that habitual coffee consumption is neutral to beneficial regarding the risks of a variety of adverse CV outcomes including coronary heart disease, congestive heart failure, arrhythmias, and stroke.
Moreover, large epidemiological studies suggest that regular coffee drinkers have reduced risks of mortality, both CV and all-cause.
The potential benefits also include protection against neurodegenerative diseases, improved asthma control, and lower risk of select gastrointestinal diseases.
A daily intake of ∼2 to 3 cups of coffee appears to be safe and is associated with neutral to beneficial effects for most of the studied health outcomes.
However, most of the data on coffee's health effects are based on observational data, with very few randomized, controlled studies, and association does not prove causation. Additionally, the possible advantages of regular coffee consumption have to be weighed against potential risks (which are mostly related to its high caffeine content) including anxiety, insomnia, tremulousness, and palpitations, as well as bone loss and possibly increased risk of fractures.
As alluded to a few things still need sorting out: contradictory studies, absence of RCTs, preparation technique, genotype effects, age-dependence of effects and risk-benefit dose-response.

Sonntag, 3. November 2013

Folic acid supplementation in primary prevention?

Increased cancer incidence could be a potential side-effect from supplementation, because folate is involved in purine and pyrimidine synthesis. What do controlled trials say?

Simply put: no risk, no benefit in recent analyses (1, 2). An earlier (now outdated?) meta-analysis suggested increased risk of cancer (3). Perhaps some time I can read the full papers:

"Our analyses suggest that cancer incidences were higher in the folic acid-supplemented groups than the non-folic acid-supplemented groups (relative risk=1.21 [95% confidence interval: 1.05-1.39]). Folic acid-supplementation trials should be performed with careful monitoring of cancer incidence" (3)

 Almost the same holds true for CVD (4). Folic acid's useless.

1. Lancet. 2013 Mar 23;381(9871):1029-36.
Effects of folic acid supplementation on overall and site-specific cancer incidence during the randomised trials: meta-analyses of data on 50,000 individuals.
Vollset et al.

Int J Cancer. 2013 Sep 1;133(5):1033-41. doi: 10.1002/ijc.28038. Epub 2013 Feb 15.
Folic acid supplementation and cancer risk: a meta-analysis of randomized controlled trials.
Qin X, Cui Y, Shen L, Sun N, Zhang Y, Li J, Xu X, Wang B, Xu X, Huo Y, Wang X.

3.  Cancer Epidemiol. 2012 Feb;36(1):78-81. doi: 10.1016/j.canep.2011.05.003. Epub 2011 Oct 21.
Meta-analysis of cancer risk in folic acid supplementation trials.
Baggott JE, Oster RA, Tamura T.

4. Eur J Intern Med. 2012 Dec;23(8):745-54. doi: 10.1016/j.ejim.2012.07.004. Epub 2012 Aug 11.
Efficacy of folic acid supplementation in cardiovascular disease prevention: an updated meta-analysis of randomized controlled trials.
Yang HT, Lee M, Hong KS, Ovbiagele B, Saver JL.

Sonntag, 20. Oktober 2013

Hypothesis Testing: Why I think Sonntag et al. are wrong

About one year ago Sonntag et al. published a superb review highlighting "progress and controversies" in the field of GH/IGF1 and aging (1). In this paper they are very critical of the whole hypothesis:
"These diverse results are incompatible with the concept that reductions in IGF-1 signaling increase life span in mammals as was reported in invertebrate models... 
Based on the current available studies, it appears that the definition of a conserved mechanism of aging requires clarification. If a “common” mechanism for increased life span does not relate to animals of different genders or more importantly to humans, it is difficult to conclude that it represents a conserved mechanism of aging. Importantly, the studies in humans on circulating GH and IGF-1 deficiency do not agree with the data from rodent models."
I believe instead they favor a model in which only early life exposure to low GH levels slows aging:
"In our opinion, it is plausible that the increase in life span observed in Ames and Snell dwarf animals as well as ghr knockout animals is the consequence of impairments in the developmental programming of key pathways... [NB: this would not explain why human patients with the same mutations fail to show a longevity phenotype. Emphasis mine.]"
So why do I think GH/IGF-1 matters, perhaps even throughout adulthood?
I do not want to delve into too much detail and I will try to keep this post short. Also note that my expertise lies outside of this field and I do not disagree that overall the issue is still controversial. However, I do consider the "optimistic" interpretation by e.g. Bartke et al. (2) to be more probable given my reading of the evidence.
"The role of hormones homologous to insulin-like growth factor (IGF, an important mediator of GH actions) in the control of aging and lifespan is evolutionarily conserved from worms to mammals with some homologies extending to unicellular yeast....there is yet no evidence of increased longevity in GH-resistant or GH-deficient humans, possibly due to non-age-related deaths. "
What's wrong with the Sonntag paper?
Some of my criticisms are more general in nature, e.g. their reliance on prospective epidemiology to draw conclusions about aging, or the absence of a discussion of GHRHR -/- and PAPA -/- mice.

As far as I can see they left out a few other papers, although, these did not clearly favor the "optimistic" or "pessimistic" view.

Their choice of words also seems poor at times: "...the studies in humans on circulating GH and IGF-1 deficiency do not agree with the data from rodent models"
Really? Simply put, the epidemiology and human data they cite suggests that IGF-1 lowers cardiovascular disease (CVD) but increases cancer incidence. There is tentative data in GH-deficient animals showing exactly the same, i.e. evidence of CVDisease/damage despite an extended lifespan (Csiszar 2008, Reddy 2013 [3-5]). CVD and delayed aging are not mutually exclusive. If GH-deficiency promotes CVD it might be unsafe in humans even if it slows aging and independently of this effect. This does not mean the GH/IGF-1 pathway isn't conserved. It means that humans are highly susceptible to CVD at middle age.

What do more recent studies say?
Broadly speaking, recent studies support the relevance and conservation of the GH/IGF pathway in aging (6-8). Although, the gender-dependent effect of the IGF1R +/- mutations still cannot be explained to my satisfaction (6) and seems inconsistent with a highly conserved mechanism. On the other hand, I would like to highlight the paper by Lorenzini et al. (7) using a hypomorphic IGF-1 gene, because it has a very large sample size and their mice show acceptable maximum lifespans (around 1100d), albeit not mean LS (around 7xx d). The authors found an increase in the all important maximum but not mean lifespan.

EDIT: Zhang et al. 2012 produced life span extension using FGF-21 overexpression (PMID: 23066506 ), which further supports a conserved role of GH/IGF-signalling. Again, female mice benefit the most. I have no clue why.

Is there a biologic explanation for the inconsistent data regarding IGF-1?
Viewed from another angle, there might be a mechanistic explanation for the discrepancies in rodent studies noted by Sonntag. Note that this is quite speculative:
Renna et al. (9) have shown that antagonizing the IGF-1 receptor inhibits autophagy by inhibiting mTORC2, PKCα/β, disrupting the actin cytoskeleton and endocytosis. The latter being important for autophagy.

What if experimental manipulation of IGF-1 used in aging studies (e.g. IGF1R +/-) also diminishes autophagy? We know that the most robust models of life extension (Snell, Ames and GHRKO) show both undetectable circulating IGF-1 and elevated autophagy. It is unclear why this is so. I do not know if autophagy studies in IGF1-deficient models have been carried out, but I have not looked very hard. This is an important direction for future research!

Finally, the authors, Renna et al., almost suggest the experiment I'm going to suggest. Almost:

“…it is tempting to speculate that one may be able to achieve synergistic benefits by inhibiting the key effectors of the IGF-1R pathway, alongside pharmacological stimulation of the autophagic pathway.”
I hope I am one of the first to actually spell it out: it is possible that inhibiting mTOR[C1] and IGF-signalling will have synergistic effects on lifespan, e.g. using rapamycin + picropodophyllotoxin (PPP, an IGF1R inhibitor).

Conclusions and Hypotheses
(Hypothesis 0: GH/IGF-1 signalling is involved and conserved in mammalian aging up to humans.)
Hypothesis 1: Inhibition of autophagy through IGF-1 antagonism may explain inconsistent lifespan data seen in mouse studies of the GH/IGF-1 pathway.
Hypothesis 2: Autophagy stimulation + IGF1R antagonism will increase lifespan to a larger extent than either of them alone.

1. J Gerontol A Biol Sci Med Sci. 2012 Jun;67(6):587-98. doi: 10.1093/gerona/gls115. Epub 2012 Apr 20.
Diverse roles of growth hormone and insulin-like growth factor-1 in mammalian aging: progress and controversies.
Sonntag WE, Csiszar A, deCabo R, Ferrucci L, Ungvari Z.

2. Somatotropic signaling: trade-offs between growth, reproductive development, and longevity.
Bartke A, Sun LY, Longo V.
Physiol Rev. 2013 Apr;93(2):571-98. doi: 10.1152/physrev.00006.2012. Review.

3. J Gerontol A Biol Sci Med Sci. 2013 May 16. [Epub ahead of print]
Young Little Mice Express a Premature Cardiovascular Aging Phenotype.
Reddy AK, Hartley CJ, Pham TT, Darlington G, Entman ML, Taffet GE.

4. Am J Physiol Heart Circ Physiol. 2008 Nov;295(5):H1882-94. doi: 10.1152/ajpheart.412.2008. Epub 2008 Aug 29.
Endothelial function and vascular oxidative stress in long-lived GH/IGF-deficient Ames dwarf mice.
Csiszar A, Labinskyy N, Perez V, Recchia FA, Podlutsky A, Mukhopadhyay P, Losonczy G, Pacher P, Austad SN, Bartke A, Ungvari Z.

5. J Gerontol A Biol Sci Med Sci. 2012 Jun;67(6):553-64. doi: 10.1093/gerona/glr197. Epub 2011 Nov 10.
Growth hormone and IGF-1 deficiency exacerbate high-fat diet-induced endothelial impairment in obese Lewis dwarf rats: implications for vascular aging.
Bailey-Downs LC, Sosnowska D, Toth P, Mitschelen M, Gautam T, Henthorn JC, Ballabh P, Koller A, Farley JA, Sonntag WE, Csiszar A, Ungvari Z.

6. Aging Cell. 2013 Jul 30. doi: 10.1111/acel.12145. [Epub ahead of print]
Longevity effect of IGF-1R+/- mutation depends on genetic background-specific receptor activation.
Xu J, Gontier G, Chaker Z, Lacube P, Dupont J, Holzenberger M.

7. 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.

8. Sasaki, T., et al. "Lifespan extension in the spontaneous dwarf rat and enhanced resistance to hyperoxia-induced mortality." Experimental gerontology (2013).

9. Hum Mol Genet. 2013 Jul 10. [Epub ahead of print]
IGF-1 receptor antagonism inhibits autophagy.
Renna M, Bento CF, Fleming A, Menzies FM, Siddiqi FH, Ravikumar B, Puri C, Garcia-Arencibia M, Sadiq O, Corrochano S, Carter S, Brown SD, Acevedo-Arozena A, Rubinsztein DC.

Samstag, 28. September 2013

Planetary boundaries: Basic Ecology for the Biogerontologist

Everyone who cares about healthy life extension should also have a basic understanding and an interest in planetary scale ecology. Our future must be sustainable or there is no future, that much we know.

A few papers on this topic:

Nature. 2009 Sep 24;461(7263):472-5. doi: 10.1038/461472a.
A safe operating space for humanity.
Rockström J, Steffen W, Noone K, Persson A, Chapin FS 3rd, Lambin EF, Lenton TM, Scheffer M, Folke C, Schellnhuber HJ, Nykvist B, de Wit CA, Hughes T, van der Leeuw S, Rodhe H, Sörlin S, Snyder PK, Costanza R, Svedin U, Falkenmark M, Karlberg L, Corell RW, Fabry VJ, Hansen J, Walker B, Liverman D, Richardson K, Crutzen P, Foley JA.

Rockström, Johan, et al. "Planetary boundaries: exploring the safe operating space for humanity." Ecology and society 14.2 (2009).

Science. 2012 Sep 21;337(6101):1458-9.
Ecology. A measurable planetary boundary for the biosphere.
Running SW.

Montag, 16. September 2013

What can you do to help? Crowdfunding!

See here for a project summary.

I am a little mouse and I want to live longer!
Life is precious. Health too. This is why communities of researchers and citizens dedicate our lives to discover new ways to gain additional years of healthy life.
As research progresses, more and more compounds are believed to be good to maintain health over long periods of time. But wouldn't that take decades of clinical trials to verify it? A key step is to do such a clinical trial... in mice : that is what we call a mouse lifespan test. Mouse lifespan tests are infrequent because of their length, their costs and the required environments; but it is crucially needed to continue adding years of healthy life.
Here, we step on the shoulders of giants : by contributing you can help us test a combination of drugs shown to extend healthy lifespan in mice. The largest life extension in mice so far resulted from a similar effort, where one mouse lived very close to 5 years (mice usually live 2-3 years)! The result should be key to to optimally search for additional years of healthy life.

Indirectly supported by the SENS Foundation -therefore tax-deductible in the USA, large enough sample size, rational polypill approach. And I assume that they will not make any obvious mistakes if they are advised by Stephen Spindler.

Funding fees of 4-9% (overhead). EDIT: Now I have found the correct number for non-profit fund raisers: "nonprofit are automatically granted a 25% discount on our platform fees..."

Animal husbandry? SPF/Hygienic Conditions? Lifespans of historical controls? What approach will be taken to exclude crypto-CR/weight-loss?

Overall, the project seems legit and methodologically sound, but I have only briefly reviewed the issue. I will try to follow the story as it develops.

Dienstag, 3. September 2013

Set up to fail: are scientists stupid?

Now that I have your attention, I am going to very briefly review several recent papers relevant to calorie restriction research.

Time and again so called studies of “calorie restriction” (CR) have failed to implement well-designed restriction, randomizing overweight subjects instead, making them no different from the thousands of weight-loss studies. But if we ever want to confirm or refute the efficacy of CR we need high quality data. Alas, rarely do we get such data. So, always remember that CR must be implemented in lean and healthy animals & humans.

Unsurprisingly, the CALERIE study did it again (1, 2). That is, failing to randomize lean people. They already once messed this up with their phase 1 pilot study, which was forgivable. At least we are getting close at a BMI of 25.1 (23.8, 26.4) and n=220, but it's not good enough. There are two reasons for this failure:

1. Americans are getting heavier and heavier and it is hard to find lean people,

1a. Therefore the maximum BMI they allowed was 28 , clearly overweight by most criteria, 
2. They excluded volunteers below a BMI of 22.

Their excuse for the latter is flimsy (2):

“The lower BMI limit was selected primarily for safety reasons. That is, the commonly used standard of underweight is BMI less than or equal to 18.5 kg/m2, and the lower limit provides an adequate buffer from this threshold as participants lose weight over the 2-year intervention.”

Oh my, oh my. And they do not even give a reference. I wonder why? Sarcasm aside, the reason is obvious, since the 18.5 BMI-cutoff is arbitrary. If you trust the epidemiology anything below some 22-25 is unhealthy (3). If you include other strands of evidence, i.e. controlled trials in animals including primates, short term trials in humans and (arguably, weaker, “cross-sectional”) epidemiology (see ref. 4. for a brief review) you must admit that we simply do not know and that the optimum might as well be at very low BMIs or rather very low calorie intakes.

Why then does a study trying to test whether low calorie diets are safe and healthy assume the conclusion that they are not?

Freitag, 16. August 2013

Another large screening effort (Spindler et al.)

Gerontologists are ingenious, and consequently the field has never suffered from a lack of theories. (Arking)
The first time I heard of a large ongoing rodent study, which was screening substances for life extension effects, must have been years ago. I did not know how large it was exactly at that time nor if it ever got completed, but finally official data is emerging (1):
[This was a] large[...] study using a total of 2400 mice in which groups of 36 treated mice and 297 control mice were used to maximize the number of treatment groups
That's 58 interventions á n=36. You may have noticed the large control group. According to Spindler this improves power, which means that 36 animals per intervention suffices - normally you would like 40-50. Either way, the study is the largest such screen today or at least in the same ballpark as NIA's ITP. As we speak, Spindler et al. must be preparing more data from his mega-study to be published. So far we got two papers. Keep in mind that he really knows how to carry out mouse studies with mean lifespans of almost 1000d (1, 2), so the data must be taken seriously.

In the first of the two published papers Spindler et al. (1) screened the following substances for life extension in mice: blueberry, cinnamon, green and black tea, pomegranate, sesame, curcumin (two doses), morin and combined [pycnogenol, quercetin, and taxifolin]
While many of these phytonutrients reportedly extend the life span of model organisms, we found no significant effect on the life span of male F1 hybrid mice, even though the dosages used reportedly produce defined therapeutic end points in mice. The compounds were fed beginning at 12 months of age. The control and treatment groups were iso-caloric with respect to one another. A 40% calorically restricted and other groups not reported here [such a tease!] did experience life span extension.

Sonntag, 4. August 2013

What is aging?

"Aging is defined as the progressive deterioration during the adult period that underlies an increasing vulnerability to challenges and a decreasing ability of the organism to survive." (adapted from Masoro & Austad, ref. 1)

And aging matters:

"Discovering the biological basis of aging is one of the greatest remaining challenges for science." (Linda Partridge, ref. 2)

1. Handbook of the Biology of Aging, Seventh Edition (Handbooks of Aging) by Edward J. Masoro and Steven N. Austad

2. Annu Rev Physiol. 2013;75:621-44. doi: 10.1146/annurev-physiol-030212-183712. Epub 2012 Nov 26.
Genetics of longevity in model organisms: debates and paradigm shifts.
Gems D, Partridge L.

Mittwoch, 17. Juli 2013

Things that do not work, studies that fail, where do we stand on n3 supplementation?

If you have not kept up with the literature, I suggest you read my two blog posts for an introduction.

Cliffnotes on Vegetarianism and Diet in general: The Big Picture
Oy vey! Fish oil fails AGAIN

I do now favor moderate ALA intakes over EPA/DHA (or fish) for the primary prevention of disease - but it's close. An appropriate combination of the two may also be acceptable.
Actual CVD outcomes are similar, both types of fatty acids are backed by rather weak evidence. The term thin gruel comes to mind. ALA has the "biogerontologic" and ecologic argument on its side. The former, is explained by Michael if you follow the link.

Recently, Hu, Mozaffarian & colleagues again published a very interesting meta-analysis re. CVD, which I take as supporting my view.
DESIGN: We searched multiple electronic databases through January 2012 for studies that reported the association between ALA (assessed as dietary intake or as a biomarker in blood or adipose tissue) and CVD risk in prospective and retrospective studies. We pooled the multivariate-adjusted RRs comparing the top with the bottom tertile of ALA using random-effects meta-analysis, which allowed for between-study heterogeneity.
RESULTS: Twenty-seven original studies were identified, including 251,049 individuals and 15,327 CVD events. The overall pooled RR was 0.86 (95% CI: 0.77, 0.97; I² = 71.3%). The association was significant in 13 comparisons that used dietary ALA as the exposure (pooled RR: 0.90; 95% CI: 0.81, 0.99; I² = 49.0%), with similar but nonsignificant trends in 17 comparisons in which ALA biomarkers were used as the exposure (pooled RR: 0.80; 95% CI: 0.63, 1.03; I² = 79.8%). An evaluation of mean participant age, study design (prospective compared with retrospective), exposure assessment (self-reported diet compared with biomarker), and outcome [fatal coronary heart disease (CHD), nonfatal CHD, total CHD, or stroke] showed that none were statistically significant sources of heterogeneity.
CONCLUSIONS: In observational studies, higher ALA exposure is associated with a moderately lower risk of CVD. The results were generally consistent for dietary and biomarker studies but were not statistically significant for biomarker studies. However, the high unexplained heterogeneity highlights the need for additional well-designed observational studies and large randomized clinical trials to evaluate the effects of ALA on CVD.
Restricted to dietary studies only, the pooled RR was 0.90 (95% CI: 0.81, 0.99; 11,277 events)…
Visual inspection of a funnel plot (see Supplemental Figure 1 under “Supplemental data” in the online issue) and Begg's test did not indicate significant publication bias (P = 0.13). A sensitivity analysis testing the influence of individual study on the results suggested that one study (35) had the largest influence; after this study was excluded (35), the pooled RR was slightly attenuated (0.91; 95% CI: 0.83, 0.99) compared with that from the main analysis.
Given concern that retrospective case-control studies may be limited by recall bias for dietary ALA…we conducted a sensitivity analysis excluding retrospective case-control studies (n = 5)…The pooled RR was modestly attenuated to 0.91 (95% CI: 0.84, 1.00; 14,617 events); however, the I2 value was also reduced from 71.3% to 45.1%
In the pooled dietary analysis, each 1-g/d increment of ALA intake was associated with a 10% lower risk of CHD death (RR: 0.90; 95% CI: 0.83, 0.99;
 Issues & future directions
dietary estimates of ALA consumption do not correlate strongly with biomarker concentrations (average correlation of 0.35 for adipose tissue and 0.24 for blood concentrations)…
endogenous conversion of ALA to EPA is limited (<10%) and generally much lower in men than in women (47, 48)…
Our findings highlight the need for an appropriately designed, randomized, placebo-controlled clinical trial to evaluate the effects of dietary ALA on incidence of CVD…
Lyon Diet Heart Study (57), 605 post-MI patients were randomly assigned to a Mediterranean diet, including margarine supplemented with ALA (1.1 g/d)…A trial in India of an Indo-Mediterranean ALA-rich diet among 1000 patients with established CHD found similar results over a 1-y follow-up (58), but the interventions were not blinded and the validity of results from this group of investigators has been questioned (59).
A larger double-blind, placebo-controlled trial among 4837 post-MI patients tested the effects on cardiovascular events of 400 mg EPA+DHA/d and/or 2 g ALA/d this study was underpowered to detect an effect on CHD death, with only 17% power to detect a 25% reduction

Unfortunately, no time to go into details.

1. Am J Clin Nutr. 2012 Dec;96(6):1262-73. doi: 10.3945/ajcn.112.044040. Epub 2012 Oct 17.
α-Linolenic acid and risk of cardiovascular disease: a systematic review and meta-analysis.
Pan A, Chen M, Chowdhury R, Wu JH, Sun Q, Campos H, Mozaffarian D, Hu FB.

Freitag, 5. Juli 2013

Hypothesis testing: maple syrup urine disease, mTOR, autophagy and premature aging

As the title says, I am speculating here.

Maple syrup disease is a rare disorder (> 1:100 000) affecting branched-chain amino acid (BCAA) catabolism. The parent molecules and their keto-acids accumulate leading, among other issues, to leucinosis, neurologic symptoms and death unless treated with a low BCAA diet. Blood levels of these amino acids remain elevated despite treatment as far as I know and this could suppress autophagy via mTOR, I speculate.

The BCAAs, especially leucine, are recognized as potent metabolic regulators of protein synthesis. This effect is mediated through mammalian target of rapamycin (mTOR)-dependent and mTOR-independent pathways (Kimball and Jefferson 2006). In the context of high BCAA levels experienced in MSUD, the effect on protein turnover has not been extensively studied.

Feel free to steal my idea, but do credit me and let me co-author.

If your urine smells funny, you can help science. Well, almost.

Donnerstag, 27. Juni 2013

A caustic reminder of the status quo: food and drink aimed for the kill

You all know the ultra-small bottles of alcohol as well as other miscellaneous items sold right next to the checkout counter. You do if you live in a country that allows such a display, for example Austria.
It is common knowledge that these items are aimed at people with low impulse control and children in particular. You do not need much knowledge of psychology to know this is true. And it works, that's why it's done.

Now, who buys that booze? Certainly not me. Nor have I ever heard or seen anyone of my friends buy these and we certainly know how to get drunk (from time to time). On the other hand, I have seen poor, ragged working class fellas' and "typical" alcoholics buy those**. So the whole scheme is most definitely aimed at alcoholics, those with the least control. Since the small bottles are always in sight and easy to hide and stash away, who else would succumb? (And to some extent it is aimed at teenagers, but I believe the laws have gotten strict enough to close this loophole)

These companies are prying on the weakest of the weak, the sick and the poor. Classy. No, really, people responsible for this, you are scum.

Literally, their bottom lines depend on killing people, because that is what alcohol does to alcoholics. It's the most pernicious kind of rent seeking (broadly, the extraction of profit at cost to others).

On a similar note
Obesity is a disease(-like) condition (1) that can be beyond a person's control. Many of those afflicted suffer from decreased impulse control or increased orexigenic drive (e.g. polymorphisms of hypothalamic effectors like NPY*) or reduced energy consumption via thermogenesis.

Companies abuse and exploit these sick people by providing ultra-easy, fast access to extremely calorie-dense and unhealthy foods (2). How could they not know that they are killing them?

Visibility and accessibility is a huge factor. I know that it is for me, and I normally do not have a problem to stay lean, but when I am unhappy or just see certain sweets/foods or both, sometimes an irresistible drive overwhelms my actual intentions of not buying them, or of buying something entirely different or a healthier alternative.
Anecdotally, this is true for most everyone else, at least to some extent. Unfortunately, right now I have no time to search the literature to confirm my suspicion.

I demand an end to this practice, as well as plain labeling, warning signs (for alcohol & probably other "ultra-processed foods"), a ban of alcohol for minors, etc.

(1) "Amid heated debate, AMA declares obesity a disease"

(2)  Lancet. 2013 Feb 11. pii: S0140-6736(12)62089-3. doi: 10.1016/S0140-6736(12)62089-3. [Epub ahead of print]
Profits and pandemics: prevention of harmful effects of tobacco, alcohol, and ultra-processed food and drink industries.
Moodie R, Stuckler D, Monteiro C, Sheron N, Neal B, Thamarangsi T, Lincoln P, Casswell S; on behalf of The Lancet NCD Action Group.

*just giving a speculative example

**edit: I forgot to add, I concede that regular, "normal" people also buy these, but the above reasoning still applies

Freitag, 14. Juni 2013

The Alzheimer's pipeline: who fails next?

There are fields of study which require deep pockets, nerves of steel and a lot of serendipity. AD is one of them. As is HIV vaccination or the search for an HIV cure. As are several cancers e.g. pancreatic.
...between 1998 and 2011...drug developers have scrapped or halted development of 101 meds for the complex disorder and brought to market only three treatments for symptoms [!] of the disease...
Read more: Pharma counts just 3 Alzheimer's drug wins in 13 years (101 losses!) - FierceBiotech

The bad luck continues:
The brutal drumbeat of Alzheimer's clinical failure continues at Eli Lilly. After the Phase III failure of their gamma-secretase inhibitor semagacestat, and a delusional attempt to pretend that the anti-amyloid antibody solanezumab succeeded, now comes word that the company has halted studies of a beta-secretase inhibitor.
This one wasn't for efficacy, but for tox...

Several drugs are in the pipeline. This one's quite interesting:
In a Phase II clinical trial of 16 patients, Gammagard effectively shut down the progression of Alzheimer's with the optimal dosage. Patients who received a placebo or did not receive the optimal dosage continued to decline.
So far, this seems to be the most promising medication in the Alzheimer's pipeline, consistently stalling the progression of the disease for four years in a small clinical trial. Baxter's goal for the medication is to maintain high levels of functionality during the early stages of the disease. Though few patients are better than no patients, Phase III data are due in the first half next year and that, as tradition demonstrates, is where prospective Alzheimer's medications go to die.
Read more: The Alzheimer's pipeline: What's next? - FierceBiotech

Samstag, 8. Juni 2013

Understanding PREDIMED and the Mediterranean diet: heart-healthy or hype?

ResearchBlogging.orgI am going to discuss the failings of the PREDIMED study, real and imagined. I will do this in a Question & Answer style. Several questions are inspired by and NEJM comments and even statements by the low fat "gurus", Essselstyn, Ornish, McDougall or Pritikin. It is no surprise they are up in arms after the study has been published. It threatens their livelihood.

Finally, I get to talk about biogerontology, diet and health in one post. For once, I may be doing justice to the blog name. I will also talk about study ethics, particularly the balance of harms and benefits you may expose participants to. In jargon: clinical equipoise.

First, a summary of the study and its results:

N Engl J Med. 2013 Apr 4;368(14):1279-90. doi: 10.1056/NEJMoa1200303. Epub 2013 Feb 25.
Primary prevention of cardiovascular disease with a Mediterranean diet.
Estruch et al.

BACKGROUND: Observational cohort studies and a secondary prevention trial have shown an inverse association between adherence to the Mediterranean diet and cardiovascular risk. We conducted a randomized trial of this diet pattern for the primary prevention of cardiovascular events.
METHODS: In a multicenter trial in Spain, we randomly assigned participants who were at high cardiovascular risk, but with no cardiovascular disease at enrollment, to one of three diets: a Mediterranean diet supplemented with extra-virgin olive oil [MED/EVOO], a Mediterranean diet [MED/nuts] supplemented with mixed nuts, or a control diet (advice to reduce dietary fat). Participants received quarterly individual and group educational sessions and, depending on group assignment, free provision of extra-virgin olive oil, mixed nuts, or small nonfood gifts. The primary end point was the rate of major cardiovascular events (myocardial infarction, stroke, or death from cardiovascular causes). On the basis of the results of an interim analysis, the trial was stopped after a median follow-up of 4.8 years.
RESULTS: A total of 7447 persons were enrolled (age range, 55 to 80 years); 57% were women. The two Mediterranean-diet groups had good adherence to the intervention, according to self-reported intake and biomarker analyses. A primary end-point event occurred in 288 participants. The multivariable-adjusted hazard ratios were 0.70 (95% confidence interval [CI], 0.54 to 0.92) and 0.72 (95% CI, 0.54 to 0.96) for the group assigned to a Mediterranean diet with extra-virgin olive oil (96 events) and the group assigned to a Mediterranean diet with nuts (83 events), respectively, versus the control group (109 events). No diet-related adverse effects were reported.
CONCLUSIONS: Among persons at high cardiovascular risk, a Mediterranean diet supplemented with extra-virgin olive oil or nuts reduced the incidence of major cardiovascular events. (Funded by the Spanish government's Instituto de Salud Carlos III and others; number, ISRCTN35739639.).

I believe the study to be well-designed - despite some short comings - and I do consider it pretty definitive results in favor of the Mediterranean diet and olive oil in primary prevention. Now it is time to act for governments!

Samstag, 25. Mai 2013

Recommended reading: CR, growth hormones

I will try to comment on both these research areas in the future.

CR in Nonhuman Primates: A Muddle for Monkeys, Men, and Mimetics
(for the advanced reader)
Calorie restriction (CR) is the most well-characterized and arguably the most robust intervention into the degenerative aging process in experimental animals. Biomedical gerontologists have therefore proposed "CR mimetics" — pharmacological modulators of the signaling pathways underlying the age-retarding effects of CR — as a route to the development of interventions against the diseases and disabilities of aging. The viability of this strategy necessarily depends upon the human translatability of CR. Lifespan studies in human CR being impracticable, studies in longevous nonhuman primates were initiated at the Wisconsin National Primate Research Center (WNPRC) and at the National Institute on Aging (NIA) to give strong surrogate evidence on the issue. Disconcertingly, the two studies have come to opposing outcomes, with CR extending life relative to controls at WNPRC and not doing so at NIA. This article explores several possible interpretations of the discrepancy, focusing on two with the greatest explanatory power. Both interpretations begin from the premise that the WNPRC control animals were overfed, and that the "CR" animals in that study — as well as the control animals at NIA — were healthier by comparison for the trivial reason that they were not suffering the metabolic consequences of obesity. In the "diminishing returns" hypothesis, there was no increase in lifespan in NIA CR animals relative to nonobese controls because there is nothing to be gained from reducing food intake beyond what is needed to remain reasonably lean; thus, CR is not translatable to human or nonhuman primates, and CR mimetics cannot even in principle be created. In the "dose-response" hypothesis, the NIA's null result is interpreted as resulting from an inadequate and progressively declining degree of CR relative to the healthy baseline of the ad libitum group; this interpretation is supported with data on food motivation, body composition, and the metabolic responses to CR, and with reference to the effects of CR on the latter parameters in laboratory rodents and in humans. While the "dose-response" hypothesis holds out hope for the human translatability of CR (and thus, the theoretical possibility of true CR mimetics), there remain inherent and likely insurmountable barriers to the development of CR mimetics as effective interventions for human use, and thus researchers are urged to redirect their efforts toward rejuvenation biotechnology for the rapid and maximally effective development of new therapies to prevent and cure the diseases and disabilities of aging.

Here, a very understandable and concise review on growth hormones and aging:
A recent report of virtually complete protection from diabetes and cancer in a population of people with hereditary dwarfism revived interest in elucidating the relationships between growth, adult body size, age-related disease and longevity. In many species, smaller individuals outlive those that are larger and a similar relationship was shown in studies of various human populations. Adult body size is strongly dependent on the actions of growth hormone (GH) and the absence of GH or GH receptor in mice leads to a remarkable extension of longevity. Many mechanisms that may account for, or contribute to, this association have been identified. It is suggested that modest modifications of the diet at different ages may extend human healthspan and lifespan by reducing levels of hormones that stimulate growth.
Gerontology. 2012;58(4):337-43. doi: 10.1159/000335166. Epub 2012 Jan 18.
Healthy aging: is smaller better? - a mini-review. Bartke A.

Donnerstag, 16. Mai 2013

Oy vey! Fish oil fails AGAIN

N Engl J Med. 2013 May 9;368(19):1800-8. doi: 10.1056/NEJMoa1205409.
n-3 fatty acids in patients with multiple cardiovascular risk factors.
Risk and Prevention Study Collaborative Group, Roncaglioni MC, Tombesi M, Avanzini F, Barlera S, Caimi V, Longoni P, Marzona I, Milani V, Silletta MG, Tognoni G, Marchioli R.

BACKGROUND: Trials have shown a beneficial effect of n-3 polyunsaturated fatty acids in patients with a previous myocardial infarction or heart failure. We evaluated the potential benefit of such therapy in patients with multiple cardiovascular risk factors or atherosclerotic vascular disease who had not had a myocardial infarction. [=primary prevention]
METHODS: In this double-blind, placebo-controlled clinical trial, we enrolled a cohort of patients who were followed by a network of 860 general practitioners in Italy. Eligible patients were men and women with multiple cardiovascular risk factors or atherosclerotic vascular disease but not myocardial infarction. Patients were randomly assigned to n-3 fatty acids (1 g daily) or placebo (olive oil). The initially specified primary end point was the cumulative rate of death, nonfatal myocardial infarction, and nonfatal stroke. At 1 year, after the event rate was found to be lower than anticipated, the primary end point was revised as time to death from cardiovascular causes or admission to the hospital for cardiovascular causes.
RESULTS: Of the 12,513 patients enrolled, 6244 were randomly assigned to n-3 fatty acids and 6269 to placebo. With a median of 5 years of follow-up, the primary end point occurred in 1478 of 12,505 patients included in the analysis (11.8%), of whom 733 of 6239 (11.7%) had received n-3 fatty acids and 745 of 6266 (11.9%) had received placebo (adjusted hazard ratio with n-3 fatty acids, 0.97; 95% confidence interval, 0.88 to 1.08; P=0.58). The same null results were observed for all the secondary end points.
CONCLUSIONS: In a large general-practice cohort of patients with multiple cardiovascular risk factors, daily treatment with n-3 fatty acids did not reduce cardiovascular mortality and morbidity. (Funded by Società Prodotti Antibiotici and others; number, NCT00317707.).
A reminder:
Arch Intern Med. 2012 May 14;172(9):686-94. doi: 10.1001/archinternmed.2012.262.
Efficacy of omega-3 fatty acid supplements (eicosapentaenoic acid and docosahexaenoic acid) in the secondary prevention of cardiovascular disease: a meta-analysis of randomized, double-blind, placebo-controlled trials.
Kwak SM, Myung SK, Lee YJ, Seo HG; Korean Meta-analysis Study Group.

"Our meta-analysis showed insufficient evidence of a secondary preventive effect of omega-3 fatty acid supplements against overall cardiovascular events among patients with a history of cardiovascular disease."

The Good: 
Other large studies are ongoing e.g. VITamin D and OmegA-3 TriaL (VITAL). If there is an effect we may be able to tease it out, but I doubt it at this point.

Freitag, 3. Mai 2013

"DEFCON 20 - Hacking Humanity: Human Augmentation and You" (video)

Here are my notes & comments:
  • it's a DEF CON 2012 talk: light-hearted fun combined with more serious ideas
  • I am feeling nostalgic since I used to be very interested in hacking.
  • I noticed that hackers are still sexist/use sexist language
  • All sorts of medical devices to mitigate health problems exist, from cardiac pacemakers to cochlear implants. In that sense, human enhancement has existed for decades or centuries. Subdermal implants are relatively advanced and it would be nice if they could run on endogenous glucose (already done in the lab).
    However, medical devices are always usually inferior to the real deal. Oscar Pistorius' leg prosthetics may trump flesh and bone.
  • What are the ethics of prosthetics if they are better than their natural counterparts? In the most brutal and simplified case: yes, people will cut off their limbs to gain an edge in sports.
  • nootropics, etc.
  • mainstreaming of this concept is important
  • early technology, implants can be very dangerous (RFID chips caused sarcomas according to the video)
  • They recommend "humanity plus" and the "singularity institute" but left out and; I am not very familiar with the first two and cannot vouch for them. The problem is there are serious thinkers considering human enhancement, but also embarrassing figures like Ray Kurzweil.

Offtopic: The Pistorius Ban
I have NOT followed this in detail, so take my reasoning with a grain of salt. I have wondered about the ethics involved since I read about this case. So why do I believe the ban was wrong and damaging to human augmentation?
How do you become a top athlete? You do it by training (internal factor) and by winning the genetic lottery (external factors like biomechanics). Since the latter is neither just nor takes any skill, it is something we would like to avoid. This is the concept of equal opportunity. While doping, for instance, may act as an equalizer* consistent with "equal opportunity", it violates another principle: safety & free choice. If doping were legal athletes would feel pressured to risk their lives to perform well, even more so than they do now.

In contrast supplementation with creatine and caffeine is entirely "unnatural", probably effective in several sports, equalizing* and tournament legal because it is safe.

I fail to see how consciously choosing artificial limbs with superior biomechanics is more unethical than winning the genetic lottery and choosing the right parents.
Every athlete who can safely increase their performance should be allowed to do so. (That is why amputation could be considered doping in this case.)

*it has been speculated that doping disproportionately helps those with lower performance

Montag, 29. April 2013

Cliffnotes on Vegetarianism and Diet in general: The Big Picture

I know how unbelievably hard it is not just to parse research, since there is so much of it, but also to understand its implications. Over time I have gotten better at this, but it does take practice. Here, I will try to put current research into context and given how popular paleo-style diets are, I will also address this issue. I think a pattern is emerging:

Ramsden et al. 2013 (2) extended their older meta-analysis that found n6 polyunsaturated fats (PUFA) to be at best health-neutral and possibly harmful. Yes, this seems to be a "win" for the paleo-diet in a sense, but better scientific arguments against excessive n6 PUFA intakes existed for a long time. For instance, a simple argument based on oxidative stress.

Notably, the next few studies are inconsistent with the "paleo-hypothesis":

The huge PREDIMED trial (3) showed that the addition of two plant foods: tree nuts and even more so virgin olive oil (EVOO) is beneficial in primary prevention; laying the foundation for Mediterranean-style moderate-to-high-fat vegetarianism. Consistent with Ramsden et al. EVOO performed slightly better!

(As a side note: There is still no good research linking moderate fructose intakes to bad health outcomes. )

Huang et al. 2012 (1) re-confirmed an older meta-analysis that found modestly reduced mortality in vegetarians.

Another research group  found a novel mechanism which may explain how and why meat is harmful to health. (4) This year the group extended their research on trimethylamines (TMA or TMAO) that gut microbiota could produce from meat constituents.

The only reasonable conclusion
Three very high impact papers (1-3) have produced concordant results. If we combine the data we are able to confirm that Mediterranean-style (3) vegetarianism (1) that emphasizes MUFA from olive oil, and to some extent "balanced" n3 and n6 from nuts over saturated fats and n6 PUFA (2), produces the best health outcomes.

This dietary recommendation rests on a sound foundation of basic (e.g. ref. 4) and translational research when compared with the classical low-fat food pyramids. Evidently, some questions need to be answered but this should not affect the above recommendation.

Just to be clear: I do endorse flexible vegetarianism. In the end it is all about your average long term intake.

(1) Ann Nutr Metab. 2012;60(4):233-40. doi: 10.1159/000337301. Epub 2012 Jun 1.
Cardiovascular disease mortality and cancer incidence in vegetarians: a meta-analysis and systematic review.
Huang T, Yang B, Zheng J, Li G, Wahlqvist ML, Li D.

*(2) BMJ. 2013 Feb 4;346:e8707. doi: 10.1136/bmj.e8707.
Use of dietary linoleic acid for secondary prevention of coronary heart disease and death: evaluation of recovered data from the Sydney Diet Heart Study and updated meta-analysis.
Ramsden CE, Zamora D, Leelarthaepin B, Majchrzak-Hong SF, Faurot KR, Suchindran CM, Ringel A, Davis JM, Hibbeln JR.

(3)  Estruch R, Ros E, Salas-Salvadó J, et al. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med 2013; DOI: 10.1056/NEJMoa200303.

*(4) Nat Med. 2013 Apr 7. doi: 10.1038/nm.3145. [Epub ahead of print]
Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis.
Koeth RA, Wang Z, Levison BS, Buffa JA, Org E, Sheehy BT, Britt EB, Fu X, Wu Y, Li L, Smith JD, Didonato JA, Chen J, Li H, Wu GD, Lewis JD, Warrier M, Brown JM, Krauss RM, Tang WH, Bushman FD, Lusis AJ, Hazen SL.

*papers I have not yet read in full, although, I am familiar with earlier work. Hope I can blog on this in the future

Samstag, 27. April 2013

The Plot Thickens

Polyunsaturated fatty acids in and of themselves may be unhealthy. Evidence to that effect has been trickling in for some time now. I hope I will be able to read the paper soon and then comment on it.

BMJ. 2013 Feb 4;346:e8707. doi: 10.1136/bmj.e8707.
Use of dietary linoleic acid for secondary prevention of coronary heart disease and death: evaluation of recovered data from the Sydney Diet Heart Study and updated meta-analysis.
Ramsden CE, Zamora D, Leelarthaepin B, Majchrzak-Hong SF, Faurot KR, Suchindran CM, Ringel A, Davis JM, Hibbeln JR.

To evaluate the effectiveness of replacing dietary saturated fat with omega 6 linoleic acid, for the secondary prevention of coronary heart disease and death.

Evaluation of recovered data from the Sydney Diet Heart Study, a single blinded, parallel group, randomized controlled trial conducted in 1966-73; and an updated meta-analysis including these previously missing data.

Ambulatory, coronary care clinic in Sydney, Australia.

458 men aged 30-59 years with a recent coronary event.

Replacement of dietary saturated fats (from animal fats, common margarines, and shortenings) with omega 6 linoleic acid (from safflower oil and safflower oil polyunsaturated margarine). Controls received no specific dietary instruction or study foods. All non-dietary aspects were designed to be equivalent in both groups.

All cause mortality (primary outcome), cardiovascular mortality, and mortality from coronary heart disease (secondary outcomes). We used an intention to treat, survival analysis approach to compare mortality outcomes by group.

The intervention group (n=221) had higher rates of death than controls (n=237) (all cause 17.6% v 11.8%, hazard ratio 1.62 (95% confidence interval 1.00 to 2.64), P=0.05; cardiovascular disease 17.2% v 11.0%, 1.70 (1.03 to 2.80), P=0.04; coronary heart disease 16.3% v 10.1%, 1.74 (1.04 to 2.92), P=0.04). Inclusion of these recovered data in an updated meta-analysis of linoleic acid intervention trials showed non-significant trends toward increased risks of death from coronary heart disease (hazard ratio 1.33 (0.99 to 1.79); P=0.06) and cardiovascular disease (1.27 (0.98 to 1.65); P=0.07).

Advice to substitute polyunsaturated fats for saturated fats is a key component of worldwide dietary guidelines for coronary heart disease risk reduction. However, clinical benefits of the most abundant polyunsaturated fatty acid, omega 6 linoleic acid, have not been established. In this cohort, substituting dietary linoleic acid in place of saturated fats increased the rates of death from all causes, coronary heart disease, and cardiovascular disease. An updated meta-analysis of linoleic acid intervention trials showed no evidence of cardiovascular benefit. These findings could have important implications for worldwide dietary advice to substitute omega 6 linoleic acid, or polyunsaturated fats in general, for saturated fats.

Clinical trials NCT01621087.

Samstag, 13. April 2013

The Hypothalamus and Aging

The hypothalamus regulates lots of things including satiety (esp. lateral and ventromedial hypothalamus), temperature and many hormones relevant to aging.

Seriously, why has no one performed these studies? At least not to my knowledge:
This review compares outcomes of lesions in the VMN, DMN [ventro- and dorsomedial nucleus], and lateral hypothalamic area (LHA) for relevance to aging. To establish a relationship between these anatomic areas of the hypothalamus and aging, it is concluded that the VMN, DMN, and LHA lesions should be examined for impact on longevity and compared with data obtained from simultaneously studied intact ad-lib-fed and 40% calorie-restricted animals. Lesioned animals also should be rigorously studied for neurotransmitters (e.g., neuropeptide Y, beta-endorphin, serotonin, corticotropin-releasing factor, and galanin), and for behavioral changes consistent with aging, for accumulation of specific tissue lipofuscin and amyloid that are associated with normal aging and for other age-dependent findings, such as incidence of tumors and cataract.

Physiol Behav. 1996 Mar;59(3):523-36.
Aging and the hypothalamus: research perspectives.
Bernardis LL, Davis PJ.

Montag, 8. April 2013

Fructose: friend or foe? Preliminary findings.
This discussion has been going on for quite some time and it is certainly not limited to the lay press and lay population. I have always been interested in double checking pop-sci claims, in this case the "evil fructose" meme.

First, I would like to emphasize that the available evidence does not change the basic Public Health Message: Yes, you should still eat more fruits unless you are already getting more than five servings/day. In that case you probably want to get more vegetables or olive oil, since a varied, plant-based Mediterranean-style diet remains the best option for health.

On to the hard science:

As of today, and as far as primary prevention is concerned, the studies I want to discuss (1-4) are only relevant for "dietary perfectionists", researchers and interested laypeople. The data is so weak and preliminary, I already feel like I am jumping the gun with my conclusions based on my ongoing, but superficial review of the data. Nevertheless I feel like sharing my hypothesis.

Reasonable fructose intakes (<60g/d) may be beneficial for cardiometabolic risk factors summa summarum (1, 2) or at the very least neutral. It has been speculated that catalytic fructose doses, below approx. 10g, free up intracellular glucokinase ("hexokinase") thereby increasing glycolytic flux. This could lower blood glucose after meals.

I am still unclear on longterm fructation vs. glycation, and their impact on aging and health. Instead I would like to highlight a different issue. Fructose and pancreatic cancer (3). Dr. "ORAC" has explained the basics if you long for an accessible review.

Mittwoch, 20. März 2013

The "paleolithic" diet

The idea that a diet containing fewer evolutionary novel foods (esp. grains and dairy) might be more healthy in some regards, always has been a plausible working hypothesis. A hypothesis. And perhaps a decent precautionary principle. So the "paleo hypothesis" always needed to be confirmed by interventional trials and epidemiology.

However, only few of its predictions have turned out true or useful, but attribution is difficult. Is the useful, but sometimes wholly inaccurate, rule of thumb "don't eat too much processed foods" an achievement of the paleolithic hypothesis? The putative dairy-IGF1-mTOR-acne/disease link? Does the latter even matter for primary prevention if we consider the benefits of low fat dairy? (my speculative answer: not at the population level, but preferring yogurt and not overdoing it with dairy might be prudent.)

I want to highlight some issues with the paleo-diet, based on recent articles I have read:

First, we do not know what our ancestors, early h. sapiens and before that, actually ate in much detail. Current evidence suggests that most of our ancestors were indeed omnivores, certainly never pure carnivores. This contradicts your typical Atkins-esque claim of a diet very high in meat, or an ultra-high fat diet.

Second, also evidence from archeology, a recent paper found atherosclerosis in mummies of both hunter-gatherers and farmers (n=137). This has been discussed on

...a study published a week ago online in The Lancet by Prof. Randall C. Thompson of Saint Luke’s Mid America Heart Institute and an international team of investigators entitled Atherosclerosis across 4000 years of human history: the Horus study of four ancient populations...
As is noted in Thompson’s article, ancient Egyptians and Peruvians were agricultural cultures with farms and domesticated animals, Ancestral Puebloans were forager-farmers, and the Unangans were hunter-gatherers without agriculture. Indeed, the Peruvians and Ancestral Puebloans predated the written word and were thus prehistoric cultures.

Third, hard evidence. I have written about vegetarianism before. It's solid. I also reviewed the data on whole grains and found little evidence of harm, certainly some benefit, particularly with non-rice, non-wheat whole-grains. The diet best supported by controlled trials (RCTs) and other data remains the "Mediterranean" diet.

Obviously, this only applies most of the time (primary prevention for the general population). Grains might be less healthy than legumes and oat bran better than whole grains, for instance. If you are gluten intolerant or want to try an experimental diet as an additional treatment for acne, you will deviate from general recommendations. Etc.

Alas, no time to get into the details.

Mittwoch, 13. Februar 2013

Finally, some good news from pharma!

Finally, some good news from pharma, as per Derek Lowe.
Thanks to Lisa Jarvis at C&E News, here's a chart (PDF) of the 39 drugs approved last year by the FDA. Last year was a good year, by almost any measure. The question as we go on will be whether this was a one-time spike, or the start of a long-awaited turnaround. If the latter, I think it will be as much of a regulatory phenomenon as a scientific one (faster reviews, etc.)
There has been concern over declining approvals for new drugs, at least for 2012, this trend was not confirmed: "Last year, the Food & Drug Administration approved 39 new products, a 16-year high."

A quick google revealed this article with approval numbers for the years past.

Dienstag, 22. Januar 2013

Embrace death... or not

The idea of death can reduce us humans to sputtering and mumbling. I know this from experience. Therefore the author of this article does not need to be embarrassed by being so horribly and totally wrong about almost everything he said.
At times death is so scary to people that they embrace it as something useful and desirable. Or they elevate quality of life on a golden pedestal as if quantity didn't matter at all. This form of cognitive dissonance is sometimes called "deathism".
I will take this opportunity to explain why living a very long and healthy life is worthwhile:

It starts with a reasonable objection: "...trying to link what is really a very small part of life to mortality. [is problematic or wrong]"
Yes, but that's a known issue in nutrition science. We use corroborative evidence and studies of dietary patterns to avoid bias.

All-cause mortality is the best (or at least it's exceptionally useful) and hardest endpoint in epidemiology, but the author does not like it, because it has something to do with dying:
You are going to die...
Everyone has their own motivations for pursuing a lifestyle that has more fitness and better nutrition in it. But one prevailing theme, not usually explicitly stated, is (and I'm going to make up a word here), "life maximization"...
Here's the thing: You don't know when you're going to die... 
Here's my main beef with long-term correlational mortality studies: The underlying assumption is that these events are not only bad, but preventable. I'm not talking about heart attack studies or stroke studies in which the subjects survive, but the ones where the subjects have heart attacks, or strokes and DIE. Or worse yet, the baffling, "All-cause mortality" variable. Somehow removing or adding a single food item or group increases or decreases ALL-CAUSE mortality (i.e. your chances of dying--from anything, including, but not limited to, being struck by a falling piece of space debris.)
So avoiding food that kills you is somehow supposed not to reduce your chance of dying during a given time-frame? How is that? (We can even show that food alters all-cause mortality during a given time-frame  in the lab!) Conceptually, this is similar to lifespan and we know for a fact that it can be increased. Since some 80% of people die due to CVD and cancer it is obvious why we can ignore meteorites and black holes as a first approximation.
All-cause mortality can tell us for instance if cancer risk offsets CVD benefits of a treatment/life-style choice, or in a real world example, perhaps, if death from bleeding offsets the cancer and heart benefits of aspirin.

Sonntag, 13. Januar 2013

HPV Vaccination: Just Do It!

Why am I writing on this topic and why now? Already in 2012, I have briefly reviewed the evidence on HPV to be able to make evidence-based recommendations. While at the same time our national insurance was cementing its anti-intellectual reputation by opting out of covering even a fraction of the vaccine cost - against international recommendations (*). Now that I am taking a class on DNA viruses I decided to take up the topic again.The following article is both a response to Medizin-Transparent (German, quoted in blue) and also a Question & Answer session on HPV. Although, I quoted them in German, everything of importance for the international reader is in English.

* alternatively the issue may be political, several of our parties despise things like Sex Ed

Why does Austrian insurance (incl. their "experts") ignore expert consensus and why do well meaning skeptics promote the status quo?
There is now consensus in favour of a very broad vaccination program. In 2012, both the "Advisory Committee on Immunization Practices of the Centers for Disease Control " and "The American Academy of Pediatrics" agreed on as much, the latter recommends (2):

"All girls and women 13 through 26 years of age who have not been immunized previously or have not completed the full vaccine series should complete the series." [all quotes emphasis mine]

"All boys and men 13 through 21 years of age who have not been immunized previously or have not completed the full vaccine series should receive HPV4 vaccine."

Vaccinating older males is also effective, but cost-effectiveness is unclear:
"Men 22 through 26 years of age who have not been immunized previously or have not completed the full vaccine series may receive HPV4 vaccine. Cost-efficacy models do not justify a stronger recommendation in this age group."