Samstag, 28. Oktober 2017

The need for a heroic effort?

If there is one thing I am particularly proud of, it is providing insights into HOW to carry out research. Whether my suggestions are useful or not, you can be the judge. Overall, this topic is related to the problem of Eroom's law in drug discovery. The latter claims that the research pace in the drug industry has slowed down, or research is becoming more and more expensive. The authors go on to speculate that the regulatory climate is one of several reasons. I will go on to suggest that the regulatory framework is even more inadequate to deal with the science of biogerontology.

Methods to accelerate research progress in biogerontology - a recap from my blog
1. We need to take Tauber's paradox and preclinical data seriously when designing human studies if we want to help our aging population. On the one hand, there is a political reason to play it slow, because any failure may lead to bad publicity and public backlash. However, from a purely intellectual point of view there is every reason to be aggressive about aging research because the risk benefit/ratio is so much better for aging interventions than any other drug. Our conservative approach has led to large studies using an inferior anti-aging agent, Metformin, and almost no useful human research on Rapamycin and derivatives (1). This fear of side-effects has also ruined human calorie-restriction research because "classic harm" and "biogerontologic benefit" were weighed incorrectly (2).

2. We have to re-consider how we carry out animal research. Regulatory bodies could leverage pre-clinical testing as a shortcut to mass screening of potential anti-aging compounds (3).

Donnerstag, 14. September 2017

Study dump: food groups, vitamin K, sleep, nuts, B12 and phosphate

In the best case we should use epidemiology and nutrition science to guide public health policy through flexible incentives and taxes. Let's be prepared when the time comes and we can make that change real. One day, maybe by sheer luck, some politician will listen to good science. Study dump based on interesting abstracts:

Food group centric view. The author Schwingshackl works or used to work at our Viennese nutrition department. This study is a thing of beauty for everyone interested in epidemiology and our dear friends who suffer from orthorexia and will outlive us all.
A 56% reduction in relative risk for mortality with optimal intakes? Interestingly we should (or could?) see a 75% reduction by very naive multiplication (RR estimated at nadir in Figure 2). At a quick glance I do not see if the authors truly prove diminishing returns or not, though.:

With increasing intake (for each daily serving) of whole grains (RR: 0.92; 95% CI: 0.89, 0.95), vegetables (RR: 0.96; 95% CI: 0.95, 0.98), fruits (RR: 0.94; 95% CI: 0.92, 0.97), nuts (RR: 0.76; 95% CI: 0.69, 0.84), and fish (RR: 0.93; 95% CI: 0.88, 0.98), the risk of all-cause mortality decreased; higher intake of red meat (RR: 1.10; 95% CI: 1.04, 1.18) and processed meat (RR: 1.23; 95% CI: 1.12, 1.36) was associated with an increased risk of all-cause mortality in a linear dose-response meta-analysis. A clear indication of nonlinearity was seen for the relations between vegetables, fruits, nuts, and dairy and all-cause mortality. Optimal consumption of risk-decreasing foods results in [ONLY] 56% reduction of all-cause mortality, whereas consumption of risk-increasing foods is associated with a 2-fold increased risk of all-cause mortality.
Optimal consumption (the smallest serving with significant results and no further substantial change in risk or no further data for larger amounts) of risk-decreasing foods [3 servings whole grains/d (RR = 0.79), 3 servings vegetables/d (RR = 0.89), 3 servings fruit/d (RR = 0.90), 1 serving nuts/d (RR = 0.85), 1 serving legumes/d (RR = 0.90), and 2 servings fish/d (RR = 0.90)] results in a 56% reduction 
Could be a problem:  "We rated the quality of meta-evidence for the 12 food groups. The NutriGrade meta-evidence rating was “very low” for eggs; “low” for refined grains, vegetables, fruits, and SSBs; “moderate” for nuts, legumes, dairy, fish, red meat, and processed meat; and “high” for whole grains"

Schwingshackl, Lukas, et al. "Food groups and risk of all-cause mortality: a systematic review and meta-analysis of prospective studies." The American Journal of Clinical Nutrition 105.6 (2017): 1462-1473.

Mittwoch, 23. August 2017

In defense of being underweight

It is common wisdom to claim that underweight people are at increased risk of death and disease. Epidemiologists, doctors and nutritionists would tend to favour this position but certainly not biogerontologists (1) because weight-loss is very similar to calorie restriction (CR), which is one of the most robust life-extending interventions known. Now the question is which science best informs health policy in an aging, obese world and were do these differences in opinion come from? This review published in 2014 by Luigi Fontana, an expert in human CR, and the distinguished epidemiologist Frank Hu is worth a read as primer (1).

First of all, weight-loss, low bodyweight, low adiposity and CR are not one and the same. CR is, however, associated with initial weight-loss, low bodyweight and adiposity. Mice can be obese but still in a CR-state because they lost weight from their individual ad libitum set point. To define our working hypothesis I favour the idea that low body-weight in healthy people is suggestive of a CR-like state (i.e. mild CR). Being thin is a similar phenotype to CR and it seems like a plausible idea.

As is often the case reality is more complicated than our assumptions. Existing associations may be real but exaggerated or not as well supported as we thought, which is the case for cancer & obesity (4). We know that adiposity is harmful, but recently the controversial idea of an "obesity paradox" was suggested. Observational studies have found that being somewhat overweight could be healthy, but before making a final judgement we have to consider other study types that are in disagreement. What is more, new evidence suggests even the very observational studies are flawed.

The three strongest study designs informing our opinion on CR and leanness are epidemiology, biomarker studies and animal experiments*. One may wonder why I would mention human and animal studies in the same breath if everyone knows that human studies are superior. However, the point is that human studies are only superior if all else is equal. A well-designed, controlled mouse experiment measures healthspan across 100% of the animal's lifespan. If these experiments can be replicated in diverse non-human species the data cannot be ignored anymore. In contrast, observational studies follow human subjects only across 25% of their lifespan and usually much shorter. They are also uncontrolled which can lead to technically insurmountable biases (residual confounding, self-selection, etc).

*other type of circumstantial evidence exists e.g. the Okinawan population, see (1)

Just to drive this point home: One could claim that the CR studies and BMI epidemiology measure something completely different. A low BMI is healthy if you arrived at it per force (e.g. experimental imposition in animal experiments and elite dieters), but not if you were always thin, i.e. "self-selected" (what the observational studies measure). In reality I think there is an intersection between the two at a CR-like state. It is also important to address the BMI literature because for better or worse it is often trotted out as a counter-argument to do human CR.

Historically, animal and biomarker studies have favoured the biogerontologist's view (thinner is better, see [1]) while epidemiology did not. Therefore in this post I will mostly discuss how observational studies have recently shifted closer to the biogerontologist's view. In addition I will mention some studies not discussed in (1), including self-selected bodyweight in animals and the anorexia nervosa literature.

Donnerstag, 20. Juli 2017

Aging across the tree of life?

Just read a beautiful paper and I am not disagreeing. Just criticizing their approach and conclusions to learn something for myself. So let's see. Aging is conserved in different species, right? The authors (2, 3) claim that there are big problems with this assumption and I will discuss the two articles together.

Here we contrast standardized patterns over age for 11 mammals, 12 other vertebrates, 10 invertebrates, 12 vascular plants and a green alga..Although it has been predicted that evolution should inevitably lead to increasing mortality and declining fertility with age after maturity, there is great variation among these species

More sophisticated analyses including both shape and pace have confirmed the importance of slow, negligible, and negative aging [44].One of the most striking findings in recent years is that demographic aging appears to be far from universal [3,39]
This finding is crucial and paradigm-shifting because it implies that there is no single, universal aging pathway. At most, there might be a pathway that is shared when aging is present but can be turned off. 

Freitag, 7. Juli 2017

Current issues in GH/IGF1 research: adult-onset studies and mediators

CR, calorie restriction
IGF, insulin-like growth factor
GH, growth hormone
GHRKO, growth hormone receptor knock out
MLS, LS, (maximum) lifespan

In this post I would like to expound on an idea that allows us to make sense of the studies on adult-onset GH/IGF1 deficiency. As a disclaimer, let me emphasize that I am not working in this field, but I do try to keep up with the literature.

The search for independent pathways: why study these animals at all?
One unresolved question is linked with the evolvability and mutability of lifespans. Given that LS is quite flexible within and between species, we would expect the existence of lifespan assurance mechanisms, and most likely they should include signalling pathways and transcription networks, because these can change quickly over reasonable time frames. This is the optimistic view that many biogerontologists agree with. In contrast, the pessimistic view holds that CR-related pathways are a curiosity and normally changes in lifespan require thousands of independent mutations in wildly different pathways, precluding significant human lifespan extension using drugs or other interventions.

So far we know that there exist partly redundant longevity-assurance pathways that are all loosely linked to CR, anabolism and perhaps cellular "quality control" and multistress resistance. It will be very important to define the degree of overlap between these pathways to clarify whether the optimistic or pessimistic view is closer to reality. We need to know if there are pathways that are truly distinct from CR or that produce additive benefits with CR even if they are redundant.

In the end, we need to know how to combine interventions to achieve the best results, i.e. which genes are epistatic and hence in the same signalling cascade. We have to answer questions such as: How much of the effect of CR is due to GH and IGF1? Is protein and methionine restriction operating through the same mechanisms as CR? It seems, both of these overlap with CR but are distinct. What about mTOR? It seems linked to GH, IGF1 and CR but distinct (long-lived GH dwarfs have diminished mTOR signalling for example but mTOR inihibtion produces a different phenotype from dwarfism). What about the two novel players, c-myc and H2S?

Donnerstag, 29. Juni 2017

Statins and mortality: fat benefits or slim pickings?

If 50% of people die from CVD, the rest from cancer, and statins halve CVD mortality. What will be the impact on all-cause mortality? What will be the impact on life expectancy? Probably less than expected.

This goes back to a very real issue with statins and all other drugs but there may be some additional confusion among lay people because statins have a bad reputation in some circles. Not that I am an expert on statins or epidemiology, but I want to offer an interesting take on this problem.

Samstag, 8. April 2017

Poem - Erich Fried - Entwöhnung (German)

Now posting a German poem I read on a political magazine cover years ago and forgot to post. A simple translation would be: change, don't endure or adapt.

The poem reminds me of the quixotic fight of scientists. We must live as the unsung - sometimes even despised - heroes, while society looks up to pop stars, businessmen and conartists. One day perhaps "society" will look back on the way they treated science and rationality and they will remember it as the great tragedy. The great suffering we caused by enduring, getting used to the status quo and distracting us with cheap booze and anti-intellectual TV and right wing xenophobia.

I am not even interested in apportioning blame in the endless chain of events, who caused what. We know there are huge issues hindering our work as scientists that are trivially obvious but without a simple solution. Sometimes it's just important to remember that we all could do a a little better.

Erich Fried

Ich soll nicht morden
ich soll nicht verraten
Das weiß ich
Ich muss noch ein Drittes lernen:
Ich soll mich nicht gewöhnen

Denn wenn ich mich gewöhne
verrate ich
die die sich nicht gewöhnen
denn wenn ich mich gewöhne
morde ich
die die sich nicht gewöhnen
an das Verraten
und an das Morden
und an das Sich-gewöhnen

Wenn ich mich auch nur an den Anfang gewöhne
fange ich an mich an das Ende zu gewöhnen

Sonntag, 19. März 2017

To be fair, I am getting ahead of myself - Is the Longevity Dividend real?

Often I like to say that Täuber's paradox (ref. 1) proves that aging research is more cost-efficient than other disease centered research. The idea is that the longevity dividend (ref. 2) strictly follows from this concept. To be fair, we don't know for certain. First of all, maybe we should rephrase it more precisely. It seems highly plausible that aging research is cost-efficient given - let's call it - the Täuber asymmetry. Slowing aging by about 1% is probably as effective as cutting cancer rates by 50%.

There are three key assumptions that must be satisfied in addition to Täuber's:
1a. Aging can be slowed as a whole, or at least many age-related diseases driven by the same underlying cause can be slowed together
1b. This is not an idiosyncratic one time deal like calorie restriction
2. The feasibility of (1a). The task must be technically achievable and cost-efficient

1a. Is close to certain. Calorie restriction (CR) is the proof of principle and despite a lot of controversy it is shaping up reasonably (ref. 3). This assumption could have been wrong if aging were driven by millions of changes and millions of genetic interactions that follow no underlying logic. The truth is definitely in-between. While aging is indeed multifactorial, it can be decelerated by the regulation of a few signaling pathways. Each pathway itself might result in thousands of important changes, but this has no bearing on the end result.

1b. If we want to use the longevity dividend for our benefit, we have to ask what comes next? Once we have CR-mimetics, for example, is there any way to do better? Perhaps CR is the only conserved anti-aging pathway and it will be impossible to easily extend lifespan beyond a certain limit? Maybe CR only affects healthspan and that's all that is reasonably achievable? (ref. 3)

Robust and additive lifespan extension by CR-related and especially unrelated interventions would strengthen assumption (1a) and especially (1b).

2. Here, the test case is probably rapamycin. CR is considered "impossible" to implement on a global scale and no true CR-mimetic has emerged until recently. Rapamycin inhibits a nutrient sensing pathway that is also suppressed by CR (mTOR signaling) and is much closer to clinical application. Let's keep in mind that current, under-funded aging research does not need to prove that (1a, 1b, 2) is completely true by finding a perfect drug. Given the funding situation, it would border on a miracle if we quickly found a drug that has fewer side-effects than rapamycin yet still slows aging by 10%. That would be like curing cancer, just considerably better and on <1% of the cancer research budget!


1. Keyfitz, N. (1977). What difference would it make if cancer were eradicated? An examination of the Taeuber paradox. Demography, 14(4), 411-418.

2. Olansky, S. J., Perry, D., Miller, R. A., & Butler, R. N. (2007). Pursuing the longevity dividend: scientific goals for an aging world. Ann NY Acad Sci, 1114, 11-13.

3. Mattison, J. A., Colman, R. J., Beasley, T. M., Allison, D. B., Kemnitz, J. W., Roth, G. S., ... & Anderson, R. M. (2017). Caloric restriction improves health and survival of rhesus monkeys. Nature Communications, 8.

Sonntag, 12. Februar 2017

What good is the Interventions Testing Program: Rapamycin & healthy people

Here, I want to highlight the findings of the recent ITP cohort and ask a "political" question about the reason for running this huge mouse lifespan study and how it should influence human studies.

First a very brief review of lifespan extension in mice:

Metformin (Met, 1000 ppm or 0.1%): the ITP findings are important because the lifespan effect of metformin is surrounded by controversy, yet (foolishly?) large human studies are already under way.

Met+Rapamycin (Rapa): the lifespan increase looks big, yet barely better than rapa alone. somehow it looks like "squaring the curve" and not real slowed aging. Why? Maybe it is too selective, too limited. I get the impression that reduced mTOR signalling is just a subset of the anti-aging phenotype of CR and dwarfism. Maybe the squaring is just a fata morgana anyway, as statistically 10% survivorship is better even if single outlier max LS seems "capped". Either way, rapa or rapa+met still come out vastly superior to met alone.

Ursodeoxycholic acid (UDCA): No effect. The drug was chosen based on what seems to be relatively weak grounds. It may upregulate xenobiotic detoxification and so the idea harks back to whole Nrf2/stress resistance theory, but seems highly speculative and singular since Nrf2 is more than just xenobiotic metabolism.

NDGA: Was chosen as a "lipoxygenase inhibitor and potent antioxidant" and they keep testing it again and again but the large heterogeneity in the ITP cohort and the Spindler study is concerning. To me, the compounds is dead as it is and it will require massive efforts to reconcile the findings.

There was, however, no effect of NDGA treatment on maximal lifespan at any dose tested in males, or in females at the 5000 ppm dose tested (Table 2). There was also no effect on maximal lifespan at any of the individual sites at any dose (Table S2, Supporting information).

Prevents the digestion and uptake of carbohydrates. It had a small effect on mean and a real effect on male max LS with a smaller one in females. Ok, I guess it's weightloss linked?

Fish oil (FO): the ITP findings are important because thre is evidence that FO could shorten lifespan, yet it is used as a dietary supplement by many people.

It is notable that FO, at the higher dose, led to a significant decline in male longevity at UM (−18%, P = 0.003, and that the lower FO dose led to a 9% increase in male lifespan (P = 0.06) at UT

Protandim: Nrf2 inducer but the evidence of actual induction does not seem strong at first glance. Either way, there was a small male only increase in meanLS.

17aE2 (so called non-feminizing estrogen): Works in males but not females. God I am so not touching this stuff. Gender dimorphism is hell to work with and so are hormonal treatments in humans. On the other hand, the lifespan effect is quite large at the tail end so maybe it is worth revisiting...

Freitag, 10. Februar 2017

The Black Swanologists are having a field day

Better late than never. My comment on the presidential election:

This is not the day of the first female president. This might be the week when millions of Americans google: "What are the policies of Donald Trump?"

As is painfully obvious history is made by unlikely events with a high impact and people like Nassim Taleb are never tired of emphasizing just how hard predictions are. These "Black Swan" events range from the second World War to the Great Recession of 2008, the failure to address greek debt in a healthy manner over to Britain's EU vote and to recent political events in Europe. An influx of asylum seekers has strengthened the extreme, authoritarian, xenophobic right in Austria, Hungary and to some extent Germany and everywhere else.

Is there anything useful we can learn from this disaster?

On the one hand, a win by Donal Trump wasn't impossible so perhaps it shouldn't be so shocking? Fivethrityeight gives the Clinton chance as 70% down from 90% a few weeks before the election. However, looking back even a year or two no one would have predicted a candidate that radical to have a chance of winning the primaries. Considering all this, yes, we have reason to be horrified and surprised.

I do not want to talk about american politics much at all. As always there was an obvious divide like in many decisions and elections. Although, a simplification we can say that voters best characterized along the lines of "old, white, male, rural, uneducated" voted against their own interests. To be fair, we do not quite understand the election outcome, but it's pretty clear we saw another phenomenon, which is successful populism. Europe has their share of populists as well.

The important take home message
First of all, perhaps biogerontology needs a populist spokesperson to be successful, so the ever colorful Aubrey de Grey might have been on to something. Look different, tell people what they want to hear, be an optimist. It's worth mulling over.

Second, we must remember the pendulum will swing back. The march towards progress doesn't end with a single setback. Sure, this could be the beginning of the end, but it seems unlikely as documented by Steven Pinker. Positive news rarely get reported, but, just to mention a small silver lining, around the election California legalized Cannabis, Americans still dislike the electoral voting system, post-election Americans successfully fight Trump policies, science papers are now much cheaper than ever, progress against poverty has been steady, drug approvals have picked up at least modestly over the last 3 years, Romanians successfully fight back pro-corruption laws, Austrians elected the first "green" president ever and are still leaving the church in droves and 2016 seems to be the least bloody year of the Syrian civil war.

Third, many scientists, especially demographic researchers, are telling us that changes in lifespan are very unlikely and a major shift in funding for aging research is not forthcoming. This is true now and when - or if - it changes, it will be likely driven by a major shift that occurred over a few years once the time was ripe and it will be an unpredictable black swan event.


Sonntag, 29. Januar 2017

Supplements, mortality and disease incidence - nothing has changed

In this post I would like to highlight the following review because a few people from our nutrition department were involved in it and I've been looking forward to their final analysis for some time. Sorry, if I'm rambling too much but whenever I am too perfectionist then no blogging gets done at all!

Schwingshackl, Lukas, et al. "Dietary Supplements and Risk of Cause-Specific Death, Cardiovascular Disease, and Cancer: A Systematic Review and Meta-Analysis of Primary Prevention Trials." Advances in Nutrition: An International Review Journal 8.1 (2017): 27-39.

Our aim was to assess the efficacy of dietary supplements in the primary prevention of cause-specific death, cardiovascular disease (CVD), and cancer by using meta-analytical approaches. Electronic and hand searches were performed until August 2016. Inclusion criteria were as follows: 1) minimum intervention period of 12 mo; 2) primary prevention trials; 3) mean age ≥18 y; 4) interventions included vitamins, fatty acids, minerals, supplements containing combinations of vitamins and minerals, protein, fiber, prebiotics, and probiotics; and 5) primary outcome of all-cause mortality and secondary outcomes of mortality or incidence from CVD or cancer.
Pooled effects across studies were estimated by using random-effects meta-analysis. Overall, 49 trials (69 reports) including 287,304 participants met the inclusion criteria. Thirty-two trials were judged as low risk-, 15 trials as moderate risk-, and 2 trials as high risk-of-bias studies. 
Supplements containing vitamin E (RR: 0.88; 95% CI: 0.80, 0.96) significantly reduced cardiovascular mortality risk, whereas supplements with folic acid reduced the risk of CVD (RR: 0.81; 95% CI: 0.70, 0.94). Vitamins D, C, and K; selenium; zinc; magnesium; and eicosapentaenoic acid showed no significant risk reduction for any of the outcomes. On the contrary, vitamin A was linked to an increased cancer risk (RR: 1.16; 95% CI: 1.00, 1.35). Supplements with β-carotene showed no significant effect; however, in the subgroup with β-carotene given singly, an increased risk of all-cause mortality by 6% (RR: 1.06; 95% CI: 1.02, 1.10) was observed.
Taken together, we found insufficient evidence to support the use of dietary supplements in the primary prevention of cause-specific death, incidence of CVD, and incidence of cancer. The application of some supplements generated small beneficial effects; however, the heterogeneous types and doses of supplements limit the generalizability to the overall population.

Mittwoch, 25. Januar 2017

Coffeehouse notes on: The Multistress Resistance Theory of Aging

It took me forever to publish another blog post, even though I wrote this one over just a few days. The problem is, every time I have a new idea for a post I start writing and end up having 50 drafts of unfinished posts, so from now on I'll try to focus. This post is a primer on the wide topic of ROS, other stressors and their impact on aging, with a focus on mitochondria.

Thanks to comparative and interventional biologists the moribund oxidative stress theory has been revitalized and transformed into what we can call the multi-stress resistance theory. Simply put, stress resistance is one of several contributors to long lifespans. Oxidative stress is just one of the many noxious agents and antioxidants are just one way to counteract them, and perhaps the least efficient one! Taken together with Täuber’s paradox it seems trivial to explain why almost all antioxidant studies failed to extend mouse lifespan (Täuber’s in a nutshell: decades ago epidemiologists were able to show empirically that one would have to modulate all causes of aging to produce large gains in life expectancy).

Stress resistance is now considered a composite of: low generation of reactive species, interception by antioxidants, prevention of damage amplification and protection of vulnerable sites, and of course robust sensing of damage/ROS is necessary to increase resistance on-demand. Importantly, all these mechanisms are just the tip of the iceberg. Damage is inevitable as ROS come in contact with biomolecules, but these may be resistant to damage or functional impairment (i.e. cope well with damage). Immediate repair is also common, especially of pre-mutagenic DNA lesions. There can be other mechanisms of “repair” or “coping” like the killing of dysfunctional cells, degradation of whole mitochondrial genomes or the autophagic consumption of damaged biomolecules and so much more.