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.

Sonntag, 13. November 2016

Large ongoing Primary Prevention Studies

In this article I want to highlight large studies that are being performed in relatively healthy populations, or which provide relevant data to further the goal of delaying aging and age-related diseases.

To provide a complete picture I looked into various reviews and the notes and ideas I already had. Keeping track of new nutraceutical and health related developments used to be a big pastime of mine so I hope the below list is somewhat complete. In addition to literature search, I queried a large clinical trials database using various terms. One variation was for example a query for "Interventional Studies | mortality | Adult | Phase 3, 4 | Studies with safety issue outcome measures" yielding 1107 hits. From this list, I selected studies with n > 1000 which yielded approx. 255 results, which were then hand search. In this way the clinicaltrials database helped me to identify a few studies I would have missed otherwise and what follows are short notes on interesting trials.