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).

Acarbose:
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.


References:
http://www.politifact.com/personalities/donald-trump/
http://projects.fivethirtyeight.com/2016-election-forecast/
http://fivethirtyeight.com/features/where-trump-got-his-edge/