Seven years ago we published a 15% heritability of life span from data in South Tyrol. The heritability of longevity increased from 0.20 to 0.35 as the longevity threshold increased.

A new study now finds that we have been exaggerating

true heritability of human longevity for birth cohorts across the 1800s and early 1900s was well below 10%, and that it has been generally overestimated due to the effect of assortative mating. … Spouse life spans correlate as much or more than those of genetic relatives, raising the possibility that correlated environments and/or assortative mating have confounded those estimates.

I think there is a misunderstanding of assortative mating (AM). AM is a form of sexual selection in which individuals with similar phenotypes mate with one another more frequently than would be expected under chance conditions. BUT the phenotype longevity is not known to anyone at mating. Instead there seems to be a simple “environmental” interaction: We know that elderly couples frequently die together, also known as broken hearts phenomenon.

Adjusting any regression model for any AM will therefore seriously reduces the heritability of longevity, which is exactly what the authors describe in their new paper.

Spousal correlation is expected on two grounds: shared-household environment during adulthood and/or assortative mating. The two can be distinguished by definition: the effects of shared-household environment are nontransferable through inheritance, whereas the factors correlated by assortative mating are transferable, allowing them to also generate correlations with family members of the spouse

This is not very convincing as A) shared-household environment can be transmitted by epigenetic factors and B) it is a myth there is any AM for lifespan.

Karel & Iris Schrijver “Living with the starts” have an intestine chapter “Dying to Live” that is about the cell turn over

Take the skin, for example: a Iiving, breathing, regenerating tissue that is the largest organ of the body and that acts as a barrier between the internal organs and the environment. In adults, it encompasses about 22 square feet (2 m2) and weighs around eight pounds (4 kg). It protects the interior of the body from injury, from harmful effects of microorganisms, and from the damaging ultraviolet rays of the Sun. It plays a role in the body’s thermal regulation through the constriction or dilatation of small blood vessels, it contains nerve endings that allow us to feel touch, temperature, pain, pressure, and vibration, and it slows the loss of fluids from the body. The skin also shelters the hair follicles, which produce the hairs that cover most of the body’s surface, and it provides storage for a variety of substances. The skin, composed of several layers, ages quickly but is remarkably effective at renewing itself. In the top layer, the epidermis, most cells eventually reach the surface as the outermost layers at cells wear off. They are replaced in a time frame of roughly a month or two, in a continuous process that culminates in the loss of approximately 30,000 cells every minute throughout our lives. This translates into roughly eight pounds (4 kg) of dead material per year. Some features of our skin are, of course, more lasting. For example, we may have seemingly permanent moles and we may have scars that persist for years. These tissues, however, are not really skin. Moles are embedded within our skin but they are in fact benign growths that are typically composed of pigmented cells that do not follow the same lifecycle as true skin cells. Likewise, scars are repairs of deep cuts in our skin.

Unfortunately they do not give any reference there. Data should have been produced by carbon 14 dating. And yes, there are references

Radioactive carbon decays slowly, such that a given amount of carbon-14 halves every 6,000 years. So detecting the subtle change in the ratio of normal to naturally occurring radioactive carbon over just a few years is incredibly hard.
But Jonas Frisén of the Karolinska Institute in Stockholm, Sweden, says it can be done if one takes advantage of the signal left by nuclear testing, which spewed high levels of carbon-14 into the air during the Cold War.
By the time a halt was called to aboveground nuclear testing in 1963, levels of carbon-14 in the atmosphere had doubled beyond natural background levels, says Frisén. Since the halt, this has halved every 11 years. By taking this into account, one can see detectable changes in levels of carbon-14 in modern DNA, he says.
“Most molecules of the cell will turn over all the time. But DNA is a material that does not exchange carbon after cell division, so it serves as a time capsule for carbon,” Frisén says.

basically referring to a Cell 2005 paper

We therefore modified established DNA-extraction protocols to minimize the risk of carbon contamination (see Experimental Procedures). DNA samples were analyzed for purity in several ways; in addition to spectrophotometric analysis, the contents of all samples were analyzed by HPLC and the amount of total carbon (12C, 13C, and 14C) was determined during graphite preparation for isotope analysis by accelerator mass spectrometry.

They needed a minimum of 15 million cells for ¹⁴C analysis with the current sensitivity of accelerator mass spectrometry while it would be  interesting to repeat this study with single cell genome sequencing.

New research shows that most genetic variants in the human genome are affected by purifying selection, so there is no “neutral” variant anymore.

Pouyet, Aeschbacher et al. created a measure of genetic diversity that is only affected by selection or transmission bias. The results showed that negative selection influences as much as 85 percent of our genome, whereas transmission bias affects a majority of the rest of the genome. After removing these two biases, less than 5 percent of the human genome is found to evolve by chance. This suggests that while most of our genetic material is formed of non-functional sequences, the vast majority of it evolves indirectly under some type of selection.

The famous Spalding paper 2005 used an interesting approach

We show that the level of 14C in genomic DNA closely parallels atmospheric levels and can be used to establish the time point when the DNA was synthesized and cells were born… Retrospective birth dating is a generally applicable strategy that can be used to measure cell turn-over in man under physiological and pathological conditions.

I was more in favor of calculating mutation rates, S. Horvath suggested methylation changes. Maybe lineage tracking will be the next big thing in single cell analysis and the human cell atlas?

Many professional cyclists are suffering from “asthma”, a diagnosis that can be easily used like “headache” if you know how to blow a typical lung function test. You are then prescribed beta2 agonists and a get the diagnosis excercise induced asthma.

For good reasons, salbutamol is prohibited by the WADA, the world anti-doping agency. So, I would expected asthmatic patients to take part in activities like the paralympics for simple reasons:  High-tech prostheses could give runners an unfair advantage and high tech drugs opening the airways of cyclists will lead to an increased air exchange with less efforts.

Nevertheless the WADA allows exceptions by providing “TUEs” until 2009, since 2009 a declaration of use:

The highest risk for developing asthmatic symptoms is found in endurance athletes and swimmers. … Asthmatic athletes commonly use inhaled ß2-agonists to prevent and treat asthmatic symptoms. However, ß2-agonists are prohibited according to the Prohibited List of the World Anti-Doping Agency (WADA). An exception can be made only for the substances salbuterol and salmeterol by inhalation, as long as a so called “therapeutic use exemption” (TUE) has been applied for and was granted by the relevant Anti-Doping authorities, and for salbutamol and salmeterol by inhalation. Since the beginning of 2011 for the latter two substances neither a TUE nor a Declaration of Use (DoU) is required as it is for formoterol from beginning of 2012).

Rules were quite clear in the past: Alessandro Petacchi was banned from November 2007 to August 2008 for salbutamol overdosing;  Diego Ulissi received a nine-month suspension ending in March 2015 after having found almost twice the permitted concentration of salbutamol in his urine.

The most recent 2 July 2018 decision of the WADA right before the start of the Tour de France 2018 was unexpected for denying any Adverse Analytical Finding (AAF) in the Froome case.

Whatever we believe is being correct, it  shows at least the inability of the WADA to reach at any conclusion within a reasonable time period. Froome was already tested positive for excessive salbutamol on 7 Sept 2017.

The WADA’s announcement follows that of the UCI earlier today, which announced that the anti-doping proceedings involving Mr. Froome have now been closed. Based on careful consideration of the facts, the Agency accepts that the analytical result of Mr. Froome’s sample from 7 September 2017 during the Vuelta a España, which identified the prohibited substance Salbutamol at a concentration in excess of the decision limit of 1200 ng/mL(1), did not constitute an Adverse Analytical Finding (AAF).

Unfortunately neither the ASO (the Tour organization) nor cycling fans wanted Christopher Froome to participate in the 2018 Tour de France. I largely agree with Velonews

At present we condemn dopers because our concept of fairness is treated as absolute and clear, but the truth is that the world is far more complex than right or wrong. It’s worth bearing in mind that what is seen as ‘unfair’ competition is not set in stone.

Tom Fordyce of the BBC was given exclusive access to data behind Chris Froome’s 2018 Grand Tour victory at the Giro d’Italia, another exceptional ride of Froome (as in the Vuelta 2017 where he was tested positive).  Fordyce published, however, only unimportant calorie intakes and irrelevant WhatsApp messages. No “fake news” as Richie Porte said, but “fog news”.
What I am interested in, is the number of hubs Froome is taking from the inhaler, his inhalation technique, any short- and longterm effects on heart rate, power output, VO2max and maybe even more. Michael Hutchinson makes the point

The problem with this kind of data is that while it is very nice and we assume it’s accurate, it needs context to make sense of it. It makes perfect internal sense. You need external data. If we knew the power output of every rider in that lead group over the hills towards the end of this stage, if there was anything that didn’t match we’d spot it.

Maybe we even need more than the WADA ever requested from Team Sky?

Chris Froome may have some unusual beta2 receptor variants as we described it as already as 2000 (amino acid positions 16, 27 and 164). Maybe a similar condition as with the Pechstein case / hereditary spherocytosis? Any increased smooth muscle relaxation profile,  more coronary artery dilation or boostered glycogenolysis? The only way to find out more, would be DNA testing, performance and excretion studies with and without beta2 agonists. From the literature I would NOT expect so much benefit of salbutamol on gas exchange but in rare and exceptional cases like Froome, there could be a fair (or unfai)r advantage: ß2-receptor variants improve the metabolic profile, they increase glucose tolerance and decrease leptin resistance, with the Arg16Gly polymorphism giving even a better endurance performance. So Froome might have indeed performance benefits from overdosing salbutamol. Did the WADA ever discussed that? It seems that the Guardian has been arguing in the same way

It had been expected that the Briton would have to undergo a controlled pharmacokinetic study, which would have attempted to replicate the “unique circumstances” that may have caused the abnormal levels of salbutamol in his body. However, in a statement, Wada accepted this was not “practicable”.

Just in the own interest of Froome and Team Sky but also in the interest of the WADA and the “post-doping” cycling era

• Team Sky should release the 1,500 page report.
• WADA can not refer to unpublished salbutamol studies or explain that they have only partially involved in the UCI decision. Salbutamol is a forbidden drug as it is increasing performance  (otherwise Froome would not take it).
• WADA need to explain in detail why they are making an exception for Froome but not for Petacchi  and Ulissi.
• I think WADA need to sponsor pharmacogenetic studies that exclude any performance enhancing effects in the therapeutic range.

11 July 2018 WADA publishes a clarification

It was accepted by the UCI, however, that in this case such a study would not have provided reliable evidence as it would be impossible to adequately recreate similar conditions to when Mr. Froome was subjected to the test, taking into account his physical condition, which included an illness, exacerbated asthmatic symptoms, dose escalation over a short period of time, dehydration and the fact that he was midway through a multi-day road cycling race.

Recreating specific conditions is never possible, so it is a weak argument. What is interesting is the detailed statistics about salbutamol use that we did not know before

From the data available to WADA in the Anti-Doping Administration and Management System (ADAMS), of the 41 completed cases that involved salbutamol as the only substance: 20% (eight out of 41 cases) resulted in acquittal. […] In the same time period, 57 cases contained salbutamol, either on its own (see above) or in combination with other prohibited substances, and of those: 14% (eight out of 57 cases) resulted in acquittal.

So 16% acquittal only… And well, no further criteria for acquittal or suspensions…

15 July 2018

Former pro rider Jens Voigt believes that money rules – the UCI fears the damage they have to pay if they are loosing a lawsuit against Froome/Sky (Katrin Krabbe received 1.2 millions).

And again the Guardian

Wada’s director general, Olivier Niggli, also raised the possibility of Wada lowering the dosage for which a TUE for salbutamol would be required. […] Niggli rejected accusations. “Maybe the finger is being pointed in the wrong direction – and maybe what needs to be done is to point the finger at how much we allow athletes to take and maybe be more restrictive. Maybe the weakness in the system is that we are being too nice,” he added. “Maybe we need to be tougher and say: ‘You are going to have to take less, otherwise you need a TUE.’”

Looks a bit like a bazaar now.

Niggli also insisted that the fact Froome was not sanctioned was not unusual for salbutamol cases and that 20% of such cases have a similar result. “These cases are not black and white, which means they require a process,” he said. “I know a lot of people would love it if it was positive or negative, but it is not the case. So until we have a different test, or the science evolves, we will have to deal with it.”

Olivier Rabin, the World Anti-Doping Agency’s director of science, is quoted as

Under current rules athletes are allowed a maximum of 1600 micograms of salbutamol over 24 hours, with no more than 800mg taken in a 12-hour period. But Wada’s director of science, Dr Olivier Rabin, suggested those limits could potentially be cut by between a quarter and a half […]
Froome provided a number of elements, some of which were specific to his case, such as the increase in concentration [compared to the tests undertaken in the preceding days], for example. There was, it seems, a worsening in his asthma due to an infection […] He took a certain number of medicines to treat it and other elements linked to his diet were also taken into account, as were dietary supplements. And other things too.

Froome seriously ill on that day? Finishing as 23rd rider of 162??

I can’t see any major illness and agree with  Bradley Wiggins who describes Chris Froome salbutamol affair as ‘a mess’ and claims Wada need more investment.

Something needs reviewing massively. I don’t think WADA have a massive amount of money, they need more investment. They were set up 20 years ago and their rules were probably written then, so perhaps they need to be re-written. But to really combat doping in sport and the more secret ways people are finding to dope in sport they need more money and funding.

And who has finally cleared the case – the WADA or the UCI?

Die Arzneimittelkommission der deutschen Ärzteschaft warnt

Eine 78-jährige Patientin (A) und ein 60-jähriger Patient (B) hatten sich eigenständig Vitamin-D-haltige Präparate besorgt und täglich hohe Dosen (A: Vitamin D3 10.000 IE/d; B: „Vitamin D“ 50.000 IE/d) eingenommen. Beide entwickelten ein akutes Nierenversagen bei ausgeprägter Hyperkalzämie (A: 3,42 mmol/l; Referenzbereich: 2,15–2,58 mmol/l; für B liegt genauer Wert nicht vor). Hinweise auf alternative Ursachen wie primären Hyperparathyreoidismus, Sarkoidose oder Tumorerkrankung gab es nicht. Der Zustand der Patientin A besserte sich unter forcierter diuretischer Therapie und peroraler Kortisongabe. Patient B entwickelte schwere Komplikationen und hat eine dialysepflichtige Niereninsuffizienz davongetragen (Nierenbiospie: schwerer tubulärer Schaden mit Mikroverkalkungen, passend zu hyperkalzämischer Schädigung).

Damit also Warnung vor Coimbra Protokoll und vor vitamind.net (David Rotter, Jörg Schweikart, u.a.). Eine Hochdosistherapie ist nur bei nachgewiesenem genetischen Defekt der Vitamin D Konversionsenzyme indiziert.