Samstag, 13. Dezember 2014

Expanded Deletions vs Mutations: an unsolved Mystery

Edit (02-18-2015)
Based on a study I read, or rather skimmed. The problem of aging (stem) cells explained (1):
A significant increase in the frequency of respiratory chain deficient colonic crypts with age correlates with the frequency of mutations detected by [next generation sequencing]
But to this day we do not know why deletions accumulate in muscle and point mutations in the colonic epithelium.

Mechanism of Action (1): Speculation
Mathematical modelling studies have suggested that clonal expansion of mtDNA mutations within an individual cell is likely to be due to random genetic drift and predict that it can take at least 20 years for an mtDNA mutation to clonally expand to high levels sufficient to cause COX deficiency [37]–[39]....Previously we examined colonic epithelial tissue from a similar ageing mouse colony and showed that clonal expansion of mtDNA mutations was a very rare event in these animals compared with aged humans [41]. This may explain the species differences in these data, consistent with modelling studies that emphasise the difficulty of generating clonal expansion through random drift in short-lived animals [39].
The question arises if mutations leading to a COX negative phenotype are additionally selected for, like in muscle? (2) If not, then why? Induction of mitochondrial biogenesis could help to answer this question in a mouse model. If I had to speculate, I guess, the aetiopathogenesis might be completely different between muscle and colonic mitochondrial dysfunction. Perhaps substantia nigra and muscle rely more on OXPHOS (aerobic) whereas stem cells do not (4), thus deletions in muscle would not trigger a vicious cycle as in (2)?

Freitag, 5. Dezember 2014

Parabiosis enabled mouse rejuvenation - will the data transfer to humans?

Two recent papers make you wonder, will the mouse aging data ever translate to humans? So far we have found out that mouse cancer data rarely applies to humans, but anti-aging interventions have never been tested in humans before.

Katsimpardi et al. 2014 (1a) (Wagers and Rubin labs)
GDF-11 leads to "Vascular and neurogenic rejuvenation of the aging mouse brain". Interestingly, the protein, which has been indentified in parabiosis experiments (3), is related to myostatin (!) and a "circulating transforming growth factor–β (TGF-β) family member". It also "reverses cardiac hypertrophy in aged mice" apparently mimicking many effects of actual parabiosis.

And as a side-note: "Systemic factors in old blood can have detrimental effects on hippocampal neurogenesis in young animals..."

Donnerstag, 4. Dezember 2014

The death of a Hypothesis: Cholesterol and Heart Disease (Ezetimibe edition)

Recent events have cast doubt on the well established "lipid hypothesis" of heart disease. In particular, the failure of Vytorin, aka ezetimibe, to lower intima media thickening. Instead the cholesterol absorption inhibitor appeared to worsen thickening, if it had any effect at all, in this rather small study. Of course, the lipid hypothesis is backed by other lines of evidence (1) but the most reliable evidence always comes from interventional studies.

So the key point of this controversy has been that no lipid lowering drug has ever reduced CVD (usually measured as a composite endpoint*) in a large study, with the exception of statins. This means it would be conceivable that some other effect of statins is responsible for their protective effects, the so called pleiotropic effects of statins.

The controversy can be put to rest given the results of the secondary-prevention study IMPROVE-IT with n ~ 18 000. I will spare you the details and just link to two other reviews instead. (Note, that the arseholes from medscape may require you to register before you can read the summary)