Mittwoch, 4. Februar 2015

Two inspiring Stories suggest how to do better Science: Parabiosis and Super Resolution Microscopy


Parabiosis
Nature has a fascinating background story on this type of research (6), but other reviews are recommended as well (7). Parabiosis was invented in the 19th century and became popular around the 1970s before interest waned again. Then some 10 years ago it was rediscovered by the biogerontology community. What I would like to emphasize is that the ebb and flow in research interest isn't uncommon. One has to wonder how many other gems are there to be found in papers from 1900-1960?
An example that I recall is research on medial calcification, which was pioneered by Blumenthal and Lansing. Although, interest in (medial) calcification has steadily risen, few studies have revisited the exact pathology they described and the idea to tackle this pathology is rather new (1).

Freitag, 30. Januar 2015

Recent advances in cancer treatment: immune checkpoint therapy, electromagnetic therapy

From time to time I like to highlight biomedical advances that caught my interest. Here are two recent examples:

Immune checkpoint therapies were first applied to advanced melanoma and, as far as I know, they were the first treatment to significantly improve the prognosis of this once intractable cancer (1, 3):
...immune checkpoint antibodies are clinically active in a variety of malignancies, including those not traditionally classified as immunogenic, such as non-small-cell lung cancer (NSCLC)....
Anti-CTLA-4 agents: ipilimumab and tremelimumab...
the number of long-term survivors exceeded the number of patients with objective responses (ORs)...immune-based therapies may generate a sustained antitumour effect in a subset of patients, long after completion of active therapy
Antitumour responses with immunotherapies are heterogenous: responses may be mixed or delayed, lesions may enlarge before shrinking, lesions may remain stable or slowly regress over time. These responses can be potentially explained by T-cell activation and tumoral infiltration by immune cells, as well as intra-patient heterogeneity of tumour–host interactions.
I always thought that a vaccine type immunotherapy would be first to market, but it turned out differently. According to a talk by James Allison I recently went to, longer term data will become available soon.

Freitag, 23. Januar 2015

The comparative study of the "mito-free radical theory of aging" hit a brick wall.

Put another way, it's all about the money

Not long ago a colleague and I briefly debated and summarised the most recent evidence regarding fatty acid (membrane) composition and aging. Importantly, mitochondrial fatty acid composition along with reduced mitochondrial ROS production in long-lived species is one of the major pillars of the "mito-free radical theory of aging" derived from comparative studies.
I would like to emphasize a few additional key points. For a broader state of the art review, the reader is refered to the literature (5, 6). Not long ago I noticed a letter by Barja (1), discussing a major headache for anyone doing comparative biology of aging. One way of putting his idea is as follows:

Samstag, 10. Januar 2015

The Tithonus Fallacy explained: The example of Nordihydroguaiaretic Acid (NDGA)

The Tithonus fallacy has been outlined elsewhere (1). Basically, it's the belief that an extension of lifespan will lead to an extension of frailty and suffering. Why this is wrong, as a rule, is obvious to a biogerontologist but not to a layperson: The diseases of aging and their underlying molecular pathologies are aging. A large extension of maximum lifespan is impossible without a delay of diseases.The 'area-under-the-curve' of health will always increase, so to say.

Border cases are substances or interventions which lead to modest changes in lifespan, particulary changes in mean lifespan. Rapamycin was assumed a potential case, but this has been refuted (2). Conceivably, lifespan may be extended somewhat by delaying a specific disease at the cost of health. Think, for instance, of a badly designed chemotherapy protocol. A substance or "longevity mutation" might also decrease the rate of aging while having some other terrible side-effects. One -- still highly speculative -- example is human dwarfism. While dwarf mice live longer than their mates, this disease is associated with (intellectual) disability and suffering in humans, yet could modestly extend lifespan in people as well (3).

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  IMPROVE-IT study 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)