Mittwoch, 18. März 2015

Don't judge the primate studies of Calorie Restriction if you haven't read them!

I despair when non-expert scientists and intelligent lay people unknowingly spread misinformation about calorie restriction (CR). Not long ago I had to read again that the primate studies somehow refute CR. The reality, however, is more nuanced than that. Do not forget: misinformation can jeopardize public understanding and acceptance of research.

I will echo Ingram and Roth on this topic and use this post as a future reference. Both were involved (principal investigators, I believe) with the CR primate studies. (emphasis mine)
The long-term study of rhesus monkeys at the University of Wisconsin reported significantly reduced morbidity and mortality in those monkeys maintained on 30% CR from adult ages (7–14 years of age) compared to controls (Colman et al., 2009 and Colman et al., 2014). In contrast, a report from the long-term study of rhesus monkeys from the NIA that we initiated in 1987 found no evidence of improved survival in monkeys initiated on 30% CR from young ages (2–6 years) or older ages (14–21 years) (Mattison et al., 2012). Differences in the design of these studies, particularly the dietary composition, are now being investigated to uncover reasons for the different outcomes. Even if the conclusion is ultimately that CR does not significantly extend lifespan in rhesus monkeys, there is ample evidence from these studies to demonstrate improved health and function at older ages in monkeys on CR. 

1. Ageing Res Rev. 2015 Mar;20C:46-62. doi: 10.1016/j.arr.2014.11.005. Epub 2014 Dec 19.
Calorie restriction mimetics: Can you have your cake and eat it, too?
Ingram DK, Roth GS.

Samstag, 14. März 2015

Senescence the gift that keeps on giving: dasatanib and quercetin to the rescue?

I wanted to highlight the recent paper by the Kirkland group (1), despite the press it has already gotten, since it is indeed deserving of praise. Starting last summer I developed an interest in the field of senescence since senescence was a focus of the "Neurobiology and Neuroendocrinology of Aging conference" in Bregenz, which I attended, and some of my colleagues work on it. The field does not cease to amaze us with promising data.

Why does senescence matter? Briefly, senescent cells accumulate in aging non-human primates (2), impede tissue function (1), and are reduced in long-lived mutant mice (3). Further, progeroid phenotypes can be alleviated by removing senescent cells (4), although, I do not quite trust models of accelerated aging and prefer other types of evidence (1, 2, 3).
Right now we are basically waiting for the (definitely already ongoing) lifespan studies, based on genetic (4) or pharmacologic (1) senescent cell ablation, to be published in Nature/Science so that we can start developing human therapies. And I do expect them to be successful. In the meantime Kirkland & co will continue publishing amuse bouches studies.
Given the paucity of data available, even though the evidence appears strong, I wonder if human studies will commence before the lifespan studies in rodents finish? All bets are off: in principle the data is promising enough to pursue pilot trials, similarly to parabiosis, but ethics boards tend to be painfully slow and conservative.

Dienstag, 10. März 2015

Safety of testosterone: I stand corrected, at least in the short-term

"Two Studies Suggest Testosterone Might Not Increase Risks of Cardiovascular Events"
http://www.medscape.com/viewarticle/841098

I predicted testoserone would lead to an elevated risk of cardiovascular events based on animal data and a recent tesosterone study that was terminated due to apparent adverse effects (ref. 1, TOM study). An older interventional study also hinted at harmful effects of testosterone (2). There was some reason to think that testosterone could explain the increased mortality of males (H. Sapiens and in some other species, see [3] for a discussion).
The new studies presented this later week at the ACC cast some doubt on those previous concerns. In the first study, Dr Zuber Ali (Aurora Health Care, Milwaukee, WI) and colleagues studied 7245 men, mean age 54 years, prescribed testosterone-replacement therapy for low testosterone (<300 ng/dL). The mean follow-up period was 1.78 years. Cardiovascular risk factors were documented in many patients, with 41% having dyslipidemia and 34% having hypertension. In the multivariate analysis, there was no increased risk of acute MI, stroke, or death at 3 years among the testosterone-treated patients compared with the untreated patients.

The short follow-up is worrying, but apparently a recent meta-analysi did not find any risk either. The last time I checked another study, the "T trial", with n=800 participants was still ongoing. We will see what this one shows.

Conclusions
Testosterone may be safer in the short-term to mid-term than we thought, but this does not rule out harmful effects in the long term (c.f. ref. 3).

References
1. Basaria S, Coviello AD, Travison TG, et al. Adverse events associated with testosterone administration. N Engl J Med 2010; DOI:10.1056/NEJMoa1000485.

2. HAMILTON J.B, & MESTLER G.E. (1969) Mortality and survival: A comparison of eunuchs with intact men and women in a mentally retarded population. J. Gerontol. 24:395

3. http://arc.crsociety.org/read.php?2,112565,112602#msg-112602

EDIT: Data added, TOM study corrected

Mittwoch, 4. März 2015

Rapalogs and Rapamycin in the healthy?

I admit that I was skeptical at first whether the immunosuppressant rapamycin could ever be used in healthy people. A number of recent findings have changed my opinion, of which I will discuss a few (1, 3). Since I saw an enthusiastic talk by Arlan Richardson on the safety of rapamycin in animal models of age-related diseases, I have been warming up to this idea. In any case, there are three "solutions" to the major side-effect of immunosuppression: 1. design more selective rapalogs (is this possible?), 2. micro-dosing without immunosuppression may be enough to shift mTOR activity towards a healthier, lower level in vivo, 3. accepting the potential trade-offs: a 5-10% increase in life-expectancy would compare favorably to mild immunosuppression, for instance.

Study I. Familial adenomatous polyposis is a condition that leads to a massive increase in colorectal cancer incidence and it is caused by APC mutations. Rapalogs (Rapamycin analogs) have been approved for some cancers and now Faller et al. (1) found that rapamycin can protect APC deficient mice from cancer.

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: