Samstag, 28. März 2015

Is complex I the culprit? Is it as easy as that?


Rapamycin, complex I and mitochondrial ROS
Despite plenty of controversy there is ample support for the mitochondrial free radical theory of aging. Here, I want to highlight some recent findings implicating complex I in mtROS production and aging.
Two recent papers (2, 4), Fok and Miwa, both find subtle reductions of specific complex I subunits after rapamycin treatment using *omic approaches. Miwa using proteomics and Fok using transcriptomics. Miwa et al. also showed decreased complex I and superoxide production after calorie restriction and reductions of complex I in a longer vs a shorter-lived strain. These changes were most pronounced in the matrix arm of complex I. Fok (4) studied chronic rapamycin feeding using transcriptomics ("Illumina Mouse Ref8 microarray") and found:
"The majority of the transcripts that change in complex I and II transcripts decrease while complex III, IV, and V transcripts that change increase in chronic Rapa-fed female and Rapa-2 male mice."

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. 
Better yet not judge any of data, if your understanding comes only from popular science articles. I welcome comments by everyone, including lay people, as long as they are informed. I'll briefly mention another controversy for the sake of completeness:

Addendum: Does CR work in wild-derived or heterogenous mice?
This is important since these mice are more representative of healthy animals than, say, gluttonous black 6 mice. As in primates, I think the preponderance of evidence says "yes". A recent paper on the "yes"-side of the equation includes a review of other studies as well (2). This includes the negative study by Liao, Rikke et al. and Harper et al. with wild-derived mice.

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.

2. J Gerontol A Biol Sci Med Sci. 2010 Dec;65(12):1275-84. doi: 10.1093/gerona/glq155. Epub 2010 Sep 5.
Life extension by diet restriction and N-acetyl-L-cysteine in genetically heterogeneous mice.
Flurkey K1, Astle CM, Harrison DE.

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).


Accumulation of senescent cells in baboon skin (2)
The majority of 53BP1 foci (62 ± 7.7%) colocalized with telomeric DNA, thus classifying them as TIFs … The frequency of TIF-positive nuclei increased exponentially with age, reaching a value of 15 to 20% in very old animals

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.