Mittwoch, 13. Mai 2015

The oxidative stress theory of aging - concepts and limitations

What do we know about the involvement of oxidative stress in disease?
Definitely not enough. The speakers at MiP-School London reminded us that researchers use the term "ROS" as explanation to hide behind with little explanatory value. Berry Halliwell (3,4) and Mike Murphy (6) gave fascinating talks on this topic. I would like to add a more biogerontologic perspective.

A deep mechanistic understanding of how ROS regulate lifespan might be called for, but I don't think we should over-emphasize detailed understanding in the field of aging as a whole. Gerontology is difficult. There are enough basic questions still unanswered. (Is calorie restriction a universal mechanism? Are current models of mouse lifespan extension redundant/convergent? etc.)

Historically, progress has come from rather crude phenotypic screens. Calorie-restriction was discovered before the Second World War, using mice without fancy molecular biology. To me, the whole Interventions Testing Programme is one big, naive phenotypic screen (readout = dead mice). The rationale for some of the tested compounds is almost cringe-worthy. Guess what? It's the most successful programme in the world, yielding multiple promising leads. Particularly, Rapamycin. To test rapamycin as a CR-mimetic we do not need to understand the underlying biology in any detail. Unsurprisingly, the first data on the mTOR pathway was generated using simple phenotypic screens in yeast and 6 years after the rapamycin lifespan study, we still do not understand the mTOR pathway very well. The big invention by the ITP, and others like Spindler, were perfect animal husbandry and a modicum of understanding.

Given how little we understand about aging, the naive phenotypic screen will remain a worthwhile strategy. Knowing "just enough" is often quite useful. However, the naive approach to the oxidative stress theory of aging has produced conflicting results. Is it time to re-consider some of the basics?

Samstag, 4. April 2015

NIA's intervention testing program (ITP) - where does the journey take us now?

While this paper briefly outlines the history of the "intervention testing program", trying to find life extending drugs in mice, I want to comment on a tangential paragraph. As is known to anyone following the literature, the ITP identified rapamycin as the first drug to robustly extend maximum life span. Now the question arises how best to translate this data to humans? One important step will certainly be a long term study in long-lived animals.

And there exists an ingenious proposal for such a project (1, 2):

Matt Kaeberlein and Daniel Promislow at the University of Washington ... have been considering the potential value of a study in dogs living freely in the same environmental conditions as humans. They propose a small trial using 60 pet dogs that typically have life spans of 8–10 years, 30 of which would receive rapamycin and 30 would not. The trial would be started at 6 years of age, and the dogs would be monitored for cardiac function and other aging phenotypes such as development of type 2 diabetes and cancer until death. Such a study might reveal whether rapamycin retards aging per se, or acts principally by reducing late-life disease, but a larger study will probably be necessary to establish this unequivocally.

This basically outsources the lab work to pet owners. The idea is obviously brilliant, though, not completely novel. I have myself briefly collaborated on a project trying to get this done with mice. One of the biggest hurdles is getting enough people to participate - since such study must be large due to increased heterogeneity inherent to its design. Thus coordinating such a project through a university or some other body that is able to promote it makes sense. It goes without saying that large scale roll-out of this study type could save billions of dollars at virtually no cost.

The dog project by Kaeberlein is open to donations (3). Curiously, his wordpress page layout is even uglier than my blog. Unbelievable!

1. Age (Dordr). 2015 Apr;37(2):9761. doi: 10.1007/s11357-015-9761-5. Epub 2015 Mar 1.
NIA's intervention testing program at 10 years of age.
Warner HR

2. Hayden EC (2014) Pet dogs set to test anti-aging drug. Nature 514: 546

3. http://dogagingproject.com/help-us/

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. 

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.