Conference: Systems Biology of Aging, Buck Institute, November 2009

From the mailbag (admittedly, it was the interdepartmental mail):

SYSTEMS BIOLOGY OF AGING SYMPOSIUM November 10-13, 2009

Buck Institute for Age Research
8001 Redwood Blvd.
Novato, CA 94945

The 2009 Buck Institute Symposium on Systems Biology and Aging will bring together renowned researchers from diverse backgrounds to discuss the emerging synergies between new technologies, integrative biology, aging, and age-related disease.

Rest assured that the scientists who work at the Buck don’t actually utter phrases like “emerging synergies”; I have no idea who they think that will appeal to. The web page for the symposium is still a work in progress, so that might just be a filler paragraph.

The roster of speakers is already damn impressive; it should be a great meeting.

 

Sexing up the soma: Long-lived mutants express germ line genes in somatic tissues

We are all descendents of an unbroken line of cell divisions, dating back to the last common ancestor of all life on Earth. At some point, long after our lineage had acquired features like nuclei and mitochondria, a less distant ancestor stumbled on a major innovation: it grew a body, bringing with it the advantages of cell and tissue specialization.

For many multicellular organisms, this specialization included a distinction between the mortal cells (the “soma”) and the potentially immortal cells (the “germ line”) that are capable of participating in the creation of new organisms. When you look at us, most of what you see is soma — the germ line is safely tucked away in the gonad, which is (usually) itself tucked away someplace safe.

But both the germ line and soma are made of cells. How is it that the soma is mortal while the germ line is, for practical purposes, immortal?

The disposable soma theory of aging begins from the premise that an organism has access to a finite amount of resources (broadly, energy and matter), and that it must distribute these resources in a way that maximizes reproductive fitness. First dibs goes to the germ line (without which it doesn’t matter, in a fitness sense, what becomes of the rest of the organism) and the rest gets divided among the cells of the soma.

For the moment, all we really need to take away from this model is that the germ line and soma are maintained in different ways, either in quality or extent. The germ line is doing something differently than the soma, the upshot of which is that the germ line is immortal. (A strict interpreter of the theory would presume that this “something” is resource-intensive, so that it wouldn’t be possible to apply the strategy to the soma. It’s also possible, however, that it’s simply inconsistent with optimal somatic functions — e.g., that making a muscle the best muscle it can be requires that myocytes not partake of the germ line strategy for immortality, for some structural reason that has nothing to do with resource allocation per se.)

One oh-wow corollary of this model is that if somatic cells could be made more like germ line cells, they would live longer. This prediction has a deliciously outrageous quality — yet is so simple that upon first hearing it, I reached for the nearest journal with the intention of rolling it up and smacking myself repeatedly on the forehead. Fortunately, there was a copy of Nature handy.

To be honest, it didn’t really happen that way. That copy of Nature contained the very article that introduced me to this concept: Curran et al. have shown that in long-lived mutants of the worm C. elegans, somatic tissues start acting like germ line cells:

A soma-to-germline transformation in long-lived Caenorhabditis elegans mutants

Unlike the soma, which ages during the lifespan of multicellular organisms, the germ line traces an essentially immortal lineage. Genomic instability in somatic cells increases with age, and this decline in somatic maintenance might be regulated to facilitate resource reallocation towards reproduction at the expense of cellular senescence. Here we show that Caenorhabditis elegans mutants with increased longevity exhibit a soma-to-germline transformation of gene expression programs normally limited to the germ line. Decreased insulin-like signalling causes the somatic misexpression of the germline-limited pie-1 and pgl family of genes in intestinal and ectodermal tissues. The forkhead boxO1A (FOXO) transcription factor DAF-16, the major transcriptional effector of insulin-like signalling, regulates pie-1 expression by directly binding to the pie-1 promoter. The somatic tissues of insulin-like mutants are more germline-like and protected from genotoxic stress. Gene inactivation of components of the cytosolic chaperonin complex that induce increased longevity also causes somatic misexpression of PGL-1. These results indicate that the acquisition of germline characteristics by the somatic cells of C. elegans mutants with increased longevity contributes to their increased health and survival.

Just to be clear: the somatic tissues of the long-lived mutants had not actually transformed into germ line cells as such, nor were the mutant worms festooned with extra gonads (though admittedly, that would be totally awesome). Rather, the somatic tissues exhibited gene expression patterns ordinarily found only in the germ line.

On the correlation vs. causation issue: The authors showed, using RNAi knockdowns, that the germ line-restricted genes were required for the longevity enhancement due to the mutation in daf-2 (worm insulin/IGF). There’s a bit of a wrinkle: in wildtype animals, blocking these same genes actually resulted in an increase in lifespan. How to explain that? The proffered rationale is that in the wildtype, germ line-restricted genes are only present in the germ line. Knocking them down has no effect on somatic tissue, but might reduce the activity of germ line cells; it’s been known for some time that ablating part of the gonad has life-extending consequences in wildtype animals.

The critical observation, in any case, is that the germ line genes are turned on in daf-2 mutants, and this activation is necessary in order for daf-2 mutation to extend lifespan.

Next questions, in rough order of difficulty:

1. Does the soma-to-germ line transition occur in other long-lived mutants, or in calorie restricted animals?
2. By what mechanisms are the germ line-restricted genes extending the somatic lifespan?
3. Will this finding generalize to other metazoans?
4. Do the germ line genes expressed in daf-2 soma contribute to germ line immortality?

Curran, S., Wu, X., Riedel, C., & Ruvkun, G. (2009). A soma-to-germline transformation in long-lived Caenorhabditis elegans mutants Nature DOI: 10.1038/nature08106

 

Unfolding the role of the hypoxic response in aging

The TOR (”target of rapamycin”) protein is a master regulator of cell growth, governing connect nutrient sensing, protein synthesis, and proliferation. It has become increasingly clear that the TOR pathway plays an essential role in longevity determination — specifically, higher TOR activity is associated with more rapid aging and shorter lifespan.

In mammals, TOR interferes with stem cell functions, and TOR activity is downregulated by exercise. It has been proposed that TOR inhibitors might even be used as anti-aging drugs (and in fact we’re going to investigate some recent relevant tests of that idea, sometime next week). The relationship between TOR and lifespan holds true across great evolutionary distances: loss of TOR function (in conjunction with other mutations) can dramatically increase the chronological lifespan of yeast.

How does TOR control the rate of aging? In order to answer this question, we must look downstream, to proteins that are controlled by TOR. A recent study from the Kapahi lab (our neighbors at the Buck Institute for Age Research) investigated the role of one such TOR target: HIF-1 (”hypoxia inducible factor”; it is also involved in metabolism). The authors find that loss-of-function mutations in HIF-1 result in longer-lived C. elegans. Chen et al.:

HIF-1 Modulates Dietary Restriction-Mediated Lifespan Extension via IRE-1 in Caenorhabditis elegans

Dietary restriction (DR) extends lifespan in various species and also slows the onset of age-related diseases. Previous studies from flies and yeast have demonstrated that the target of rapamycin (TOR) pathway is essential for longevity phenotypes resulting from DR. TOR is a conserved protein kinase that regulates growth and metabolism in response to nutrients and growth factors. While some of the downstream targets of TOR have been implicated in regulating lifespan, it is still unclear whether additional targets of this pathway also modulate lifespan. It has been shown that the hypoxia inducible factor-1 (HIF-1) is one of the targets of the TOR pathway in mammalian cells. HIF-1 is a transcription factor complex that plays key roles in oxygen homeostasis, tumor formation, glucose metabolism, cell survival, and inflammatory response. Here, we describe a novel role for HIF-1 in modulating lifespan extension by DR in Caenorhabditis elegans. We find that HIF-1 deficiency results in extended lifespan, which overlaps with that by inhibition of the RSKS-1/S6 kinase, a key component of the TOR pathway. Using a modified DR method based on variation of bacterial food concentrations on solid agar plates, we find that HIF-1 modulates longevity in a nutrient-dependent manner. The hif-1 loss-of-function mutant extends lifespan under rich nutrient conditions but fails to show lifespan extension under DR. Conversely, a mutation in egl-9, which increases HIF-1 activity, diminishes the lifespan extension under DR. This deficiency is rescued by tissue-specific expression of egl-9 in specific neurons and muscles. Increased lifespan by hif-1 or DR is dependent on the endoplasmic reticulum (ER) stress regulator inositol-requiring protein-1 (IRE-1) and is associated with lower levels of ER stress. Therefore, our results demonstrate a tissue-specific role for HIF-1 in the lifespan extension by DR involving the IRE-1 ER stress pathway.

The mutants’ life extension was observed when the worms could eat ad libitum but not when they were dietarily restricted (DR), implying that the mechanism of the HIF-1 mutation is similar to that of DR. Conversely, activation of HIF-1 expression (by mutating EGL-9, which ubiquitinates HIF-1) decreases the lifespan extension due to DR. Taken together, the findings imply that downregulation of HIF-1 expression is both necessary and sufficient for DR-mediated longevity enhancement.

One more step down the rabbit hole, then: What are HIF-1 and DR doing? The authors find that lifespan extension requires the IRE1-gene, a principle mediator of the unfolded protein response (UPR). The UPR is activated when the endoplasmic reticulum (ER) is stressed — when protein folding is inefficient, or the secretory machinery is overloaded; the pathway returns the cell to homeostasis by inducing expression of genes that fold, sort, and process proteins in the ER (or degrade the proteins that can’t be saved). Perhaps lifespan extension requires increased ER capacity, or more efficient degradation of misfolded proteins?

On a closing note: Attentive readers will have recalled that not very long ago, we reported on a paper that appears to have reached the opposite conclusion — specifically, that high expression of HIF-1 (induced the same way as here, by mutation in the ubiquitin E3 ligase EGL-9) results in extended lifespan and decreased proteotoxicity. I don’t want to get in the middle of this controversy, except to point out that the systems were different in a number of ways, and that it is a formal possibility that a gene’s activity could be “tuned” such that either an increase or a decrease in expression could increase lifespan (implying that the wildtype expression levels are at a “sweet spot” of lower lifespan but presumably higher fitness, due to some sort of tradeoff between longevity and reproductive success). I am sure that the authors of both studies are working to reconcile the apparent contradiction. We’ll look forward to learning more as the story develops.

Chen, D., Thomas, E., & Kapahi, P. (2009). HIF-1 Modulates Dietary Restriction-Mediated Lifespan Extension via IRE-1 in Caenorhabditis elegans PLoS Genetics, 5 (5) DOI: 10.1371/journal.pgen.1000486

 

Hourglass X

Welcome to the tenth edition of Hourglass, our blog carnival about the biology of aging. This month, the carnival has returned home to Ouroboros. In this issue, we have submissions from six bloggers, including a nice mix of veterans and new participants. Several of the posts are united by common themes: we have heavy representation from the neuroscience community, and multiple discussions of the clinical and social payoffs that are likely to result from progress in lifespan extension.

At psique (which hosted Hourglass IX), Laura Kilarski describes an important, evolving online tool for biogerontologists: the Human Aging Genomics Resources:

As I was reading a paper earlier about chromosomal region 11.5p and its putative association with aging (Lescai et al, 2009) I came across an interesting sounding url, namely http://genomics.senescence.info. Turns out that the website is home to HAGR, an interdisciplinary project devoted to the genetic study of aging … GenAge constitutes a major part of the site, and is a manually curated database of genes which could possibly be associated with human aging, largely based on studies done on the usual suspects: Mr. Mouse, Drosophila, C. elegans, and yeast. … The AnAge database on the other hand contains entries for over 4000 animals and some basic life-span-related facts. … And then there’s the ‘Δ Project’, the aim of which is to figure out transcriptional differences between young and old organisms.

Laura describes HAGR in depth and also provides some of her own analysis of the available resources.

On another age-related subject, neurodegeneration, Laura discusses the potential value of regular brain scans for early ascertainment of diseases such as Parkinson’s. Free brain scans for all! It’s a moving piece, which underscores the human cost of neurodegenerative illness and describes the author’s personal reactions on the subject, while also addressing important clinical and scientific issues.

As we age, we all suffer from some level of neurodegeneration, though in most cases this falls below the threshold of a clinical pathology. Slow chronic change isn’t the only form of age-related brain damage: let’s not forget about strokes, which can wipe out otherwise healthy neurons in macroscopic regions of the brain. While the risk factors for stroke and neurodegeneration are distinct, therapies might ultimately be quite similar — since in both cases, the goal is to regrow neurons to replace those that have been lost. At Brain Stimulant, Mike tell us about a clinical trial that will use stem cells to treat stroke:

The company Reneuron has just recently gotten the go ahead to commence a new trial that will use stem cells to treat patients with stroke damage. The trial will use stem cells to replace missing brain matter in those who have had stroke brain trauma. They are injecting doses of approximately 20 million stem cells into the stroke patients brain. Interestingly these ReN001 stem cells will not require a patient to have immunosuppression therapy.

He goes on to discuss the future challenges posed by the prospect for brain engineering: precise cell delivery, control of axon sprouting and pathfinding, and the possibility of using non-invasive methods to encourage the growth of new cells.

Also coming from a neuroscience perspective, Christopher Harris of Best Before Yesterday writes about What we need to accelerate biomedical research and fight aging.

A few hundred years ago I could not have been born. I was massive – 5.5kg – and the birth eventually turned caesarean and took many long hours. I owe my life to medical science. One day, 11 years later, I was out biking and realized for the first time that the annihilation following my death would be infinite. Now, 25 years after my complicated birth, I think a lot about whether medical science, rejuvenation research of the SENS variety in particular, will save me a second time.

What do we need? According to Harris: (1) Safe and inexpensive brain surgery (to install devices that can manipulate the reward circuitry of the brain); (2) Widespread use of enhanced motivation through deep brain stimulation (specifically to encourage exercise and healthy living); and (3) Rewarding brain stimulation for research centers (to accelerate scientific progress).

One of my favorite new sites, the Science of Aging Timeline, has a new entry about the Sinclair lab’s discovery of sirtuin-activating compounds:

Working off a model of calorie restriction via sirtuins David Sinclair et al. worked to find molecules which could modulate sitruins activity, and thus longevity.

They accomplished this by screening a number of small molecule libraries, which included analogues of epsilon-acetyl lysine, NAD+, NAD+ precursors, nucleotides and purinergic ligands. Results from the screening where assayed against human SIRT1 to identify potential inhibitors, and the following molecules where found: Resveratrol, Butein, Piceatannol, Isoliquiritigenin, Fisetin, and Quercetin. Of all of these, resveratrol proved to be the most potent …

In the copious spare time left when he’s not working on the comprehensive history of biogerontology, timeline curator Paul House has started another ambitious project: a catalog of all the labs working on aging. It’s early days yet, and only a few labs are listed, but I’ve already seen Paul take one great idea (the timeline) from seed to oak, so I have every confidence that this page will grow substantially in the weeks and months to come. Those who are interested in having their labs listed on the page can send Paul an email.

Over at Fight Aging!, Reason continues excellent coverage of recent papers in biogerontology; I daresay that the detail of coverage on primary scientific literature has improved even further in the past month or so, concomitant with the site’s participation in the ResearchBlogging tracking system for blog posts about journal articles. For this edition of Hourglass, Reason has submitted two excellent analyses of recent papers, and a third piece of a more philosophical bent:

• Autophagy and cellular senescence
• Accumulating Mitochondrial DNA Damage: More Harm or Less Repair?
• Lazy immortality

It is from the last piece that I’ve chosen an excerpt:

Wouldn’t it be nice to wake up and find that we were all immortal? That would save a whole lot of work, uncertainty, and existential angst – and we humans are nothing if not motivated to do less work. The best of us toil endlessly in search of saving a few minutes here and a few minutes there. So it happens that there exist a range of metaphysical lines of thought – outside the bounds of theology – that suggest we humans are immortal. We should cast a suspicious eye upon any line of philosophy that would be extraordinarily convenient if true, human nature being what it is.

Moving on from a philosophical post written by a scientifically minded life-extension advocate, our next posts are scientific posts written about life extension from a political philosopher. Colin Farrelly of In Search of Enlightenment has submitted two long, thoughtful articles, the first about the clinical and social importance of tackling aging, the second about the cognitive biases that affect the way we think about risk and the significance of aging as a cause of mortality:

• Idealism Meets Realism: Tackling Chronic Disease Via Age Retardation
• The Availability Heuristic and the Inborn Aging Process

The “availability heuristic” was a new one on me. Here’s an operational definition as it applies to our thinking about aging:

In a rational world, aging research would be at the forefront of a global collaborative initiative to improve the health and economic prospects of today’s aging populations (and all future generations).

But humans are not rational. We suffer many cognitive biases. One prominent bias is the availability heuristic. Risks that are easily brought to mind are given a higher probability; and conversely, the less vivid a risk, the more likely we are to underestimate the probability of their occurring.

The two tests above reveal how prominent this heuristic is in your own comprehension of the risks facing yourself, your loved ones and humanity. Because death by aging is not something that is vivid is most people’s minds (though it is in the minds of the scientists who study the biology of aging and thus know all too well how it affects a species functional capacities), odds are you probably underestimated it as a risk of mortality.

The benefits of lifespan extension, both with regard to human health and society as a whole is sometimes called the Longevity Dividend. Alvaro Fernandez from SharpBrains sent in a long piece about the Longevity Dividend (written by a contributor from the Kronos Longevity Research Institute). Ever heard of the Longevity Dividend? Perhaps Gray is the New Gold:

The Longevity Dividend is a theory that says we hope to intervene scientifically to slow the aging process, which will also delay the onset of age-related diseases. Delaying aging just seven years would slash rates of conditions like cancer, diabetes, Alzheimer’s disease and heart disease in half. That’s the longevity part. … The dividend comes from the social, economic, and health bonuses that would then be available to spend on schools, energy, jobs, infrastructure—trillions of dollars that today we spend on healthcare services. In fact, at the rate we’re going, by the year 2020 one out of every $5 spent in this country will be spent on healthcare. Obviously, something has to change.

Alvaro, the editor of SharpBrains and founder of the parent website, has recently published a book, The SharpBrains Guide to Brain Fitness, which is the subject of this recent (and quite favoriable) review. If you’re interested in learning more, here’s list of cognitive fitness references, based on the authors’ research for the book.

That’s all for now. If you’d like to host a future installation of Hourglass, please email me.

 

How life imitates pranks: Issues and ethics of cognitive enhancement

In 2008 I was involved in an April Fool’s Day prank: a horde of science bloggers, under the sway of a charismatic yet psychotic leader, all conspired to publish the same fake story: that the NIH and European science funding bodies had decided to ban the use of grant funds by scientists who engage in “brain doping”, i.e., mental performance enhancement through the use of pharmaceuticals.

The prank was relatively successful — enough so that mastermind Jon Eisen got calls from reporters pursuing it as a legitimate story — but we can’t take all the credit. The fake story was believable in large part because it was so close to the truth: “brain doping” is actually very widespread, enough so that several entities in the mainstream media had already pondered its potential effects on the “level playing field” of academic science (see the list in the original prank post).

Margaret Talbot’s recent New Yorker piece is probably the longest and most comprehensive treatment of the subject I’ve seen so far. It starts with a discussion of brain doping by students but also considers their role in the workplace and the medical, ethical and sociological implications of cognitive enhancement (though, happily, it doesn’t spend very much energy hand-wringing over worst-case scenarios resulting from use and abuse of such approaches). There’s even a connection to lifespan extension (link):

BRAIN GAIN: The underground world of “neuroenhancing” drugs

And on Internet forums such as ImmInst, whose members share a nerdy passion for tweaking their cognitive function through drugs and supplements, people trade advice about dosages and “stacks”—improvised combinations—of neuroenhancers. …

Seltzer considers himself a “transhumanist,” in the mold of the Oxford philosopher Nick Bostrom and the futurist writer and inventor Ray Kurzweil. Transhumanists are interested in robots, cryogenics, and living a really, really long time; they consider biological limitations that the rest of us might accept, or even appreciate, as creaky obstacles to be aggressively surmounted. On the ImmInst forums—“ImmInst” stands for “Immortality Institute”—Seltzer and other members discuss life-extension strategies and the potential benefits of cognitive enhancers.

I’ve argued before that there are profound similarities between some of the ethical issues raised by cognitive enhancement and those raised by lifespan extension, especially in the structure of the arguments underlying opposition to these kinds of intervention. For those of us interested in expanding human longevity, it will be wise to keep abreast of the discussion.

 

Hourglass X: Call for submissions

The tenth installation of Hourglass, a monthly blog carnival devoted to the best blogging about biology of aging, will appear here at Ouroboros on Tuesday, June 9th.

The carnival’s mission:

Topics of posts should have something to do with the biology of aging, broadly speaking — including fundamental research in biogerontology, age-related disease, ideas about life extension technologies, your personal experience with calorie restriction, maybe even something about the sociological implications of increased longevity. Opinions expressed are not necessarily those of the management, so feel free to subvert the dominant paradigm. If in doubt, submit anyway.

Submissions should be emailed to [hourglass.host][at][gmail][dot][com].

In the meantime, feel free to check out previous editions of the carnival.

By the way, if you’d like to volunteer to host, please email me directly — basically the rest of 2009 is wide open. If you’ve already hosted before, don’t let that hold you back; while the carnival is young, some repeat hosting is going to be par for the course.

 

Did aging evolve to prevent epidemics?

How did aging evolve? Some evolutionary theories invoke tradeoffs between maintenance/repair and reproduction. Others postulate that genes that cause age-related decline can be positively selected, so long as these same genes confer a fitness advantage early in life.

A common feature of these theories is that they operate at the level of the individual organism, rather than the species. Models based on group selection usually have logical problems. For example, suppose that aging evolved in order to eliminate post-reproductive old organisms to preserve resources for the reproductively competent young. This is circular: Why are the old organisms were post-reproductive in the first place? i.e., the model presupposes some age-related decline in organ system function in order to rationalize the evolution of aging.

OK, so suppose that the old remain fertile, but eliminate themselves to avoid competition with their own offspring; reproductive senescence then evolves later since there’s no positive selection pressure for maintaining reproductive function over the long term. Problem: What’s the point? If both old and young are making copies of the same genes, there’s no fitness advantage in eliminating the old — especially in light of the fact that most of the offspring’s competition would be coming not from their own parents and grandparents but from more distantly related members of the same species. (And in sexual organisms, you are a better copy of your own genes than your offspring, who have only half of your alleles. Far better to stick around and show the kids how it’s done, than ride off into the sunset to clear the path for these dilutions of oneself.)

Group selection of aging is also vulnerable to “defectors” — mutants who take advantage of the situation to spread their own selfish genes. Suppose that there is some species-level advantage to aging, such that it emerges as a positively selected trait. As organisms age, they actively decrease their own viability in such a way that they have an increased mortality. The species benefits (somehow) at the cost of the individual fitness of these “cooperators.” But then along comes a defector mutant, who doesn’t age and continues to reproduce while the cooperators are pushing up the daisies. Unless the species-level advantage is overwhelming, it’s clear that the defector trait will spread within the population.

Ultimately, then, the reason why group selection models don’t satisfactorily explain the evolution of aging is that it’s hard to imagine a scenario in which a species-level advantage conferred by aging could outweigh the organism-level advantage conferred by not aging.

Such a scenario might now have been imagined. Mitteldorf and Pepper postulate that senescence could have evolved in order to prevent the spread of disease epidemics in populations:

Senescence as an adaptation to limit the spread of disease

Population density is a robust measure of fitness. But, paradoxically, the risk of lethal epidemics which can wipe out an entire population rises steeply with population density. We explore an evolutionary dynamic that pins population density at a threshold level, above which the transmissibility of disease rises to unacceptable levels. Population density can be held in check by general increases in mortality, by decreased fertility, or by senescence. We model each of these, and simulate selection among them. In our results, senescence is robustly selected over the other two mechanisms, and we argue that this faithfully mirrors the action of natural selection. This picture constitutes a mechanism by which senescence may be selected as a population-level adaptation in its own right, without mutational load or pleiotropy. The mechanism closely parallels the ‘Red Queen hypothesis’, which is widely regarded as a viable explanation for the evolution of sex.

OK, so, how might this work?

Epidemiology is, by definition, a population-level issue, and there’s already precedent for selection pressure based on disease susceptibility guiding evolution at the species level (e.g., the diversity of major histocompatibility loci).

The trick is to get the pressures at the individual and group levels to point in the same direction: If I (an organism) am more susceptible than average to a given disease, and that susceptibility has a genetic component, then my closest relatives (who share most of my genes) are likelier than the general population to be susceptible as well. Therefore, my continued existence poses a risk for my progeny, because I represent one more potential host for a pathogen that might infect them – potentially killing us all and ending the line altogether. One way to deal with that problem is to eliminate hosts, and the authors’ model shows that senescence is a reasonable way to achieve that end.

Mitteldorf, J., & Pepper, J. (2009). Senescence as an adaptation to limit the spread of disease Journal of Theoretical Biology DOI: 10.1016/j.jtbi.2009.05.013

 

“What if you could think a thought at the world and have the world think back?”

In collaboration with the estimable Vivan Siegel, I’m writing a series of op/ed articles on the future of scientific publishing. The first of these was about the challenges of filtering the scientific literature. The second piece, explores the prospect of using “Web 2.0″ approaches to accelerate scientific progress. The article starts from the assumption that sharing is a good thing, and considers the ways in which social networking and other types of internet-powered tools might help scientists share more efficiently. We begin with a description of a long-term, somewhat pie-in-the-sky goal before returning to earth to evaluate the current state of the art (link):

This revolution will be digitized:
online tools for radical collaboration

But let us entertain the thought that the ideal size of the collaborative unit might be much larger than the average research group of today, and that we lived in a world in which scientific efforts were organized around this principle. How might evolving information technologies allow science to progress more rapidly? In such a world, we might choose to organize scientific efforts differently: not according to physical proximity in labs or departments, but rather by aptitude, expertise and availability. Rather than thinking of projects as the virtual property of small groups, we would simply broadcast ideas (or data) until they reached the right person(s) to take the next step. …

In other words, what if you could think a thought at the world and have the world think back? What if everyone in the world were in your lab – a ‘hive mind’ of sorts, but composed of countless creative intellects rather than mindless worker ants, and one in which resources, reagents and effort could be shared, along with ideas, in a manner not dictated by institutional and geographical constraints?

There’s another piece in the works, probably about the publication of results that fall below the threshold of a “publishable unit”. Others have written extensively on this subject, and there are a number of solutions to this problem out in the wild, so I’m currently absorbing all of that information and determining whether I have original thoughts on the subject.

Patil, C., & Siegel, V. (2009). This revolution will be digitized: online tools for radical collaboration Disease Models and Mechanisms, 2 (5-6), 201-205 DOI: 10.1242/dmm.003285

 

Why We Blog

A couple of months ago I lamented that scientific blogging would probably be unable to serve as an effective “filter” for the scientific literature. Scientists struggle to keep up with the literature in their own field (let alone related fields), and it would be nice if someone could pre-screen emerging papers in a way that would decrease the time and effort involved in keeping current. For a variety of reasons, I think it’s unlikely that science blogs will be able to serve this function.

But filtering isn’t the only justification for the existence of science blogs, as is made clear by a recent bumper crop of blog posts and articles about science blogging. Blogging can help an individual scientist share ideas with colleagues and spread the word about one’s own work. Some see blogs as increasingly essential to the process of self-promotion, whereas others see an opportunity to fill growing holes in the fabric of conventional science journalism. There is a consensus that blogging is less prestigious than other kinds of scientific publishing, but as participation grows, this may change.

In rough order of the ideas presented in the previous paragraph, I present these pieces here for your delectation:

• It’s good to blog (Nature editorial)
• Is it becoming dangerous to not blog? (Useful Chemistry)
• Scientific blogging: Ignore it and be ignored? (Depth-First)
• Filling the void (Nature editorial)
• Science journalism: Supplanting the old media? (Nature news feature)
• Science Blogging plus/vs Science Journalism (A Blog Around The Clock)
• How to broaden the reach and legitimacy of blogging to practicing scientists (Terra Sigillata)

 

Found in (mis)translation: A novel role for protein synthesis fidelity in aging

The idea that translation fidelity might play a role in aging dates back at least as far as 1963, when Leslie Orgel proposed the “error catastrophe” theory of aging: in this model, mistranslation of the translational machinery creates a feedback loop that leads to further translation errors, ultimately causing loss of cell viability. From the Science of Aging Timeline:

Orgel considers two types of proteins: those involved in metabolism, and those involved in information processing. For metabolic proteins, translational error isn’t a long-term problem for the cell, since a malfunctioning protein is simply one of many. Likewise, for translational errors causing loss of function in information processing proteins: the error isn’t heritable, and a small decrease in the efficiency of gene expression is unlikely to pose a serious problem.

However, information processing proteins can be altered in another way: by mutations that decrease the fidelity with which they process or propagate genetic information. Lower-fidelity transcription and translation will result in more mutations. This is the core of Orgel’s idea: “errors which lead to a reduced specificity of an information-handling enzyme lead to an increasing error frequency. Such processes are clearly cumulative and…in the absence of an imposed selection for “accurate” protein-synthesizing units, must lead ultimately to an error catastrophe; that is, the error frequency must reach a value at which one of the processes necessary for the existence of viable cell becomes critically inefficient.”

The logic of the feedback loop is compelling, but the theory suffered for lack of experimental verification. While there is still some controversy over whether error catastrophe has received a full and fair experimental test, the consensus appears to be that while error catastrophe can take place under some systems (e.g., viral replication in the presence of drugs that reduce polymerase fidelity), this phenomenon does not play a role in mammalian aging: the measured values of the relevant parameters (basal translation error rates; the likelihood that a given error will result in further alteration to translation fidelity; protein lifetimes; etc.) appear to be such that the feedback loop doesn’t actually occur.

The error catastrophe theory is still an important waypoint in the evolution of theories of aging, and it has had tremendous influence in other areas within biogerontology. For example, similar logic has been applied to the role of autophagy in aging, where the feedback loop is called the garbage catastrophe.

And even if the feedback-loop logic doesn’t hold up to experimental scrutiny, recent findings have revealed that there may nonetheless be a relationship between protein translation fidelity and aging. Writing in PLoS ONE, Silva et al. report that in yeast, increasing the rate of translation errors might increase the activity of the longevity assurance gene SIR2:

The Yeast PNC1 Longevity Gene Is Up-Regulated by mRNA Mistranslation

Translation fidelity is critical for protein synthesis and to ensure correct cell functioning. Mutations in the protein synthesis machinery or environmental factors that increase synthesis of mistranslated proteins result in cell death and degeneration and are associated with neurodegenerative diseases, cancer and with an increasing number of mitochondrial disorders. Remarkably, mRNA mistranslation plays critical roles in the evolution of the genetic code, can be beneficial under stress conditions in yeast and in Escherichia coli and is an important source of peptides for MHC class I complex in dendritic cells. Despite this, its biology has been overlooked over the years due to technical difficulties in its detection and quantification. In order to shed new light on the biological relevance of mistranslation we have generated codon misreading in Saccharomyces cerevisiae using drugs and tRNA engineering methodologies. Surprisingly, such mistranslation up-regulated the longevity gene PNC1. Similar results were also obtained in cells grown in the presence of amino acid analogues that promote protein misfolding. The overall data showed that PNC1 is a biomarker of mRNA mistranslation and protein misfolding and that PNC1-GFP fusions can be used to monitor these two important biological phenomena in vivo in an easy manner, thus opening new avenues to understand their biological relevance.

PNC1 is a longevity gene because its biochemical activity feeds into the sirtuin pathway: Pnc1p synthesizes nicotinic acid from nicotinamide, which is an inhibitor of Sir2p, one of the canonical longevity factors in S. cerevisiae. Overexpression of PNC1 increases lifespan, presumably by increasing the activity of Sir2p. (The authors show that Sir2p silencing activity is elevated under conditions that cause mistranslation, and that this is inhibited by exogenous nicotinamide. Missing, as far as I can tell, is the same experiment in ∆pnc1 cells, which according to the authors’ model would not induce silencing during mistranslation.)

Is this simply an example of a general stressor activating a general stress response, whose constitutive activation in turn makes cells more stress-resistant and therefore longer-lived? For example, one could imagine a translation fidelity problem resulting in synthesis of lots of poorly folded proteins, leading to activation of the heat shock response and expression of chaperones (indeed, in the worm, heat shock transcription factor HSF-1 is required for life extension by daf-2 mutations). This doesn’t appear to be that. Instead, loss of protein fidelity causes upregulation of a major longevity assurance pathway, which acts primarily at the level of transcriptional silencing.

A couple of questions:

• What is the relevant molecular correlate of translation infidelity? Unfolded proteins would be the most likely culprit (prediction: whether or not it’s involved in the lifespan extension, there should be some heat shock response under these conditions), but one can imagine more elaborate scenarios: Suppose an inhibitor of PNC1 translation is encoded by an mRNA that is particularly likely to be mistranslated under normal conditions (e.g., because of weird codon usage, secondary structure, or some other quirk) and is now translated so poorly that it loses its inhibitory activity altogether (or acquires a new activity).

• How is the translational upregulation of PNC1 mediated? This is particularly curious given that, by assumption, a cell with a high rate of translation infidelity is having difficulty with translation. Teleologically, there’s no reason not to regulate gene expression at this level — if the gene were upregulated transcriptionally, the mRNA would still have to be translated — but it still strikes me as odd. If this is a bona fide evolved response to translation problems, wouldn’t it be better to pre-synthesize PNC1 and then activate it post-translationally (e.g. by proteolysis)?

• Is SIR2 involved in translation fidelity? Looking at this story as a straightforward stress response, one would expect some action of SIR2 to help mitigate the stress that started the whole process. So I’d be curious to know whether SIR2 mutants have lower translation fidelity, and if so, how it is that SIR2 is involved in improving the accuracy of translation?

Silva, R., Duarte, I., Paredes, J., Lima-Costa, T., Perrot, M., Boucherie, H., Goodfellow, B., Gomes, A., Mateus, D., Moura, G., & Santos, M. (2009). The Yeast PNC1 Longevity Gene Is Up-Regulated by mRNA Mistranslation PLoS ONE, 4 (4) DOI: 10.1371/journal.pone.0005212