Labs


(For the liveblog of the meeting as it unfolds, see here.)

Earlier this year, the biogerontologists of the San Francisco Bay Area held the first of a series of biannual research meetings, the Bay Area Aging Club. More or less right on schedule, the next meeting is in a couple of weeks on Saturday, December 4th.

It’s now the slightly more official-sounding Bay Area Aging Meeting, but the format is the same: A full day of talks from labs from all around the Bay Area, with lunch, and an opportunity to network with the large and growing local community of researchers in biogerontology and allied subjects. Last time the meeting was at UCSF; this time it’s at Stanford.

Here’s the initial event announcement from Stuart Kim. Note the registration link, which contains more detailed information about time and location. Registration is free.

Eric Verdin (Gladstone), Danica Chen (Berkeley) and I are organizing the next Bay Area Aging Meeting. This is a one day meeting to hear talks from students and post-docs from the Bay Area on aging. The meeting is on Saturday Dec. 4, 2010 at Stanford University, from 900 am to 5 pm. The last meeting in April at Gladstone was very successful with about 150 attendees.

There will be talks from students/post-docs in Bay Area Aging labs, as well as a poster session. The labs and topics are:

lab/topic
Brian Kennedy (Buck) Yeast aging
Simon Melov (Buck) worm aging
Martin Brand (Buck) mitochondrial biochemistry
Melanie Ott (Gladstone)SirT1 in T cells
Bob Farese (Gladstone) mouse metabolism
Cynthia Kenyon (UCSF) worm aging
Hao Li (UCSF) systems biology of yeast aging
Kunxin Luo (Berkeley) P53 and aging
Randy Schekman (Berkeley) intracellular traficking of APP
Anne Brunet (Stanford) mouse, worm or fish aging
Tom Rando (Stanford) stem cells and aging
Mark Davis (Stanford) human immune aging

Please reserve the day for the meeting. We will send out more information including the schedule soon. To receive more information about the meeting, register for the meeting, and sign up to give a poster, please go to:

https://www.onlineregistrationcenter.com/register.asp?m=288&c=2

Sincerely,
Eric, Danica and Stuart

The April meeting was a lot of fun. I live-blogged the event, which definitely kept my fingers flying. This year I’ll be doing that again, with some degree of official blessing/support. We’ll make some kind of an announcement at the beginning of the talks directing people to Ouroboros and encouraging them to participate in comments on the posts for each session or talk. I’ll also be spreading the word Twitter and/or FriendFeed, using hashtag #baam10, and hoping that others join in that as well.

Please come! The organizers want to reach “hard core aging people,” so if your research falls under that umbrella, register now. For a sense of how the meeting went last time, here are my posts:

P.S.: There’s no official website for BAAM yet. I’m thinking of whipping something up for them – basically for announcements and abstracts – but if anyone with experience would like to pitch in, drop me a line in the comments.

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:

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:

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.

My former collaborator, Professor Hao Li of UCSF’s Department of Biopharmaceutical Sciences, is looking for a postdoc to lead a project on “genomic approaches to understanding the mechanisms of aging,” using yeast as the model organism.

Candidates should have an interest in genomics and training in yeast as an experimental system. The project will involve analyzing the yeast proteome using tagged libraries and flow-cytometric methods, and will also involve design, development and implementation of microfluidics assays suitable for assaying yeast lifespan. Details of the project are still very much in a dynamic state, so there’s lots of room for creativity and input from the person who eventually takes the position.

Inquiries to haoli@genome.ucsf.edu.

The Li lab began as a primarily computational lab (the mission statement on Hao’s faculty page describes the group’s mission as “Development of theoretical and computational tools to extract biological information from genome sequences and the large quantity of data generated from experiments facilitated by various genome projects”), but in the past few years has definitely moved in a more experimental direction. Furthermore, the UCSF Tetrad program (the effectively borderless amalgam of departments and programs in which the Li lab operates) is a very collaborative environment, in which labs exchange knowledge and expertise very willingly. So this would be a great spot for a yeast biologist looking to add more quantitative and genome-scale approaches to their work.

(Speaking from my own direct experience, Hao is a great person to work with, and the UCSF Mission Bay campus is as close to scientific paradise as I’ve ever come.)

As I mentioned, I spent most of last week and weekend attending two unconferences, BioBarCamp and Scifoo.

By their very nature, unconferences tend not to converge on a single topic; over the past week, I paricipated in discussions whose topics ranged from the importance of database annotation to how mushrooms could save the world to the current technical considerations involved in settling Mars. Nonetheless, even in the anarchic environs of an unconference, self-reinforcing trends arise over the course of the discussions, and themes do emerge (though each participant might perceive different patterns and come away with a completely different report of an event’s most important themes).

For me, the most powerful and important theme emerging from the week was the idea of “open science.” This term refers not to any one initiative or project, but the cloud of concepts that includes open access publication, use of open source solutions (especially for protocols and software), commons-based licensing, and full publication of all raw data (including “failed” experiments). It also incorporates more radical ideas like opening one’s notebook in real time, prepublishing unreviewed results, replacing current models of peer review with annotation and user ratings, and redesigning (or ditching) impact factors. The world implied by these concepts is one of radical sharing, in which credit still goes where credit is due but by dramatically different mechanisms.

Open science isn’t so much “pay it forward” (though there is a bit of that) as an effort to create a (scientific) world in which no one is paying at all, a world in which there’s no incentive to withhold or protect ownership of data. The science fiction writer Iain M. Banks once wrote that “money implies poverty” — indeed, many of the current models of data ownership and publication, and their accompanying “currencies” of proprietorship, prestige and closed-access publication, imply a world in which data is scarce and must be hoarded. But data is not scarce anymore.

Given a suitable set of one-to-one and one-to-many agreements between the stakeholders, then, the benefits of sharing could come to outweigh any conceivable advantage derived from secrecy. Perhaps “open science” could be defined (for the moment) as the quest to design and optimize such agreements, along with the quest to design the best tools and licenses to empower scientists as they move from the status quo into the next system — because (and this is very important) if it is to ever succeed, open science has to work not because of governmental fiat or because a large number of people suddenly start marching in lockstep to an unnatural tune, but because it works better than competing models. Proof of that particular pudding will be entirely in the eating.

During the meetings, I met quite a few people involved in this mission, and I want to mention their organizations and projects here:

  • OpenWetWare, “an effort to promote the sharing of information, know-how, and wisdom among researchers and groups who are working in biology & biological engineering” – including tools for protocol sharing and open notebooks;
  • Epernicus, a social networking site for scientists that automatically connects peers based on institution, history, skills and research focus;
  • JournalFire, “a centralized location for you to share, discuss, and evaluate published journal articles” (still in beta);
  • Science Commons, the scientific wing of the Creative Commons, which “designs strategies and tools for faster, more efficient web-enabled scientific research. We identify unnecessary barriers to research, craft policy guidelines and legal agreements to lower those barriers, and develop technology to make research data and materials easier to find and use.”;
  • Nature Precedings, “a free online service launched in 2007 enabling researchers in the life sciences to rapidly share, discuss and cite preliminary (unpublished) findings”; and
  • UnPubDatabase, a discussion of ways for scientists to rapidly and efficiently publish “negative” results, both to allow re-analysis of data and to prevent the scientific community from following the same blind alley more than once.

Academic scientists aren’t the only ones to potentially benefit, by the way — pharmaceutical companies routinely run the same experiments as one another and often find that expensive trials could be avoided if they’d only had access to data mouldering in a competitor’s vault — so open science can benefit the profit sector as well, and there are already plans underway to make that possible.

I’m enthusiastic about bringing open science into my own project and my own laboratory — indeed, in a fit of post-conference ecstasy I basically put myself on record promising to do so. For reasons that have everything to do with available energy levels, I suspect that full-blown openness is probably easier to accomplish when it’s present from the beginning of a project, so I’m especially eager to put these ideas to the test in a large-scale collaboration that is just getting underway. I have no idea how it will go — I expect to meet resistance, especially to the more radical ideas like open notebooks — but it’s nonetheless an exciting time. Will I be able to convince my collaborators to try out open science approaches? Once implemented, will they work? I don’t know, but I am convinced that it’s a hypothesis worth testing.

Our understanding of aging in animals owes a great debt to a large body of careful work in a single-celled organism, the brewer’s yeast Saccharomyces cerevisiae. Indeed, as I’ve argued before, yeast is one of the two organisms with the strongest credible claim to have started modern biogerontology. An unusually large crop of yeast aging papers have appeared over the last few months, and I thought it would be appropriate to spend a few paragraphs describing them — in honor of this humble organism that rises our bread, ferments our beer, and has done so much to open our eyes to the fundamental mechanisms of aging.

For those unfamiliar with the yeast field or simply wishing a clearly written and nearly comprehensive summary, Steinkraus et al. provide the historical perspective. The piece thoroughly reviews the development of yeast as a model system in aging, as well as the arguments in favor of a connection between results in yeast and well-established (but sometimes hard-to-test) hypotheses in animals.

Based on the influence that yeast has already had on biogerontology as a whole, it seems fair to claim that it will continue to reveal fundamentals of aging that are conserved across evolution. Now, however, there is quantitative evidence to back up that claim: Smith et al. have used bioinformatic and genomic approaches to study the conservation between known longevity genes in yeast and worm, and they show that yeast mutants in worm longevity genes are significantly more likely to be long-lived than randomly chosen mutants — suggesting that

genes that modulate aging have been conserved not only in sequence, but also in function, over a billion years of evolution.

Given this functional conservation, it is reasonable to use yeast to help answer questions about aging in general, so long as these questions are cell-biological in scope.

For instance: NAD+/NADH ratios are thought to be an important metric of the cellular energy balance, and appear to have effects both within the mitochondria and the cytosol. The mitochondrial inner membrane, however, is impermeable to both NAD+ and NADH. How, then, is information about energy balance communicated between the two cellular compartments? Easlon et al. report that two components of the malate-aspartate NADH shuttle (which transports metabolites across the mitochondrial membrane, resulting in equilibration of the cytosolic and mitochondrial NAD+/NADH pools) are involved in controlling longevity. The two proteins, Mdh1 and Aat1, are required for longevity enhancement by calorie restriction (CR), and overexpression of both proteins can increase lifespan independent of caloric conditions (but in a Sir2-dependent manner, about which see more below).

Another outstanding question involves how cellular energy balance is coordinated with the rates of catabolic and anabolic processes, and how this coordination impinges on regulation of longevity. We know that in yeast, the effects of CR are mediated by pathways involving the nutrient sensor TOR and the kinase Sch9. (Brief aside: longevity-enhancing mutations of Sch9 can also suppress genomic instability; new results from Qin et al. show that genomic instability is also associated with lifespan variation in yeast). Sch9 regulates, among other things, ribosome biogenesis; both CR and Sch9 mutation cause ribosome synthesis to decrease — but are the ribosome and longevity phenotypes related? Very likely yes: Steffen et al. report that multiple means of downregulating ribosome synthesis all extend lifespan, implying that reducing production of ribosomes is essential in order to reap the benefits of CR.

As the tools of biology have adapted, so has the yeast field (sometimes leading the charge, as in the case of the earliest microarray-based expression profiling experiments). Murakami et al. have developed a high-throughput method for measuring yeast lifespan. In this first report, the authors primarily demonstrate the use of their method on known mutants, arguing that their results are similar but with lower variance. (Brief aside: they also demonstrate that CR-induced lifespan extension does not require SIR2 or any other yeast sirtuin, adding fuel to the controversy about whether sirtuins play any role in CR in yeast; for more, see here and here.) The increased precision of their technique will allow detection of subtler aging-related phenotypes than were previously detectable, very likely allowing us to add to the list of genes known to regulate lifespan. The high-throughput aspects of the method, of course, open the door to testing small-molecule drugs that could delay aging in yeast — historically a fruitful approach though not without its potential pitfalls.

If you’ve made it this far, feel free to toast S. cerevisiae, perhaps with a beer.

(Before I depart, I just want to mention — since it’s not necessarily clear from the first authors’ names — that four of the papers mentioned above, as well as many of the papers described in earlier Ouroboros posts linked above, are the result of the combined work of the Kaeberlein and Kennedy labs at U-Wash Seattle. Both of them worked together in the Guarente lab back in the day, and they’ve been in the yeast aging field from its very beginning. Clearly, their combined work is continuing to advance the field.)

One of my favorite aspects of blogging is the contact it affords with the biogerontology community. Many readers have reached out, sometimes to say hello and other times to engage in discussions — sometimes of scholarly topics, and other times regarding professional considerations like how to look for a postdoc.

Unfortunately, it’s hard for me to share the contents of those interactions with the community at large; one consequence of this is that I end up having similar conversations with multiple people who might benefit from interacting more directly with each other. Thanks to some relatively recent conversations with readers (you know who you are, and I thank you), it occurred to me that social networking tools — despite their faults — might allow for a more efficient (and democratic) sharing of ideas, and maybe even create a repository of good advice and “stored thought” to which new community members might refer.

The first step I’m taking in this direction is to initiate a group on Facebook, the social networking system that I use most often. The group is named after the site (Ouroboros: Research in the biology of aging), and is open to anyone with a Facebook account. You can join the group without “friending” me (which I would prefer. One thing I don’t like about Facebook is that it only acknowledges one kind of connection, “friend.” I’m trying to keep my friend list limited to people I actually know, but this group allows for a different kind of connection. Even better, the group is many-to-many rather than one-to-many, i.e., everyone in the group is equally well connected to each other). I just created it, with a few discussion topics (“What are you up to?” and “Hot topics“), and I’m eager to see how the community responds.

The idea here is to create a place where readers of this site can get together and discuss matters of interest to the current (and future) biologists of aging. If you’re interested in kicking around ideas, making connections with other biogerontologists, or simply learning more, please join.

P.S.: I’m probably going to branch out in other social-networking directions; the Nature Network will probably be next, just as soon as I figure out how it works.

Given the significance of the humble worm to the field of biogerontology, I thought I’d remind everyone that the application deadline for the worm course at Cold Spring Harbor is tomorrow. If you’ve got $3500 burning a hole in your pocket and want to learn about this system, run (don’t walk) to your nearest internet-capable appliance and register.

Here is the web page; here are the details:

C. ELEGANS
August 9 – 24
Application Deadline: March 15, 2008

Instructors:
Shawn Ahmed, University of North Carolina
Arshad Desai, University of California San Diego
Mei Zhen, Samuel Lunenfeld Research Institute, Canada

This course is designed to familiarize investigators with C. elegans as an experimental system, with an emphasis on both classical genetic analysis and reverse genetic approaches. A major goal is to teach students how to successfully exploit the information generated by the C. elegans genome project. The course is suited both for those who have a current training in molecular biology and some knowledge of genetics, but have no experience with C. elegans, as well as students with some prior worm experience who wished to expand their repertoire of expertise. The following topics will be covered both in the laboratory and by lectures from experts in the field: worm pushing, C. elegans databases and worm bioinformatics, anatomy and development, forward genetics, chemical and transposon mutagenesis, generation of transgenic animals, expression pattern analysis, reverse genetics, construction and screening of deletion libraries, and RNA inactivation. The course is designed to impart sufficient training to students in the most important attributes of the C. elegans system to enable students to embark on their own research projects after returning to their home institutions.

Next Page »