Profit sector


Newsweek has a nice article written for the masses on the biology of aging. It covers a broad spectrum of aging topics, including calorie restriction and telomeres. Major projects like the New England Centenarian Study and work with the Calorie Restriction Society are also mentioned. Newsweek interviewed some major players in aging research for the article, including Cynthia Kenyon about her work on the genetics of aging in C. elegans and Elizabeth Blackburn about her recent paper on the changes of telomerase expression because of diet.

Since the days of Ponce de León, if not before, people have been seeking the elusive Fountain of Youth. Until recently, such pursuits were the realm of quacks and charlatans. And there are still plenty of snake-oil salesmen out there on the Internet and in so-called anti-aging clinics, hawking everything from longevity-bestowing Ecuadoran waters (which are probably harmless) to growth hormones (which could be downright dangerous for adults). But serious scientists are now bringing respectability to the field, unraveling the secrets of aging on a cellular level and looking for ways to slow it down. And while the science is still young (so to speak), legitimate longevity-boosting treatments could be available in 10 to 15 years—although the gains would be more modest than in Kenyon’s worms.

The article follows a trend of aging research being covered by the popular press, something all of us here at Ouroboros support.

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For its sixth edition, Hourglass returns home to Ouroboros. I think the holidays have resulted in a bit of contraction of effort all around the blogosphere, so this installment is a little…”cozy”. Still, I think we have quite a range of excellent articles featured in this issue:

predicated

The Predicated Life is a blog by Matt Farrell, who is engaging in alternate day fasting (ADF) in part for general health reasons and in part to help alleviate joint inflammation. (This idea is theoretically well-motivated if not yet widely tested: ADF increases levels of the longevity assurance factor SIRT1, and SIRT1 activity decreases inflammation.) Matt shares two pieces about his experience: On Knees and Inflammation, which isn’t especially about either topic but rather about strategies for controlling appetite when one is engaging in ADF; and The Nuts and Bolts of How Alternate Day Fasting Actually Works, where Matt delves into the evolutionary explanation of why one might expect ADF to be a good idea.

Mmmm…nuts and bolts.

Reason at Fight Aging! submitted posts describing two different aging-related organizations.

millard

One is the Millard Foundation, a California-based non-profit whose “primary purpose is to promote bringing true regenerative medicine and greater, healthy longevity to humanity.” MF is just starting to stretch its wings in the funding arena, and is focusing its largesse on strategies devoted to repair (rather than delay) of age-related damage.

sierra

The second post regards a commercial enterprise, Sierra Sciences, currently working to develop telomerase-related therapeutics; Reason takes the opportunity to talk about the ways in which telomere-centric theories of aging have evolved over the course of the past decades, and emphasizes that the jury is still out on the ultimate role that telomerase will play in regenerative medicine.

While the role of telomerase in aging-related therapeutics remains undecided, biogerontologists remain convinced of the merits of studying telomere biology. Fueling the fire are studies like the recent report (blogged here) that telomerase expression slows aging — at least in a mouse that’s already tricked out to be highly cancer resistant. While it’s unlikely that we’ll be engineering cancer-resistant humans anytime soon, results like this suggest that ways to conditionally activate telomerase (and then shut it off again) might have profound effects on tissue regeneration.

brainhealth

Wrapping up the carnival, Ward Plunet at brainhealthhacks shares a length, thoughtful and wide-ranging post entitled Longevity: Think of yourself now, and yourself in the future. Ward discusses the future of the longevity field, and then describes at length a study that has evaluated the human capacity — or lack thereof — to think rationally about the future.

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

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.

Following closely on news that products in their pipeline can decrease blood glucose and may have tumor suppressor potential, Sirtris Pharmaceuticals (SIRT) has been snapped up by GlaxoSmithKline (GSK).

Sirtris has focused on the commercial development of clinically useful sirtuin activators, which are predicted to be useful as anti-diabetic drugs. Data from academic labs have suggested they could be of even wider use, e.g., in increasing exercise tolerance or treating inflammatory disease. Underneath it all, of course, is the knowledge that the the sirtuins were initially identified as longevity assurance genes; the subtext of all discussions of sirtuin activators is that they may mediate their beneficial effects by slowing aspects of the aging process itself.

The acquisition of an small company at a large premium (the offer was more than 80% higher than Sirtris’ market cap) by a pharmaceutical giant is one of the first demonstrations that the drug industry is taking seriously the idea that there’s money to be made in treating aging per se rather than all of the associated conditions separately (link):

“Through the acquisition of Sirtris, GlaxoSmithKline will significantly enhance its metabolic, neurology, immunology and inflammation research efforts by establishing a presence in the field of sirtuins, a recently discovered class of enzymes that are believed to be involved in the aging process,” the companies said in a joint release.

Then again, even in the best case, those who take sirtuin activators will get age-related diseases eventually anyway, so the question of whether to treat aging or age-related disease isn’t really an either/or choice.

I am currently wondering whether recent findings that indiscriminate activation of SIRT1 might lead to cancer (e.g., when DBC1 is deleted) will temper the enthusiasm for these compounds.

Over the weekend I had a novel experience: my first presentation about the biology of aging to an audience consisting entirely of non-scientists. The occasion was the 40th birthday of a dear friend, who invited each guest to give a five-minute talk about a topic of our choosing. (Other topics ranged from how to pick the perfect pair of jeans to the evils of California Chardonnay.)

Rather than drill down into technical details, I decided to use my five minutes to motivate the problem: Why should people care about biogerontology? I structured the talk around several questions and issues that often arise when I discuss aging with non-scientists; judging from the audience reaction and comments afterward, I felt satisfied that I got through to a lot of people. Sadly I wasn’t able to record the talk, but I wanted to recap some of the talking points that were well-received by the crowd.

  • Why would I want to live another ten years? This is the “living longer vs. dying longer” question. As my generation ages, we see our grandparents and parents slowly decline physically and mentally. Who wants another ten years in a hospital bed? The answer that got them nodding is simply this: We don’t want to add years to the end of life; we want to add them to the middle.
  • Aging is a natural process; who are we to interfere? There are a lot of potential responses to this one, but the most effective ones have to do with pointing out how many benefits we reap from behaving unnaturally. Before antibiotics, a bad cut could cause sepsis or death, all from naturally occurring bacteria. A hundred years ago, one in three women would die from childbirth-related complications. The state of nature is nasty, brutish and short; we’re mostly all descended from a long line of people who have chosen to take an unnatural course. Why is aging any different?
  • Isn’t our money better spent on specific age-related disease? My professional opinion is that this is a false dichotomy and that we should do both disease-specific research and basic studies of the biology of aging; this is a hugely rich civilization and to the extent that we behave in a civilized manner (which we don’t: the US misadventure in Iraq spends the annual NIH budget every month), there’s very little reason to make either/or choices of this sort. It turns out, however, to be easier to make the argument for increasing resources devoted to aging research, as follows:

    Surprisingly, comprehensive cures for all heart disease, stroke, diabetes and cancer are predicted to have rather modest effects on average lifespan (e.g., see Olshansky et al.). Such cures, in any event, are still far away even after years of study. Aging is the primary risk factor for these (and many other) diseases; as a relatively new science, biogerontology holds greater promise for near-term radical improvements in healthspan. The Olshansky projections really blew them away, especially when coupled with a few words about the longevity increases we’ve achieved with single-gene changes and dietary restriction in model organisms. Then I showed a pie chart comparing the NIH funds spent on diseases to those spent on basic aging research. Gasps.

  • If this is possible, won’t the market take care of it? The subtext here is that the NIH allocations are a red herring; the deeper subtext is that government can’t solve problems. This is a hard question to answer in the context of ideology: folks who ask it are often quite powerful believers in the omnipotence of the Invisible Hand, and it tends to be fruitless to debate the role of states vs. markets in general.

    Over the years I’ve learned that it’s more effective to steer away from political theory and address the specific situation: Basic research funded at the federal and state level constitutes a gargantuan “risk subsidy” for the pharmaceutical and biomedical industries. We work cheap. We explore blind alleys and reveal the rare tunnels with a light at the end, and then we publish our results for the world to see. We assume risks, gambling chunks of our limited time on this planet against the calculated hope of major discovery. Private entities skim the cream of the crop and then embark on commercial development — at that point, shouldering their share of the risk. It’s hard to imagine either publicly funded research or private development alone making rapid progress in truly novel directions. Each needs the other; this is how this works.

Overall, the audience was energized and excited by the talk; I felt like I’d informed and educated them. I hope the points above will be useful to Ouroboros readers as we spread the word about biogerontology, not only within science but within the world at large.

If you have a favorite talking point or good answer to a common question on this subject, feel free to share it in the Comments.

Last year, we learned that the sirtuin activator resveratrol extends the healthspan of mice and increases exercise tolerance. Resveratrol occurs naturally in several plants, most famously the skins of red grapes; unfortunately for the would be life-extensionist, a human would have to consume upwards of 1000 bottles of red wine in order to approach the dose of resveratrol used in the rodent studies. What we needed was an orally bioavailable, clinically useful drug with the same specificity but much higher activity.

One year later, a collaboration between the pharmaceutical company Sirtris and the research group of David Sinclair (who co-founded Sirtris, and whose lab was responsible for the observation that resveratrol extends the lifespan of mice eating an unhealthy diet) has resulted in the development of sirtuin activators that are a thousand times more efficacious than resveratrol (link). While longevity data is not yet forthcoming, the compounds do have a significant influence on glucose homeostasis, and are being touted as a potential prophylactic or therapy against type II diabetes:

Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes

Calorie restriction extends lifespan and produces a metabolic profile desirable for treating diseases of ageing such as type 2 diabetes. SIRT1, an NAD+-dependent deacetylase, is a principal modulator of pathways downstream of calorie restriction that produce beneficial effects on glucose homeostasis and insulin sensitivity. Resveratrol, a polyphenolic SIRT1 activator, mimics the anti-ageing effects of calorie restriction in lower organisms and in mice fed a high-fat diet ameliorates insulin resistance, increases mitochondrial content, and prolongs survival. Here we describe the identification and characterization of small molecule activators of SIRT1 that are structurally unrelated to, and 1,000-fold more potent than, resveratrol. These compounds bind to the SIRT1 enzyme–peptide substrate complex at an allosteric site amino-terminal to the catalytic domain and lower the Michaelis constant for acetylated substrates. In diet-induced obese and genetically obese mice, these compounds improve insulin sensitivity, lower plasma glucose, and increase mitochondrial capacity. In Zucker fa/fa rats, hyperinsulinaemic-euglycaemic clamp studies demonstrate that SIRT1 activators improve whole-body glucose homeostasis and insulin sensitivity in adipose tissue, skeletal muscle and liver. Thus, SIRT1 activation is a promising new therapeutic approach for treating diseases of ageing such as type 2 diabetes.

Standard qualifications: humans and mice have quite different metabolic needs, and it remains to be seen whether the drugs will work in humans. Even in the rodent, I’ll want to see next year’s paper (by that time, there should be lifespan curves available for animals that have taken the compounds for a long periods of time) before getting too terribly excited about the prospects of the first longevity drugs. It’s also important to keep in mind that the effect of long-term systemic sirtuin activation is unknown, and may even be harmful in certain key tissues (like the brain). In other words: I retain my skepticism; nonetheless, for the rest of this post I’m going to take these results at face value and look toward the future.

The work represents the culmination of a huge amount of progress in a relatively short time: in less than 15 years, the sirtuin story has evolved from basic biology in the simplest model organisms, through exhaustive (though essential) testing in larger animals, into a source of potential therapies for a major human disease.

Furthermore, for the first time we have a clearly defined path toward the regulatory approval and widespread use of a compound that could be used as a frank anti-aging drug. There are significant practical barriers to testing a longevity-enhancement therapy, not least of which is the timescale of the necessary studies. There are also institutional barriers: despite the inefficiency of treating every disease of aging separately, there’s still major reluctance on the part of funding and regulatory agencies to see aging as a disease per se (though even over my relatively short career in biogerontology, I have seen this changing for the better).

But a drug for which a clear clinical indication existed, shown to be efficacious against a widely acknowledged disease, could pass over regulatory hurdles and enter the clinic much more smoothly. Since clinicians could point to a specific short-term benefit of the drug, public acceptance (sometimes curiously hard to achieve in discussions of explicit longevity enhancement) might also come more readily. (One question: in advertisements, would the manufacturer have to warn patients that the drugs “may slow aging and extend the lifespan”?)

Continuing with his recent favorite theme of sending people your body fluids in the mail, Attila Csordás at Partial Immortalization has a very thorough treatment of Silicon Valley “personal genomics” startup 23andMe.

Attila’s treatment is as detailed as any in the popular press, bringing to bear his own scholarly/scientific viewpoint and approaching the issues from multiple perspectives (including that of hobbits). If you haven’t been following the big launch of a company that’s sure to drive discussion on the personal impact of the genomics revolution (at least, among those with $1000 to spend on a profile), rush on over and check it out.

Oh — almost forgot — the aging connection: While the company is initially devoted to assessment of disease risk based on known associations, they’re also going to attempt to use a novel application of social networking to bring private citizens into studies that will seek to define heretofore unknown genetic risk factors for other conditions. With clever study design (and possibly simply with shrewd data-mining techniques), one can imagine any number of ways for longevity researchers to capitalize on the sudden influx of people willing to volunteer their genetic information for analysis and follow-up.

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