My attention was drawn today to a recent open access paper that theorizes on how evolution came to produce the calorie restriction response. Given that calorie restriction notably improves health and longevity, why isn't this beneficial metabolic state switched on all the time?

Stresses like dietary restriction or various toxins increase lifespan in taxa as diverse as yeast, Caenorhabditis elegans, Drosophila and rats, by triggering physiological responses that also tend to delay reproduction. Food odors can reverse the effects of dietary restriction, showing that key mechanisms respond to information, not just resources. Such environmental cues can predict population trends, not just individual prospects for survival and reproduction. When population size is increasing, each offspring produced earlier makes a larger proportional contribution to the gene pool, but the reverse is true when population size is declining.

...

We conclude that the beneficial effects of stress on longevity (hormesis) in diverse taxa are a side-effect of delaying reproduction in response to environmental cues that population size is likely to decrease. The reversal by food odors of the effects of dietary restriction can be explained as a response to information that population size is less likely to decrease, reducing the chance that delaying reproduction will increase fitness.

The bulk of the paper consists of the mathematical model used to argue this point: evolutionary changes that allow animals to delay reproduction at opportune times will be more successful, as will any adaptation that makes metabolism more likely to identify when those opportune times occur. This seems like a solid theory, given the evidence to hand. Population size and its relationship to the availability of food are very fundamental properties, in play for even the earliest and most primitive species, and similar for many diverse species. Thus we should expect to see what we do see in nature: that the calorie restriction response is a very old aspect of animal metabolism, present in almost all species tested, and governed by very similar genetic mechanisms in species ranging from flies to humans.

In the years ahead, researchers will work out how to permanently and safely turn on the calorie restriction response in humans. This seems like a fairly safe prediction absent a specific timeline, given that the research community for this field is well established and companies continue to raise venture funding to develop methods of metabolic manipulation. They will most likely improve on the natural version to some degree once it is fully understood. The flow of newly discovered longevity mutations in lesser species strongly suggests that all species are far from optimized for longevity, and we should expect to find longevity mutations in humans as well.

That said, a likely 20 year timeline to produce tools that do no more than slow aging will be a grand disappointment for those in middle age today. A 2030 in which we cannot repair aging and reverse its effects to any significant degree would be a death sentence - and a well deserved one, given that we had two decades in which to develop more effective medical technologies than metabolic manipulations to mimic the effects of a natural process.

Ratcliff, W., Hawthorne, P., Travisano, M., & Denison, R. (2009). When Stress Predicts a Shrinking Gene Pool, Trading Early Reproduction for Longevity Can Increase Fitness, Even with Lower Fecundity PLoS ONE, 4 (6) DOI: 10.1371/journal.pone.0006055

Posted by Reason at 4:25 PM
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This is the age of biotech and wonders, for all it seems far too slow and prosaic when you're living it a day at a time. By way of a reminder, here's a piece from the U.S.News on tissue engineering of new organs that focuses on the work of Tengion and Anthony Atala:

Growing a bladder or a body part such as a blood vessel takes about six weeks. To create an artery, say, Atala plucks some of the immature cells that make up arterial lining and muscle from a sample of the patient's blood and incubates them by the billions in liquid nutrient. The cell-rich soup is then painted on a tube-shaped scaffold made from flexible collagen, like the tissue that forms the nose. (The collagen will gradually disintegrate once the vessel is in place.) The cells mature, multiply further, and form an artery. A small machine exercises the vessel, conditioning it to function normally after it is implanted.

Building organs such as bladders and blood vessels, which have only a few different types of cells, has become almost routine for Atala's lab. A heart or pancreas is far more complex and challenging.

This is the heroic story template in which the field of vision is narrowed (one might say dumbed) down to a single face, emblematic of thousands who are performing important work in the field. That's the way the popular press works, but remember that when journalists point out one groundbreaking fellow, there are dozens of others left unmentioned in the backdrop, folk with their own labs, important projects, and promising results. Tissue engineering is a large and very active field now, constrained far more by regulatory costs and barriers than by any technical hurdles.

Given the present pace of development, I don't think it's unreasonable to expect a couple of different methods of producing organic replacements for all the major human organs (except for the brain of course) to be ready for use by 2020 - though whether they will be legally available in the US given the state of the FDA is another question entirely. The state of medical regulation is so far removed from sensible considerations of risk and readiness that countless potential therapies languish unused, undeveloped, and unrefined, along with whatever new information researchers might have learned from more widespread usage.

Posted by Reason at 5:19 PM
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One of the fellows at young biotech company Genescient, who has also volunteered for the Methuselah Foundation in the past, has been bugging me to talk about the company. So here I am, talking about Genescient. The company website does a better job than I would do in explaining what they're up to and where they're going:

Genescient has a proprietary screen for substances that can extend human lifespan and healthspan. Using genetically selected long lived Drosophila and the latest genetic tools, Genescient has identified over 100 gene networks that are altered in long lived strains of Drosophila melanogaster and that are also linked to longevity and age-related diseases in humans.

In essence, you might envision Genescient as what you get when you add very rapid progress in biotechnology (and falling cost in biotech tools) to the basic aims of Sirtris. Find longevity genes and manipulate their expression for benefit and profit in other words, but where Sirtris's initial development back before 2004 focused on just a few genetic networks, Genescient is aiming for "all of them." Even in five years, costs have fallen and tools improved significantly - think about the computer you were using in 2003, for example, and compare it to the machine you're using today.

Like Sirtris, Genescient is firmly an outgrowth of the "work to slow down aging via metabolic and genetic manipulation" faction of aging research. They are not aiming to identify and repair biochemical damage, but rather shift the operation of human biochemistry into a more beneficial state for long-term operation. I'd insert the obligatory comment on how this approach is not the Strategies for Engineered Negligible Senesence, and even if wildly successful in decades to come will do little for those already old, but you're all probably all tired of hearing it by now.

Reading between the lines ("nutrigenomic supplements?"), it looks like the Genescient founders might choose to monetize the results of their work in the supplement marketplace rather than take the Sirtris path of big pharma and the FDA. If that's the case, I couldn't say I blame them: you'd have to be extraordinarily dedicated - or foolish - to want to deal with the state of medical regulation in the US if there was a viable alternative option to make your investors happy. This is one of the reasons why the US research industry is basically doomed absent a revolution. That all said, the supplement industry is what it is; if you want to relegate yourself to irrelevance in the ongoing quest to cure aging, history suggests that entering the supplement market will achieve that end. Scylla on the one hand, Charybdis on the other - and going overseas to less oppressive regulatory regions in order to develop research into applications is looking ever more like the best option.

Regardless, I think the most useful output for the long term arising from the work taking place at Genescient will likely be a wealth of data on how gene expression changes occurring with aging relate to forms of biochemical damage that are thought to cause aging. Are gene expression changes responses to damage, or are they genetic programs that themselves cause damage? Or both, or neither? How important is each particular change? These are vital questions if your goal is to revert gene expression changes in search of beneficial effects, but this data will also help those who seek to directly repair the damage itself. There's no such thing as useless information in biotechnology.

Posted by Reason at 3:12 PM
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I'm pleased to see that the Immortality Institute folk have set up an $8000 matching fund to help contribute to one line of research aimed at removing one cause of the damage of aging. This is exactly the sort of positive development enabled by falling costs in biotechnology - small groups of interested people can raise enough money to support meaningful early stage research:

In case you have not yet heard or read, the Immortality Institute is providing a matching grant for research into laser ablation of lipofuscin.

Read all about it here: http://www.imminst.org/archive/articles/laser-research-grant

Listen to Nason Schooler describe the proposed research here (2008), or here (2009)

I am particularly interested to see the results of the worm lifespan studies to confirm whether or not lipofuscin is one of the key pieces of cellular junk affecting the aging process. The funding drive will continue through August 17th. Please consider saving up a couple dollars to donate to this research project.

The SENS Foundation will be overseeing this research:

SENS Foundation is pleased to announce an initiative by the Immortality Institute, funding us in our fight against aging. The Institute will match every contribution up to $8,000 for the study of laser ablation of lipofuscin - research that will be conducted by Nason Schooler at the SENS Foundation Research Center.

Validating the use of lasers as an approach to remove the buildup of lipofuscin in our cells and thereby help long-term health and longevity won't cost much - a few tens of thousands of dollars. So give a little of your spare change to help move this research to its conclusion: it's a good bet, and supporting this per-project grassroots methodology of funding biotechnology research is also a good bet. If this one is well funded, we'll be seeing more diverse SENS research projects put forward and funded by the community in the future.

Posted by Reason at 5:53 PM
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As Michael Anissimov notes, the technological singularity as a concept seems to have wormed its way into the public eye to a greater degree than transhumanism as a concept has managed to date. There's probably a lesson or two in there somewhere.

Are we going to see a very steep uptrend in new technologies enabled by biotechnology and computing power? If present exponential trends in the amount of data that can be organized and manipulated continue then we should expect such things as emulated minds, near-complete control over our biochemistry, and molecular manufacturing to exist in the 2040s. The nature of an exponential curve in progress is to produce surprise: growth looks linear for a while, and then all of a sudden an explosion of progress occurs.

We'd all like to lazily find out that we're going to live for a long time in the future thanks to all the hard work being done by other people. For example, there's a contingent who argue that recursively self-improving artificial intelligences will basically allow us to solve all of our information-processing-related problems - the most interesting of which is controlling and repairing age-related damage in our own biology - and that the advent of such AIs within our lifetime is pretty much a given under present trends.

Imagine a future where engineers build a computer with greater-than-human intelligence. This hyper-intelligent being expands its knowledge and brainpower exponentially over days and weeks as it learns how to improve on its own hardware and software design. It starts building 'offspring' even smarter than itself. The sudden arrival of these offspring - cheap, mass-produced super-intelligent machines - sparks explosive economic growth, triggering a series of cascading events.

Nothing in the laws of physics prevents such an outcome, and the production of such artificial intelligences seems inevitable in the long term. But I've long thought that visions of the future allowed by the laws of physics and the nature of present growth curves in biotech and computing inspire a certain complacency in many people. The future will be great, it will bloom from nowhere when the curve takes off, and so no-one has to lift a finger to help now. Our collective fat will be pulled from the fire of aging by the deus ex machina we build.

Or not. For so long as we humans are in the driving seat, I'd argue that you can't compress progress down below a certain pace - the exponential trends will turn linear at some point. We're apparently not at that point yet, given that the trends are all still in place, but I think it's near. If you cut the time taken to produce a good applicable result in science from one year to six months for example, it's still going to take the same amount of time after that point to pull together a company, get funded, sort out the paperwork, and work around the regulations:

I'm dubious about large reductions in the length of business or research cycles through technology while humans are still in the loop. You can certainly make the process cheaper and better, meaning that more attempts at a given business or research model will operate in parallel, but there is a point past which the length of the business cycle cannot be easily compressed. That point is very much a function of the human element: meetings, fundraising, decisions, organizational friction, and so forth - all very time-consuming and proven very resistant to improvements in the time taken. Regulations don't help either - if you want to slow progress, ensure that the end results are not as reliable or effective as they could be, and make the product more expensive, you can't do better than regulation.

My point here is that you shouldn't be dazzled. The future is far from certain, as it is still being built. The trends look very promising, but are by no means a guarantee that the applications of future technology actually built within our lifetimes will include the ones you and I desire. I'm sure we can all rattle off a list of large scale projects that have been possible for decades but never happened - colonizing the oceans, irrigating the Sahara, and so forth. The end of aging and radical life extension in particular will only happen if enough people understand that it can happen, and from that a large enough research and development community is generated to make it happen. Wishful thinking only works when someone, somewhere is getting the job done.

Posted by Reason at 4:29 PM
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