Aging is an inevitability, or so we have to assume: the processes of evolution blindly but efficiently explore the space of possible living creatures, and have been doing so for a very, very long time. Surely a very long-lived or ageless species would have a great advantage in evolutionary competition, its individual members able to produce descendants for far longer than their competitors in a short-lived species that ages. Yet virtually all species – with only a very few exceptions – age in easily measured ways. The species that age are also the species that have won in evolutionary terms, and therefore prospered and spread. Why is this?

A recent open access paper (in PDF format) explores one of the approaches used to answer this question, and does so in a very readable fashion:

Living organisms shouldn’t age, at least if that could be helped (many of use would certainly like that, but our wishes are not a valid argument). Evolution works in a way that any species whose representatives have any distinct disadvantage will be driven to extinction. It makes sense then to assume that, if aging could be avoided, species that showed senescence as the individuals grow older should be replaced by others where aging does not happen (or happens at a much slower rate). Senescence increases mortality and an individual who dies of old age will leave, in average, a smaller number of descendants than another individual that does not age and manages to live and reproduce for a longer time. And yet many known living organisms show senescence. The time it takes for an individual to show signs of old age varies greatly among species, but aging seems so natural that many people fail to realize there is an apparent contradiction between senescence and evolution.

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Understanding why we age is a long-lived open problem in evolutionary biology. Aging is prejudicial to the individual and evolutionary forces should prevent it, but many species show signs of senescence as individuals age. Here, I will propose a model for aging based on assumptions that are compatible with evolutionary theory: i) competition is between individuals; ii) there is some degree of locality, so quite often competition will between parents and their progeny; iii) optimal conditions are not stationary, mutation helps each species to keep competitive.

When conditions change, a senescent species can drive immortal competitors to extinction. This counter-intuitive result arises from the pruning caused by the death of elder individuals. When there is change and mutation, each generation is slightly better adapted to the new conditions, but some older individuals survive by random chance. Senescence can eliminate those from the genetic pool. Even though individual selection forces always win over group selection ones, it is not exactly the individual that is selected, but its lineage. While senescence damages the individuals and has an evolutionary cost, it has a benefit of its own. It allows each lineage to adapt faster to changing conditions.

We age because the world changes.

And there is illustrated one of the present competing viewpoints on the origins of aging.

Researchers continue to investigate the link between germ cells and longevity in lower animals. In this open access paper, changes to fat metabolism are implicated as an important mechanism: “Removing the germ line of Caenorhabditis elegans extends its lifespan by approximately 60%. Eliminating germ cells also increases the lifespan of Drosophila, suggesting that a conserved mechanism links the germ line to longevity … Reproduction and aging are two processes that seem to be closely intertwined. Experiments in Caenorhabditis elegans and Drosophila have shown that depletion of the germ line increases lifespan and that this process depends on insulin and lipophilic-hormone signaling. Recently, it was demonstrated that when germline stem cells (GSCs) cease to proliferate, fat metabolism is altered and this affects longevity. In this study, we have identified a nuclear hormone receptor, NHR-80, that mediates longevity through depletion of the germ line by promoting fatty acid desaturation. … Our results reinforce the notion that fat metabolism is profoundly altered in response to GSC proliferation, and the data contribute to a better understanding of the molecular relationship between reproduction, fat metabolism, and aging.”

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3057950/

An example of the sort of immune system engineering that is presently taking place in the laboratory: “Until this research, we thought the immune system needed to attack the cancer directly in order to be effective. Now we know that isn’t necessarily so. Attacking the dense tissues surrounding the cancer is another approach, similar to attacking a brick wall by dissolving the mortar in the wall. Ultimately, the immune system was able to eat away at this tissue surrounding the cancer, and the tumors fell apart as a result of that assault. These results provide fresh insight to build new immune therapies for cancer. … pancreatic cancer patients received standard gemcitabine chemotherapy with an experimental antibody [that] binds and stimulates a cell surface receptor called CD40, which is a key regulator of T-cell activation. The team initially hypothesized that the CD40 antibodies would turn on the T cells and allow them to attack the tumor. The treatment appeared to work, with some patients’ tumors shrinking substantially and the vast majority of tumors losing metabolic activity after therapy, although all of the responding patients eventually relapsed. When the researchers looked at post-treatment tumor samples, obtained via biopsy or surgical removal, there were no T cells to be seen. Instead, they saw an abundance of another white blood cell known as macrophages. … When the investigators treated mice that developed pancreatic cancer with gemcitabine in combination with CD40 antibodies, the results looked like those of the human trial. Some mouse tumors shrank and were found to be loaded with macrophages but contained few or no T cells. Closer inspection showed that the macrophages were attacking what is known as the tumor stroma, the supporting tissue around the tumor. Pancreatic tumors secrete chemical signals that draw macrophages to the tumor site, but if left to their own devices, these macrophages would protect the tumor. However, treating the mice (or patients) with CD40 antibodies seemed to flip that system on its head. … It is something of a Trojan horse approach. The tumor is still calling in macrophages, but now we’ve used the CD40 receptor to re-educate those macrophages to attack – not promote – the tumor.”

Link: http://www.eurekalert.org/pub_releases/2011-03/uops-pru031611.php

The Vegas Group: a so far fictional community of the next ten years that will merge the longevity advocacy and open biotech communities in order to (a) reverse engineer the most promising life-span-enhancing techniques demonstrated in the laboratory, (b) translate that work into human rejuvenation biotechnologies, and (b) make these therapies available for use via medical tourism to Asia-Pacific region clinics.

So I have been pondering how best to make the vision of the Vegas Group a reality: what steps do we take so that we wake up six or seven years from now to an open source biotech community whose members are working on enabling the best longevity therapies produced by the formal research community – and who have the overseas connections to enable responsible use of resulting therapies in a clinical setting.

The path to this future involves networking and community building in a whole new and different direction from that taken by much of the longevity advocacy community – and the construction of a codex of information, a how-to manual of recipes for replicating specific products of the formal research community in longevity science. Networking makes the world go round, and that is the most important part of any attempt to create the Vegas Group, or indeed any human endeavor: making relationships and persuading people to join in. But this is not where I can be the most effective.

So any step one for me will involve considering the codex: what it is, and how it will be constructed, maintained, and made useful to the seeds of what will be the Vegas Group – however that organization ultimately comes about, and whatever form it ultimately takes. It is very clear to me that open biotechnology will grow into a massive semi-professional sphere of activity, exactly like the open source software community today. I want to take advantage of the wave that is coming, and produce a work that will both aid that wave and in turn be aided by it.

When thinking about the way in which contributions of content are made voluntarily to any given community or site – such as Wikipedia, or blogs such as this one, or the documentation repository at your workplace – it is self-evident that very, very few people step up to produce good content. Wikipedia works because a great many people each contribute just a little, a continual process of polishing, one grain of sand at a time, applied to the bulk outlines contributed by the motivated few. But for smaller groups, you don’t get polishing, you just get next to nothing in the way of contributions.

So I’m fairly certain that for the Vegas Group codex, while a wiki model may be helpful as an adjunct to a motivated community further down the line, it isn’t a way to get things written at the outset – it’s not a way to provide the corpus of work that a community can later polish. There are few biotechnologists in the world in comparison to, say, football fans. Look at the number of science bloggers as compared with other topics, for example. Despite this, there are still initiatives out there, however, working on pulling together repositories of techniques and knowledge: OpenWetWare for example. So the concept of producing an open collection of techniques and recipies is not a foreign one to the biotechnology community – it’s just not very advanced at this stage, at least not in comparison to the bodies of knowledge associated with larger communities.

Thus I think that a larger seed, a bigger online repository of freely available and reliable recipes for longevity-related biotechnology, would act as an attractor for people willing to tinker and help out. The same class of supporters and advocates who produced initiatives like OpenWetWare will contribute to help polish its contents. Overall, the concept of a codex seems to me to be where a comparatively small amount of money could be leveraged to good effect. Consider this:

• Creating an initial repository website and content management system isn’t a significant cost given the present state of open source content management software – it’s almost something I could undertake myself.
• People with significant knowledge of biotechnology are remarkable cheap to engage at the post-graduate level. Consider that a few thousand dollars of post-graduate time can net you a long and well-informed analysis, or detailed explanation of a specific methodology.
• It wouldn’t be a good piece of writing of course – no offense is intended when I say that few post-graduate scientists can write well. Writing well is hard, and just as much a specialty as is becoming a scientist; few people have the time and inclination to specialize in more than a few things, and why should one of them be writing?
• Fortunately, people who can write well are always in supply, desperate for work, and inexpensive. It is a buyer’s market.

So I can envisage a guiding council of advisors putting together a plan for the hierarchy of topics they would like to see in the Vegas Group codex, from basic methods in biotechnology through to best attempt reverse engineering of things we know to be possible and that have been published: such as Cuervo’s work on restoring youthful levels of autophagy, or protofection to replace mitochondrial DNA. The end result of that process might look something like a distillation of Fight Aging! mixed with the very elegant materials produced by the Science for Life Extension Foundation.

Codex project volunteers would then run an ongoing process of hiring post-graduates and interested researchers to write, and passing the results to starving authors who improve the output to a quality suitable for the open biotechnology community. There would of course be some back and forth between the post-graduates and the starving authors in order to reduce the inevitable translation errors, but I see this as a viable way to produce a body of knowledge that is sufficiently good to begin with – not perfect, not even necessarily very good, but sufficient.

Since only a comparatively limited reach of biotechnology is under consideration, the cost of bootstrapping such a project might be less than a few hundred thousand dollars. The things I would need to understand before getting seriously underway on a Vegas Group codex are largely related to validating that price tag. A few hundred thousand dollars would mean that it is worth starting with ten thousand dollars, some volunteers, spare time, and raising funds as we go based on the quality of work exhibited. That would be true bootstrapping, but I’d have to give thought in advance to:

• The actual cost of generating the materials – something that I suspect won’t be clear until the project is at least twenty articles in. I have a fair grasp on the range of costs for writing for hire, in fields that range from very specialist (pricey) and completely generalist (a few cents a word), but I’ve no idea where this market falls in that spread of values, nor how much management and general cat-herding of writers would be required.
• The predicted size of a sufficiently large body of information, as set out by guiding experts. Is it a hundred articles, a hundred videos, a thousand images, or half that, or ten times that?
• How to make this project attractive to the existing open biotechnology community even in its earliest stages. There is no such thing as “build it and they will come” – if anything building in isolation guarantees that you’ll have few visitors.

Which comes right back around to networking and relationships: as I said, they make the world go round. On that topic, I am sadly lacking in a knowledge of the current state of the open biotechnology community – something that will have to change as I give more thought to the Vegas Group idea. No sense in reinventing the wheel if there is a wheel out there already … or even a half-built wheel, a project where lessons were learned.

Nuclear DNA damage accumulates with age, but is it a cause of aging? This open access paper illustrates why there is a question – as for many studies, the results do not point unambiguously in one direction or another. “Accumulation of DNA damage leading to adult stem cell exhaustion has been proposed to be a principal mechanism of aging. Here we tested this hypothesis in healthy individuals of different ages by examining unrepaired DNA double-strand breaks (DSBs) in hematopoietic stem/progenitor cells matured in their physiological microenvironment. … The highest inter-individual variations for non-telomeric DNA damage were observed in middle-aged donors, [where] the individual DSB repair capacity appears to determine the extent of DNA damage accrual. However, analyzing different stem/progenitor subpopulations obtained from healthy elderly (>70 years), we observed an only modest increase in DNA damage accrual, [but] sustained DNA repair efficiencies, suggesting that healthy lifestyle may slow down the natural aging process. … Based on these findings we conclude that age-related non-telomeric DNA damage accrual accompanies physiological stem cell aging in humans. Moreover, aging may alter the functional capacity of human stem cells to repair DSBs, thereby deteriorating an important genome protection mechanism leading to exceeding DNA damage accumulation. However, the great inter-individual variations in middle-aged individuals suggest that additional cell-intrinsic mechanisms and/or extrinsic factors contribute to the age-associated DNA damage accumulation.” Meaning that nuclear DNA damage may or may not be a primary cause of aging, and may or may not be important in comparison to other factors.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3049780/

Small steps: “The notion of transplanting adult stem cells to treat or even cure age-related macular degeneration has taken a significant step toward becoming a reality. … researchers have demonstrated, for the first time, the ability to create retinal cells derived from human-induced pluripotent stem cells that mimic the eye cells that die and cause loss of sight. Age-related macular degeneration (AMD) [gradually] destroys sharp, central vision needed for seeing objects clearly and for common daily tasks such as reading and driving. AMD progresses with death of retinal pigment epithelium (RPE), a dark color layer of cells which nourishes the visual cells in the retina. While some treatments can help slow its progression, there is no cure. The discovery of human induced pluripotent stem (hiPS) cells has opened a new avenue for the treatment of degenerative diseases, like AMD, by using a patient’s own stem cells to generate tissues and cells for transplantation. For transplantation to be viable in age-related macular degeneration, researchers have to first figure out how to program the naïve hiPS cells to function and possess the characteristics of the native retinal pigment epithelium, RPE, the cells that die off and lead to AMD. … This is the first time that hiPS-RPE cells have been produced with the characteristics and functioning of the RPE cells in the eye. That makes these cells promising candidates for retinal regeneration therapies in age-related macular degeneration.”

Link: http://www.eurekalert.org/pub_releases/2011-03/gumc-sct031811.php

Exercise slows many of the degenerations of aging and – much like calorie restriction – this appears to be the result of changes in a multitude of biological processes and systems. In effect exercise adjusts the operation of your metabolism, moving it into a better configuration.

If you’d like a look under the hood, an overview of what is presently known of the biology that links exercise to improved long term health, you might read this recent open access review paper. It focuses on the heart, but the underlying mechanisms are of general interest:

It is generally accepted that regular exercise is an effective way for reducing cardiovascular morbidity and mortality. Physical inactivity and obesity are also increasingly recognized as modifiable behavioral risk factors for a wide range of chronic diseases, including cardiovascular diseases. Furthermore, epidemiologic investigations indicate that the survival rate of heart attack victims is greater in physically active persons compared to sedentary counterparts. Several large cohort studies have attempted to quantify the protective effect of physical activity on cardiovascular and all cause mortality. Nocon et al. in a meta-analysis of 33 studies with 883,372 participants reported significant risk reductions for physically active participants. All-cause mortality was reduced by 33%, and cardiovascular mortality was associated with a 35% risk reduction. Exercise capacity or cardiorespiratory fitness is inversely related to cardiovascular and all-cause mortality, even after adjustments for other confounding factors.

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Physical inactivity is increasingly recognized as modifiable behavioral risk factor for cardiovascular diseases. A partial list of proposed mechanisms for exercise-induced cardioprotection include induction of heat shock proteins, increase in cardiac antioxidant capacity, expression of endoplasmic reticulum stress proteins, anatomical and physiological changes in the coronary arteries, changes in nitric oxide production, adaptational changes in cardiac mitochondria, increased autophagy, and improved function of sarcolemmal and/or mitochondrial ATP-sensitive potassium channels. It is currently unclear which of these protective mechanisms are essential for exercise-induced cardioprotection. … A better understanding of the molecular basis of exercise-induced cardioprotection will help to develop better therapeutic strategies.

Being sedentary appears to be just as self-sabotaging as letting yourself become obese. It will lower your odds of living in good health for as long as you might like – and that is enormously important in this age of biotechnology. Every additional year is another year of progress in the laboratories, of progress in advocacy for longevity science, of progress towards rejuvenation therapies that could arrive in time for those of us reading this today. Failing to take care of your health will shift the odds against you, and it’s already the case that far too many people will die before the advent of repair technologies for the biological damage of aging. Why add to your risk becoming one of them?

From Science News: “the cells of organisms from yeast to humans regularly engage in self-cannibalism. Cells chew on bits of their cytoplasm – the jellylike substance that fills their bellies – and dine on their own internal organs … It may sound macabre, but gorging on one’s own innards, a process called autophagy, is a means of self-preservation, cleansing and stress management. … A munch here gets rid of garbage that might otherwise clog the system. A nibble there rids cells of malfunctioning parts. One chomp disposes of invading microbes. In lean times, all that stands between a cell and starvation may be the ability to bite off and recycle bits of itself. And in the last decade or so it has become clear that self-eating can also make the difference between health and disease. … Starvation inhibits an important biological signaling system, known as the mTOR pathway – named for a key protein involved in regulating cell growth and survival, cell movement and protein production. The inhibition of mTOR sets off a cascade of reactions inside the cell that end in autophagy and may be crucial to prolonging cell life and ultimately fending off cancer. A drug that inhibits mTOR, called rapamycin, has been shown to extend life span in mice. It and calorie restriction are [amongst a handful of] methods proven to prolong longevity, suggesting both may work through autophagy to make cells live longer.”

Link: http://www.sciencenews.org/view/feature/id/70887/title/Dining_In

The SENS Foundation will be hosting the SENS5 conference in Cambridge, England at the end of August. Registration is open, and this note arrived in my in-box today:

I am writing to inform you that June 15th is the deadline for discounted registration and abstract submission for the fifth Strategies for Engineered Negligible Senescence (SENS) conference … The conference program features 33 confirmed speakers so far, all of them world leaders in their field. As with previous SENS conferences, the emphasis of this meeting is on “applied gerontology” – the design and implementation of biomedical interventions that may, jointly, constitute a comprehensive panel of rejuvenation therapies, sufficient to restore middle-aged or older laboratory animals (and, in due course, humans) to the physical and mental robustness of young adults.

I notice that Caleb Finch will be giving the SENS Lecture, entitled “Regenerative medicine for aging: a new paradigm worth trying” – now there’s an example of progress in winning over the mainstream of aging research to the SENS approach of repair rather than slowing down aging. In this context, “regenerative medicine” means SENS; SENS Foundation founder Aubrey de Grey uses the term more expansively than the general public and media, who use it only in reference to stem cell therapies.

The SENS Foundation also recently issued a research report (in PDF format) for the first ten months of last year, with a year end report to follow. You should find it interesting to see funding amounts listed for the varying strands of SENS research, as well as insight into exactly what the researchers are up to at present:

I’m delighted to be able to share with you our research report, prepared for the first 10 months of 2010, by Tanya Jones (our Director of Research Operations), working with our researchers and my CSO Team. I thought it would be of interest to our supporters, and serve as a precursor to our 2010 Year End Report, which is currently under production as part of our finalizing our 2010 accounts.

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SENS Foundation conducts intramural research in its Research Center in Mountain View, California. The primary focus of our intramural work is LysoSENS – investigating novel lysosomal hydrolases against intracellular aggregates that impair cell function – and we recently produced a detailed and comprehensive LysoSENS planning document in collaboration with our extramural project at Rice University.

We have also arranged for research in the MitoSENS strand – obviating mitochondrial DNA deletions – to be conducted at the Research Center, following the negotiation of a transfer agreement with Dr Corral-Debrinski covering materials produced, and used in, previous successful work by her group. Dr Matthew “Oki” O’Connor joined us in September to initiate this project.

The relative amounts devoted to each project clearly illustrate that the Foundation’s primary focus at this time is the LysoSENS project, and I can guess at some of the strategic reasoning there. Much money and many connections with industry might be gained through success in the LysoSENS platform. Not just aging, but many diseases could be effectively treated in their late stages through progress in bioremediation of this sort, and that means that big pharma and big biotech would be very interested in licensing agreements – which in turn would assist the Foundation in greatly expanding its purview and influence.

It is, however, frustrating to see far less funding devoted to MitoSENS, the project aimed at removing the contribution of mitochondrial DNA damage to aging. Everyone has an opinion, and mine (for what it’s worth, which isn’t all that much in this case, and nor should it be) is that mitochondrial repair would make a better primary focus. Irrespective of the methodology chosen, it seems clear that the research community as a whole is frustratingly close to something that will work to completely reverse mitochondrial damage, whether it is through allotopic expression as advocated by the SENS Foundation or periodic whole-body replacement of mitochondrial DNA as demonstrated in mice some years ago.

Yet the funds going towards mitochondrial repair – both here and generally – are in no way proportionate to the degree to which the research community believes mitochondrial DNA damage to be a cause of aging and longevity.

The advice I give myself on this issue is the same as I’ll give to anyone else in the same position: if you believe that too little funding is devoted to any given research goal, then get out there and do something about it. Earn money and donate it, and persuade others to do the same. After all, that’s exactly what Aubrey de Grey did in order to arrive at his present position: helping to direct a Foundation of his own creation where enthusiastic people are now writing annual reports on their progress towards engineering the end of aging.

As noted in this paper, many researchers still fail to control for calorie intake in their studies – and thus their experimental results are largely worthless, given the impact of even mild calorie restriction on the life spans of laboratory animals: “Much of the literature describing the search for agents that increase the life span of rodents was found to suffer from confounds. One-hundred-six studies, absent 20 contradictory melatonin studies, of compounds or combinations of compounds were reviewed. Only six studies reported both life span extension and food consumption data, thereby excluding the potential effects of caloric restriction. Six other studies reported life span extension without a change in body weight. However, weight can be an unreliable surrogate measure of caloric consumption. Twenty studies reported that food consumption or weight was unchanged, but it was unclear whether these data were anecdotal or systematic. Twenty-nine reported extended life span likely due to induced caloric restriction. Thirty-six studies reported no effect on life span, and three a decrease. The remaining studies suffer from more serious confounds. Though still widely cited, studies showing life span extension using short-lived or ‘enfeebled’ rodents have not been shown to predict longevity effects in long-lived animals. We suggest improvements in experimental design that will enhance the reliability of the rodent life span literature. First, animals should receive measured quantities of food and its consumption monitored, preferably daily, and reported. Weights should be measured regularly and reported. Second, a genetically heterogeneous, long-lived rodent should be utilized. Third, chemically defined diets should be used. Fourth, a positive control (e.g., a calorically restricted group) is highly desirable. … These procedures should improve the reliability of the scientific literature and accelerate the identification of longevity and health span-enhancing agents.”

Link: http://www.ncbi.nlm.nih.gov/pubmed/21424790