Fight Aging!

There are three days left - until September 1st - in which to vote and comment on the submitted Amex Members Projects to determine the top 25 that will move on to the next stage. The combination of votes and public interest will ultimately determine how American Express awards $2.5 million in philanthropic funding. From the website:

We're inviting you to come together to share ideas for projects that could make a difference in the world. Then it's up to you to support, and ultimately vote on, which projects get $2.5 million in funding from American Express.

As you no doubt know, the Methuselah Foundation volunteers have a well-formed longevity science proposal in the running:

Create a program that utilizes college undergraduates to perform research in a variety of scientific venues surrounding fighting age related diseases such as Alzheimer’s, Parkinson’s, Heart Disease and Cancer and overall extension of healthy human life. Hiring researchers is exceedingly expensive. By outsourcing projects to undergraduate students, laboratory use and labor costs are negligible, and the students receive college credit for their work.

...

People who believe that one day they will peacefully die in their sleep are living in ignorance. The vast majority of age related deaths are a slow, painful, and degrading process over many years of later life. Watching my beloved grandmother die as a result of an age related disease and seeing our adored family friend fall prey to cancer has inspired me to learn more about death and aging pathology, and more importantly, to do something about it.

This is a well-planned project, sized to the funds available. With the backing of the Methuselah Foundation, already very involved in organizing undergraduate and graduate research volunteers, it would do well if victorious. As the vote counts ramp up in the final days of selecting the top 25 projects, it's up to us to help keep longevity science in the spotlight. It is by far the most discussed project, but it needs more votes. Tell your friends!

You don't have to be an Amex cardholder, but you do have to be a US resident in order to register and vote. Some instructions via the Methuselah Foundation blog:

1. Go to this website: http://www.membersproject.com/

2.a. If you are not an Amex Card Member: Click on "Guest Members Log In" in the upper right corner of the screen. Then click on "Guest Members Sign Up Here" at the bottom of the next screen.

2.b. If you are an Amex Card Member: Click on "Cardmembers Log In" on the right side of the screen. If you don't already have an online login click on "Create a Log In" in the next screen.

3. Complete the Registration Form which will give you your Login ID.

4. Once you are logged in on the home page, you can either a) Enter 'Undergrads Fighting Age Related Disease' in the Search box or b) click on 'Health' then 'Diseases and Disorders' at the bottom right of the home page, and scroll down to 'Undergrads Fighting Age Related Disease'. Alternately, here is a direct link to the project page:

http://www.membersproject.com/project/view/BVVE2C

5. Click on the project and then click on the 'Nominate this Project' button. Then click on 'Post Your Comments' at the bottom of the screen to have your say, as discussion board activity counts towards the nomination of the top 25 projects.

Opportunities to take a few minutes to step in and help secure funds for research don't come along every day for most of us. Take advantage here and know that you made a difference!

Plenty of people never get over their acceptance of death. A FutureBlogger post here offers some insight into the better half of the deathist position: someone who is happy to step aside and let progress continue, but doesn't quite understand why anyone would want to greatly extend the healthy human life span. "Since being exposed to the idea of extreme life extension, which admittedly was only several months ago, I've found myself reacting in a more skeptical and reactionary manner than I often do when confronted with other radical new futuristic ideas and technologies. When I read about possibilities of faster than light travel, I get excited. Predictions of nano-assemblers make me hopeful. I find designs for colonies on the Moon and Mars fascinating. But when I read about trends in regenerative medicine and nanotechnology that some experts believe will conquer death, I am not enthusiastic. Instead I become very skeptical, nervous and even angry. On one level, I am surprised that I could be anything other than overjoyed that ending death could be a possibility, I very much enjoy life and, as a living organism, I have a strong instinct to stay alive. Yet I find it extremely difficult to wrap my head around the idea of life without death."

Link: http://www.memebox.com/futureblogger/show/823-my-thoughts-on-the-demise-of-death

Some thoughts on the decades following the biotechnology revolution from FutureBlogger: once nanotechnology is as far advanced as biotechnology is today, what sorts of capabilites start to look plausible? "By the mid-2030s, we could be replacing brain cells with damage-resistant nanomaterials that process thoughts much faster than today's biological brains. ... The new brain would include our same consciousness, memories and personality that existed before the conversion, but it would run much faster and would increase our memory a thousand-fold. ... a daily pill would supply nanomaterials and instructions for nanobots to format new neurons and position them next to existing biological brain cells to be replaced. These changes would be unnoticeable to us, but within six months, we would be enjoying our new brain. ... Should a person with the new damage-resistant brain die in an accident, their body could be a total loss, but the brain would survive. Biological brains die within minutes after the heart stops; our new brain will simply turn itself off and wait for a new power supply. All memories and consciousness would remain intact after a fatal accident. Rescue workers would remove the brain from the deceased body and reinstall it into a newly-cloned body." A lot of work remains to be accomplished before the golden future becomes a reality - first things first.

Link: http://www.memebox.com/futureblogger/show/827-our-future-brain-damage-resistant-with-unique-new-abilities

The latest issue of Rejuvenation Research (volume 11, number 4) is available online. As usual, the contributions come from a broad range of fields in the life sciences applicable to extending healthy life span and repairing the damage of aging. Here are a couple of examples that focus on the nuts and bolts of pushing aging cells to perform greater feats of regeneration:

Aging, Stem Cells, and Mammalian Target of Rapamycin: A Prospect of Pharmacologic Rejuvenation of Aging Stem Cells

What is the relationship between stem cell aging and organismal aging? Does stem cell aging cause organismal aging or vice versa? Will stem cell aging aggravate age-related diseases? And what is stem cell aging?

As suggested herein, hyperstimulation of signal transduction pathways can render cells compensatorily irresponsive. And the hallmark of stem cell aging is poor responsiveness to activating stimuli. On the basis of the hypothesis that insensitivity to stimuli is in part due to hyperactivation of the target of rapamycin (TOR), this article suggests a means of pharmacologic rejuvenation of stem cells and wound-healing cells.

This is a useful way of looking at the issue of aging stem cells. I'm not sold on the specific details - the focus on TOR - but the general strategy of exploration and experimentation with stem cell response sounds good. If the cells are still good to go, a great deal of good might be accomplished with some comparatively simple targeted manipulations.

By way of an aside, you might recall that TOR is associated with the biomechanisms of calorie restriction, but then it's one of the pathways associated with everything of importance in the realm of metabolism.

Host Cell Mobilization for In Situ Tissue Regeneration

The goal of the present study was to investigate whether host biologic resources and environmental conditions could be used for in situ tissue regeneration, which may eliminate the need for donor cell procurement and subsequent in vitro cell manipulation. To address this aim, we implanted a common biomaterial into mice and characterized the infiltrating cells to determine their regenerative potential.

...

the infiltrating cells are capable of differentiating into multiple cell lineages, including osteogenic, myogenic, adipogenic, and endothelial lineages, if appropriate conditions are provided. These results suggest that it is possible to recruit a predominance of cells with multilineage potential into a biomaterial scaffold. Therefore, it may be possible to enrich the infiltrate with such cell types and control their fate, provided the proper substrate-mediated signaling can be imparted into the scaffold for in situ tissue regeneration.

Which is a rather long-winded way of saying that suitably designed nanostructures and control over stem cell signaling should be able to replace first generation cell delivery therapies in many situations. In theory, medical science could move the apparatus of programming and activating stem cells entirely inside the body - no need to pull cells out for culturing and manipulation or find transplant sources. It's a promising vision.

The Methuselah Foundation volunteers are looking for more signatures in the next five days to help put the "Undergrads Fighting Age Related Disease" project high in the top 25 Amex Members Projects - and thus eligible for some of the $2.5 million in funding offered by American Express. There are five days left to put your name to this project in support: 1200 signatures have been gathered in the past two weeks, putting longevity science solidly in the running. At least that many more votes are needed before voting closes - which is where you and your friends come in. Visit the Methuselah Foundation blog or the project Facebook group to find out how to sign up - or just click through to this project and follow the directions. You don't have to be an American Express member, but you do have to be a US resident. One last thing: it's important to note that of all the projects submitted to date, Undergrads Fighting Age Related Disease has by far the most comments. This counts heavily in the final selection, so jump into the project comments section and tell the world why you support longevity science and the defeat of age-related disease.

Link: http://www.membersproject.com/project/view/BVVE2C

As ScienceDaily notes, researchers "report having achieved what has long been a dream and ultimate goal of developmental biologists - directly turning one type of fully formed adult cell into another type of adult cell. ... the team is able to turn mouse exocrine cells, which make up about 95 percent of the pancreas, into precious and rare insulin-producing beta cells. ... Unlike the process involved in creating induced pluripotent stem cells (iPS) [this] direct reprogramming technique does not require turning adult cells into stem cells and then figuring out how to induce them to differentiate into a desired cell type. ... We're intrigued by the possibility that this approach, which has worked for pancreatic insulin-producing cells, could be more widely applied to many kind of cells, especially those that are lost in disease or following injury. And at the same time, we are exploring the possibility of using this general approach in a clinical context to make new beta cells for patients."

Link: http://www.sciencedaily.com/releases/2008/08/080828082819.htm

I consider it to be unfortunate that the bulk of the pro-longevity aging research camp is focused on an inefficient path forward that will in the end lead to lesser benefits. It is their belief that this is the only practical way ahead: a laborious slog towards complete understanding of aging and metabolism, followed by an even more complex navigation through re-engineering that metabolism to age more slowly. The sheer scale and difficulty of that task is why many scientists feel that meaningful engineered longevity - more healthy years through science - is a long way away indeed.

This true in a way: extension of healthy life will be a long time coming if metabolic manipulation is the only path taken by the research community. Fortunately, metabolic re-engineering is not the only way ahead. It's not the most efficient way ahead either. The better path is to refrain from changing the way in which our metabolic processes work. Instead we should indentify the biochemical differences between an old, damaged metabolism and a young, healthy metabolism - and then repair them, thus reversing aging.

It is likely to be easier and less costly to produce rejuvenation therapies than to produce a reliable and significant slowing of aging. A rejuvenation therapy doesn't require a whole new metabolism to be engineered, tested, and understood - it requires that we revert clearly identified changes to return to a metabolic model that we know works, as it's used by a few billion young people already. Those rejuvenation therapies will be far more effective that slowing aging in terms of additional years gained, since you can keep coming back to use them again and again. They will also help the aged, who are not helped at all by a therapy that merely slows aging.

All that said, I noticed that Pure Pedantry is commenting today on an analysis by researchers Jan Vijg and Judith Campisi. It's a view from the metabolic re-engineering camp, dug in for the long, slow haul:

All in all, this a very good review that I recommend reading in its entirety. They strike a note of cautious optimism that I think is right on: we are learning more about this field but there is no justification for irrational exuberance.

Not on that path, in any case. It's hard to be hugely overwhelmed by progress that might, maybe, do a little good for young people fifty years from now. What is needed today is a determined effort to do good for the aged people of twenty to thirty years from now.

Chris Patil is in search of co-authors for the science of aging blog Ouroboros: "I originally conceived of Ouroboros as a community weblog for biogerontologists - which meant, primarily, that it would serve the community, but it was also my hope that others within the community would want to pitch in. So far so good on the primary mission, but I've been remiss in recruiting other biologists to contribute to the content on the web site. Furthermore, as I get busier and busier with science, it gets harder and harder to stay on top of the literature, and the primary mission sometimes suffers as well. So: Do you want to write for Ouroboros? The three main criteria are as follows: (a) Be a working scientist in a field relevant to the biology of aging. (b) Have strong English writing skills, and a perfectionist streak about your prose. (c) Be willing and able to commit to writing a ~500-word post based on a recent journal article about the biology of aging, around once a week. ... If you’re not interested in writing but are still interested in pitching in, there's another job to be filled: 'beach-comber.' I follow the literature through a system of PubMed RSS feeds, but I don’t scour the journals' tables of contents as thoroughly or rapidly as I'd like. So there's definitely room for a few folks to comb through the ToCs of journals as they're released."

Link: http://ouroboros.wordpress.com/2008/08/27/help-wanted/

The Technology Review interviews researcher Doug Melton: "If a patient has Parkinson's disease, their dopamine-producing cells are gone. We don't understand anything about what makes those cells go away - the field is kind of stuck because you can't watch the progression of the disease. Stem cells can make neurons in a dish. Imagine you have iPS cells from a healthy person and from a Parkinson's patient. If you make dopamine neurons from both sets of cells in separate dishes, you can look at what went wrong with the diseased stem cell. The same approach will work with different degenerative diseases, such as diabetes or ALS. ... I think it will change the way degenerative diseases are studied - we'll reduce the whole process of disease to a petri dish. Within a few years, researchers the world over should have access to disease-specific cells that can be turned into cell types defective in a particular disease. ... Science clearly works best when you have a lot of bright, motivated people working on these problems. The institute has sent thousands of human embryonic stem-cell lines to hundreds of labs all over the world. We like to think that has been helpful in encouraging basic research on embryonic stem cells."

Link: http://www.technologyreview.com/printer_friendly_article.aspx?id=21307

You might recall that it was back in 2007 I first mentioned research into links between age-related changes in mitochondria, the power plants of the cell, and telomeres, the structures at the end of your chromosomes that form a counter for cell state. Your cell is a complex, unified machine, so in many ways its not surprising to find links between portions of the clockwork that are known to be important in aging. You should wander back into the archives and refresh your memory:

Linking Telomere Shortening and Mitochondrial Damage?

We know that mitochondrial damage is tied to aging via mechanisms such as the production of damaging free radicals such as [reactive oxygen species] - and that some researchers are working on solutions, such as the ability to replace all mitochondrial DNA in the body via protofection. We also know that progessive telomere shortening is tied to aging and age-related disease, and a number of different groups are working on strategies to safely lengthen telomeres.

There is strong evidence to believe that "tied to aging" in this context means "contributes to aging as a cause." Remember that aging is no more than an accumulation of damage in biochemical systems; when we look at these changes that take place with aging, we are looking at damage. This paper offers the possibility that if we repair or prevent the progressive accumulation of mitochondrial degeneration and damage, then the telomeres will take care of themselves - if the results are replicated, of course.

More On Telomere Shortening and Mitochondrial Dysfunction

So, poorly functioning mitochondria lead to telomere shortening, and telomerase somehow improves mitochondrial function to prevent that shortening. This is in place of the more expected path of undoing ongoing telomere shortening by adding extra repeat sequences to the end of the telomeres - that being the better understood function of telomerase.

As I said back then, this cries out for more research - which seems to be taking place. A recent paper pulls the antioxidant catalase into the mix:

Telomerase deficiency promotes oxidative stress by reducing catalase activity:

We used cultured mouse embryonic fibroblasts (MEF) isolated from mice lacking telomerase activity (Terc(-/-)) to analyze the redox balance and the functional consequences promoted by telomerase deficiency.

...

6-month-old Terc(-/-) [mice] showed higher oxidant capacity, lower catalase activity, greater oxidative damage, and higher TGF-beta1 and fibronectin levels ... In summary, telomerase deficiency reduces catalase activity, determining a redox imbalance that promotes overexpression of TGF-beta1 and extracellular matrix proteins.

Back a few years, researchers demonstrated that pouring extra catalase onto the mitochondria - via a genetic mutation to target the chemical to where it was needed - extends healthy life span. Catalase soaks up some fraction of damaging free radicals before they can degrade the mitochondria that produce them, and slowing mitochondrial damage is very beneficial to health and longevity. Is catalase level the mechanism by which telomerase helps out the mitochondria? Stay tuned: the more we know, the easier it will be to develop repair technologies that can set things back to the way they were when we were young.

Researchers are attempting to convince the body's defences to attack the amyloid plaques of Alzheimer's disease (AD): "by stimulating a brain cell called a microglia the cells will partially engulf the senile plaques ... [this is] the first time that this phenomenon, believed to take place in living brain, has been duplicated in the laboratory. ... the plaques themselves are not sufficient microglial activators. But when the microglia were treated with inflammatory stimulants, they attacked the plaques. ... In AD patients, microglia are not coping with the plaque build-up. Therefore plaques accumulate faster than the microglia can digest them. If we can enhance microglial digestion of these plaques, we will have a fighting chance to eliminate AD ... The next step is to find a therapeutic drug that will stimulate the microglia to devour the plaques." Time will tell whether new methods of removing amyloid prove to be as futile as the one method demonstrated to date.

Link: http://www.sciencedaily.com/releases/2008/08/080825194705.htm

Via Science News, something for those of us interested in the biochemistry of calorie restriction: "Less food doesn't always mean less energy. Restricting the diet of yeast cells makes them live about 30 percent longer than normal, scientists have known. But new research shows that these calorie-restricted cells make just as much ATP - the energy currency of cells - as do yeast cells fed a normal diet. The cells have just as much energy available, so [it's] not a starvation; it's just a specific sort of remodeling of the cells' metabolism in a way that also causes the organism to live longer ... the cells cut back on making lipids and instead rerouted energy to making ATP ... Normally, lipid molecules such as free fatty acids accumulate in yeast cells. This impairs the cells and can even cause them to self-destruct. So diverting energy away from making these lipids could help explain why calorie restriction prolongs the cells' lifespan. ... that some of the changes in the cells stimulate mitochondria, the 'power plants' of cells. As a consequence, these mitochondria churn out free radicals such as hydrogen peroxide at doses too low to do much damage to the cells but high enough to activate the cells' stress-response proteins. These groups of proteins go around fixing damage in the cells, a kind of house cleaning that can also help the cells live longer."

Link: http://www.sciencenews.org/view/generic/id/35835/title/Live_long_and_alter

As you might recall, one reason that the immune system declines with age relates to its capacity of cell types. An aged immune system is clogged with useless memory cells, leaving few resources for capable cells to fight new threats. The other reason is the decline of the thymus, source of immune cells:

The immune system undergoes dramatic changes with age - the thymus involutes, particularly from puberty, with the gradual loss of newly produced naive T cells resulting in a restricted T cell receptor repertoire, skewed towards memory cells. Coupled with a similar, though less dramatic age-linked decline in bone marrow function, this translates to a reduction in immune responsiveness

But what if we could regenerate the thymus, restoring it to a vigorous production of new immune cells? That could be one way of pushing out the limits, and making the accumulation of memory cells less harmful at any given age. One of the long-time Fight Aging! readers kindly pointed me to a recent article at Scientist Live on this topic:

Successfully combating illness in elderly individuals can potentially add years to a life. At the centre of this struggle lies an immune system that becomes compromised with age, subsequently leaving the body susceptible to diseases younger bodies would normally keep at bay.

Dr. Claude Perreault and a team of Canadian and Finnish scientists has identified a protein able to stimulate the production of T-cells, the white blood cells involved in the recognition and the elimination of infectious agents.

...

why does the thymus involute early in life so that it leaves older people immunodeficient. For example, thymic atrophy begins as early as one year of age. Progressive thymic involution is responsible for the fact that elderly individuals have very poor thymic function. They produce very little T-Lymphocytes and because of that they are more susceptible to infections, cancer, and autoimmune disease.

We also found that one major characteristic of the thymus found nowhere else in [the] lymphoid organs is the expression of a protein called Wnt4. We hypothesised that Wnt4 had a role in T-Lymphocyte development and that by providing high levels of Wnt4 to hematopoietic progenitor cells we would enhance [production of immune cells]. That is how it began.

We did two series of experiments. In the first set, we induced over-expression of Wnt4 in hematopoietic stem cells and found that compared to mice that received standard cells those that received cells producing high levels of Wnt4 had a bigger thymus and produced 3-4 times more T-Lymphocytes. ... when we knocked out Wnt4 there was thymic atrophy.

Overall, these studies suggest that Wnt4 is necessary for normal T-cell production and that over-expression of Wnt4 is sufficient to improve [production of immune cells]. In the future, we hope to evaluate the best way to give Wnt4 to animals or humans in order to find whether this molecule can be used to treat thymic involution.

An interesting start; I suspect we'll hear more along these lines in the years ahead.

You have to keep an eye on what's going on in infrastructural science. It's the improvements in cost, accuracy, and efficiency - that tend not to get as much press - that create an environment in which real breakthroughs can happen. Take this for example, via GEN News: "An international team of investigators determined that pluripotent stem cell lines display significant chemical similarity. The cell samples used in the study all had a particular protein-protein network in common. ... the profiles uniquely characteristic of the pluripotent populations, whether they came from embryonic stem cells or induced pluripotent cells. The researchers also found these profiles were shared by mouse embryonic stem cells, induced mouse pluripotent stem cells, and human oocytes. Detailed analysis showed that the interacting protein elements can be used to predict whether genetically induced stem cells will be pluripotent." Standardization is another thing to watch for - it will certainly speed things up.

Link: http://www.genengnews.com/news/bnitem.aspx?name=40923389

There are plenty of good trends in medicine research and development. The trend in bioinformatics and computational power, for example. Unfortunately, some of the bad trends are blocking movement of research into the clinic. Via FuturePundit: "Why do terminally ill patients have to wait so long to get access to the only treatments that hold any promise of saving their lives? And why is it not their right to decide? ... The FDA approved just 16 new drugs last year, and is on pace to approve only 18 this year. That's down from a high of 53 in 1996 and 39 in 1997. ... This trend does not bode well for the development of rejuvenation therapies. The FDA will hold off approval of an anti-cancer drug for people who have a fatal disease. Never mind that people who have a fatal disease are going to die anyway. The FDA won't let people take a risk when they have little to lose. That makes no sense to me. Rejuvenation therapies are going to treat that fatal disease called aging. Absent those therapies we are all going to die from complications of aging. ... Faced with rising risks of death combined with increasing pain and disablement people should be given wider latitude to try new and unproven therapies." The FDA should torn down completely; it is a roadblock to progress, and the cause of great and ongoing suffering.

Link: http://www.futurepundit.com/archives/005479.html

As you age, your mitochondria become ever more damaged and dysfunctional, a process that causes further biochemical damage throughout your body, and is in fact an important component of aging.

cells entirely populated with damaged mitochondria start churning out large quantities of free radicals - through another, more forceful mechanism - into the body at large. That's a path to age-related degeneration and fatal conditions like atherosclerosis. The free radical theory of aging is based upon the harm done to tissues, structures and processes by these damaging biochemicals.

Can ongoing mitochondrial degeneration be slowed? Well, yes - calorie restriction appears to slow down every catalogued aspect of aging, and evidence suggests that regular exercise is just about as good for everything except extending maximum species longevity. But can we do better than this for failing mitochondria via new medical technologies?

I stumbled over recent research that suggests there are comparatively simple genetic changes that will slow the rate at which your mitochondria cause the damage that leads to aging:

Mitochondrial DNA (mtDNA) is highly susceptible to injury induced by reactive oxygen species (ROS). During aging, mutations of mtDNA accumulate to induce dysfunction of the respiratory chain, resulting in the enhanced ROS production. Therefore, age-dependent memory impairment may result from oxidative stress derived from the respiratory chain.

...

Mitochondrial transcription factor A (TFAM) is now known to have roles not only in the replication of mtDNA but also its maintenance. TFAM transgenic (TG) mice exhibited a prominent amelioration of an age-dependent accumulation of lipid peroxidation products and a decline in the activities of complexes I and IV in the brain.

In the aged TG mice, deficits of the motor learning memory, the working memory, and the hippocampal long-term potentiation (LTP) were also significantly improved. The expression level of interleukin-1beta (IL-1beta) and mtDNA damages, which were predominantly found in microglia, significantly decreased in the aged TG mice.

...

an overexpression of TFAM is therefore considered to ameliorate age-dependent impairment of the brain functions through the prevention of oxidative stress and mitochondrial dysfunctions in microglia.

Doing something about the decay of mitochondrial function has a number of evident benefits, as demonstrated above. But slowing things down is a second rate strategy at best - especially if it involves genetic engineering, a technology unlikely to be in widespread use for humans for another ten to twenty years. A slowing of damage does little for those who are already damaged and aged. What we really want to be capable of achieving is reversal of existing damage - to be able to restore old and damaged mitochondria to a pristine state.

This goal is unlikely to be any more expensive or time-consuming than engineering a slowing of mitochondrial decay, so it should be the first priority. If you look back in the Fight Aging! and Longevity Meme archives, you'll find mention of a range of potential technologies at varying stages of research:

• Moving Mitochondria
• Can Damaged Mitochondria Repair Their DNA?
• Can We Build a Longevity Therapy Atop Mitoptosis?
• Eating Mitochondria
• Mitochondrial Protofection
• Xenotransplanting New Mitochondria
• MitoSENS Research at the Methuselah Foundation

Here is another study to add to the huge stack of research telling us that exercise is good for healthy longevity: "We determined whether reduced insulin sensitivity, mitochondrial dysfunction and other age-related dysfunctions are inevitable consequences of aging or secondary to physical inactivity. ... Insulin-induced glucose disposal and suppression of endogenous glucose production were higher in the trained young and older people but no age-effect was noted. Age-related decline in mitochondrial oxidative capacity was absent in endurance-trained individuals. Although endurance trained individuals exhibited higher expression of mitochondrial proteins, mtDNA, and mitochondrial transcription factors there were persisting effects of age. SIRT3 expression was lower with age in sedentary but equally elevated in endurance trained individuals. ... The results demonstrate that reduced insulin sensitivity is likely related to changes in [level of body fat] and physical inactivity rather than an inevitable consequence of aging. The results also show that regular endurance exercise partly normalizes age-related mitochondrial dysfunction, although there are persisting effects of age at the level of mtDNA abundance, nuclear transcription factors, and mitochondrial protein expression. Furthermore, exercise may promote longevity through pathways common to effects of caloric restriction."

Link: http://www.ncbi.nlm.nih.gov/pubmed/18716044

From Ouroboros: "How old are you? At present, the best experimental approach to that question is to inspect your driver's license; we are very good at measuring chronological age, but far worse at measuring physiological age. ... Until we have such a tool, questions like 'how rapidly is this individual aging?' and 'is this treatment having a positive effect on the rate of aging?” will be meaningless. ... So, the race is on to find useful biomarkers of aging. ... Telomere length is a tantalizing biomarker for the aging process: it's positively correlated with life expectancy and negatively correlated with stress and disease. If telomere shortening is a biomarker of aging, then the measurable consequences of telomere shortening should also function as biomarkers, i.e., aging bodies should contain high levels of factors secreted by cells with dysfunctional or critically short telomeres. According to a recent paper by Jiang et al., this is indeed the case. ... The proteins identified here accumulate with age - [and] they accumulate faster in subjects who are both aged and suffering from age-related disease; in other words, in people whom we might intuitively assign to the 'more rapidly aging' category."

Link: http://ouroboros.wordpress.com/2008/08/21/telomere-dysfunction-markers-as-biomarkers-of-aging/

I noticed a rather interesting open access paper the other day: researchers found strong similarities in the gene expression changes with age in several types of mice. On the one hand normally aging mice, on the other hand various long-lived mice (calorie restricted, Ames dwarf mice, etc), and on the third hand progeroid mice suffering from a form of accelerated aging. Changes in gene expression represent, amongst other things, a part of the feedback loop whereby an organism responds to circumstances by changing its own cellular programming. Calorie restriction is a great example of that in action, and demonstrates that this sort of evolved metabolic reprogramming can make a real difference to health and lifespan.

In all the mice examined, the same sorts of gene expression changes were kicking in:

Contrary to expectation, we find significant, genome-wide expression associations between the progeroid and long-lived mice. Subsequent analysis of significantly over-represented biological processes revealed suppression of the endocrine and energy pathways with increased stress responses

...

we subsequently confirmed these findings on an independent aging cohort. The majority of genes showed similar expression changes.

Our tissues react to stress in the same way, whether that stress is accelerated aging, calorie restriction, or the biochemical damage of normal aging. This is a beneficial adaptation - as calorie restriction demonstrates - but it isn't enough to hold back the consequences of either accelerated aging or the accumulated damage of very late stage "normal" aging.

The angle of the researchers here is the search for biomarkers of aging and predictors of longevity. They believe that because so many different biological states cue the same responses, you must look at gene expression of the whole genome to determine whether the state is good or bad:

The correlations we found between certain groups of mice are most likely due to distinct groups of differentially expressed genes, i.e. there might be one large set of genes similarly affected in short-lived and long-lived mice and a separate large group of genes similarly affected in progeroid and naturally aged mice. This appears indeed to be the case. Nonetheless, there are also groups of genes, such as genes of the somatotropic axis that are similarly affected in accelerated, delayed and natural aging.

...

However, the [progeroid] and long-lived animals employed in this study had a biological age of ~50% and 10-15% of their lifespan respectively. Thus, these findings also indicate that a genome-wide correlation analysis may serve as a powerful tool to determine the biological age of animals and might hence allow prognosis of longevity.

Determination of biological age is indispensable for the assessment of anti-aging treatments. Although reliable biomarkers of aging are long sought after, they have yet remained elusive. To this end, single genes or limited sets of genes used as biomarkers of aging may poorly reflect a true biological age; ... In diagnostic terms, a CR treatment might [induce] a similar age-related biomarker [as] treatment with a DNA damaging agent does.

We, therefore, propose the facilitation of comprehensive genome-wide correlation analyses to evaluate pro- and anti-aging effects of treatments aimed at health-span extension.

Hopefully you don't need more reasons to eat a sensible diet by now, but here's another. EurekAlert! passes on a theory to account for what happens to those of us who load up the carbohydrates over the years: "key appetite control cells in the human brain degenerate over time, causing increased hunger and potentially weight-gain as we grow older ... appetite-suppressing cells are attacked by free radicals after eating and [the] degeneration is more significant following meals rich in carbohydrates and sugars ... People in the age group of 25 to 50 are most at risk. The neurons that tell people in the crucial age range not to over-eat are being killed-off. ... When the stomach is empty, it triggers the ghrelin hormone that notifies the brain that we are hungry. When we are full, a set of neurons known as POMCs kick in. ... However, free radicals created naturally in the body attack the POMC neurons. This process causes the neurons to degenerate over time, affecting our judgement as to when our hunger is satisfied ... The free radicals also try to attack the hunger neurons, but these are protected by the uncoupling protein 2 (UCP2)." So eat more over the years and suffer neural damage that makes it harder not to eat more. We all have free will, but why make it harder for yourself?

Link: http://www.eurekalert.org/pub_releases/2008-08/mu-kc082108.php

Over at the Methuselah Foundation forums Michael Rae adds a lot more detail to news of lysosomal manipulations that halt liver aging in mice: "I think that we should regard this [as] supportive evidence for LysoSENS, rather than as an intervention that we should seek to translate for human use. I don't want to give the impression that this is anything less than an amazing result - I'm very impressed with the work itself, and excited by the actual effects on the animals --however, I think it's important to also see how [even] this sweeping result still suffers the standard flaws in the 'gerontological' approach to anti-aging medicine. ... note that in order to get the full effects of the intervention, the transgene had to be activated when the animals were 6 mo old - quite young ... because such 'gerontological' interventions slow down, but cannot reverse, the accumulation of aging damage, they are necessarily less effective the older people get. [This is] both because of their progressive rise in pre-existing aging damage, and the impairments in ability to adapt to and exploit such improvements due to other, independently-acting aging processes, making it hard to really benefit people who (as Dr. de Grey often puts it) 'have the misfortune to be already alive' - and especially people who are significantly older, in whom the need is greatest." You'll also find a detailed discussion of the science to back up those points.

Link: http://www.mfoundation.org/forums/showthread.php?p=4153#post4153

Following on from my last post on the attitudes of pro-longevity bioethicists, here's an open-access piece by Tom Koch. It opens with these questions:

Why has longevity become a source of dismay rather than a cause for celebration? How did we turn the greatest triumph of 20th century public health and medicine into a problem for the 21st century?

This is the view from inside the paradigm of state-regulated, state-controlled medicine. Centralized systems of privilege, cut loose from price signals, inevitably devolve to rationing and crumble beneath increased demand. That increased demand is feared even when it is a great good, such as medical technology. This state of affairs stands in stark opposition to the free market, in which increased demand is a sign of great success - it is the opportunity to create progress through trade, research, and competition. A monolithic system crumbles under growth, while the competitive market thrives. Looking back at the SAGE Crossroads podcasts on (political) economics and engineered longevity, we have this:

Again I say if this were a privatized system, we would all say "gee it’s wonderful. All these people want more health care, this industry is thriving". Let me put one other analogy. Suppose we made cars a government entitlement. Instead of cheering when auto production went up, we’d say, "Oh my God, we can’t afford this!". How you finance it may greatly affect the psychology and actually the freedom of the economy to take advantage of these new opportunities.

Koch concludes in his article:

much of what we think of as geriatric [medicine] is in fact medicine for fragile persons. Geriatric expertise in the maintenance of people with multiple conditions can serve the critically ill of every age.

Blaming people who are over the age of 65 for the rising costs of our publicly funded health care systems permits us to focus on one class of patients. In truth, health care is expensive at every age and not something to be begrudged anyone because of age. The alternative is that we should all die young, at the first hint of illness, or figure out how to live healthily and forever.

If we lived in a world in which government had nothing to do with the provision of medicine, there would be no begrudging, no need for battles over centrally planned resource assignment, no rationing by fiat of the uncaring and distant. There would instead be a ferociously competitive marketplace, responsive to needs, and there would be generous medical charity for the unfortunate; we would do very well by that. It is a great pity that we stand very far indeed from such an ideal.

Like heart damage, peripheral artery disease is open to comparatively simple stem cell therapies based on cell transplants. All that is needed is a low-cost source of suitable stem cells. From ScienceDaily: "Cells obtained from menstrual blood, termed 'endometrial regenerative cells' (ERCs) are capable of restoring blood flow in an animal model of advanced peripheral artery disease. A new study demonstrates that when circulation-blocked mice were treated with ERC injections, circulation and functionality were restored. ... [Researchers have] already performed clinical trials with adult stem cells for patients with peripheral artery disease. .... The advantage of ERCs is that they can be used in an 'off the shelf' manner, meaning they can be delivered to the point of care, do not require matching, and are easily injectable without the need for complex equipment." The ease with which a therapy can be implemented makes a great deal of difference to the speed with which it moves from laboratory to clinic.

Link: http://www.sciencedaily.com/releases/2008/08/080818220609.htm

The Times has more on growing blood from stem cells: "Vials of human blood have been grown from embryonic stem cells for the first time during research that promises to provide an almost limitless supply suitable for transfusion into any patient. The achievement by scientists in the United States could lead to trials of the blood within two years, and ultimately to an alternative to donations that would transform medicine. If such blood was made from stem cells of the O negative blood type, which is compatible with every blood group but is often in short supply, it could be given safely to anybody who needs a transfusion. ... One of the biggest safety hurdles that must be cleared before stem-cell therapies enter clinical trials is the risk of uncontrolled cell growth causing cancer. Red blood cells, however, do not have nuclei that carry the genetic material that goes wrong in cancer, and thus should not present this danger. ... While a few red blood cells have been created from embryonic stem cells before, the ACT team is the first to mass-produce them on the scale required for medical use. They also showed that the red cells were capable of carrying oxygen, and that they responded to biological cues in similar fashion to the real thing."

Link: http://www.timesonline.co.uk/tol/life_and_style/health/article4567387.ece

It seems I somehow missed a rather good interview with biomedical gerontologist Aubrey de Grey that was published at Betterhumans earlier this month. There are some good questions in there, touching on areas the average interviewer skips over. For example:

BH: [The Strategies for Engineered Negligible Senescence, or SENS] describes a whole battery of medical treatments that could theoretically defeat the aging process. These treatments range from relatively simple ones like injecting people with enzymes that can break down tough wastes inside of cells, to highly advanced ones like genetically altering trillions of somatic cells in full grown adults. Considering the differential technical challenges, what SENS therapies will most likely become available first, and which will be developed last?

AdG: Some of them are already pretty close: probably the closest is in fact not the enzyme therapy you mention, but the use of vaccines to eliminate extracellular aggregates (especially amyloid). But when we consider the others, actually I wouldn't like to make the call, because the hardest ones are the ones that the Methuselah Foundation and I are prioritising in terms of the early research. In other words, we're hoping that they will start to catch up with the easier ones. I suspect that the challenge of genetically modifying a high proportion of cells by somatic gene therapy will have been largely solved before we complete the development of all the genes that we want to introduce.

...

BH: At one point in your book, you criticize the Food and Drug Administration’s (FDA) drawn-out medical approval process and suggest that drugs should instead be approved after completion of Phase 2 trials. Why do you want such a change, and won’t it lead to more deaths thanks to unsafe drugs and medical procedures becoming available?

AdG: I want this change because it will save more lives than it costs. This question has been carefully analysed by experts and it’s clear that we are vastly over-cautious now in approving drugs. That over-caution is not the fault of the FDA or the government, because it reflects public attitudes: every death from an unsafe medical treatment causes an outcry and a lot of legal action, whereas we turn a blind eye to death from the unavailability of good drugs. But when aging is recognised as defeatable, public opinion will become more rational in this regard, and so will public policy.

It's a long piece - there's much more to read though, so head on over and do just that.

Discover Magazine looks at one of the noteworthies of the stem cell research community: "The value of therapeutic cloning has long been clear to Lanza, who did his early work with South African heart transplant pioneer Christiaan Barnard. Starting from those early days, Lanza understood that the barrier to tissue transfer was rejection by the recipient. From an entire organ to a dose of embryonic stem cells, if the tissue's DNA came from anyone else, the transplant would be rejected without the aid of harsh immunosuppressive drugs. 'The treatment could be worse than the problem,' Lanza found. But embryonic clones, the source of an endless supply of stem cells imprinted with one's personal DNA, could alter the equation in favor of the patient and augur a paradigm shift in medicine on par with the changes brought about by antibiotics and vaccines ... With the ability to become all of the blood cells - including your immune cells, red blood cells, all of your blood system, as well as vasculature, [hemangioblasts] have been biology's holy grail. What we discovered is that we can create literally millions or billions of these from human embryonic stem cells. ... we can use transient, intermediate cells like hemangioblasts as a toolbox to fix the adult so you don't have to have limbs amputated, so you may not have to go blind, to prevent heart attacks."

Link: http://discovermagazine.com/2008/sep/19-fighting-for-the-right-to-clone/article_print

From the Technology Review: "While all animals can regenerate tissue to a certain extent - we can grow muscle, bone, and nerves, for example - salamanders and newts are the only vertebrates that can grow entire organs and replacement limbs as adults. When a leg is lost to injury, cells near the wound begin to dedifferentiate, losing the specialized characteristics that made them a muscle cell or bone cell. These cells then replicate and form a limb bud, or blastema, which goes on to grow a limb the same way that it forms during normal development. Scientists have identified some of the molecular signals that play a key role in the process, but the genetic blueprint that underlies regeneration remains unknown. Researchers hope that by uncovering these molecular tricks, they can ultimately apply them to humans to regrow damaged heart or brain tissue, and maybe even grow new limbs. ... One of the key questions yet to be answered is whether the salamander has unique genetic properties that enable regeneration, or whether all animals have that innate capability. ... If we come up with some totally unique gene only present in [salamanders], that would make it really hard to replicate."

Link: http://www.technologyreview.com/printer_friendly_article.aspx?id=21265

The writing of Collin Farrelly is a reasonable median point in the range of views amongst bioethicists in favor of engineering far greater human longevity through medical science. Arthur Caplan might be another good median example.

Personally, I'm not fond of bioethics as a field - its members all too often serve as no more than useful mouthpieces for those who work to suppress freedom of research and development. There will always be demagogues and popular opinion-mongers, but that arena would much more constructive in the absence of empowered bureaucrats and political appointees who delight in shackling a ball and chain to progress. As things stand, modern bioethics all has the air of supplicants to majesties, of begging for scraps and the simple freedom to make progress.

If unelected, unaccountable, uncaring government employees didn't have the power to control the future of your access to medical technology, you could cheerfully ignore bioethicists as another bunch of crazies - men and women busy overthinking the issue of common sense - if you so decided. The world would be a better place for that freedom.

In any case, take a look at this piece that references the Longevity Dividend Initiative:

Given that many people see longevity science itself as unethical, it is not surprising that proposals to invest greater funding into tackling aging, rather than research on specific diseases, will likely be met with strong opposition and protests that this is unfair. For the latter proposal implicates the allocation of scarce resources, and thus it raises complex questions of distributive justice. Is it fair, the critic will ask, to divert resources dedicated to saving lives (e.g. with possible treatments for cancer, AD, etc.) to medical research that seeks to merely extend lives? Let us call this the Fairness Objection to prioritizing aging research.

In this paper I will examine, and critique, this Fairness Objection to making aging research a greater priority than it currently is. The Fairness Objection presumes that support for the Longevity Dividend is limited to a simplistic utilitarian justification. Utilitarians invoke a mode of justification that is, at base, aggregative. Thus the critics of utilitarianism charge that it is a moral theory that maintains that imposing high costs on a few could be justified by the fact that this confers benefits on others, no matter how small these benefits may be as long as the recipients are sufficiently numerous.

On the other hand, given that the course of one's life is a private matter, how about we all just get on with supporting, advocating, fundraising, and conducting longevity research as we see fit? Unfortunately, that delightful thing called government allows naysayers to grab the reins of power and interfere in every private endeavor. Plurity of choice is crushed beneath the battle over control. It is a despicable state of affairs, and I don't see how playing within the system - according any legitimacy to those who would use force to remake your every private choice - will make things better in the long term.

At first glance, Laron dwarfs appear to be the Ames dwarf mice of the human world - long-lived and resistant to cancer, due to a genetic mutation that suppresses the somatotrophe axis: "There are a little more than 300 people in the world with the condition Laron dwarfism, a third of whom live in remote villages in Ecuador's southern Loja province. Sufferers of Laron - believed to be caused by inbreeding - lack a hormone called Insulin-like Growth Factor 1, or IGF1. Research [suggests] this is the reason for their longevity and apparent immunity to cancer. ... We've discovered that people with Laron simply don't get cancer. Cancer can be detected in their relatives of a normal size, but never in my patients - not one single case. ... Laboratory work in mice, flies and worms has shown that if IGF1 is removed, the animals tend not to get cancer and to live longer. This is now mirrored in recent research into small humans, who turn out to have little or no IGF1." There are a few large factual mistakes in the article, as might be expected given the source, but it is most interesting to see this work in mice translate so faithfully to humans.

Link: http://www.dailymail.co.uk/news/worldnews/article-1045987/Immune-cancer-The-astonishing-dwarf-community-Ecuador-hold-key-cure.html

What does nuclear DNA damage have to do with aging? The correlation is clearly there - older animals have more random nuclear DNA damage - but the mechanism by which increased damage might lead to some portion of degenerative aging is up for debate. A recent paper shows that the correlation extends to calorie restriction and some genetic manipulations that extend life: "Genetic instability has been implicated as a causal factor in cancer and aging. Caloric restriction (CR) and suppression of the somatotroph axis significantly increase life span in the mouse and reduce multiple symptoms of aging, including cancer. To test if in vivo spontaneous mutation frequency is reduced by such mechanisms, we crossed long-lived Ames dwarf mice with a C57BL/6J line [to] measure mutant frequencies. ... Four cohorts were studied: (1) ad lib wild-type; (2) CR wild-type; (3) ad lib dwarf; and (4) CR dwarf. ... results indicate that two major pro-longevity interventions in the mouse are associated with a reduced mutation frequency. This could be responsible, at least in part, for the enhanced longevity associated with Ames dwarfism and CR."

Link: http://www.ncbi.nlm.nih.gov/pubmed/18565572

Increased understanding and control of the immune system will be just as important to enhanced human health and longevity as advances in stem cell science. The decline of the immune system with age has many detrimental effects, some direct, some indirect. But with greater control our immune systems - even just a little more control than we presently have - many of these age-related problems can be done away with. An immune system that remains efficient and active for many more years will bring increased healthy longevity.

One measure of progress in immune system engineering is the degree to which inroads are made in repairing autoimmune diseases. This is a direct application of new knowledge, run through the existing medical regulatory system. One less subtle approach presently in the works involves destroying and recreating the entire immune system to remove the configuration issue at the root of the disease - it seems to work. A wide variety of other research and development is taking place, such as this recent example:

Hope for arthritis vaccine 'cure':

A single injection of modified cells could halt the advance of rheumatoid arthritis, [one] of a family of "autoimmune" diseases, in which the body's defence systems launch attacks on its own tissues.

...

The precise trigger for these attacks is not known, but the latest technique, so far tested only on cells in the laboratory, aims to "reset" the immune system back to its pre-disease state.

A sample of the body's white blood cells is taken and treated with a cocktail of steroids and vitamins which transforms a particular type of immune cell called a dendritic cell into a "tolerant" state. These cells are then injected back into the joint of the patient.

Professor John Isaacs, who is leading the research, said: "Based on previous laboratory research we would expect that this will specifically suppress or down regulate the auto-immune response."

Just as with stem cell science, a great breadth of work in immunological engineering produces a body of knowledge and research community that can be turned to the repair of aging in years ahead. If today researchers are attempting to repair broken immune systems, tomorrow they will be adding new immune system capabilities - such as a resistance to poor configurations brought on by aging, enhanced cancer and senescent cell destruction, or removing certain damaging biochemicals that build up with age.

The immune systems of the future will be a merging of the natural and the engineered, and will be extremely efficient and long-lasting compared to our present version. Keep an eye on present day immunological research, as it is one of the foundations of tomorrow's enhanced longevity.

From the Hindustan Times: "Half a dozen eye hospitals in India are collaborating with a research centre in Chennai to create the inner layer of the cornea, the vital window of the human eye. ... Nichi-In Centre for Regenerative Medicine (NCRM) hopes to make corneal endothelium (inside cell layer) available on a commercial scale ... About 100,000 people are in need of eye transplant every year, yet only about 10,000 are able to get donated eyes. The wait for a donor can be endless for the other 90,000. Imagine what a boon it will be if an eye stem cell bank could provide these lab generated endothelial layer of the cornea ... The eye has three main parts. The first is the cornea, which is a transparent film like structure that transmits light into the eye. The other two are the lens and retina. During eye transplant, only the cornea is taken from the donor, not the whole eye. ... Nichi-In is now growing the animal and human corneal inner layer cells on a nano-scaffolding. The research centre is hoping to begin phase I clinical trials on humans in six months."

Link: http://www.hindustantimes.com/storypage/storypage.aspx?id=34901c8e-1148-44b8-ae83-395922ea0f64

Open science, analogous to open source software development, is the way of the future. It greatly increases diversity and speed of work by lowering the cost of information, and thereby allowing many more people to participate in research. In a world in which information transmission is easy, it makes no sense to lock up scientific data. Publish early, publish often should be the mantra. From Ouroboros: "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."

Link: http://ouroboros.wordpress.com/2008/08/14/opening-science-how-unconferences-changed-my-life/

How do you determine a person's age from a biomedical perspective? Not how many years they have amassed, but to what degree has the body aged relative to some median measure. This is an important question in aging research and longevity engineering - if you have no measurable metric for age, then you can't know whether or not a supposed rejuvenation medicine is working, never mind how well it is working. So a great deal of time and energy has been devoted to establishing biomarkers of aging, and you'll find some discussion on this topic back in the Fight Aging! archives:

How can you rapidly determine that you have successfully developed an anti-aging technology that works in humans if you cannot tell how advanced the aging process is in any given individual, or if you cannot even agree on a working scientific definition for aging? Obviously you can wait around to count years and deaths, but that reliable fallback is not a good approach for those of us who would like to see working healthy life extension medicine in our lifetimes.

As I mentioned back then, I think that damage repair approaches to rejuvenation science - i.e. identify and then revert biochemical changes - sidestep some of these concerns. An array of specific identified biochemical changes (such as the forms of biochemical damage listed in the Strategies for Engineered Negligible Senesence) becomes the metric for aging, and you attempt to fix or revert every change you can identify until you can prove that any specific change is benign.

In any case, we are revisiting this topic today because the most recent batch of podcasts at SAGE Crossroads discuss biomarkers of aging. Head on over and take a look.

#44 - Biomarkers of Aging - Setting the stage: What are biomarkers of aging?

a biomarker is a way to measure a parameter in a biological system or subject. All of us have in our minds how old we are. We use it as we use a clock to count the passage of time. Over a human life, we measure the passage as months, years, decades and so on, but for medical purposes, if we are going to try to develop interventions that modify the rate of aging in individuals, first we have to find a way to validate measuring aging separate from chronological age. We know that not all 50 year olds are the same. The same for all 60 years olds or 80 years olds or any other age. People vary despite their same chronological age, so we have to have measures that get at how old a person really is biologically and how to measure that, and that’s how biomarkers come in.

#45 - Biomarkers of Aging - What came out of the National Institute of Aging's biology of aging program?

it was a 10 year effort to try to find biological markers of aging that are different than chronological markers of aging. ... what we did was to create a very large colony of a variety of mice, inbred mice and inbred rats, as a source for studies looking for biomarkers of aging. ... All together of a 10 year span we had, if I remember right, 14 different laboratories involved and the biomarker research spanned the scientific spectrum from cellular and molecular model searches to whole organism behavior and sort of everything in between.

#46 - Biomarkers of Aging - Another perspective on the NIA research into the biology of aging

It’s been a very difficult process. The NIA ran a program for ten years back in the 1980s and 90s to try to identify such biomarkers and in fact was essentially not successful in that activity. The NIA invested a fair amount of money in this process, perhaps 20 million dollars, to come up with a panel of biomarkers and in the end did not come up with such and informative panel of biomarkers that could predict the chronological age of an individual within a species or the length of remaining life the individual could anticipate.

#47 - Biomarkers of Aging - What's holding the research community back?

[One stumbling block] is a lack of interest or a lack of research effort devoted to the topic. There have been major complicated human data sets where people have been tested for lots of different things, and there is some end point measure, whether they die, whether they get cancer, or whether they develop a hearing problem and so forth, and the data sets exist, but they haven’t really been evaluated by people who combine high class statistical skills and also a clear conceptual appreciation of the difference between a biomarker of aging and a risk factor for mortality.

The other stumbling block is that data sets could be improved. If this were really the major goal of the project, you would want to measure in each person or each rodent, if it’s a rodent study, a batch of different kinds of changes. Changes in kidney function, liver function, cognitive function, skin composition, and gene expression. Highly enriched data sets of that sort would have to be prepared to provide the information needed for a high level evaluation of the biomarkers of the aging rate itself.

#48 - Biomarkers of Aging - How are we going to find biomarkers of aging?

It’s gone through various times of when it was a high priority and then given a lack of success in identifying biomarkers, it lost some its priority, but I see a resurgence now given what I said in response to the previous question that we are at an important state in gerontological research where there are specific interventions that can be evaluated.

...

There is a lot of extrapolation that can be done in terms of whether our success in pre-clinical studies will translate to clinical studies, but this can only be proven by the format that is accepted in the scientific world and that’s well-controlled clinical studies. These well-controlled clinical studies can only move forward when there’s consensus on what a biomarker of aging is and how it can be applied to such clinical studies.

It is an interesting topic, wherever your views may lie.

Via Depressed Metabolism, arguments for a present focus on the development of cryonics over the development of rejuvenation medicine: "In his article 'Why Cryonics Will Probably Help You More Than Antiaging' (2004), cryonics activist Thomas Donaldson contrasts cryonics with antiaging as a means to life extension and argues that a major advantage of cryonics is that cryobiology research can move at a much faster pace than anti-aging research, especially as it pertains to humans ... Not only that, but its progress almost totally lacks the problems of proving that an advance has happened. The state of a brain, or even a section of brain, after vitrification and rewarming to normal temperature, shows directly whether or not the method used improved on previous methods. ... cryonic suspension able at least to preserve our brains in a reversible form, allowing restoration of vital functions, looks likely to come much sooner [than rejuvenation medicine]." Which is all true - but problems left to other people to solve have a way of remaining unsolved. We should work on both cryonics and rejuvenation medicine, not leave the latter for future generations.

Link: http://www.depressedmetabolism.com/2008/08/13/thomas-donaldson-on-cryonics-and-anti-aging/

The Methuselah Foundation is asking supporters to vote for aging science in the Amex Members Project program: "we are supporting a project named 'Undergrads Against Age Related Disease,' submitted as part of the Amex Members Project initiative. In order to move forward, this project must obtain more than 2000 votes in the next 2 weeks - by September 1st, 2008. You can help by voting: it's free and won't take more than a few minutes. We just need you to go to the Members Projects website and nominate the "Undergrads Against Age Related Disease" project. You don't need to be an Amex card holder, but you do need to be a US resident." From the project description: "a program that utilizes college undergraduates to perform research in a variety of scientific venues surrounding fighting age related diseases such as Alzheimer's, Parkinson's, Heart Disease, [Cancer, and] overall extension of healthy human life. Hiring researchers is exceedingly expensive. By outsourcing projects to undergraduate students, laboratory use and labor costs are negligible, and the students receive college credit for their work."

Link: http://blog.methuselahfoundation.org/2008/08/2000_votes_needed_for_the_unde.html

As I've noted in the past, accumulation of senescent cells over the years is one of the root causes of age-related damage, disease, degeneration, and ultimately death:

So-called 'senescent' cells are those that have lost the ability to reproduce themselves. They appear to accumulate in quite large numbers in just one tissue (the cartilage in our joints), but even in these small numbers they appear to pose a disproportionate threat to the surrounding, healthy tissues, because of their abnormal metabolic state. Senescent cells secrete abnormally large amounts of some proteins that are harmful to their neighbours, stimulating excessive growth and degrading normal tissue architecture. These changes appear to promote the progression of cancer.

Why do senescent cells accumulate with age? It is possible that the aging immune system, suffering issues of its own, no longer destroys senescent cells efficiently enough. It is also possible that accumulation of senescent cells has a lot to do with the shortening of telomeres with age: telomeres, after all, shorten with each cell division to act as a clock that moves cells from the life cycle of division and growth into either a quiescent or senescent phase.

You'll find a couple of interesting posts over at Anti-Ageing Research summarizing the issue of senescent cells and outlining ways to approach the repair and reversal of this age-related change in our bodies:

Cellular Senescence in Anti-Ageing Research:

Since senescent cells are potentially detrimental to the tissues in which they reside, anti-ageing research has three main aims for dealing with this problem:

(1) Prevention: prevent cells from becoming senescent.
(2) Removal: remove senescent cells as they appear.
(3) Replacement: replacement of cells which have naturally or artificially been removed.

..

Therapeutic agents have the potential to specifically target senescent cells and induce programmed cell death (apoptosis). At present, no such drug is available. However, drugs that are being developed to specifically target cancer cells could one day be adapted to target senescent cells. For this to be made possible, a cell surface marker specific to all senescent cells needs to be identified. A drug can then be developed which specifically identifies that marker, binds to it and induces apoptosis.

The removal of senescent cells using therapeutic agents:

One promising area of research in the development of drug delivery systems incorporates the use of nanotechnology. Such technology has been used to create dendrimers, spheroid or globular nanostructures which are highly branched. The branched regions of these dendrimers can be used to attach molecules such as targeting and therapeutic agents. To test this nano-delivery system, [investigators] attached a targeting agent, a therapeutic agent and an imaging agent to the surface of dendrimers. The investigators chose folic acid as the tumour-targeting agent (a molecule which binds to a high-affinity receptor found on many types of tumour cells).

...

The dendrimer construct was highly toxic to [cancer cells with folic acid receptors] but had no effect on cells without the folic acid receptor. It is research like this that could one day be adapted to specifically target senescent cells.

The tools of biotechnology being developed for specific uses today - often in the cancer research community - will have very broad future applications. Nanoparticles like dendrimers are one example of many.

An important aspect of immune system aging is the lack of naive T cells resulting from long periods of chronic infection by viruses like cytomegalovirus. What if we could reconfigure the immune system to behave more rationally when presented with recurring threats, and thus not exhaust its resources? That might be a possibility: "preventing white blood cells' circulation by trapping them in the lymph nodes can help mice get rid of a chronic viral infection ... laboratory mice can fight off infection by the Armstrong strain of lymphocytic choriomeningitis virus (LCMV), but are vulnerable to chronic infection by a variant called clone 13. ... infecting mice with the Armstrong strain sequesters white blood cells in the lymph nodes, while clone 13 does so less stringently. ... Our hypothesis was that if we could artificially induce conditions like those produced by the Armstrong strain, it would help the immune system clear an infection by clone 13 ... an experimental drug called FTY720 [prevents] white blood cells from leaving lymph nodes ... Even if mice have a stable chronic LCMV clone 13 infection, treatment with FTY720 can still improve their immune response against LCMV enough to have them rid it from their systems ... FTY720 appears to prevent 'exhaustion' in the group of white blood cells called CD8+ T cells."

Link: http://www.eurekalert.org/pub_releases/2008-08/eu-twb_1080808.php

From Ouroboros: "Welcome to the second installation of Hourglass, a blog carnival devoted to the biology of aging. The entries are representatives of the excellent (and growing) community of bloggers who are writing about biogerontology, lifespan extension technologies, and aging in general. ... Anne C. shares a parable about taking care of her friend Nigel the Fish and what that led her to realize about longevity: specifically, that environment is critical, and that the combination of extrinsic factors that one might collectively term 'nurture' can make all the difference between a short unhappy life and a long fulfilled one. ... Old and damaged cells enter a permanent growth arrest known as senescence, which is both good (because they can’t initiate tumors) and bad (because persistent senescent cells behave in a ridiculously antisocial manner, secreting growth factors and proteases that both encourage nearby tumors to metastasize and degrade tissue function). ... At his new site Anti-Ageing Research, Dominick Burton discusses ways in which specifically targeted cancer therapies might be adapted to attack senescent cells instead."

Link: http://ouroboros.wordpress.com/2008/08/12/hourglass-ii-a-carnival-of-biogerontology/

I thought I'd direct your attention to a generally sensible blog post I noticed recently:

As a general matter, many people are reluctant to say that a person is ethically obligated to sacrifice herself (i.e. end her life prematurely) for the sake of others. This principle may run afoul of our ethical intuitions in at least one case.

Suppose that Jeff makes several billion dollars on Silicon Valley. When asked which causes he plans on donating to, Jeff replies: "Just one. I will fund research on life extension (cryogenics, therapeutic cloning, xenotransplantation, etc.) so that I can live for as long as possible." Are Jeff's actions unacceptably selfish?

As it becomes more apparent to a wider audience that engineered healthy longevity - medicine to repair the biochemical damage of aging - is a very plausible prospect for the decades ahead, we'll see much more discussion on the topic. As that discussion broadens, I fully expect it to follow much the same lines as bioethical handwringing over past advances: a decade or so of public idiocy that is followed by an era in which people quickly forget that anybody ever claimed the advance in question was a bad idea. Look at in vitro fertilization back a ways, or the changing public discussion over stem cell science.

Sadly, I don't think much can be done about the contingent who do actually believe it is "unacceptably selfish" to invest in research that will benefit many people, one of which happens to be the investor. They are a millstone about the neck of human civilization, and an unfortunate consequence of prosperity - beneficiaries ignorant of the processes by which their comparatively great wealth is created and maintained. To be ignorant of how to create wealth is a luxury good.

But when it comes down to it, people are usually individually positive about living longer, healthier lives. Few would volunteer to die tomorrow while healthy and vigorous, and most people invest a great deal of time and energy into anticipating and defeating threats to life and limb. So I think it'll work out in the end; we just have to suffer the decade of public idiocy first, in which every dumb justification for forcing billions of people to suffer and die is trotted out and given a good airing.

Laboratory tissue engineering continues to improve in sophistication, as noted by the New Scientist: "only now have researchers managed to make different tissues blend into one another, as they do naturally in the body. Such gradients are necessary for some structures and organs to function properly ... In the body, gradients like this strengthen the ends of tendons that attach to bones. Currently, lab-grown tendons put into the body often fail at the attachment end because they lack this property ... [the] new technique should lead to more lifelike artificially-grown tendons, and better treatments for injuries like ruptured Achilles tendons. The technique could also be applicable to other tissues, such as blood vessels .. At the heart of the new technique is a gene that triggers the fibroblast cells that make up tendons to start forming bone. The team used viruses carrying that gene to transform a tendon made from normal fibroblasts into one with a gradient of bony properties ... So far, the researchers have shown that tendons made this way are stable when implanted under the skin of rats. The next step is to graft a tendon to connect bone and muscle in a rat and see if it really does perform better."

Link: http://technology.newscientist.com/article/dn14512-labgrown-tendons-gradually-fade-to-bone.html

Via Medical News Today, another reminder of the value of exercise: "US scientists comparing middle aged and older regular runners with healthy equivalents for more than 20 years found that vigorous regular exercise was linked to longer life and less disability in old age. ... Fries and his team had 538 members of a nationwide running club and 423 healthy controls from northern California fill in questionnaires every year for as long as they could, from 1984 to 2005 ... The mean disability score was higher for the controls than the runners at all stages of the study and went up with age in both groups, but on average, for runners the onset of disability started later. ... Runners' initial disability was 16 years later than nonrunners ... Runners had a significantly lower risk of having a disability score of 0.5. ... 19 years into the study, 15 per cent of the runners and 34 per cent of the controls had died, and after adjusting for possible confounders, runners showed a greater chance of living longer. ... The differences in disability and longevity between the runner group and the control group continued to diverge at the end of the study, as the participants approached their 80th birthday."

Link: http://www.medicalnewstoday.com/articles/117929.php

As I pointed out over at the Longevity Meme this morning, some exciting news materialized over the weekend. Researchers have apparently halted an important biochemical aspect of aging in liver tissue, and have the measurements of liver function to back up that claim:

The cells of all organisms have several surveillance systems designed to find, digest and recycle damaged proteins. ... One of these surveillance systems - responsible for handling 30 percent or more of damaged cellular protein - uses molecules known as chaperones to seek out damaged proteins. After finding such a protein, the chaperone ferries it towards one of the cell's many lysosomes ... Dr. Cuervo found that the chaperone surveillance system, in particular, becomes less efficient as cells become older, resulting in a buildup of undigested proteins within the cells. She also detected the primary cause for this age-related decline: a fall-off in the number of lysosomal receptors capable of binding chaperones and their damaged proteins. Could replenishing lost receptors in older animals maintain the efficiency of this protein-removal system throughout an animal's lifespan and, perhaps, maintain the function of the animal's cells and organs as well?

Yes, it could: the researchers demonstrated old mouse livers functioning as well as young mouse livers. On the one hand, this is solid support for a range of scientific initiatives aimed at lysosomal issues and buildup of damaging material in cells. For example, the work of the Methuselah Foundation under the LysoSENS program. On the other hand, this result suggests that - in the liver at least - the problem simply goes away if you deal with the missing receptors. This is interesting, as I was under the impression that a large portion of the issue in old humans stemmed from material that would never be broken down - the human lysosome just doesn't have the tools for the job.

This work on liver function was performed in mice; will this same sort of result hold in longer-lived mammals? We humans have tens of mouse life spans in which to build up even more impressive collections of gunk in our cells. Work on AGE-breaker drugs has demonstrated that old rodents and old humans don't necessarily have a lot in common when it comes to what sorts of biochemical gunk predominantly cause degeneration:

There are many, many different types of AGEs, and researchers have no exhaustive catalogue of them all; any given AGE-breaker is going to tackle one subset at most. Alagebrium most likely attacks a type of AGE much more common in old animals than old humans, for example - which is why it works so much better for rats than us.

Well, we shall see. I can't imagine the scientists failing to find funding to continue this line of research in one form or another.

One last item that caught my eye today was buried at the bottom of this article:

In research yet to be published, Cuervo has found that calorie restriction prevents the age-related decrease in [the chaperone system].

It's quite uncanny to see calorie restriction beneficially affect every new measure of age-related change and decline, even when that is what I'd expect based on evidence to date.

You may recall a solid demonstration that visceral fat tissue negatively affects longevity from earlier this year. The full paper is now open access and available at PubMed Central: "Visceral fat (VF) accretion occurs in obesity and with aging, and a reduction in VF is a common phenotypic change in calorie-restricted [CR] mammals. VF has been shown to be the single most important determinant of metabolic syndrome, and its removal in rats results in improved insulin action and delays the onset of diabetes. Given the hazards associated with abdominal obesity, it seems plausible that the beneficial effects of CR on longevity may be due at least in part to an attenuation of VF. ... Our data clearly demonstrate that in mammals, VF removal and CR are associated with an increase in mean and maximum lifespan. ... The mean and maximum lifespan of CR rats was greater than that seen in VF-removed animals, suggesting that the life-prolonging benefit of CR is mediated in part by pathways other than those modulated by an attenuation of VF. By comparing median lifespans, we estimate that the contribution of CR to longevity in this model was 47 weeks, whereas VF removal was 9.5 weeks, as compared to [ad libitum]-fed rats, suggesting that VF reduction offered approximately 20% of the effect of CR on longevity."

Link: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2504027

ScienceDaily reports on a promising demonstration: "The cells of all organisms have several surveillance systems designed to find, digest and recycle damaged proteins. ... One of these surveillance systems - responsible for handling 30 percent or more of damaged cellular protein - uses molecules known as chaperones to seek out damaged proteins. After finding such a protein, the chaperone ferries it towards one of the cell's many lysosomes ... Dr. Cuervo found that the chaperone surveillance system, in particular, becomes less efficient as cells become older, resulting in a buildup of undigested proteins within the cells. She also detected the primary cause for this age-related decline: a fall-off in the number of lysosomal receptors capable of binding chaperones and their damaged proteins. Could replenishing lost receptors in older animals maintain the efficiency of this protein-removal system throughout an animal's lifespan and, perhaps, maintain the function of the animal's cells and organs as well?" As it turned out, this strategy does indeed work to maintain liver function at young levels in older animals.

Link: http://www.sciencedaily.com/releases/2008/08/080810213958.htm

I'm a firm believer in brands and names. If you can't say a few short words in response to "what is it you work at?" and be immediately understood, then you have one more hurdle to surmount every time you're out looking for funding, deals, and partnerships. "Cancer research" is a good example. The life sciences are fantastically complex, but everyone knows where you stand with "cancer research" - those words carry a great deal of weight and shared understanding.

Unfortunately, "aging research" doesn't carry the same weight. Cancer research is well-understood to mean searching for the cure, but "aging research" has no such connotation. Something better is needed for those of us in search of a recognizable brand for engineering a cure for aging.

Back a ways, I decided to jettison use of the term "anti-aging science" as a bad deal. It carries a lot of shared understanding, but not the right sort of shared understanding - it's a gateway to communities of magical thinking and glittery cosmetics. If that was going to help serious attempts to engineer the repair of aging, the benefits to the research community would have been clear already. They are not, needless to say, and "anti-aging science" is a poisonous swamp - it is white-coated actors playing cosmetics researchers in TV commercials.

So what do you tell people you support? Once upon a time I had hopes for "healthy life extension," but I think that life extension is on the way out as a name with promise. It suffers from too much contact with the "anti-aging" community, and is at once too vague and too clinical. I'm presently in favor of "longevity science," - or "engineered healthy longevity," or the like - in absence of other good candidates. This seems to have legs, as I've seen "longevity science" used out there in other parts of the online world. It's snappy and to the point, and not yet subverted by the horrible children in the anti-aging marketplace. The only downside that springs to mind is that it does nothing to dispel the Tithonus Error - that many people think engineered longevity means being old for longer rather than young for longer.

But these are just my views. I'd be interested to see what other people think about nomenclature and branding in initiatives aimed at the repair of aging through applied science.

Some solid correlations in this paper, but I'm not sold on the suggested mechanism of action. Eating fewer calories definitely slows down the manifestations of aging, but researchers have a way to go yet to fully explain why this is so in each case: "iron accumulates with senescence in several organs, but little is known about iron accumulation in muscle and how it may affect muscle function. In addition, it is unclear if interventions which reduced age-related loss of muscle quality, such as calorie restriction, impact iron accumulation. We investigated non-heme iron concentration, oxidative stress, [and] key indices of sarcopenia (muscle mass and grip strength) in male [rats] fed ad libitum (AL) or a calorie restricted diet ... iron levels in the gastrocnemius muscle of AL rats increased progressively with age. Between 29 and 37 months of age, the non-heme iron concentration increased by approximately 200% in AL-fed rats. Most importantly, the levels of oxidized RNA in gastrocnemius muscle of AL rats were significantly increased as well. The striking age-associated increase in non-heme iron and oxidized RNA levels and decrease in sarcopenia indices were all attenuated in the calorie restriction (CR) rats. These findings strongly suggest that the age-related iron accumulation in muscle contributes to increased oxidative damage and sarcopenia, and that CR effectively attenuates these negative effects."

Link: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2481398

Less chronic inflammation, less cancer: "Cancer is generally recognized as an age-related disease. In fact, incidence and mortality rates of most human cancers increase consistently with age up to 90 years, but they plateau and decline thereafter. A low-grade systemic inflammation characterizes ageing and this pro-inflammatory status underlies biological mechanisms responsible for age-related inflammatory diseases. On the other hand, clinical and epidemiological studies show a strong association between chronic infection, inflammation and cancer and indicate that even in tumours not directly linked to pathogens, the microenvironment is characterized by the presence of a smouldering inflammation, fuelled primarily by stromal leukocytes. ... Centenarians are characterized by a higher frequency of genetic markers associated with better control of inflammation. The reduced capacity of centenarians to mount inflammatory responses appears to exert a protective effect towards the development of those age-related pathologies having a strong inflammatory pathogenetic component, including cancer. All in all, centenarians seem to carry a genetic background with a peculiar resistance to cancer which is also an anti-inflammatory profile."

Link: http://www.ncbi.nlm.nih.gov/pubmed/18671998

An interview with Cryonics Institute president and long-time healthy life extension advocate Ben Best can be found at Depressed Metabolism: "I believe that arrogance and complacency are poison for cryonics organizations, and competition is of value in shaking complacency (sometimes). I definitely think that it would be a bad idea for cryonics to have all the eggs in one organizational basket. ... There is already too much vulnerability to lawsuits and legal/political threats. More organizations in more locations (including more countries) would reduce this vulnerability. ... Eliminating or greatly reducing cryoprotectant toxicity would be the greatest possible step toward suspended animation through cryopreservation with vitrification. If suspended animation through cryopreservation became a reality there would be immediate acceptance and adoption by conventional medicine. Patient stabilization would be perfected by researchers all over the world and adopted in hospitals and other medical facilities. I think that too much research effort in cryonics is devoted to whole body vitrification, which is a side issue. Cryoprotectant toxicity needs to be [studied] with experiments directed toward understanding the molecular mechanisms on a theoretical level - not simply trial and error. Whole body vitrification could very well be achieved more quickly if cryoprotectant toxicity was the focus of study."

Link: http://www.depressedmetabolism.com/2008/08/06/interview-with-cryonics-institute-president-ben-best/

EurekAlert! reminds us of the second main application for stem cell science: researchers "have produced a robust new collection of disease-specific stem cell lines, all of which were developed using the new induced pluripotent stem cell (iPS) technique. ... The cell lines the researchers produced carry the genes or genetic components for 10 different diseases, including Parkinson's Disease, Type I diabetes, Huntington's Disease, Down Syndrome, a form of combined immunodeficiency ('Bubble Boy's Disease'), Lesch-Nyhan syndrome, Gaucher's Disease, and two forms of Muscular Dystrophy, among others. ... the suite of iPS cell lines [marks] an important achievement and a very significant advance for patients suffering from degenerative diseases. These disease-specific iPS cells are invaluable tools that will allow researchers to watch the development diseases in petri dishes, outside of the patients. And we have good reason to believe that this will make it possible to find new treatments, and eventually drugs, to slow or even stop the course of a number of diseases." Advances that reduce the cost of research and increase efficiency will speed further progress. This is an excellent example of the type.

Link: http://www.eurekalert.org/pub_releases/2008-08/chb-dac080508.php

A large portion of the aging research community is engaged in understanding the relationship between the endocrine system and longevity. The endocrine system is an extremely complex web of biochemical interactions, feedback loops, and specialized tissues that controls metabolism and growth. It is highly influential on the longevity of a species or an individual, but understanding this system is a vast and complex undertaking. I have no doubt that researchers will still be toiling at this labor when we're well into the era of tissue engineered replacement organs and early medical nanorobots.

Some differences in life span between species can be ascribed to differences in endocrine configuration:

The complex, highly integrative endocrine system regulates all aspects of somatic maintenance and reproduction and has been widely implicated as an important determinant of longevity in short-lived traditional model organisms of aging research. Genetic or experimental manipulation of hormone profiles in mice has been proven to definitively alter longevity.

...

Here, we examine the available endocrine data associated with the vitamin D, insulin, glucocorticoid and thyroid endocrine systems of naturally long-living small mammals. Generally, long-living rodents and bats maintain tightly regulated lower basal levels of these key pleiotropic hormones than shorter lived rodents. Similarities with genetically manipulated [mammals] suggest that evolutionary well-conserved hormonal mechanisms are integrally involved in lifespan determination.

Interestingly, scientists in search of the underlying mechanisms of enhanced longevity are linking one of the first discovered longevity mutations - knockout of growth hormone receptors in mice, a large alteration to the function of the endocrine system - with changes in methionine metabolism. Methionine is one of the essential dietary amino acids, and you may recall that we have good reason to think methonine restriction plays a large role in the enhanced longevity provided by calorie restriction. We can speculate - well in advance of a good weight of evidence - that this mechanism might underlie a range of diverse longevity mutations.

Long-living growth hormone receptor knockout mice: Potential mechanisms of altered stress resistance:

Endocrine mutant mice have proven invaluable toward the quest to uncover mechanisms underlying longevity. Growth hormone (GH) and insulin-like growth factor (IGF) have been shown to be key players in physiological systems that contribute to aging processes including glucose metabolism, body composition and cellular protection.

Examination of these mutant mice across several laboratories has revealed that differences exist in both the direction and magnitude of change, differences that may result in variation in life span. Growth hormone receptor knockout mice lack a functional GH receptor, therefore GH signaling is absent. These mice have been shown to lack the heightened oxidative defense mechanisms observed in other GH mutants yet live significantly longer than wild type mice.

In this study, glutathione (GSH) and methionine (MET) metabolism was examined to determine the extent of variation in this mutant in comparison to the Ames dwarf, a mouse that exhibits delayed aging and life span extension of nearly 70%. Components of GSH and MET were altered in [growth hormone receptor knockout mice] compared to wild type controls. The results of these experiments suggest that these pathways may be partially responsible for differences observed in stress resistance and the capacity to respond to stressors, that in the long term, affect health and life span.

Look around you at the bodies of the extremely old - when was the last time you recall seeing an obese centenarian? Excess fat held over the years is a killer, and the oldest people are very rarely overweight. I noticed a paper today that works backwards from medical and mortality data to further support the same conclusion:

There has been ongoing debate about the health risks associated with increased body weight among the elderly population. One issue has not been investigated thoroughly is that body weight changes over time, as both the reasons and results of, the development of chronic diseases and functional disabilities.

Structural models have the ability to unravel the complicated simultaneous relationship between body weight, disability, and mortality along the aging process. Using longitudinal data from the Medicare Current Beneficiary Survey from 1992 to 2001, we constructed a structural model to estimate the longitudinal dynamic relationship between weight, chronic diseases, functional status, and mortality among the aging population.

A simulation of an age cohort from 65 to 100 was conducted to show the changes in weight and health outcomes among the cohorts with different baseline weight based on the parameters estimated by the model. The elderly with normal weight at age 65 experience higher life expectancy and lower disability rates than the same age cohorts in other weight categories. The interesting prediction of our model is that the average body size of an elderly cohort will converge to the normal weight range through a process of survival, senescence, and behavioral adjustment.

Become fat and stay fat, in other words, and you'll remove yourself from the picture much sooner than would otherwise be the case. In addition, your health in the years ahead will be much the worse for it. Do as you will with your life, but don't say you weren't warned.

Via Time: "Another more complicated possibility [for women's longevity] is that women have two X chromosomes, while men have one. (Men have an X and a Y.) When cells go through aging and damage, they have a choice in terms of genes - either on one X chromosome or the other. Consider it this way: you have a population of cells, all aging together. In some cells, the genes on one X chromosome are active; in other cells, by chance, the same set of genes, with different variations, are active on the other X chromosome. Don't forget, we all have the same genes - the reason we differ is because we express different variations of those genes, like different colors of a car. Now, if one set of variations provides a survival advantage for the cells versus another, then the cells with the advantage will persist while the other ones will die off, leaving behind more cells with the genes on the more advantageous X chromosome. So, in women, cells can perhaps be protected by a slightly better variation of a gene on the second X chromosome. Men don't have this luxury and don't get this choice."

Link: http://www.time.com/time/health/article/0,8599,1827162,00.html

From the Hartford Advocate: "Transhumanism is the idea that it's OK to transcend the limitations of the body and brain ... Technologies, both large and small, could radically change the human experience. The mind reels with possibilities. Could we become cyborgs, with circuitry and metallic components seamlessly integrated into our bodies? Will there be nano-machines with artificial intelligence coursing through our bodies, fixing medical problems? Will we be able to dump our consciousness into computers or other machines? ... The possibilities are endless but, at least for now, human lives are not. ... Slowing body degeneration is a modest goal, and doesn't go far enough for some national anti-aging researchers. Aubrey de Grey, an energetic Englishman with a ZZ Top-length beard, is the chief researcher and evangelist for an anti-aging movement that views aging as a disease that can be cured, and cured soon. ... I think we have a 50 percent chance of getting there in around 25 years, so long as the early proof-of-concept work in mice is well-enough funded for the next 10 years or so."

Link: http://www.hartfordadvocate.com/article.cfm?aid=9076

Aschwin de Wolf continues to build up a fascinating library of work on cryonics and its history at Depressed Metabolism. The early cryonicists of the 1960s were the cultural ancestors of the transhumanist movement, and thus also of many present initiatives in other areas of the healthy life extension community. It was the transhumanist community that helped launch the Methuselah Foundation with their early generosity in donations and volunteerism, for example. One of these days I have to mock up an evolutionary diagram of branching arrows to show the creation and diversification of pro-life-extension communities from the 1950s to the present.

But back to cryonics: two new articles at Depressed Metabolism caught my eye, both looking at the early days.

A Freezing Before Bedford's

James Bedford’s freezing in January 1967 is usually regarded as the first true cryonic suspension, done immediately after legal death under controlled conditions which, though primitive by today’s standards, may have opened the possibility of eventual reanimation. Yet there was an earlier freezing that, while more problematic from the standpoint of viability, was nonetheless important in the beginning cryonics movement.

Historical Steps Toward the Scientific Conquest of Death

In December 1963 the Life Extension Society was founded in Washington, D.C., with Cooper as president, to promote the freezing idea. The September 1965 issue of the LES periodical Freeze-Wait-Reanimate carried stirring headlines: ASTOUNDING ADVANCE IN ANIMAL BRAIN FREEZING AND RECOVERY …. Dr. Isamu Suda and colleagues, at Kobe University in Japan, had detected electrical activity in a cat brain that had been frozen to -20 C ( 4 F) for more than six months and then restored to body temperature. The cat had been anesthetized and the brain removed. The blood was replaced with a protective solution of glycerol prior to freezing; the glycerol was again replaced with blood on rewarming. Not only did the brain revive and resume activity, but the brain wave pattern did not appear to differ greatly from that of a live control. Here, then, was dramatic evidence that cryonics might work, especially if possible future advances in repair techniques were taken into account.

As we continue in our endeavors to engineer the sort of future we'd like to live in, I think it behooves us to look back at past generations of advocates, activists, and entrepreneurs who had the same goal in mind. Those who ignore history are doomed to repeat its low points, and there is much to be learned from a survey of the healthy life extension communities of the past.

InformationWeek looks at one of the organizations that's putting stem cell research into clinical practice in China. The absence of stifling regulation means that this work proceeds much more rapidly, but rigorous data tends to come later in the process. The benefits of patient choice and researcher freedom should be obvious, however. "The company, Beike Biotechnology, uses nonembryonic stem cells to treat a variety of ailments including heart disease and neurological disorders such as cerebral palsy, spinal cord injury, muscular dystrophy, and optic nerve hypoplasia, a primary cause of blindness in children. Beike's technology, which hasn't been subjected to double-blind clinical trials of the sort required by the U.S. Food and Drug Administration, uses a combination of umbilical cord cells and stem cells derived from the patient being treated." The article notes that the company is working towards the near future use of induced pluripotent stem cells in therapy - a pace of development that is impossible in the present US regulatory system.

Link: http://www.informationweek.com/news/management/compliance/showArticle.jhtml?articleID=209902855

Mainstream articles on longevity science are slowly improving in quality - hopefully a sign of progress in advocacy for this research. From the Globe and Mail: "It's not pleasant to think about, but every cell type, every body part, has its own story of decline and decrepitude. Researchers [are] piecing together how we fall apart in the hope of finding ways to keep our bodies functioning well for longer. ... Figuring out a way to stop aging - or at least slow it down - is the modern version of Spanish explorer Ponce de Leon's quest for the fountain of youth. If researchers succeed, they could offer people the chance not only to live longer, but also to extend the healthy, active, even Olympian prime of their lives. ... Some researchers argue that aging is a simple matter of wear and tear. The average human lifespan has extended beyond 30 years only in the past couple of centuries. Different body parts are bound to break down in different ways now that we are regularly living past 80, half a century more than our hunter-gatherer ancestors. This damage is why age is a major risk factor in heart disease, cancer, diabetes and Alzheimer's. But others argue that aging is not the result of random breakdowns and failures but involves general processes common to many different cell types."

Link: http://www.theglobeandmail.com/servlet/story/RTGAM.20080801.wolympicage0802/BNStory/Science/home

Does the level of random damage to your nuclear DNA - genomic instability - have anything to do with general manifestations of aging? We know the correlation with cancer, but beyond that it's up for debate. This open access paper provides a new line of evidence: "Increasing genomic instability is associated with aging in eukaryotes, but the connection between genomic instability and natural variation in life span is unknown. We have quantified chronological life span and [genomic instability] in [yeast]. We show that genomic instability increases [during] chronological aging. The age-dependent increase of genomic instability generally lags behind the drop of viability and this delay accounts for ~50% of the observed natural variation of replicative life span in these yeast isolates. We conclude that the abilities of yeast strains to tolerate genomic instability co-vary with their replicative life spans. To the best of our knowledge, this is the first quantitative evidence that demonstrates a link between genomic instability and natural variation in life span."

Link: http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2441830

An interesting open access paper via PubMed Central: "Strictly speaking, 'epigenetics' refers to chromatin and DNA modifications that are heritable through cell division, but do not involve changes in the underlying DNA sequence ... Chromatin structure is not fixed. Instead, chromatin is dynamic and is subject to extensive developmental and age-associated remodeling. In some cases, this remodeling appears to counter the aging and age-associated diseases, such as cancer, and extend organismal lifespan. However, stochastic non-deterministic changes in chromatin structure might, over time, also contribute to the break down of nuclear, cell and tissue function, and consequently aging and age-associated diseases. ... it is apparent that chromatin structure does change with aging, in organisms as diverse as yeast and mammals. However, with the exception of Sir2 in yeast, the extent to which this impacts the aging process has not yet been defined. ... the effects of chromatin on aging are likely to be complex and bidirectional. To test and define the impact of specific epigenetic determinants on aging will be a challenging task."

Link: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2464300

I missed a social interest paper from earlier this year, in which gerontologists were questioned on their views of healthy life extension and longevity science. The abstract is a fair summary of what I've seen of ongoing debates on the subject:

It is often assumed that there is broad public support for strong life extension research (i.e. research aimed at the dramatic extension of human life beyond the current maximum), and that there would be a near universal interest in using any life extending technologies that this research may produce.

In this paper we report the opinions of researchers in ageing on the controversial promise of life extension, and compare these views. This paper describes the professional attitudes, personal interest and concerns expressed by Australian and international researchers in ageing (n = 14) as expressed during semi-structured, in-depth interviews.

Researchers held varying opinions about the possibility of significantly extending human life. Some saw a limit to the extension of human life, while others did not. Some felt that research into the fundamental ageing process was a priority; others did not. Researchers tended to weigh up the potential risks and benefits of life extension with most expressing a personal interest in life extension that was contingent on the technology providing a good quality of life. Some participants were not interested in the prospect of life extension for personal reasons, because they felt the potential risks outweighed the potential benefits, or because life extension raised issues of justice and equity.

Compare this with another social science paper from earlier this year that investigates attitudes in the general populace. The results are very similar. On the one hand, it's good to see more researchers publicly expressing positive attitudes towards healthy life extension - that hasn't always been the case. But as always, those of us interested in living longer, healthier lives through science should be concerned that a good fraction of the aging research community - the people best placed to work on the fundamentals of future longevity therapies - is not all that interested in getting the job done.

"Justice and equity" in particular is a poisonous ideal when you attempt to bring it into the real world:

I find it very strange that apparently intelligent people can field this sort of argument. Replace working anti-aging medicine with, say, working heart transplants, or working kidney dialysis and see how far you get in trying to convince people that suppliers in the developed world are keeping such technologies out of the hands of others, or that we must stop using medicine that is not universally available. Quite aside from the glaring failure to understand simple economics, it is deeply depressing that we live in a world in which people argue for the enforcement of large-scale, preventable suffering and death.

Life is unfair, make no mistake. People are unequal in opportunity, capacity and the hand they were dealt at birth. To think that this truth can be removed in any way, shape or form is to betray a profound ignorance of economics and the human condition. You cannot make life better at the bottom by tearing down the top; the top is where progress happens, progress that lifts the quality of life for everyone. Punishing success in order to reward failure has predictable results - more failure and less success. The wealthy of 1950 were far worse off than the poor of today precisely because progress brings economic rewards to the successful.

The work of advocacy for longevity research is as much focused on those within the scientific community as it is on the general public. Not to convince everyone to walk in step, but to at least create a sizeable community of enthusiastic scientists - large enough to get the work done, and to sway conservative regulatory and grant organizations into ceasing their discrimination against this body of research.

It takes 20 years, give or take, for a new technology to move through multiple cycles of development, commercialization, and competition necessary to evolve from experimental prototype to widespread maturity. A look back at the past few decades of medical progress suggests that 30 years is more likely in that field - there's one effect of regulation for you, a slowing of the technologies that manage to make it over the regulatory hurdle in the first place.

What does this pace of progress in medicine mean for middle-aged and younger people today? It means that the 2030s will see widespread, cost-effective use of the medical technologies you presently read about in the science press. A small selection:

• Replacement organs will be grown to order from your own cells.
• Stem cells will be created, manipulated, and transplanted to direct extraordinary regeneration
• Age-damaged immune systems will be wiped clean and replaced afresh.
• Gene therapy will be a mature technology, and genetic disorders curable.
• Everyone will know their DNA sequence, and have access to a vast database of knowledge that describes risks, therapies, and best practices.
• Cancer will be detected early, and even late-stage metastasis cured with few side-effects by nanoparticle-based, viral, or other therapies.
• The important mitochondrial DNA will be replaced when damaged by disease or age.
• Many of the biochemical processes underlying the benefits of exercise, calorie restriction, and known human longevity-associated genes will be reproduced by cheap drugs.

These are just a few that spring to mind after watching the technology demonstrations in laboratories across the past few years. I've left out much that is promising but not confirmed - and notice that many technologies required for the repair of age-related damage are not yet at the stage where we can be confident that they'll be solved, mature, and widespread 30 years from now. The technology demonstrations haven't yet occurred, or there are too few research groups presently working on the science.

We have years - not too many, but some - to do something about that problem. I'm sure we all know what sort of capabilities in medicine we'd like to see awaiting us 30 years from now. No-one wants to be sick and crippled by age-related degeneration. But based on a survey of work taking place today, there is much left to do before we can look ahead with great confidence.

Remember that even if specific goals in medicine are possible, and even if this is an era of general progress in biotechnology, people still must work to deliberately bring those goals to fruition. The world is filled with examples of the possible and the plausible that have failed to come to pass because no-one has worked to make them real. We'll all be sorry if plausible rejuvenation technologies remain no more than a vision in the decades ahead due to lack of deliberate effort.

From Canada.com: "Aging - and more specifically, the aspiration to slow human aging - is the most important neglected issue of our time. There are many things that could kill the world's current 6.5 billion plus people, but the vast majority of those currently alive today, especially in the developed world, will die from age-related causes. The diseases of aging could be the real scourge of the 21st century. That is, unless we do something to remedy the biological vulnerabilities we have inherited from our evolutionary history. The current approach to medical research is to tackle individual diseases, one at a time. So we spend large amounts of public funding on basic research into cancer, heart disease, diabetes, Alzheimer's, etc. But we invest very little in understanding the biology of aging and how it impacts our health prospects. Supplementing the current medical approach with one that also tackles aging would help us take a more inclusive approach to health extension. ... Even if we find a cure for one of the diseases of aging - like cancer - it would only extend life by a few years, as most people will likely be afflicted by one of the other diseases of aging. But if we could modify the biological mechanisms underlying aging, we may be able to significantly increase the number of disease-free years humans can expect to live. This would reap enormous individual and societal benefits."

Link: http://www.canada.com/components/print.aspx?id=924ef76b-5103-4aad-a596-13278777f8eb

It's almost time for the second Hourglass blog carnival on the science of aging and longevity. Chris Patil of Ouroboros is looking for submissions: "The second installation of Hourglass, a blog carnival devoted to the biology of aging, will occur on August 12th. So, we're soliciting entries in the general subject area of aging and biogerontology ... Topics of posts should have something to do with the biology of aging, broadly speaking - including fundamental research in biogerontology, age-related disease, ideas about life extension technologies, your personal experience with calorie restriction, maybe even something about the sociological implications of increased longevity. Opinions expressed are not necessarily those of the management, so feel free to subvert the dominant paradigm. If in doubt, submit anyway." If you're one of the many bloggers who touch on these topics, here's a chance to see your work more widely considered.

Link: http://ouroboros.wordpress.com/2008/07/31/hourglass-ii-submissions-and-host-wanted/