Does Medicine for Aging Exist?

Published at Impact Aging you'll find descriptions of the presentations given at the Second International Conference on the Genetics of Aging and Longevity, held in Moscow recently. It's a good representative sample if you'd like to know what the mainstream of aging and longevity science looks like. What I wanted to draw your attention to was this presentation and question:

Vladimir Anisimov (N.N. Petrov Research Institute of Oncology, Russia) in his presentation "Do we really have a medicine against aging?" showed results of experiments on effects of antidiabetic biguanides and rapamycin on biomarkers of aging, life span, spontaneous and chemically-induced carcinogenesis in outbred, inbred and transgenic HER-2/neu mice and in rats.

The mTOR inhibitor rapamycin prevents age-related weight gain, decreases rate of aging, increases life span and decreases carcinogenesis in transgenic HER-2/neu cancer-prone mice. Rapamycin dramatically delayed tumors onset, decreased a number of tumors per animal and tumor size. Lifelong administration of rapamycin extends lifespan in female 129/Sv mice characterized by normal mean lifespan of 2 years. Importantly, rapamycin was administrated intermittently (every other 2 weeks) starting from the age of 2 months. Rapamycin inhibited age-related weight gain, decreased aging rate, increased lifespan (especially in the last survivors) and delayed spontaneous cancer. 22.9% of rapamycin-treated mice survived the age of death of the last mouse in control group.


Treatment of female outbred SHR mice with metformin started at the age of 3 months increased mean life span by 14% and maximum life span by 1 month. Same treatment started at the age of 9 months insignificantly increased mean life span by 6%, whereas treatment started at the age of 15 months failed to increase life span. When started at the age of 3 and 9 months, metformin delayed time of the first tumor detection by 22% and 25%, correspondingly.


These results suggest that both metformin and rapamycin may be useful in prevention of cancer and extension of lifespan when used in rational and appropriate ages, doses and schedules.

Asking and attempting to answer questions like "does medicine for aging exist" is going to make you unpopular in some quarters no matter how you answer. The large and energetic "anti-aging" marketplace, eternally plagued by the dishonesty of its bad apples, has been crying "yes, yes, get your treatments for aging here" for about as long as mankind has existed. The invention of fraud no doubt followed the discovery of the concepts of value and trade by only a few heartbeats. When no-one could in fact do much of anything about aging, one might say "so what?" Fraud and lies about extending life were no different then than fraud and lies about anything else that didn't exist and couldn't be made to exist - such as the ownership rights to certain bridges, for example.

In these later days of science and reason, however, in which we stand upon the verge of building real and meaningful ways to treat aging, that commercial "anti-aging" market is a millstone around the necks of the scientific community. It is in fact a large part of the reason why up until very recently the aging research field was extremely hostile towards anyone talking seriously about treating aging.

So you are going to see care taken when people in the scientific community speak on such topics. For my part, I think it's completely fair to put forward that, by modern standards of drug development, you could point to rapamycin and metformin and say "these are candidate treatments for aging." By this I mean that they are likely to produce minimal benefits, have potentially ugly side-effects, and are not yet really tested for that specific usage in humans - which describes both a fair chunk of the drug discovery pipeline and many drugs out there in widespread use. We are willing to call those therapies for the conditions they are used to treat.

But let's be clear: as prospective therapies for aging, these drugs are terrible. Truly bad. They are far worse than exercise or calorie restriction - they produce lesser benefits and you get unpleasant side-effects into the bargain. So given all of that I don't think it is unreasonable to say that yes, treatments for aging exist at the present time, and they are awful.

(It is worth pointing out that a gain in life span of 20% in mice is not all that in the grand scheme of things. Exercise can do better, and calorie restriction does twice as well. Further, it is not seriously expected that any gain of 20% in life span in mice through metabolic alteration will translate to a similarly meaningful gain in human life span - which has to do with many of the differences that cause us to be long-lived already for our size. For example, calorie restriction is not thought to be capable of producing more than a few years of gain in maximal human life span, even while it produces large gains in health and resistance to age-related disease).

The real path to the future, to my eyes, is to skip over all of this longevity-enhancing drug discovery nonsense, interesting though it may be, and focus on repair of specific forms of cellular and molecular damage - such as the detailed methodologies proposed in the SENS vision. If SENS or similar programs for research and development fail to become a dominant approach to longevity science, and the foreseeable future thus remains a heaping helping of more longevity-enhancing drug discovery nonsense, then therapies for aging will continue to be generally awful.

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.


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 than 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.

Work on Restoring Function in Huntington's Disease

Researchers "have collaborated on a project to restore neuron function to parts of the brain damaged by Huntington's disease (HD) by successfully transplanting HD-induced pluripotent stem cells into animal models. ... Induced pluripotent stem cells (iPSCs) can be genetically engineered from human somatic cells such as skin, and can be used to model numerous human diseases. They may also serve as sources of transplantable cells that can be used in novel cell therapies. In the latter case, the patient provides a sample of his or her own skin to the laboratory. In the current study, experimental animals with damage to a deep brain structure called the striatum (an experimental model of HD) exhibited significant behavioral recovery after receiving transplanted iPS cells. The researchers hope that this approach eventually could be tested in patients for the treatment of HD. ... the transplanted cells will be genetically identical to the patient and therefore no medications that dampen the immune system to prevent graft rejection will be needed. ... transplanted iPSCs initially formed neurons producing GABA, the chief inhibitory neurotransmitter in the mammalian central nervous system, which plays a critical role in regulating neuronal excitability and acts at inhibitory synapses in the brain. GABAergic neurons, located in the striatum, are the cell type most susceptible to degeneration in HD."


Effects of Exercise and Diet on Mortality in the Old

Via EurekAlert!: researchers "studied 713 women aged 70 to 79 years who took part in the Women's Health and Aging Studies. This study was designed to evaluate the causes and course of physical disability in older women living in the community. ... A number of studies have measured the positive impact of exercise and healthy eating on life expectancy, but what makes this study unique is that we looked at these two factors together. ... Researchers found that the women who were most physically active and had the highest fruit and vegetable consumption were eight times more likely to survive the five-year follow-up period than the women with the lowest rates. ... Study participants' physical activity was measured through a questionnaire that asked the amount of time the spent doing various levels of physical activity, which was then converted to the number of calories expended. The women were then followed up to establish the links between healthy eating, exercise and survival rates. Key research findings included: More than half of the 713 participants (53%) didn't do any exercise, 21% were moderately active, and the remaining 26% were in the most active group at the study's outset. During the five-year follow up, 11.5% of the participants died. Serum carotenoid levels were 12% higher in the women who survived and total physical activity was more than twice as high. Women in the most active group at baseline had a 71% lower five-year death rate than the women in the least active group. Women in the highest carotenoid group at baseline had a 46% lower five-year death rate than the women in the lowest carotenoid group. When taken together, physical activity levels and total serum carotenoids predicted better survival."


Aubrey de Grey at TEDxUChicago 2012

Aubrey de Grey of the SENS Foundation presented at TEDxChicago 2012 a month ago or so, and video of the event recently made its way to YouTube:

Dr. Aubrey de Grey is a biomedical gerontologist. As the Chief Science Officer of the SENS Foundation (a foundation working to develop widespread access to rejuvenation biotechnologies), author of numerous journal articles and books, and board member of a handful of editorial and scientific advisory boards, it is incontestable that Dr. Aubrey de Grey has dedicated his life to the science of combating the aging process. He received his BA and Ph.D. from the University of Cambridge, however, his original field was computer science.
 Dr. de Grey is a Fellow of both the Gerontological Society of America and the American Aging Association and sits on the editorial and scientific advisory boards of numerous journals and organisations. He has appeared on countless shows, was even featured in the Max Wexler documentary, How to Live Forever, and has also spoken at a number of world-renowned events, including TED.

A great many of de Grey's conference presentations and other appearances are archived in the depths of YouTube, as it happens. At some point when you have a spare few minutes, you might take a look at the full list. There are probably a few in there that you haven't seen, such as this presentation given earlier this year at TechFest 2012 in Bombay:

A High Level View of What is Known of Aging

The Guardian talks to researcher Tom Kirkwood: "We've known for some time that ageing is extremely variable; that everybody is different and that the differences of individuals' experience of ageing are greater than differences in earlier stages of life ... And why so variable? ... Because of the nature of the ageing process. I've been involved in this field for more than 35 years and when I entered it people fondly believed that ageing was programmed; that there was a mechanism inside our bodies that determined how long we would live. It was kind of written into our genes that we would die at a certain age. What we've been able to show is that the idea of this genetically programmed ageing makes no sense at all. There is no evidence. ... But, surely, genetic influences - a family susceptibility to cardiovascular problems, for instance - play a part in determining longevity? Only to a degree. [For example] a Danish study shows that such influences only explain about a quarter of the factors determining a lifespan. ... What we now know is that the genetic factors that influence your longevity are not genes that measure out the passage of time; the reason we age and die is because, as we live our lives, our bodies accumululate a great variety of small faults in the cells, and the molecules that make up the cells in our body - so ageing is driven by this accumulation of faults. The genes that influence longevity are those that influence how well the body copes with damage, how aggressive our repair mechanisms are; they're genes that regulate the house-keeping and maintenance and repair." All the more reason to focus research on the development of biotechnologies that can do a far better job of repair.


Fibroblast Growth Factor and Zebrafish Regeneration

Small steps towards understanding the greater regenerative capacity of one species: "When the spinal cord is severed in humans and other mammals, the immune system kicks in, activating specialised cells called glia to prevent bleeding into it. ... Glia are the workmen of the nervous system. The glia proliferate, forming bigger cells that span the wound site in order to prevent bleeding into it. They come in and try to sort out problems. A glial scar forms. ... However, the scar prevents axons, threadlike structures of nerve cells that carry impulses to the brain, of neighbouring nerve cells from penetrating the wound. The result is paralysis. ... The axons upstream and downstream of the lesion sites are never able to penetrate the glial scar to reform. This is a major barrier in mammalian spinal cord regeneration. In contrast, the zebra fish glia form a bridge that spans the injury site but allow the penetration of axons into it. The fish can fully regenerate its spinal cord within two months of injury. ... Scientists discovered the protein, called fibroblast growth factor (fgf), controlled the shape of the glia, and accounted for the difference in the response to spinal cord injury between humans and zebra fish. The scientists showed the protein could be manipulated in the zebra fish to speed up tissue repair even more. ... The hope is that fgf could eventually be used to promote better results in spinal cord repair in people."


Civilization as a Side-Effect of the Urge to Immortality

A thesis on culture and the urge to longevity is discussed by Ronald Bailey at Reason Magazine:

Cave's fascinating new book, Immortality, posits that civilization is a major side effect of humanity's attempts to live forever. He argues that our sophisticated minds inexorably recognize that, like all other living things, we will one day die. Simultaneously, Cave asserts, "The one thing that these minds cannot imagine is that very state of nonexistence; it is literally inconceivable. Death therefore presents itself as both inevitable and impossible. This is what I will call the Mortality Paradox, and its resolution is what gives shape to the immortality narratives, and therefore to civilization."


Cave identifies four immortality narratives that drive civilizations over time which he calls; (1) Staying Alive, (2) Resurrection, (3) Soul, and (4) Legacy. Cave gracefully marches through his four immortality narratives citing examples from history, psychology, and religion up to the modern day. "At its core, a civilization is a collection of life extension technologies: agriculture to ensure food in steady supply, clothing to stave off cold, architecture to provide shelter and safety, better weapons for hunting and defense, and medicine to combat injury and disease," he writes.

Cave is something of a deathist, at first glance looking like he believes that progress means overcoming the primal urge to immortality of the self and the fear of death, but at least he is a deathist who has produced an interesting work on our deep cultural heritage. It should go without saying that history is silent when it comes to the choices we make now in building the future - it can only persuade, not veto. Preferences on life, death, and the quest for rejuvenation biotechnology are personal choices.

But onwards: I think that it is useful to realize that much of our present culture - and that includes the culture of longevity science and its supporters - has very ancient roots indeed. Unbroken lines can be traced from the incentives and psychology of stone age shamans through to the magical thinking and oral fixations of today. Little but technology separates us from our ancestors of five or ten thousand years past, and what to what use do we put that technology? We use it to make our greatest myths real: we are building the world that our ancestors chose to imagine, and which we too imagine, driven by our shared human condition and neural physiology.

Spend a little time with ancient myth, and you'll soon see there is little fundamental difference between the tales of thousands of years past and the folktales of a few hundred years ago. Our present popular entertainments merely continue the theme, a thousand more frills but the same underlying psychology at work. We humans identify with a certain set of stories, and those stories are found repeated throughout our mythologies. In turn, mythology drives technology, as technology is, at heart, a way to satisfy human desires.

As to those parts of mythology that we haven't got to yet - such as unbounded longevity, enabled through biotechnology - well, give it time. We have managed flight, standing atop mountains, journeying to the moon, transmuting the elements, growing food in abundance beyond the wildest dreams of past centuries, changing the course of floods and rivers, and far more. Even the oldest myths will in due course be reconstructed in the real world, even if that means we will build cities in the clouds, cats that can talk, and spirits for companionship. Given sufficiently advanced biotechnology and an understanding of the fundaments of intelligence, the world of a century from now will be populated by people who do not age and disembodied machine intelligences - easily enough matched to the roles of hidden peoples and household spirits in legend.

Interestingly, in the past I have sketched more or less the opposite thesis to Cave above - that our heritage of myths surrounding progress, death, and mortality are a basis for the widespread knee-jerk rejection of longevity science observed in present day populations:

"Every story is the story of the Fall" - except the one that matters, the one we're all writing together with quills of science, will and toil in the real world. That story is a grand arc of irresistible rise, of the defeat of obstacles and surpassing of limitations to our true potential. But you wouldn't know it from the myths that we find most comforting, as illustrated by their widespread nature.


The story of the Fall is an old and simple one; the world is one of shortages, pain, suffering and death, yet we humans can conceive of a world absent these troubles. Nostalgia is a part of the human condition also - we see earlier times in our own lives as better than they were, and it's a short leap from there to draw a line of decay from an imagined golden age to the imperfect present. The Fall is an alignment of the mythic world - a better, imaginary world - with the arrow of time; for a variety of reasons, we have come to put that mythic world in the past rather than the future.


This is an age of progress and biotechnology. Yet we folk who might be the first ageless humans stand atop a bone mountain. Its slopes are the stories of the dead, created, told, and appreciated by people who knew their own mortality. It is an enormous, pervasive heritage, forged by an army of billions, and no part of our culture or our endeavors is left untouched by it. This is one part of the hurdle we must overcome as we strive to convince people that a near future of rejuvenation biotechnology is plausible, possible, and desirable.

This dichotomy might be another facet of the difficulty in explaining modern attitudes towards longevity and aging. Why are people on the one hand so enthused by the "anti-aging" marketplace, and at the same time so quick to reject real and meaningful science aimed at extending the health human life span? I've thought on this for a decade and still have no satisfying answer.

Tissue Engineering of Small Blood Vessels

Researchers are increasingly able to produce networks of small blood vessels - here in a way that is only immediately applicable to testing, but which will no doubt lead to further progress: "bioengineers have developed the first structure to grow small human blood vessels, creating a 3-D test bed that offers a better way to study disease, test drugs and perhaps someday grow human tissues for transplant. ... with this, we can really dissect what happens at the interface between the blood and the tissue. We can start to look at how these diseases start to progress and develop efficient therapies. ... [Researchers] first built the structure out of the body's most abundant protein, collagen, [created] tiny channels and injected this honeycomb with human endothelial cells, which line human blood vessels. During a period of two weeks, the endothelial cells grew throughout the structure and formed tubes through the mold's rectangular channels, just as they do in the human body. When brain cells were injected into the surrounding gel, the cells released chemicals that prompted the engineered vessels to sprout new branches, extending the network. A similar system could supply blood to engineered tissue before transplant into the body. ... The engineered vessels could transport human blood smoothly, even around corners. And when treated with an inflammatory compound the vessels developed clots, similar to what real vessels do when they become inflamed. The system also shows promise as a model for tumor progression. Cancer begins as a hard tumor but secretes chemicals that cause nearby vessels to bulge and then sprout. Eventually tumor cells use these blood vessels to penetrate the bloodstream and colonize new parts of the body. When the researchers added to their system a signaling protein for vessel growth that's overabundant in cancer and other diseases, new blood vessels sprouted from the originals. These new vessels were leaky, just as they are in human cancers. ... With this system we can dissect out each component or we can put them together to look at a complex problem. That's a nice thing - we can isolate the biophysical, biochemical or cellular components. How do endothelial cells respond to blood flow or to different chemicals, how do the endothelial cells interact with their surroundings, and how do these interactions affect the vessels' barrier function?"


A Cheap and Abundant Source of Heart Muscle Cells

Researchers find a low-cost way of creating cardiomyocytes on demand: they can "transform human stem cells - both embryonic and induced pluripotent stem cells - into the critical heart muscle cells by simple manipulation of one key developmental pathway. ... manipulating a major signaling pathway known as Wnt - turning it on and off at prescribed points in time using just two off-the-shelf small molecule chemicals - is enough to efficiently direct stem cell differentiation to cardiomyocytes. ... The technique promises a uniform, inexpensive and far more efficient alternative to the complex bath of serum or growth factors now used to nudge blank slate stem cells to become specialized heart cells. ... Our protocol is more efficient and robust. We have been able to reliably generate greater than 80 percent cardiomyocytes in the final population while other methods produce about 30 percent cardiomyocytes with high batch-to-batch variability. ... The ability to make the key heart cells in abundance and in a precisely defined way is important because it shows the potential to make the production of large, uniform batches of cardiomyocytes routine. [The] cells are in great demand for research, and increasingly for the high throughput screens used by the pharmaceutical industry to test drugs and potential drugs for toxic effects. ... Scientists also have high hopes that one day healthy lab-grown heart cells can be used to replace the cardiomyocytes that die as a result of heart disease. ... Many forms of heart disease are due to the loss or death of functioning cardiomyocytes, so strategies to replace heart cells in the diseased heart continue to be of interest. For example, in a large heart attack up to 1 billion cardiomyocytes die. The heart has a limited ability to repair itself, so being able to supply large numbers of potentially patient-matched cardiomyocytes could help."


Updates on the Longecity Crowdfunded Microglia Study

The Longecity community (formerly the Immortality Institute) has for some years been one of the pioneers of the current phase of crowdfunding for scientific research, and community members have raised a few tens of thousands of dollars for life science projects connected to longevity science. You might recall that last year they raised the funds for a study of microglia:

Cognitive functions of the brain decline with age. One of the protective cell types in the brain are called microglia cells. However, these microglia cells also loose function with age. Our aim is to replace non-functional microglia with new and young microglia cells derived from adult stem cells. We will inject these young microglia cells into 'Alzheimer mice' - a model for Alzheimers disease. After giving the cells some time to work, we will sacrifice the mice and measure microglia activity, neurogenesis, proliferation of neuroprogenitors and plaque density in the brain. A reduction in plaque density of Alzheimer mice would be a first proof that the transplanted microglia are performing their expected function.

Some interim results and comments are posted to the study blog at Longecity - note that English is not the first language of the researchers involved.

To visualize microglia and amyloid plaques in vivo, we established different staining protocols (including histology and immunohistology) to later evaluate microglia number after transplantation and also amyloid load. ... Most of our measurements will take place in the hippocampus, one of the brain regions where many of the degenerative changes happen in Alzheimer's disease. ... In summary we have established all necessary methods for brain staining, tested the sterology method using non-transplanted mice and are now ready to transplant. We finally got the approval from our animal guys after waiting for 10 month (they are a bit over-correct here in Germany).

One thing to note about animal studies, and medical research in general, is the exceedingly heavy layer of regulation that exists in much of the world. There are boards and reviews and an endless procession of paperwork, all apparently devoted to slowing things down. It really can take the better part of a year to obtain institutional approval to perform a comparatively simple study - and it is usually impossible to have that approval timed to allow research to proceed without delay. Another thing to note is that even the comparatively simple work in the life sciences involves many, many details of measurement, cell cultures, and other line items. Much of that is largely hidden from the outside world and glossed over in the popular science press, which prefers to focus on the end results or new achievements rather than all of the well known but time-consuming foundation work that goes into any study.

Autoantibodies in Alzheimer's Disease

Via ScienceDaily, an example of a more recent form of theory to explain the development of Alzheimer's disease: "dying or damaged brain cells release debris into the bloodstream and give rise to specific autoantibodies that appear to be reliable biomarkers for early diagnosis of Alzheimer's and other neurodegenerative diseases. The researchers also identify a key mechanism in the development of Alzheimer's that mirrors a process that is common in such autoimmune disorders as rheumatoid arthritis. ... human blood contains perhaps thousands of autoantibodies for clearing cellular debris, and that some of these autoantibodies can potentially be used to accurately diagnose neurodegenerative diseases ... The researchers focused on the role of enzymes, called PADs, in citrullination, a process that converts one type of amino acid into another (amino acids are the building blocks of proteins). After examining postmortem human brain tissue from individuals with Alzheimer's disease and healthy controls, the researchers found that neurons located in the area of the brain first affected by Alzheimer's disease accumulate both citrullinated proteins and a PAD enzyme. ... Their results suggest that when neuron cells die, they release their contents into the fluid that surrounds the brain. The cellular remains then enter the bloodstream and their presence generates the production of specific autoantibodies that target this neuronal debris. ... Our previous studies provided evidence that some of these autoantibodies may be able to return to the brain through breaches in the blood-brain barrier. Once there, they selectively bind to the surfaces of neurons, disrupting the function of the brain cells and accelerating the accumulation of beta amyloid deposits. This chronic cycle of protein-debris-generating autoantibodies that can then seep through the blood-brain barrier helps explain the long-term, progressive degeneration that results from Alzheimer's disease."


Thoughts on the de Grey/Blakemore Debate on Longevity Science

Filmmaker Robert Pappas, who produced To Age or Not to Age, here offers some thoughts on the recent academic debate between Aubrey de Grey and Colin Blakemore: "The debate's title was: 'Resolved this house wants to defeat aging entirely' and was to cover the feasibility and desirability of bringing aging under medical control. After watching the video of the debate; among other things, it strikes me that the title itself helps obscure the nature and process of the scientific research currently underway to extend healthspan, and by implication, lifespan. The problem waxes ironic. To a large degree, Aubrey became 'famous' by uttering the following on camera: 'I'm claiming that the first person to live to a 1,000, subject of course to global catastrophes, is actually, probably only about 10 years younger than the 1st 150 year old, and that's quite a thought.' On the one hand, Aubrey's thesis is provocative and possibly true - but there is a downside to such a framing of the discussion. The viewer or reader reacts - 'What, 10 years after 150, what? A 1,000 years, people from the middle ages would be alive, what? Population, resources? Bombs? - Who wants to live that long, the world sucks now, ahhhhhhh....!' I personally observed similar reactions in a portion of the audience who watched my film." This is a framing of the standard debate in advocacy for any bold new step forward in science: do you plant a flag right out there to set the bounds of the debate, or do you take the softly-softly incremental approach? In this age of pervasive death cult environmentalism, to the point at which the average man in the street thinks - falsely - that living longer will in some way cause catastrophe, I'm in favor of the former approach lest the middle position in the debate become suppression of research and development in medicine.


The Three Types of Research into Aging and Longevity

I view the world of aging and longevity science as divided into three broad classes of research and researchers - something that will already be apparent to regular readers, but which I don't recall having outlined explicitly. This crude model of the research community informs the ways in which I read research and evaluate the state of progress towards meaningful goals: both extension of healthy human life, and - more importantly - forms of medicine capable of repair and reversal of aging.

Class 1: Investigating Aging

By far the largest component of the aging science community is made up of researchers who are not working on ways to alter or repair the aging process. They investigate only, and thus the majority of funds devoted to the science of aging still go towards studies that aim to make no difference to the world beyond gathering data. This group include most of those who run demographic studies of human longevity, for example.

Aging research is unusual in the medically-relevant life sciences by virtue of this preponderance of "look but don't touch." Up until comparatively recently it was extremely hard to find funding or respect for work that aimed to do more than gather data on aging; the scientific community worked to exclude those who had such goals in mind, and funding sources closed their doors to anyone known to harbor heretical thoughts about extending human life through biotechnology.

Class 2: Working to Slow Aging

The larger minority class in aging research is made up of researchers and funding institutions who are working towards ways to slow aging, or working on related areas that will be used in constructing therapies to slow aging. The typical approach here is to reverse engineering the genetic and other low-level biochemical roots of known differences in longevity (such as the effects of calorie restriction, or the differences in life span between similar species), and then try to reproduce some of those differences using drugs, gene therapies, and other similar means. The view of these researchers is largely that we are a long way from any practical results, and those results will only offer incremental gains - a viewpoint I agree with.

Nonetheless, this class is where much of the energy and vigor is in funding and growth for aging research. This may be because this general research strategy is easily understood by traditional sources of funding, and is only an incremental alteration to previous forms of old-school drug development work.

The sea change in the aging research community over the past decade or so has largely manifested as a transformation of researchers from the bulk of class 1 into up and coming enthusiasts of class 2. As it became respectable to talk about doing something about aging - thanks to the hard work of a comparatively small number of advocates and visionary scientists - there has been a steady shifting of research priorities. The investigators still outnumber research groups working on ways to alter the course of aging, but the trend is clearly towards a field that develops clinical applications in medicine rather than only informing the medical profession of what to expect in their patients.

Class 3: Working to Reverse Aging

The smallest and most important cohort of researchers are those who are working on ways to repair, reverse, or work around the root causes of aging - the SENS Foundation research network being the archetype, though not the only set of researchers and laboratories involved in this work. This class are the most important because their approach is the only viable path we can see that has a good chance of producing rejuvenation biotechnology capable of greatly extending healthy life in the elderly - through restoring youthful function and vigor. This is the smallest cohort because we do not live in a particularly rational world.

I have discussed in the past why it is that repair based strategies are so very much better than approaches based on slowing down aging. The short of it is that aging is a matter of damage: slowing down the pace of damage will do little for people who are already old, while repairing damage will be beneficial to everyone. You can only achieve rejuvenation through actual repair, not by slowing down the rust. Given that the cost of producing therapies from the two very different strategic approaches to medicine for aging will likely be in the same ballpark, we should evidently aim for the better outcome.

There is also the matter of time - it will be decades before either side of the house has a mature base of therapies in place, and by the time those therapies are available those of use with the greatest vested interest in using them will be old. So only the strategy of aiming for rejuvenation offers the chance of an outcome that grants additional decades at the end of the day - enough time to push past actuarial escape velocity and thus be able to wait out the advent of even better therapies.

But cogent arguments aside, the greatest growth in aging research is still amongst class 2, those working on the slow road to a poor end result. Now that the research community is essentially persuaded to the view that work on aging is good, interesting, and plausible, the next - and equally important - goal of advocacy is to persuade a great many more researchers to work on the SENS vision for rejuvenation biotechnology or equivalent scientific programs.

Many, many lives depend on it.

Amyloidosis as the Present Limited Factor on Human Lifespan

A theory that has emerged in recent years points to forms of amyloidosis as the final limiting process for human life span. Extremely long-lived people, who have survived or evaded all the common fatal age-related conditions, appear to die because of amyloid buildup. The evidence is good enough for the SENS Foundation to start funding work on a therapy - like all the mechanisms of aging, this is something that can be fixed through appropriate use of biotechnology. Here's a little more on the topic (and a link to a PDF format research paper): "Supercentenarians are persons who have lived beyond the age of 110. Currently there are only about 80 such known individuals in the world whose age is verified. These people represent the limit of human lifespan. For a variety of reasons not fully understood but including lifestyle choices, genetic variants, and chance, these individuals have escaped the usual causes of death including cancer, heart disease and stroke. However, eventually they too die, with the world record holder being Jeanne Calment who survived until age 122. In a newly published review Drs. Stephen Coles and Thomas Young of the UCLA Gerontology Research Group point out what it may be that is killing supercentenarians: amyloidosis. Amyloidosis is a disease state hallmarked by the deposition of fibers of abnormally clumped masses of transthyretin. The protein transthyretin normally acts to carry thyroid and other hormones. Mutations in the gene make the fibers abnormally sticky and they tend to clump into long fibers which are deposited in multiple organs. Through early onset amyloidosis leads to disease, it is of interests that supercentanarians all seem to have significant amounts of it. Though not proven it is possible the amyloid is killing them. These persons have already escaped the typical causes of death however they have lived for so long, the normally innocuous amounts of amyloid that increase with age may actually become toxic to them because they have lived so many years. Where this line of reasoning gets exciting is that experimental drugs exist which may eliminate amyloid."


A Gene that Influences Aging, Cancer, and Inflammation

An example of the way in which the machinery of cells is very intertwined, components reused by evolution in many different mechanisms: "This was certainly an unexpected finding. It is rather uncommon for one gene to have two very different and very significant functions that tie together control of aging and inflammation. The two, if not regulated properly, can eventually lead to cancer development. It's an exciting scientific find. ... For decades, the scientific community has known that inflammation, accelerated aging and cancer are somehow intertwined, but the connection between them has remained largely a mystery ... What was known [was] that a gene called AUF1 controls inflammation by turning off the inflammatory response to stop the onset of septic shock. But this finding, while significant, did not explain a connection to accelerated aging and cancer. When the researchers deleted the AUF1 gene, accelerated aging occurred, so they continued to focus their research efforts on the gene. ... The current study reveals that AUF1, a family of four related genes, not only controls the inflammatory response, but also maintains the integrity of chromosomes by activating the enzyme telomerase to repair the ends of chromosomes, thereby simultaneously reducing inflammation, preventing rapid aging and the development of cancer. ... [Researchers are now] examining human populations for specific types of genetic alterations in the AUF1 gene that are associated with the co-development of certain immune diseases, increased rates of aging and higher cancer incidence in individuals to determine exactly how the alterations manifest and present themselves clinically."


p16INK4A and Biological Age at Extreme Longevity

A post at Extreme Longevity touches on an area of interest in aging research, and comes with a link to a PDF versions of the paper in question. It is another study confirming the link between levels of the protein p16INK4A and aging, something that has been known for some years. In particular, it shows up in the senescent cells that accumulate with age, something that researchers have managed to make use of: you might recall last year's study that showed beneficial effects from destroying senescent cells in rats. That research group used p16INK4A as a basis for their method of selective destruction, targeting only those cells that had become senescent and thus removing their contribution to the aging process.

It is worth noting that p16INK4A is a gene with a lot of aliases - which tends to happen when many different researchers have been working on the biochemistry independently. The official name is CDKN2A, or cyclin-dependent kinase inhibitor 2A, but it can be referred to as p16 as well. In any case, here is the Extreme Longevity post, a PubMed reference, and the PDF version of the paper:

In this study the researchers examined skin cells from middle aged people aged 43 to 63. They compared a group who had a strongly family history of extreme longevity to age-matched controls. They found that p16 expression in skin cells was significantly lower in the group that had the strong family history of longevity. They conclude "a younger biological age associates with lower levels of p16INK4a positive cells in human skin."

This study supports the idea that p16 expressing cells are linked to age both from a chronological as well as biological perspective. Work needs to be done to find a way to remove p16 positive cells from all tissues of the body on a regular basis. Such a therapy, if it existed, may act to reduce aging.

This all ties back in to cancer suppression versus tissue proliferation. Increased senescence in cells is one way of biasing the average over time to a lower rate of cancer - because the cells most likely to cause issues have been taken out of circulation and are no longer replicating. They should be destroyed by the immune system, but the immune system has its own age-related issues and falls down on that job, leaving the senescent cells to lurk and emit harmful signaling chemicals that damage surrounding tissue.

The flip side of the coin is that less replication among cells translates to less resilient tissues and organs, and thus faster aging. As mammalian biochemistry is set up by default, you can either be generating lots of fresh cells with a higher cancer risk, or aging faster due to poor tissue maintenance, but with a lower cancer risk. Biotechnology will let us escape from this Hobson's choice in due course - a method for tweaking the system associated with another cancer suppression gene to generate both less cancer and slower aging has been demonstrated in mice, for example. More and better technologies will emerge in human medicine in the fullness of time.

In particular, rather than focusing on metabolic tinkering to incrementally improve matters, the better approaches would be to (a) repair the ability of the immune system to eliminate senescent cells at a youthful level, and (b) develop therapies to regularly completely sweep senescent cells from the body. The effects of reducing senescent cell numbers in rats were sufficiently good that more work will be devoted to that sort of strategy in the future - and a good thing too.

Methods of Working with Stem Cells are Improving

The underlying infrastructural methods and technologies for working with stem cells are consistently improving - which lowers cost, thus allowing more research and development to take place. Here is an example: "researchers have proven that a special surface, free of biological contaminants, allows adult-derived stem cells to thrive and transform into multiple cell types. Their success brings stem cell therapies another step closer. An embryo's cells really can be anything they want to be when they grow up: organs, nerves, skin, bone, any type of human cell. Adult-derived 'induced' stem cells can do this and better. Because the source cells can come from the patient, they are perfectly compatible for medical treatments. ... We turn back the clock, in a way. We're taking a specialized adult cell and genetically reprogramming it, so it behaves like a more primitive cell. ... Before stem cells can be used to make repairs in the body, they must be grown and directed into becoming the desired cell type. Researchers typically use surfaces of animal cells and proteins for stem cell habitats, but these gels are expensive to make, and batches vary depending on the individual animal. ... human cells are often grown over mouse cells, but they can go a little native, beginning to produce some mouse proteins that may invite an attack by a patient's immune system. ... [A] polymer gel created by [researchers] in 2010 avoids these problems because researchers are able to control all of the gel's ingredients and how they combine. ... [Researchers] had shown that these surfaces could grow embryonic stem cells, [but] the polymer surface can also support the growth of the more medically promising induced stem cells, keeping them in their high-potential state. To prove that the cells could transform into different types, the team turned them into fat, cartilage and bone cells. They then tested whether these cells could help the body to make repairs. Specifically, they attempted to repair five-millimeter holes in the skulls of mice. The weak immune systems of the mice didn't attack the human bone cells, allowing the cells to help fill in the hole. After eight weeks, the mice that had received the bone cells had 4.2 times as much new bone, as well as the beginnings of marrow cavities. The team could prove that the extra bone growth came from the added cells because it was human bone."


Delaying the Aging of Stem Cells in Flies

Changes in the stem cell niche are a good part of the age-related decline in stem cell activity, which explains why old stem cells can perform like young stem cells if put into a young environment, and vice versa. Here researchers compensate for one of those niche changes: "Stem cells reside within a microenvironment of other cells - the niche - that is known to play a role in stem cell function. For example, after a tissue is injured, the niche signals to stem cells to form new tissue. It is believed that stem cells and their niche send signals to each other to help maintain their potency over a lifetime. But while the loss of tissue and organ function during aging has been attributed to decreases in stem cell function, it has been unclear how this decline occurs. [There are] a number of possible scenarios, such as whether the loss of tissue function is due to a decrease in the number of stem cells, to the inability of stem cells to respond to signals from their niche, or to reduced signaling from the niche. ... researchers discovered that as the stem cell niche [in flies] ages, the cells produce a microRNA (a molecule that plays a negative role in the production of proteins from RNA) known as let-7. This microRNA is known to exist in a number of species, including humans, and helps time events that occur during development. This increase in let-7 leads to a domino effect that flips a switch on aging by influencing a protein known as Imp, whose function is to protect another molecule, Upd, which is secreted from a key area of the niche. In short, Upd promotes the signaling that keeps stem cells active and in contact with the niche so that they can self-renew. And as aging advances, increasing expression of let-7 ultimately leads to lower Upd levels, decreasing the number of active stem cells in the niche. What leads to accumulation of let-7 in the niche of aged flies still remains an open question. The researchers also demonstrated they could reverse this age-related loss of stem cells by increasing expression of Imp."


Never Too Late to Exercise

Exercise already! Regular readers are no doubt sick and tired of hearing about it, but until such time as sensibly directed funding and hard work in the life sciences produce medical technologies that can do better for humans, regular exercise remains one of the two best tools we have to slow our inexorable slide into frailty and disease. It allows us to somewhat shift our life expectancy, and greatly reduce the risk of suffering all of the common chronic conditions of aging.

For those in the middle of life, looking at an ever-uncertain future of technological development, a few years added or subtracted might make all the difference in the world. When it comes down to the wire, will you make far enough to benefit from the first commercial rejuvenation biotechnologies, or will you fall short and be forced to take the second worst end of life option, with an unknown chance of eventual restoration? These are weighty questions, and burying your head in the sand is essentially the same as picking the poorest answer for yourself.

An article on this general theme from the popular press, which goes on to point out a range of data on exercise and specific age-related conditions:

"There's compelling data that older individuals participating in exercise programs show dramatic improvement in function and abilities," says Cedric Bryant, chief science officer for the American Council on Exercise in San Diego. In fact, experts suggest that many ills once attributed to normal aging are now being viewed as a result of chronic inactivity.

Despite this promising message, fewer than 5 percent of seniors follow the recommended guidelines for physical fitness (30 minutes of moderately intense exercise on most days). "Levels of activity in people 65 and older haven't budged in decades," says Miriam Nelson, director of the John Hancock Research Center on Physical Activity, Nutrition, and Obesity Prevention at Tufts University in Medford, Mass.

Even if they've never exercised, the middle-aged and older can still benefit by beginning now. Experts say sedentary people will actually fare better in percentage gains relative to active people, since they're starting from zero. "It doesn't matter how old you are," says Colin Milner, founder and CEO of the International Council on Active Aging in Vancouver, British Columbia. "It's never too late to start exercising."

As a specific example of the sort of low-level mechanisms by which exercise impacts long-term health, you might look at this paper:

A decline in mitochondrial biogenesis and mitochondrial protein quality control in skeletal muscle is a common finding in aging, but exercise training has been suggested as a possible cure. In this report, we tested the hypothesis that moderate intensity exercise training could prevent the age-associated deterioration in mitochondrial biogenesis in the gastrocnemius muscle of Wistar rats.

Exercise training, consisting of treadmill running at 60% of the initial VO2max, reversed or attenuated significant age-associated (detrimental) declines in mitochondrial mass ... Exercise training also decreased the gap between young and old animals in other measured parameters ... We conclude that exercise training can help minimize detrimental skeletal muscle aging deficits by improving mitochondrial protein quality control and biogenesis.

Mitochondrial damage - and thus processes such as autophagy that attempt to reduce levels of mitochondrial damage - seems to be very important in aging. Given that many mechanisms associated with longevity are seen to influence autophagy, it should not be surprising to find exercise on that list.

Working on Optic Nerve Regeneration

Researchers are working on creating regeneration in mammals where it does not normally happen: "Researchers have long tried to get the optic nerve to regenerate when injured, with some success, but no one has been able to demonstrate recovery of vision. A team [now] reports a three-pronged intervention that not only got optic nerve fibers to grow the full length of the visual pathway (from retina to the visual areas of the brain), but also restored some basic elements of vision in live mice. ... [the mice were able to] regain some depth perception, the ability to detect overall movement of the visual field, and perceive light. ... Previous studies [have] demonstrated that optic nerve fibers can regenerate some distance through the optic nerve, but this is the first study to show that these fibers can be made to grow long enough to go from eye to brain, that they are wrapped in the conducting 'insulation' known as myelin, that they can navigate to the proper visual centers in the brain, and that they make connections (synapses) with other neurons, allowing visual circuits to re-form. ... [Researchers] combined three methods of activating the growth state of neurons in the retina, known as retinal ganglion cells: stimulating a growth-promoting compound called oncomodulin, [elevating] levels of cyclic adenosine monophosphate (cAMP) and deleting the gene that encodes the enzyme PTEN. ... these interventions have a synergistic effect on growth of optic nerve fibers. ... The eye turns out to be a feasible place to do gene therapy. The viruses used to introduce various genes into nerve cells mostly remain in the eye. Retinal ganglion cells are easily targetable."

Update in 07/2016: Since this post seems to have risen in the search engines and attracts a lot of interest from patients, passing readers may want to know that a different approach to stimulating retinal ganglion cell axons to regrow has achieved partial vision restoration in mice. It is an early and very qualified victory, and you should read the details carefully before becoming excited. Nonetheless, there is progress, albeit slow progress.


Skin Cells from the Old Made into Beating Heart Muscle Cells

Ongoing work in regenerative medicine: "scientists have succeeded in taking skin cells from heart failure patients and reprogramming them to transform into healthy, new heart muscle cells that are capable of integrating with existing heart tissue. The research [opens] up the prospect of treating heart failure patients with their own, human-induced pluripotent stem cells (hiPSCs) to repair their damaged hearts. As the reprogrammed cells would be derived from the patients themselves, this could avoid the problem of the patients' immune systems rejecting the cells as 'foreign'. ... Recent advances in stem cell biology and tissue engineering have enabled researchers to consider ways of restoring and repairing damaged heart muscle with new cells, but a major problem has been the lack of good sources of human heart muscle cells and the problem of rejection by the immune system. Recent studies have shown that it is possible to derive hiPSCs from young and healthy people and that these are capable of transforming into heart cells. However, it has not been shown that hiPSCs could be obtained from elderly and diseased patients. In addition, until now researchers have not been able to show that heart cells created from hiPSCs could integrate with existing heart tissue. [Researchers] took skin cells from two male heart failure patients (aged 51 and 61) and reprogrammed them by delivering three genes or 'transcription factors' ... Crucially, this reprogramming cocktail did not include a transcription factor called c-Myc, which has been used for creating stem cells but which is a known cancer-causing gene. ... The resulting hiPSCs were able to differentiate to become heart muscle cells (cardiomyocytes) just as effectively as hiPSCs that had been developed from healthy, young volunteers who acted as controls for this study. Then the researchers were able to make the cardiomyocytes develop into heart muscle tissue, which they cultured together with pre-existing cardiac tissue. Within 24-48 hours the tissues were beating together. ... The tissue was behaving like a tiny microscopic cardiac tissue comprised of approximately 1000 cells in each beating area. ... Finally, the new tissue was transplanted into healthy rat hearts and the researchers found that the grafted tissue started to establish connections with the cells in the host tissue."


A Tale of Telomerase

Michael Rae has written a long post at the SENS Foundation on the topic of the recently published Spanish study that produced life extension in mice through a telomerase gene therapy. He has been following this line of research closely for some years, and has been critical of the results reported in the past. The post is well worth reading for a better view of both the chronology and the limitations of the work that led to this latest result.

Tale of Telomerase: Lessons and Limits in a Late-Life Launch

The connection between telomeres, telomerase, and cellular and organismal "aging" was a matter of significant scientific interest but little public awareness until the early 1990s, when Dr. Michael West founded Geron Corporation. In the process of launching that venture, and in the following years, West succeeded in embedding a controversial thesis deeply into the public imagination: that the (re)activation of telomerase in somatic cells could retard or even reverse the degenerative aging process. There were always problems with this thesis, and with public (mis)understandings of it, but its sheer simplicity and public prominence has in direct and indirect ways advanced scientific research that has answered many of the questions that thesis forced upon the scientific community, and opened up important new avenues for research in telomre biology and in biomedical gerontology.

The most direct and important fruits of that expansion of research into telomerase have been studies on the pharmacological and transgenic activation of telomerase in the tissues of aging mice. Several such reports have appeared over the years, each hailed prematurely as evidence of the life- and health-extending power of the enzyme. The most important of these studies have been a series of experiments by María Blasco, PhD, SENS Foundation Research Advisory Board member and Director of the Molecular Oncology Programme at Spain's National Cancer Research Centre (CNIO). A tantalizing new report in this series has just appeared -- but to understand it in context, we will first review those that led up to it.

You should read the whole thing; it is very educational, and a good illustration of the way in which there are no sudden breakthroughs in science - just sudden attention paid to steadily ongoing progress. Each new advance rests upon decades of past work and the efforts of a range of other research groups. It also illustrates the need to look past the headlines to pick at the details of heralded research. For example:

several caveats must be noted about the results themselves, and their implications for medical therapies against the degenerative aging process in humans. As in the previous studies, the apparent increases in survival in this new report were, in fact, ambiguous. The study was substantially underpowered to detect a true increase in maximal lifespan; and even taking the results at face value, the reported survival data - even for treated animals - were, once again, well within the range typical for well-husbanded, untreated control mice reported in other studies.


Additionally, there was relatively little effort invested in ruling out a possible effect of Calorie restriction (CR) in this study.


Presuming, however, that the life- and healthspan benefits reported in this study should be taken at face value, the ultimate question is their human translatability - and there are reasons to be skeptical that a similar therapy could be safely used to retard the degenerative aging process in humans. Some would note first that safe and effective gene therapy is not yet available for our species - but that, like many other matters in biomedical gerontology, is only a matter of time and investment. Of greater concern is the safety of telomerase therapy, granted the very different body plans of humans as compared to mice.

Rapamycin Slows Aging in Mice

Researchers conclude that the extension of life in mice due to rapamycin is in fact a slowing of aging due to the breadth of its effects: "Rapamycin increases lifespan in mice, but whether this represents merely inhibition of lethal neoplastic diseases, or an overall slowing in multiple aspects of aging is currently unclear. We report here that many forms of age-dependent change, including alterations in heart, liver, adrenal glands, endometrium, and tendon, as well as age-dependent decline in spontaneous activity, occur more slowly in rapamycin-treated mice, suggesting strongly that rapamycin retards multiple aspects of aging in mice, in addition to any beneficial effects it may have on neoplastic disease. We also note, however, that mice treated with rapamycin starting at 9 months of age have significantly higher incidence of testicular degeneration and cataracts; harmful effects of this kind will guide further studies on timing, dosage, and tissue-specific actions of rapamycin relevant to the development of clinically useful inhibitors of TOR action." You might also look at recent research focused on separating the beneficial effects of rapamycin from the undesirable side-effects.


Removal of Abdominal Fat Reduces Cancer Risk

As an addendum to research showing that removal of visceral fat in mice extends life, here is work showing that it reduces risk of some cancers as well: "obesity increases the risk of heart disease, diabetes and cancer. But there have not been clinical studies to determine if the surgical removal of fat tissue would decrease cancer risk in humans. ... researchers found that surgical removal of abdominal fat from obese mice fed a high-fat diet had between 75-80 percent fewer UV-induced skin cancers than mice that did not undergo fat-removal surgery. Although scientists understand that tissue fat may play a role in tumor formation, there has been little research on the molecular mechanisms of how a high-fat diet increases the formation of skin cancer. This new study suggests that abdominal fat in mice secretes proteins that enhance the risk of cancer. Once the original fat tissue is removed, the biochemical properties of new fat tissue that appear after surgery are less harmful. ... It would be interesting to see if surgical removal of fat tissue in animals would prevent obesity-associated lethal cancers like those of the pancreas, colon and prostate. Whether removal of tissue fat in humans which has certain risks would decrease the risk of life-threatening cancers in humans is not known." A better approach is not to gain the fat tissue, and thus its unfortunate metabolic effects, in the first place - or work to lose it the traditional way, through improved diet and exercise, both of which have broad health benefits.


An Interview on Radical Life Extension

Today I'll point out an interview with Bennett Foddy, the author of The Right and Wrong of Growing Old: Assessing the Argument from Evolution, who fits into the interesting - and possibly small - category of people who both (a) see the only viable way forward in longevity science as being the same old slow boat of small, expensive gains achieved by slowing aging through metabolic manipulation, and (b) think that we'll make good progress that way. From the blurb to his book:

One argument which is frequently levelled against the enhancement of human biology is that we do not understand the evolved function of our bodies well enough to meddle in our biology without producing unintended and potentially catastrophic effects. In particular, this argument is levelled against attempts to slow or eliminate the processes of human ageing, or 'senescence', which cause us to grow decrepit before we die. In this article, I claim that even if this argument could usefully be applied against attempts to enhance other human traits, it cannot be valid in the case of attempts to enhance the various processes that constitute senescence.

Now I completely agree with the argument noted in the first sentence above, if not the rest of it - that we don't understand enough about metabolism to make good progress in manipulating it to slow aging to a great enough degree to matter. By which I mean we'll be old and dying by the time that useful results are produced, at staggering cost - and those results won't do much at all for people who are already old and dying, because all they will do is slow down aging. It is far better to focus on the SENS vision of repairing damage rather than just slowing down the pace at which it occurs. For one, repair should be easier as it isn't anywhere near as large a swamp of unknowns: the list of biochemical damage that we need to repair is known, means of repair have been planned in some detail, and effective repair biotechnologies for these known forms of age-related damage will actually produce rejuvenation in the old.

But on to the interview at the Atlantic, which makes for interesting reading. It would be pleasant to live in a world in which all we argued over was how exactly we should work to extend the healthy human life span and rescue the old from their degenerations. I should note that Foddy is a philosopher rather than a life scientist, so he's not quite as careful with his language as he should be - using "life span" in place of "life expectancy at birth", for example. But the general points he makes stand, and it is always good to see another member of the philosophy-slash-bioethics class explicitly place himself in opposition to the deathism of Fukuyama and Kass:

But there is another, deeper argument against life extension - the argument from evolution. Its proponents suggest that we ought to avoid tinkering with any human trait borne of natural selection. Doing so, they argue, could have unforeseen consequences, especially given that natural selection has such a sterling engineering track record. If our bodies grow old and die, the thinking goes, then there must be a good reason, even if we don't understand it yet. Nonsense, says Bennett Foddy, a philosopher (and flash game developer!) from Oxford, who has written extensively about the ethics of life extension. "We think about aging as being a natural human trait, and it is natural, but it's not something that was selected for because it was beneficial to us." Foddy told me. "There is this misconception that everything evolution provides is beneficial to individuals and that's not correct."

Foddy has thought long and hard about the various objections to life extension and, for the most part, has found them wanting. This is our conversation about those objections, and about the exciting new biology of aging.


[The Atlantic]: People usually regard life extension as a futuristic technology, but you begin your paper by discussing the ways that we've already extended the human lifespan. What's driven that?

Foddy: The reason I present it that way, is that there's always this background moral objection in enhancement debates, where a technology is perceived to be new, and by virtue of being new, is depicted as threatening or even strange. That goes for everything from genetic engineering to steroids to cloning and on and on. I think it's always worth contextualizing these things in terms of the normal. So with human cloning it's worth remembering that it's exactly the same as twinning. With steroids, it's worth remembering that in many ways it's not that different from training and exercise, and also that people have been taking testosterone since ancient times. I think this way you can kind of resist the idea that something is wrong just because it's strange.

When you're talking about medicines that help us live longer, it's important to realize how much we've already accomplished. In the last 150 years or so, we've doubled our life span from 40 to 80 years, and that's primarily through the use of things you can characterize as being medical science. In some cases it's clear that we're talking about medical enhancement - vaccines, for instance, or surgical hygiene and sterilization.

You should certainly read the whole thing.

Alcor Featured in Phoenix Magazine

Cryonics provider Alcor gets a section in this Phoenix Magazine article on the industries associated with end of life management. It starts half way down the third page of the piece: "Max More, [the] CEO of the Alcor Life Extension Foundation is discussing the existential benefits of cryonics - i.e. the preservation of clinically-dead human beings at super-cold temperatures for the purpose of resuscitating them, presumably far in the future. Founded in 1972 by California couple Fred and Linda Chamberlain, Alcor relocated to Arizona in 1994 and currently hosts 110 cryopreserved patients in its hangar-like headquarters near the Scottsdale Airport. ... More isn't just the CEO of Alcor - he's also a longtime member. Known and respected as an advocate of transhumanist principles - a movement that proposes to eliminate aging and elevate the human condition to near godly heights - More first became hooked on cryonics as a 22-year-old undergraduate at the University of Oxford. At the time, Alcor was enjoying a surge in membership and positive international publicity. More, a young deep-thinker steeped in the science fiction classics of Philip K. Dick and Robert Heinlein, was intrigued. So he took out a life-insurance policy on himself ('At that age, it cost nothing...') to pay for his eventual one-time Alcor cryopreservation fee, which runs $200,000 for full-body patients and $80,000 for neuropatients. More chose the neuropatient option. 'To revive a cryopreserved patient, science and technology would have to advance to the point where minute repairs could be made to a hundred billion neurons. It seems to me that regenerating or cloning a new body would be relatively easy by comparison,' he says reasonably. 'No reason to preserve my broken down old body.' ... More's main focus is to bolster Alcor's membership rolls, which he concedes have stagnated in recent years, due both to the flagging economy and lax public-outreach efforts by previous CEOs. As of February 2012, Alcor had 957 members - still-living future 'patients' who had paid the one-time cryonics fee or taken out life insurance and made Alcor the beneficiary. The members sustain the nonprofit's day-to-day operations by paying $800 yearly dues until their legal deaths. (More is careful not to use the word 'death' without a qualifier; the foundation's entire doctrine is predicated on the idea that its patients aren't dead in the absolute sense.)"


Autophagy and Rapamycin

A recent paper: "The biological aging process is commonly associated with increased risk of cardiovascular diseases. Several theories have been put forward for aging-associated deterioration in ventricular function, including attenuation of growth hormone (insulin-like growth factors and insulin) signaling, loss of DNA replication and repair, histone acetylation and accumulation of reactive oxygen species. Recent evidence has depicted a rather unique role of autophagy as another important pathway in the regulation of longevity and senescence. Autophagy is a predominant cytoprotective (rather than self-destructive) process. It carries a prominent role in determination of lifespan. Reduced autophagy has been associated with aging, leading to accumulation of dysfunctional or damaged proteins and organelles. To the contrary, measures such as caloric restriction and exercise may promote autophagy to delay aging and associated comorbidities. Stimulation of autophagy using rapamycin may represent a novel strategy to prolong lifespan and combat aging-associated diseases. Rapamycin regulates autophagy through inhibition of the nutrient-sensing molecule mammalian target of rapamycin (mTOR). Inhibition of mTOR through rapamycin and caloric restriction promotes longevity."


An Aubrey de Grey Video AMA Gathering Questions at Reddit

One of the many popular and distinct online communities that make up Reddit is IAmA ("I am a"), which runs verified question and answer sessions (AMAs, or "ask me anything") with all sorts of folk in interesting positions, with interesting jobs, or who are just plain interesting. You might consider it the crowdsourced, irreverent, collaborative offspring of chat shows, radio call-in programs, and the last ten years of online bulletin board evolution - this is what the kids do nowadays in place of turning on the TV or radio. In any case, I somehow entirely missed noting that a video AMA for Aubrey de Grey of the SENS Foundation has been running at Reddit to accumulate questions these past few days. Most AMAs are real-time posting sessions, but in this case the most upvoted questions will be passed on to de Grey to be answered in a video which will then be posted back to the community:

Aubrey de Grey is a leading scientist in the field of biomedical gerontology, the quest to develop true medical control of aging.

Dr. de Grey wrote in this week and mentioned that he had been urged on several occasions in the past few months to do an AMA. There was a lot of interest in the possibility that he could do his AMA as a video reply to a selection of representative questions, in the way that Richard Dawkins did some time ago ... We'll take your top ten best questions for Aubrey de Grey and send them to him later this week to be answered on video.

Once you get past the lowest common denominator popular communities - Reddit really doesn't work well unless you create an account and start ruthlessly pruning what you see - Reddit is a fairly pro-longevity, pro-biotechnology, and pro-science community, supportive of the goal of extending the healthy human life span through medical science, and the sooner the better. It has been pleasant to see that emerging ever more readily in the online communities of the past ten years.

Old Calorie Restricted Rats Act Younger Than Their Peers

No great surprise here, given that calorie restriction in mammals slows almost all measures of aging investigated to date: "Long-term caloric restriction (CR) has been reported to extend the life spans, delay the onset and decrease the incidence of a broad spectrum of age-associated diseases. However, its effect on rat explorative behaviour is still unclear. In the present study, a number of behavioural measures were continuously monitored in 3-, 12-, 24-25-, 28-29- and 35-44-month-old male Wistar rats that were fed either ad libitum or placed on a caloric restricted diet. A gradual decline in locomotor activity of the ad libitum fed rats has been determined during aging in the open field test. In the CR groups, 3-month-old rats exhibited lower levels of exploratory behavior, compared to rats on the control diet. 24-25-month-old CR rats exhibited higher levels of exploratory behaviour, compared to ad libitum fed animals of the same age. Chronic dietary restriction nullified the age-dependent decline in locomotor activity and explorative behaviour of rats."


A Brief Layperson's Tour of the Philosophy of Nonexistence

It is taken as a tenet around here that involuntary death is a bad thing, and the process of getting to be dead despite your own wishes on the matter is arguably worse - it involves a great deal of ongoing suffering and pain as the body progressively fails. Greatly diminishing the incidence of death is one aim of the longevity science movement, achieved through the elimination of degenerative aging, the greatest cause of death. Can we say why being dead is bad, however? That is supposedly a harder job than declaring suffering to be bad and worthy of amelioration - though most philosophers fail to consider the economic costs of destruction, and in the end it should all come down to "I've decided I don't like it, and so I'll work towards doing something about it through progress in medical science." Reasons beyond personal choice are unnecessary, but here is a brief tour of some of the philosophy of death and nonexistence: "We all believe that death is bad. But why is death bad? In thinking about this question, I am simply going to assume that the death of my body is the end of my existence as a person. But if death is my end, how can it be bad for me to die? After all, once I'm dead, I don't exist. If I don't exist, how can being dead be bad for me? ... there's a puzzle raised by the Roman philosopher Lucretius, who thought it a mistake to find the prospect of my death upsetting. Yes, as the deprivation account points out, after death we can't enjoy life's pleasures. But wait a minute, says Lucretius. The time after I die isn't the only period during which I won't exist. What about the period before my birth? If nonexistence is so bad, shouldn't I be upset by the eternity of nonexistence before I was born? But that's silly, right? Nobody is upset about that. So, he concludes, it doesn't make any sense to be upset about the eternity of nonexistence after you die, either. It isn't clear how best to reply to Lucretius. One option, presumably, is to agree that we really do need to treat those two eternities of nonexistence on a par, but to insist that our prebirth nonexistence was worse than we thought. Alternatively, we might insist that there's an asymmetry that explains why we should care about the one period but not the other. But what is that difference? Perhaps this: When I die, I have lost my life. In contrast, during the eternity before my birth, although I'm not alive, I have not lost anything. You can't lose what you never had. So what's worse about death is the loss."


The Maintenance Gap

Much of the mainstream aging research community has little interest in building therapies for aging, being focused on investigation only - though, fortunately, this situation is changing rapidly these days. The past stigma associated with public discussion of treating and ultimately preventing aging has largely evaporated within the scientific world.

Among those researchers who are interested in therapies for aging, most are focused on the slow boat of metabolic alteration: work that will have comparatively little pay-off even if successful, but which fits more readily into established research programs and the prejudices of research funding institutions.

The principal downside of metabolic alteration strategies, from my point of view, is that even if successful they cannot produce any significant longevity benefit in a person already old. All it can do is slow down aging by a modest amount - which isn't terribly useful those already aged and damaged. Even under the most optimistic estimates it will take another twenty years and many billions of dollars to see the evolution of a robust market in commercially available human metabolic enhancements to slow aging. It is a challenging field of research, and progress to date has been slow even in this era of rapid advances in biotechnology.

There is another disadvantage, which is illustrated by the different degrees to which life span is enhanced by similar strategies applied in mice versus humans. It is taken for granted in the literature, and thus probably not emphasized to the degree it should be, that an extension of life by 50% in mice based on some genetic or metabolic alteration - such as calorie restriction or growth hormone knockout - is probably not going to map to a similar extension of life in humans. If humans could achieve that sort of life extension through simply eating well and eating less or being growth hormone mutants, we'd have known about it by now. Consider Laron dwarfism, for example, or the generation after generation of practitioners of various degrees of calorie restriction that exist in many cultures.

With an eye to this second disadvantage, I'll point out an open access paper that considers the evolution of aging from the point of view of the maintenance gap. This is the gap between the cost of maintenance required to keep an organism from aging and the resources actually devoted to maintenance - both of which are subject to evolutionary selection pressures, which operate to maximize success in genetic propagation rather than the comfort or longevity of individual members of a species. The paper was published last year, but showed up in a recent issue of Biogerontology.

The maintenance gap: a new theoretical perspective on the evolution of aging

One of the prevailing theories of aging, the disposable soma theory, views aging as the result of the accumulation of damage through imperfect maintenance. Aging, then, is explained from an evolutionary perspective by asserting that this lack of maintenance exists because the required resources are better invested in reproduction. However, the amount of maintenance necessary to prevent aging, 'maintenance requirement' has so far been largely neglected and has certainly not been considered from an evolutionary perspective. To our knowledge we are the first to do so, and arrive at the conclusion that all maintenance requirement needs an evolutionary explanation.

Increases in maintenance requirement can only be selected for if these are linked with either higher fecundity or better capabilities to cope with environmental challenges to the integrity of the organism. Several observations are suggestive of the latter kind of trade-off, the existence of which leads to the inevitable conclusion that the level of maintenance requirement is in principle unbound. Even the allocation of all available resources to maintenance could be unable to stop aging in some organisms.

This has major implications for our understanding of the aging process on both the evolutionary and the mechanistic level. It means that the expected effect of measures to reallocate resources to maintenance from reproduction may be small in some species. We need to have an idea of how much maintenance is necessary in the first place. Our explorations of how natural selection is expected to act on the maintenance requirement provides the first step in understanding this.

The point to take away from this argument is that we should expect to find a broad variation between species in their response to similar forms of metabolic and genetic alteration aimed at extending life span. So far, that is what is seen, with we humans having the short end of the stick - though obviously there is an ocean of data yet to be obtained on this topic. On the whole, though, it seems like one more slowly building argument for the research community to focus on repair-based strategies for treating aging: build biotechnologies that are explicitly designed to repair forms of biological damage that existing repair systems either cannot handle or handle too slowly. SENS is the most obvious example, though I expect other, competing repair-focused visions to emerge in the years ahead as the SENS Foundation obtains further scientific support and promising research results.

IGF-1 Receptor Variations and Sheep Longevity

Insulin-like growth factor 1 (IGF-1) is one of the more studied areas of known overlap between metabolism and longevity, but given the innate complexity of biology in mammals there is always some debate over the degree to which IGF-1-related mechanisms are actually determinants of life span, or even correlated with life span. Here is a study in sheep, not the usual species in investigations of the biochemistry of aging: "Longevity in livestock is a valuable trait. When productive animals live longer fewer replacement animals need to be raised. However, selection for longevity is not commonly the focus of breeding programs as direct selection for long-lived breeding stock is virtually impossible until late in the animal's reproductive life. Additionally the underlying genetic factors or genes associated with longevity are either not known, or not well understood. In humans, there is evidence that insulin-like growth factor 1 receptor (IGF1R) is involved in longevity. Polymorphism in the IGF1R gene (IGF1R) has been associated with longevity in a number of species. Recently, 3 alleles of ovine IGF1R were identified, but no analysis of the effect of IGF1R variation on sheep longevity has been reported. In this study, associations between ovine IGF1R variation, longevity and fertility were investigated [in] 1716 New Zealand sheep belonging to 6 breeds and 36 flocks. ... Ovine IGF1R C was associated with age when adjusting for flock [and] a weak negative [correlation] between fertility and longevity traits was observed."


Investigating the Association of ApoE4 with Alzheimer's

Researchers continue to investigate why the ApoE4 gene variant is associated with Alzheimer's disease: "A well-known genetic risk factor for Alzheimer's disease triggers a cascade of signaling that ultimately results in leaky blood vessels in the brain, allowing toxic substances to pour into brain tissue in large amounts, scientists report ... a gene called ApoE4 makes people more prone to developing Alzheimer's. People who carry two copies of the gene have roughly eight to 10 times the risk of getting Alzheimer's disease than people who do not. [Scientists] found that ApoE4 works through cyclophilin A, a well-known bad actor in the cardiovascular system, causing inflammation in atherosclerosis and other conditions. The team found that cyclophilin A opens the gates to the brain assault seen in Alzheimer's. ... In the presence of ApoE4, increased cyclophilin A causes a breakdown of the cells lining the blood vessels in Alzheimer's disease in the same way it does in cardiovascular disease or abdominal aneurysm ... In studies of mice, the team found that mice carrying the ApoE4 gene had five times as much cyclophilin A compared to other mice in cells known as pericytes, which are crucial to maintaining the integrity of the blood-brain barrier. Blood vessels died, blood did not flow as completely through the brain as it did in other mice, and harmful substances like thrombin, fibrin, and hemosiderin, entered the brain tissue. When the team blocked the action of cyclophilin A, either by knocking out its gene or by using the drug cyclosporine A to inhibit it, the damage in the mice was reversed. Blood flow resumed to normal, and unhealthy leakage of toxic substances from the blood vessels into the brain was slashed by 80 percent."


Resilient Biochemistry in Naked-Mole Rats

Naked mole-rats are becoming very well studied. Researchers are attempting to find the root causes of cancer immunity and exceptional longevity in this species, with an eye to creating beneficial medical biotechnologies for humans. Fight Aging! has seen a couple of items on naked mole-rats already this month, which is illustrative of the present pace:

Present theories are varied, but on the longevity side of the house the consensus appears to lean towards an increased resistance to forms of cellular membrane damage - naked mole rat membranes are built of a more resilient mix of proteins than those of comparable species. This is known as the membrane pacemaker hypothesis of aging:

The membrane pacemaker hypothesis predicts that long-living species will have more peroxidation-resistant membrane lipids than shorter living species. ... Resistance to oxidative damage is of particular importance in mitochondria, cellular power plants that progressive damage themselves with the reactive oxygen species they produce as a byproduct of their operation - and that gives rise to a chain of further biochemical damage that spreads throughout the body, growing ever more harmful as you age. Less damage to the mitochondria should mean slower aging, and thus more resistant mitochondrial membranes should also mean slower aging.

Continuing the naked mole-rat theme for May, here is another just-published open access paper on the resilience of naked mole-rat biology (abstract, and full article):

Studies comparing similar-sized species with disparate longevity may elucidate novel mechanisms that abrogate aging and prolong good health. We focus on the longest living rodent, the naked mole-rat. This mouse-sized mammal lives ∼8 times longer than do mice and, despite high levels of oxidative damage evident at a young age, it is not only very resistant to [cancer] but also shows minimal decline in age-associated physiological traits.


Like other experimental animal models of lifespan extension, naked mole-rat fibroblasts are extremely tolerant of a broad spectrum of cytotoxins including heat, heavy metals, DNA-damaging agents and xenobiotics, showing [median lethal dose] values between 2- and 20-fold greater than those of fibroblasts of shorter-lived mice. Our new data reveal that naked mole-rat fibroblasts stop proliferating even at low doses of toxin whereas those mouse fibroblasts that survive treatment rapidly re-enter the cell cycle and may proliferate with DNA damage. Naked mole-rat fibroblasts also show significantly higher constitutive levels of both p53 and Nrf2 protein levels and activity, and this increases even further in response to toxins.


Enhanced cell signaling via p53 and Nrf2 protects cells against proliferating with damage, augments clearance of damaged proteins and organelles and facilitates the maintenance of both genomic and protein integrity. These pathways collectively regulate a myriad of mechanisms which may contribute to the attenuated aging profile and sustained healthspan of the naked mole-rat. Understanding how these are regulated may be also integral to sustaining positive human healthspan well into old age and may elucidate novel therapeutics for delaying the onset and progression of physiological declines that characterize the aging process.

You might also look back a few years at other research into the role of Nrf2 in determining species longevity. The details can be a little overwhelming, but the big picture remains one of damage at the level of cells and protein machinery: less damage and more resilience to damage means a longer life span.

Arguing a Role for the Hypothalamus in Aging

Researchers here analyze the proteome of the hypothalamus and argue for an important role in coordinating bodily responses to ongoing changes caused by aging: "The aging process affects every tissue in the body and represents one of the most complicated and highly integrated inevitable physiological entities. The maintenance of good health during the aging process likely relies upon the coherent regulation of hormonal and neuronal communication between the central nervous system and the periphery. Evidence has demonstrated that the optimal regulation of energy usage in both these systems facilitates healthy aging. However, the proteomic effects of aging in regions of the brain vital for integrating energy balance and neuronal activity are not well understood. The hypothalamus is one of the main structures in the body responsible for sustaining an efficient interaction between energy balance and neurological activity. Therefore, a greater understanding of the effects of aging in the hypothalamus may reveal important aspects of overall organismal aging and may potentially reveal the most crucial protein factors supporting this vital signaling integration. In this study, we examined alterations in protein expression in the hypothalami of young, middle-aged, and old rats. ... Based upon our rigorous analyses, we show that endogenous physiological responses to aging may be strongly orchestrated by the expression level of the GIT2 protein. The relevance of the hypothalamic expression level of this protein to the aging process in both neuronal and energy-controlling tissues reinforces the importance of this organ in the potential future development of targeted pharmacotherapeutics designed to interdict a multitude of age-related disorders."


S1P and Stimulation of Muscle Satellite Cells

A possible method of boosting muscle repair, and thus treating muscle wasting conditions - such as the sarcopenia that attends aging: "a lipid signaling molecule called sphingosine-1-phosphate or 'S1P' can trigger an inflammatory response that stimulates the muscle stem cells to proliferate and assist in muscle repair. ... mdx mice, which have a disease similar to Duchenne Muscular Dystrophy, exhibit a deficiency of S1P, [and] boosting their S1P levels improves muscle regeneration ... The ability of muscles to regenerate themselves is attributed to the presence of a form of adult stem cells called 'satellite cells' that are essential for muscle repair. Normally, satellite cells lie quietly at the periphery of the muscle fiber and do not grow, move or become activated. However, after muscle injury, these stem cells 'wake up' through unclear mechanisms and fuse with the injured muscle, stimulating a complicated process that results in the rebuilding of a healthy muscle fiber. S1P is a lipid signaling molecule that controls the movement and proliferation of many human cell types. ... S1P is able to 'wake up' the stem cells at the time of injury. It involves the ability of S1P to activate S1P receptor 2, one of its five cell surface receptors, leading to downstream activation of an inflammatory pathway controlled by a transcription factor called STAT3. [This results] in changes in gene expression that cause the satellite cell to leave its 'sleeping' state and start to proliferate and assist in muscle repair. ... If these findings are also found to be true in humans with Duchenne Muscular Dystrophy, it may be possible to use similar approaches to boost S1P levels in order to improve satellite cell function and muscle regeneration in patients with the disease. Drugs that block S1P metabolism and boost S1P levels are now being tested for the treatment of other human diseases including rheumatoid arthritis. If these studies prove to be relevant in Duchenne patients, it may be possible to use the same drugs to improve muscle regeneration in these patients. Alternatively, new agents that can specifically activate S1P receptor 2 could also be beneficial in recruiting satellite cells and improving muscle regeneration in muscular dystrophy and potentially other diseases of muscle."


More Health, Longevity, and Medical Cost Data from the Ohsaki Cohort Study

You might recall that late last year I pointed out a large Japanese longitudinal study on incidental moderate exercise and lifetime medical costs:

The authors followed up 27,738 participants aged 40-79 years and prospectively collected data on their medical expenditure and survival covering a 13-year-period. ... The present results indicate that the multiadjusted lifetime medical expenditure from the age of 40 years for those who walked ≥1 h per day was significantly lower by 7.6% in men and non-significantly lower by 2.7% in women than for those who walked <1 h per day. This decrease in lifetime medical expenditure was observed in spite of a longer life expectancy (1.38 years for men and 1.16 years for women) among those who walked ≥1 h per day.

In another, more open access recent paper, the same authors have crunched the numbers for variations in weight among study participants. The story is much the same, as one would expect:

Although four previous studies have examined the association between obesity and lifetime medical expenditure, the results were inconsistent. ... We therefore conducted a 13-year prospective observation of 41,965 Japanese adults aged 40-79 years living in the community, which accrued 392,860 person-years. We examined the association between BMI and lifetime medical expenditure, based on individual medical expenditure and life table analysis. We collected data for survival and all medical care utilisation and costs, excluding home care services provided home health aides, nursing home care and preventive health services in participants of this cohort study.


In spite of their short life expectancy, obese men and women had approximately 14.7% and 21.6% higher lifetime medical expenditure in comparison with normal weight participants, respectively.

Don't get fat, don't stay fat, and don't be a couch potato. Thus speaks the weight of evidence - but then we all knew that, right? Being unhealthy has definitive material costs in the long term: years of life shaved off, the rot of your body and mind, and the monetary cost of medical services you would otherwise not have needed. There are plenty of people in this world, far too many, who don't presently have the luxury of choice when it comes to being healthy: the genetically impaired, the immune-damaged, the infected, the wounded. Why fritter away your choice for the sake of eating and laziness? It is almost a gesture of contempt.

A Popular Press Article on Longevity Science

The media and public at large have been trained to think of medicine, and especially longevity-related medicine, in terms of pills - things you can consume, colorful drug capsules produced in the old-style fashion by Big Pharma. This is somewhat ridiculous, and leads to a focus on the entirely the wrong branches of research, those unlikely to deliver meaningful healthy life extension. The future of rejuvenation biotechnology involves gene therapies, infusions of bacterial enzymes, and so forth; for the foreseeable future little of that will be stuff that you stick into your mouth. Calling these medicines drugs rather than procedures cheapens the complexity of what is being designed and developed. Nonetheless, the oral fixation in regard to public perceptions of medicine continues, fed by the lazy press and the self-interested supplement industry. Here is an example of that sort of headlining: "But imagine if there were a drug that would slow down the aging process itself, a drug that didn't just treat a single disease but instead targeted multiple diseases of old age at once? It may sound far-fetched, but that's precisely what longevity scientists are working hard to produce. ... It's not just that we're trying to make people live longer; we're trying to make people live healthier. This is an exciting time for research. ... Indeed, top-notch research labs are rolling out studies at a rapid rate, and a growing chorus of experts believe the advances being made will ultimately lead to a crop of drugs capable of extending healthy lifespans. Signs of progress are abundant in medical journals. ... [researchers] published results showing they could markedly delay the onset of age-related diseases in mice by killing off the rodents' senescent cells. Senescent cells have stopped dividing and accumulate as organisms age. Though seemingly dormant, they're not: Just as old cars in junkyards can leak oil for years, they emit harmful substances that appear to fuel many of the diseases that strike older people. ... And it's not just senescence research that is stoking excitement. Another team of scientists [has] managed to control the aging process by targeting specialized structures at the tips of chromosomes called telomeres. ... Other scientists have found that feeding aging mice rapamycin - an immunosuppressant that's used to prevent organ rejection after transplants - can extend the lifespan of mice significantly."


Methionine Restriction Beneficial in Old Rats

Calorie restriction extends healthy life span, and that seems to largely work through the level of methionine in the diet, though minimizing visceral fat tissue looks to be an important effect as well: "It is known that a global decrease in food ingestion (dietary restriction, DR) lowers mitochondrial ROS generation (mitROS) and oxidative stress in young immature rats. This seems to be caused by the decreased methionine ingestion of DR animals. This is interesting since isocaloric methionine restriction in the diet (MetR) also increases, like DR, rodent maximum longevity. However, it is not known if old rats maintain the capacity to lower mitROS generation and oxidative stress in response to MetR similarly to young immature animals, and whether MetR implemented at old age can reverse aging-related variations in oxidative stress. In this investigation the effects of aging and 7 weeks of MetR were investigated in liver mitochondria of Wistar rats. MetR implemented at old age decreased mitROS generation, percent free radical leak at the respiratory chain and mtDNA oxidative damage without changing oxygen consumption. Protein oxidation, lipoxidation and glycoxidation increased with age, and MetR in old rats partially or totally reversed these age-related increases. ... In conclusion, treating old rats with isocaloric short-term MetR lowers mitROS production and free radical leak and oxidative damage to mtDNA, and reverses aging-related increases in protein modification. Aged rats maintain the capacity to lower mitochondrial ROS generation and oxidative stress in response to a short-term exposure to restriction of a single dietary substance: methionine."


Telomerase Gene Therapy Extends Life, Eliminates Cancer in Adult Mice

A few years ago, a Spanish research team created transgenic mice that lived significantly longer than normal by combining increased p53 with increased telomerase. p53 is a cancer suppressor that under usual circumstances reduces the ability of stem cells to replace worn cells in aging tissue - less cell proliferation means a lower chance of cancer over time, but also faster aging as the tissues of the body wear and fail more readily. More telomerase, on the other hand, achieves the opposite end: dynamic, longer lasting cells that also produce way more cancers in the course of their more energetic operations. This, in any case, is the consensus view of how these elements work in the biochemistry of mammals:

The standard reading is that the "Super p53" mice are getting less cancer, but are having their [life spans] restrained by lack of tissue replenishment due to stem cell loss, while the telomerase transgenics are on the opposite horn of the same dilemma. It seems at least possible that if one overlaid the strong cancer resistance conferred by the former, with the increase in stem cell mobilization and proliferative capacity of the latter, you'd wind up with a long-lived, slow-aging mouse.

I should note in passing that it is possible through clever techniques to have enhanced p53 provide both a cancer and longevity benefit in and of itself. But in the case of the Spanish research team, their work is more simply a case of balancing one mixed benefit with the opposite mixed benefit - and coming out ahead of the game. The researchers recently published results for the next stage of their research program: taking the modifications that had been transgenic to date and instead applying them as gene therapies to adult mice. This is a step on the road to building some form of beneficial medical technology for humans:

CNIO scientists successfully test the first gene therapy against aging-associated decline:

Mice treated at the age of one lived longer by 24% on average, and those treated at the age of two, by 13%. The therapy, furthermore, produced an appreciable improvement in the animals' health, delaying the onset of age-related diseases - like osteoporosis and insulin resistance - and achieving improved readings on ageing indicators like neuromuscular coordination.

The gene therapy utilised consisted of treating the animals with a DNA-modified virus, the viral genes having been replaced by those of the telomerase enzyme, with a key role in ageing. Telomerase repairs the extremes of chromosomes, known as telomeres, and in doing so slows the cell's and therefore the body's biological clock. When the animal is infected, the virus acts as a vehicle depositing the telomerase gene in the cells.


In 2007, Blasco's group proved that it was feasible to prolong the lives of transgenic mice, whose genome had been permanently altered at the embryonic stage, by causing their cells to express telomerase and, also, extra copies of cancer-resistant genes. These animals live 40% longer than is normal and do not develop cancer. The mice subjected to the gene therapy now under test are likewise free of cancer. Researchers believe this is because the therapy begins when the animals are adult so do not have time to accumulate sufficient number of aberrant divisions for tumours to appear.


As Blasco says, "ageing is not currently regarded as a disease, but researchers tend increasingly to view it as the common origin of conditions like insulin resistance or cardiovascular disease, whose incidence rises with age. In treating cell ageing, we could prevent these diseases".

You'll have to wait for the paper to show up at the EMBO Molecular Medicine website to get more details on the lifespan data, degree to which cancer is removed from the picture, and what type of mouse is being used here - e.g. are they using the transgenic enhanced p53 mouse as a baseline? That shouldn't take too long, and it is an open access publication so we'll all have a chance to read the details.

As an aside, aging defined as a disease is a topic that crops up frequently - but only because of the structure of medical regulation. Regulators in the US, for example, will only approve medical technologies for named, defined diseases. Aging is not on their list, but the problem is not that fact, but rather that a list of what is permitted and an organization to enforce it even exists in the first place.

The employees and appointees of the US Food and Drug Administration have caused an incredible destruction of value and progress over the time that the agency has existed. Their regulatory policies become ever more onerous with each passing year, as unaccountable bureaucrats follow their incentives: nothing good can happen to their careers as a result of approving new technologies, and nothing bad tends to happen to their careers as a result of making it really, really hard to bring new medicine to the clinic. So of course you wind up with an organization whose members collectively pay nothing more than lip service to their declared mission, while working to make sure that medicine stays moribund in a slow-motion stasis.

BMP-2 Delivered in Hydrogel to Guide Bone Regrowth

Bone morphogenetic protein 2 (BMP-2) has been used to spur healing in regenerative medicine research in past years. Here researchers are investigating its use in bone regrowth: scientists are "concentrating on the creation of new bone tissue with the aid of a biomolecule called BMP-2, which is a protein that makes bones grow. The problem with BMP-2 is that it breaks down in the body in just a few minutes. ... What's new, and what I show in my dissertation, is that by having a gel-like substance carry the protein, a so-called hydrogel, you can control both how and where the new bone is to grow ... This hydrogel can be injected and is moreover made from a type of sugar (hyaluronic acid). It occurs naturally in the body in humans and animals and is otherwise used in cosmetic products for treating wrinkles. This offers major advantages. ... On the one hand, you avoid open surgery and the risk of complications and infections that entails, and, on the other hand, there is no risk that the body will reject it. ... Applications in healthcare include both healing complicated bone fractures and growing bone tissue where there is too little or none at all. This involves defects following bone fractures and cancer or when the jawbone is too weak to support a tooth implant. Clinical testing is already underway. ... The tests show that it's working well, but the problem we need to solve is how to determine the optimal dosage of the protein. Otherwise inflammations can occur in surrounding tissue."


Diversity of Regulatory T Cells in Rheumatoid Arthritis

Researches make an incremental step forward in understanding the root causes of rheumatoid arthritis: "Untangling the root cause of rheumatoid arthritis has been a difficult task for immunologists, as decades of research has pointed to multiple culprits in our immune system, with contradictory lines of evidence. Now, [researchers] announce that it takes a diverse array of regulatory T cells (a specialized subset of white blood cells) to prevent the immune system from generating the tissue-specific inflammation that is a hallmark of the disease. Regulatory T cell diversity, the researchers say, provides a cumulative protective effect against rheumatoid arthritis. ... regulatory T cells (or Tregs) are a necessary component to either restrain (or encourage) the immune system's inflammatory response. Tregs are activated as molecules on their surface membranes called T cell receptors interact with 'friendly' or 'self' molecules - a way for the immune system to recognize friend from foe. Mismanagement of these Tregs, which normally serve to restrain the immune system from over-reacting to healthy tissue, could then lead to runaway inflammation. In this study, the researchers sought to examine how T cell receptors affect the ability of Tregs to suppress arthritis in a mouse that had been bred to express a 'self' molecule that drives arthritis. They showed that an array of Tregs given to the mice effectively stops arthritis. Unexpectedly, however, Tregs that are specific for the surrogate 'self' molecule do not prevent arthritis. ... We find that [a] diverse repertoire of Tregs are very effective. All of these Tregs, together, influence other components of the immune system which serves to slow down the inflammatory process that causes RA."


Metformin, a Review

Metformin is a drug that shows up in discussion here every so often. It is thought to be a calorie restriction mimetic, recapitulating some of the metabolic changes caused by the practice of calorie restriction. Its effects on life span in laboratory animals are up for debate and further accumulation of evidence - the results are on balance more promising than the generally dismal situation for resveratrol, but far less evidently beneficial than rapamycin. Like rapamycin, metformin isn't something you'd want to take as though it were candy, even if the regulators stood back to make that possible, as the side effects are not pleasant and potentially serious.

I should note as an aside that while ongoing research into the effects of old-school drugs of this nature is certainly interesting, it doesn't really present a path to significantly enhanced health and longevity. It is a pity that such research continues to receive the lion's share of funding, given that the best case outcome is an increase in our knowledge of human metabolism, not meaningful longevity therapies. Even if the completely beneficial mechanism of action is split out from the drug's actions - as seems to be underway for rapamycin - the end results will still only be a very modest slowing of aging. You could do better by exercising, or practicing calorie restriction.

For the billions in funding poured into these drug investigation programs, there should be a better grail at the end of the road - such as that offered by the SENS vision of rejuvenation biotechnology. Targeted repair of the biological damage of aging is a far, far better strategy than gently slowing the pace of damage accumulation through old-style drug discovery programs. This is a biotechnology revolution: time to start acting like it.

Anyway, aside done, let me point you to a recent open access review on metformin: the interesting work that won't really be in any way relevant to the future of your longevity, but which I'll wager has raised more funding as an object of study than the entire present extant SENS program and directly related scientific studies:

Metformin, an oral anti-diabetic drug, is being considered increasingly for treatment and prevention of cancer, obesity as well as for the extension of healthy lifespan. Gradually accumulating discrepancies about its effect on cancer and obesity can be explained by the shortage of randomized clinical trials, differences between control groups (reference points), gender- and age-associated effects and pharmacogenetic factors. Studies of the potential antiaging effects of antidiabetic biguanides, such as metformin, are still experimental for obvious reasons and their results are currently ambiguous.


The wave of interest, with periodical decays and increasing surges, was associated with the attempts to use antidiabetic biguanides [such as metformin] to control body weight and tumor growth. Another facet of the situation is that almost 45 years ago these drugs were suggested to promote longevity. Over the last years, the expanding bodies of relevant evidence, which mainly related to metformin, started to merge and occupy increasing place in current literature. The objective of the present essay is to attract more attention to accumulating inconsistencies. The first two sections of the essay, which are related to obesity and cancer, are based mostly on clinical data. The third section, which is related to aging or, rather, antiaging, is based predominately on experimental evidence obtained in rodents. Clearly, obesity and cancer have numerous interrelationships with aging, [however], we will separate these aspects for the sake of clarity in discussing the relevant effects of metformin.

See what you think; it makes for an interesting read - and includes a table of results from a number of life span studies that are, indeed, all over the map. It somewhat reinforces the point that unambiguous success in extending healthy life is not going to arrive from this quarter. Think SENS, not drug discovery - what will come from the drug discovery clade is a slow, grinding, and expensive cataloging of the fine details of genetics, metabolism, and aging in mammals.

Still Working on and Debating Resveratrol and SIRT1

In recent years resveratrol has clearly fallen below the dividing line for work that is useful from a longevity perspective - if it could extend life significantly in mice, that would have been demonstrated by now. You might compare with the size of the effects on mouse lifespan for rapamycin to provide an example of a compound that is worth investigating. There is, however, a lot of money sunk into work on resveratrol and the underlying mechanisms of sirtuins, so don't expect that to halt any time soon. Research and developer institutions are prone to inertia, just like all other fields of human endeavor. In any case, here is some of the latest work on SIRT1: "If resveratrol needs SIRT1 to improve health, then animals lacking the gene should not get any benefits from the chemical. His lab published that experiment in yeast in 2003. But mice lacking SIRT1 die in the womb, or they are born with developmental defects such as blindness. To get around that problem, [researchers] engineered 'conditional knockout' mice whereby SIRT1 can be inactivated in adulthood. ... It took us two weeks to do the experiment in yeast, and five years in mouse, but finally we're there ... In normal mice, resveratrol combated the effects of a high-fat diet by boosting the efficiency of energy-generating organelles called mitochondria in skeletal muscle tissue. This effect vanished in adult mice without a working version of SIRT1. Yet SIRT1 wasn't responsible for all the beneficial effects of resveratrol ... Resveratrol stabilized the blood glucose levels of both normal and SIRT1-lacking mice on fatty diets. The chemical also improved liver health in mice without SIRT1. [The researchers also contend] that a lot the confusion over how resveratrol works comes down to dosage. At very high doses it binds other proteins besides SIRT1 ... For instance, a signalling protein called AMPK is also important to resveratrol's beneficial effects on metabolism. ... low doses of resveratrol boosted AMPK levels in various cells that expressed SIRT1, but not cells without the sirtuin. Much higher doses of resveratrol, however, activated AMPK irrespective of whether the cells expressed SIRT1."


On the Tissue Engineering of Teeth

Singularity Hub looks at the tissue engineering of teeth: "For years, researchers have investigated stem cells in an effort to grow teeth made for a person's own cells. Toward this end, [scientists] have developed methods to control adult stem cell growth toward generating dental tissue and 'real' replacement teeth. [The] researchers' approach is to extract stem cells from oral tissue, such as inside a tooth itself, or from bone marrow. After being harvested, the cells are mounted to a polymer scaffold in the shape of the desired tooth. The polymer is the same material used in bioreabsorable sutures, so the scaffold eventually dissolves away. Teeth can be grown separately then inserted into a patient's mouth or the stem cells can be grown within the mouth reaching a full-sized tooth within a few months. So far, teeth have been regenerated in mice and monkeys, and clinical trials with humans are underway, but whether the technology can generate teeth that are nourished by the blood and have full sensations remains to be seen. Teeth present a unique challenge for researchers because the stem cells must be stimulated to grow the right balance of hard tissue, dentin and enamel, while producing the correct size and shape."


Learning from the Regrowth of Feathers and Hair?

For some years researchers have been investigating the mechanisms of limb and organ regrowth in lower animals like salamanders, with an eye to finding out how easy or hard it would be to recreate those same capabilities in mammals - such as we humans. Do we retain the core mechanisms, lying dormant in our biochemistry, or have they been completely lost? Time and ongoing research will tell.

But these are not the only areas of regrowth wherein researchers might learn something of interest to regenerative medicine. Consider that elk regularly regrow their antlers, for example - not a simple organ by any means. Further down the scale of impressiveness, we might consider the many higher animals that regularly regrow feathers or coats of hair. Is there anything in their biochemistry that might be discovered and adapted to cause humans to regenerate in situations where they normally do not?

If you buy into the argument that salamander biochemistry is worth investigation, then it's hard to reject similar investigations in other species capable of the lesser forms of regrowth mentioned above. An open access paper is presently doing the rounds on this topic; you can read the summary in the release, or look at the paper itself:

Physiological Regeneration of Skin Appendages and Implications for Regenerative Medicine

The concept of regenerative medicine is relatively new, but animals are well known to remake their hair and feathers regularly by normal regenerative physiological processes. Here, we focus on 1) how extrafollicular environments can regulate hair and feather stem cell activities and 2) how different configurations of stem cells can shape organ forms in different body regions to fulfill changing physiological needs.

Regenerative medicine has great potential. The main challenge is how to elicit and harness the power of regeneration. Currently, the major issues are how to obtain stem cells, how to pattern stem cells into organized tissues and organs, and how to deliver stem cell products to patients. Although human beings have very limited powers of regeneration, many animals have robust regenerative powers, distilled and selected over millions of years of evolution. Here, we review fundamental principles of regenerative biology learned from nature in the hope that they can be applied to help the progress of regenerative medicine.


Using the episodic regeneration of skin appendages as a clear readout, we have the opportunity to understand and modulate the behavior of adult stem cells and organ regeneration at a level heretofore unknown. Through this work, we hope to be able to establish or improve the stem cell environment so it can be applied to regenerative medicine.

In conclusion, we think it will be very productive to learn how nature manages the physiological regeneration process. This is a reprogramming process in which the genetic and epigenetic events converge to generate complex functional forms, depending on the physiological need in different parts of the body and at different stages of life. Principles learned from regenerative biology can then be applied toward regenerative medicine.

On Engineering Functional Cartilage

An article from the Wellcome Trust: "Researchers have been engineering cartilage in the laboratory for 15 years or more, but as yet the tissues they have created don't function properly in human joints. [Researchers] are taking a new approach to try to bridge the gap between laboratory-created cartilage and the tissue our bodies make. ... Biological texts show that these lab-grown tissues have the appearance, texture, and protein and mineral components of bone and cartilage. But once they are tested in an animal, these tissues simply don't behave quite like the natural tissues they are supposed to replicate. ... Joints are remarkable feats of engineering, but efforts to grow them in the lab have focused mostly on their biology. ... Biologists attempting to create cartilage and bone over the past 15 years have typically tested the mechanical properties of their laboratory-grown tissue - for example, whether it is rubbery and resilient enough when pressure is applied. ... Just because biological tests indicate a tissue looks like bone and feels like bone, doesn't actually mean it is bone ... This is where an engineering perspective becomes important. To look at how close a match these laboratory-generated tissues really are to native bone and cartilage, [researchers] supplemented the biological analyses with engineering tests, such as bio-Raman microspectroscopy. ... You shine a laser on the material, and the way the light scatters gives you an idea of the bonds between its components. Different mineral types form different bonds, so you get a much more precise picture of what is actually present. ... If a lab-grown tissue seems from some tests to be the real thing but isn't really, then it won't behave like it once it has been implanted in a human body. ... [The researchers aim] to use an engineering approach to create a whole osteochondral interface in which bone and cartilage transition seamlessly into each other like they do in the body. ... That's the only way it will effectively transmit loads to the underlying bone. And because bone will heal, it will heal the construct into the joint."


Seeking Control Over Thymic Involution

Following on from a recent post on the involution of the thymus in adults, the process by which it ceases to generate immune cells and atrophies, here is a another paper that considers some of the possible paths to interventions that maintain the thymus into old age. Given experiments in mice showing that transplant of a young thymus extends life, this seems worthy of further investigation: "The thymus is the primary organ for T-cell differentiation and maturation. Unlike other major organs, the thymus is highly dynamic, capable of undergoing multiple rounds of almost complete atrophy followed by rapid restoration. The process of thymic atrophy, or involution, results in decreased thymopoiesis and emigration of naïve T cells to the periphery. Multiple processes can trigger transient thymic involution, including bacterial and viral infection(s), aging, pregnancy and stress. Intense investigations into the mechanisms that underlie thymic involution have revealed diverse cellular and molecular mediators, with elaborate control mechanisms. This review outlines the disparate pathways through which involution can be mediated, from the transient infection-mediated pathway, tightly controlled by microRNA, to the chronic changes that occur through aging."


A Report from the Moscow Genetics of Aging and Longevity Conference

Maria Konovalenko of the Science for Life Extension Foundation here reports on the recent Genetics of Aging and Longevity Conference, held last month in Moscow and attracting researchers in the field from around the world.

It has been a while since I've posted my blog updates. The reason was the Genetics of Aging and Longevity conference. I have been involved in preparations of this meeting since December and the last month before the event was especially tough. Anyway, the conference turned out to be pretty good. I was surprised to hear so many good responses and impressions from the attendees and the speakers, so I am proud to say that the meeting was a success. The talks were superb, a lot of new and even unpublished data, a lot of discussions during the breaks and meals. I saw quite many people walking around with burning eyes - from excitement of science, of course) Some of those eyes are in the photos below. I believe this was a ground braking event on life extension topic in Russia, a truly unique gathering of minds. The more meetings like this we have, the more attention they get in the media, the better chances we have to live longer.

The post includes a great many photographs of folk from the aging research community; browse through if you are interested in putting faces to the names you read about in the science press. Konovalenko concludes with this note:

Quite a lot of researchers said that we are on the verge of a breakthrough in the area of life extension. Maybe we have already discovered something fantastic, but haven't yet realized it'd effective for people. Even if we have a drug that slows aging down, we still need a panel of biomarkers to prove the effect. I do hope we will have both the breakthrough and the markers soon.

I'll point you to something I said a while back about concrete and conferences:

I'm a fan of the "concrete and conferences" metric for measuring the health of science. Two side effects of increasing research funding in a field are new buildings at universities and research centers (the "concrete" part of the metric) and new gatherings of researchers (the conferences). Both of these symptoms are also fairly easy to track. The more of both, the better, with new buildings indicating more money entering the system than new conferences.

More conferences generally indicates a larger population of researchers with budgets, interest in the field, and progress in their laboratories to talk about.

Towards Regenerative Medicine for Atherosclerosis

An update on the LysoSENS research project from the SENS Foundation, which aims to discover and adapt bacterial enzymes to break down the damaging buildup of unwanted metabolic byproducts in the aging body: "SENS Foundation-funded research shows that expression of a modified microbial enzyme protects human cells against 7-ketocholesterol toxicity, advancing research toward remediation of the foam cell and rejuvenation of the atherosclerotic artery. ... Atherosclerotic cardiovascular disease is the principal cause of ischaemic heart disease, cerebrovascular disease, and peripheral vascular disease, making it the root of the leading cause of morbidity and mortality worldwide. Atherosclerosis begins with the entrapment and oxidation of low-density lipoprotein (LDL) cholesterol in the arterial endothelium. As a protective response, the endothelium recruits blood monocytes into the arterial wall, which differentiate and mature into active macrophages and engulf toxic oxidized cholesterol products (oxysterols) such as 7-ketocholesterol (7-KC). Although initially protective, this response ultimately leads to atherosclerotic plaque: oxidized cholesterol products accumulate in the macrophage lysosome, and impair the processing and trafficking of native cholesterol and other materials, leading macrophages to become dysfunctional and immobilized ... more and more of these disabled "foam cells" progressively accumulate in the arterial wall, generating the fatty streaks that form the basis of the atherosclerotic lesion. Rejuvenation biotechnology can be brought to bear against this disease of aging through the identification, modification, and therapeutic delivery of novel lysosomal enzymes derived from microbes to the arterial macrophage - enzymes which are capable of degrading oxidized cholesterol products. SENS Foundation-funded researchers have been making steady progress in the identification and characterization of candidate enzymes for several years now, and a new report represents a substantial advance in the research: the rescue of cellular oxysterol toxicity by an introduced microbial lysosomal enzyme."


More on NRG-1 in Naked Mole-Rats

You might recall research published last near on NRG-1 levels in naked mole-rats. Here is an update: "The typical naked mole rat lives 25 to 30 years, during which it shows little decline in activity, bone health, reproductive capacity and cognitive ability. ... Naked mole rats have the highest level of a growth factor called NRG-1 in the cerebellum. Its levels are sustained throughout their life, from development through adulthood. ... NRG-1 levels were monitored in naked mole rats at different ages ranging from a day to 26 years. The other six rodent species have maximum life spans of three to 19 years. The cerebellum coordinates movements and maintains bodily equilibrium. The research team hypothesized that long-lived species would maintain higher levels of NRG-1 in this region of the brain, with simultaneous healthy activity levels. Among each of the species, the longest-lived members exhibited the highest lifelong levels of NRG-1. The naked mole rat had the most robust and enduring supply. ... In both mice and in humans, NRG-1 levels go down with age ... The strong correlation between this protective brain factor and maximum life span highlights a new focus for aging research, further supporting earlier findings that it is not the amount of oxidative damage an organism encounters that determines species life span but rather that the protective mechanisms may be more important."


Considering the Choroid Plexus in Alzheimer's Disease

The choroid plexus is, amongst other things, a filter for cerebrospinal fluid - you might think of this role as analogous to that of the kidney as a filter for blood, though the two organs are very different in structure at every level, and the choroid plexus also produces the fluid it filters. Like all of the systems in the body and brain, the choroid plexus progressively fails in its function with age, and researchers have reason to believe that this failure contributes to conditions such as Alzheimer's disease:

An organ in the brain called the choroid plexus apparently plays a critical role in preventing the accumulation of a protein associated with Alzheimer's disease. The researchers found that the choroid plexus acts as a sort of 'fishnet' that captures the protein, called beta-amyloid, and prevents it from building up in the cerebrospinal fluid, which surrounds and bathes the brain and spinal cord. Moreover, tissue in the organ is able to soak up large amounts of the protein and may contain enzymes capable of digesting beta-amyloid.

Levels of beta-amyloid in the brain are more dynamic than their slow buildup over the years implies. You might think of the condition - and indeed the increase in amyloid levels in aging in general - as a slowly progressing imbalance of amyloid creation and clearance mechanisms rather than a slow and irrevocable deposition of amyloid. That in turn implies that a working therapy could quickly reverse all but the latest stages of the disease, when neurons are dying in large numbers.

Do rising brain levels of a plaque-forming substance mean patients are making more of it or that they can no longer clear it from their brains as effectively? ... Clearance is impaired in Alzheimer's disease. We compared a group of 12 patients with early Alzheimer's disease to 12 age-matched and cognitively normal subjects. Both groups produced amyloid-beta (a-beta) at the same average rate, but there's an average drop of about 30 percent in the clearance rates of the group with Alzheimer's. ... Scientists calculate this week [that] it would take 10 years for this decrease in clearance to cause a build-up of a-beta equal to those seen in the brains of Alzheimer's patients. The results have important implications for both diagnosis and treatment.

Here is a more recent paper that reviews what is known of the role of the choroid plexus:

Pathological Alteration in the Choroid Plexus of Alzheimer's Disease: Implication for New Therapy Approaches

In the recent years, much attention has been directed to the roles of the choroid plexus in the central nervous system (CNS) under both normal and pathological conditions. This specialized ventricular structure has recently emerged as a key player in a variety of processes that monitor and maintain the biochemical and cellular homeostasis of the CNS.

The main role of the choroid plexus is to produce cerebrospinal fluid (CSF) and to maintain the extracellular environment of the brain by monitoring the chemical exchange between the CSF and the brain tissue. This involves the surveying of the chemical and immunological status of the extracellular fluid and the removal of toxic substances as well as important roles in the regenerative processes following traumatic events. In addition to CSF, the plexus produces various peptides which can have nourishing and neuroprotective properties.


Morphological alterations of choroid plexus in Alzheimer's disease (AD) have been extensively investigated. These changes include epithelial atrophy, thickening of the basement membrane, and stroma fibrosis. As a result, synthesis, secretory, and transportation functions are significantly altered resulting in decreased cerebrospinal fluid (CSF) turnover. Recent studies discuss the potential impacts of these changes, including the possibility of reduced resistance to stress insults and slow clearance of toxic compounds from CSF with specific reference to the amyloid peptide.

Considering the Thymus

The thymus is the source of immune cells, but involutes in adults - it shrinks and loses its functionality. Restoring the thymus is one possible way around some of the built-in limitations of the immune system that contribute to age-related immune failure and a shorter life: "Emerging evidence indicates that the immune and metabolic interactions control several aspects of the aging process and associated chronic diseases. Among several sites of immune-metabolic interactions, thymic demise represents a particularly puzzling phenomenon because even in metabolically healthy middle-aged individuals the majority of thymic space is replaced with ectopic lipids. The new T cell specificities can only be generated in a functional thymus and, peripheral proliferation of pre-existing T cell clones provides limited immune-vigilance in the elderly. Therefore, it is hypothesized that the strategies that enhance thymic-lymphopoiesis may extend healthspan. Recent data suggest that byproducts of thymic fatty acids and lipids result in accumulation of 'lipotoxic DAMPs' (damage associated molecular patterns), which triggers the innate immune-sensing mechanism like inflammasome activation which links aging to thymic demise. The immune-metabolic interaction within the aging thymus produces a local pro-inflammatory state that directly compromises the thymic stromal microenvironment, thymic-lymphopoiesis and serves a precursor of systemic immune-dysregulation in the elderly. [This has] implications for developing future therapeutic strategies for living well beyond the expected."


Enhanced Proteasome Activity in Naked Mole Rats

Long-lived naked mole-rats appear to have more effective housekeeping and maintenance activity in their cells: the naked mole-rat "maintains robust health for at least 75% of its 32 year lifespan, suggesting that the decline in genomic integrity or protein homeostasis routinely observed during aging, is either attenuated or delayed in this extraordinarily long-lived species. The ubiquitin proteasome system (UPS) plays an integral role in protein homeostasis by degrading oxidatively-damaged and misfolded proteins. In this study, we examined proteasome activity in naked mole-rats and mice in whole liver lysates as well as three subcellular fractions to probe the mechanisms behind the apparently enhanced effectiveness of UPS. ... We found that when compared with mouse samples, naked mole-rats had significantly higher [activity]. ... the 20S proteasome was more active in the longer-lived species and that 26S proteasome was both more active and more populous. Western blot analyses revealed that both 19S subunits and immunoproteasome catalytic subunits are present in greater amounts in the naked mole-rat suggesting that the observed higher specific activity may be due to the greater proportion of immunoproteasomes in livers of healthy young adults. It thus appears that proteasomes in this species are primed for the efficient removal of stress-damaged proteins. Further characterization of the naked mole-rat proteasome and its regulation could lead to important insights on how the cells in these animals handle increased stress and protein damage to maintain a longer health in their tissues and ultimately a longer life."


Maintain Yourself

The human body needs to be taken care of in a variety of ways for best performance over the long term. Exercise, keep the weight off, try to avoid stabbing yourself. It's a considerable disadvantage that in our formative years that sort of maintenance just happens as a natural consequence of being a child - so the additional work that has to go into maintaining health as an adult comes as an unexpected chore.

So: many of us get successful, then get fat, and then suffer age-related conditions more frequently and sooner, and then on average die younger. This isn't rocket science - most people know what they are doing to themselves, even if they aren't up to speed on the details of the biochemistry involved. But the siren song of life in a time of wealth and plenty lures you in. Maybe medical science will save you from yourself ... but I wouldn't count on it.

So maintain yourself. You stand on the verge of a golden age in biotechnology, one that will offer unlimited healthy, youthful lifespans to those who claw their way over the threshold. Slacking on your health is turning your back on that future, it is making it harder for you to live long enough to benefit from rejuvenation biotechnologies that can be clearly envisaged today.

An item to reinforce the point on maintenance:

Exercise can counteract muscle breakdown, increase strength and reduce inflammation caused by aging and heart failure. The benefits for heart failure patients are similar to those for anyone who exercises: there's less muscle-wasting, and their bodies become conditioned to handle more exercise. Age of the patients didn't matter, either, researchers found. ... These findings offer a possible treatment to the muscle breakdown and wasting associated with heart failure and suggest that exercise is therapeutic even in elderly heart failure patients. The findings also suggest an avenue for drug development to slow muscle breakdown in heart failure patients. ... Exercise switches off the muscle-wasting pathways and switches on pathways involved in muscle growth, counteracting muscle loss and exercise intolerance in heart failure patients.

A secondary point is that you have to be proactive; maintenance doesn't just happen. This is likely why there are correlations between age-related disease and depression, or other measures of mental state. The influence of exercise and other forms of maintenance are strong enough to cause many other secondary correlations - so to my eyes it's not the purpose, it's what you do with it.

Purpose in life may protect against harmful changes in the brain associated with Alzheimer's disease:

Our study showed that people who reported greater purpose in life exhibited better cognition than those with less purpose in life even as plaques and tangles accumulated in their brains ... These findings suggest that purpose in life protects against the harmful effects of plaques and tangles on memory and other thinking abilities. This is encouraging and suggests that engaging in meaningful and purposeful activities promotes cognitive health in old age.

Lifelong depression may increase risk of vascular dementia:

People who had depressive symptoms in both midlife and late life were much more likely to develop vascular dementia, while those who had depressive symptoms in late life only were more likely to develop Alzheimer's disease.

An Example of the Proliferation of Studies of Human Longevity

Extensive studies of the genetics of human longevity are growing more common - the flow of data is becoming a flood. Here is an example: "we chose to investigate 1,200 individuals of the Danish 1905 birth cohort, which have been followed since 1998 when the members were 92-93 years old. The genetic contribution to human longevity has been estimated to be most profound during the late part of life, thus these oldest-old individuals are excellent for investigating such effect. The follow-up survival data enabled performance of longitudinal analysis, which is quite unique in the field of genetic epidemiology of human longevity. ... However, this study explores the genetic contribution to survival during the ninth decade of life, hence, in order to investigate the genetic contribution to survival in younger elderly we also included 800 individuals of the Study of Middle-aged Danish twins (MADT). ... The analyses of the data set verified the association [with longevity of] SNPs in the APOE, CETP and IL6 genes, [and] pointed to new candidate genes of human longevity: especially SNPs in the INS, RAD52 and NTHL1 genes appeared promising. As part of these investigations, replication studies of the single-SNP level findings were conducted in German case-control samples of 1,613 oldest-old (ages 95-110) and 1,104 middle-aged individuals and in a Dutch prospective cohort of 563 oldest-old (age 85+). ... Interesting aspects of the study were that the majority of the rare alleles of the identified SNPs were longevity variants, not mortality variants, indicating that at least in our study population, longevity is primarily affected by positively acting minor alleles. ... Furthermore, the genotype data generated were used for a number of replication studies on variation in the FOXO3A, TERT and TERC genes. These studies were performed in response to new data being published on the association of genetic variation in the genes with longevity (FOXO3A and TERT) and with telomere length (TERT and TERC). Our studies verified a role of TERC in human telomere length and of FOXO3A in human longevity (survival from middle age to old age), while a novel role of TERC in human longevity was found."


A Look at Tissue Engineering of Noses and Ears

Tissue engineering is steadily advancing into the easier areas of growing replacement parts: "Other groups have tried to tackle nose replacement with implants but we've found they don't last. They migrate, the shape of the nose changes. But our one will hold itself completely, as it's an entire nose shape made out of polymer. ... Inside this nanomaterial are thousands of small holes. Tissue grows into these and becomes part of it. It becomes the same as a nose and will even feel like one. ... When the nose is transferred to the patient, it doesn't go directly onto the face but will be placed inside a balloon inserted beneath the skin on their arm. After four weeks, during which time skin and blood vessels can grow, the nose can be monitored, then it can be transplanted to the face. At the cutting edge of modern medicine, [researchers] are focusing on growing replacement organs and body parts to order using a patient's own cells. There would be no more waiting for donors or complex reconstruction - just a quick swap. And because the organ is made from the patient's own cells, the risk of rejection should, in theory, be eliminated. ... We seed the patient's own cells on to the polymer inside a bioreactor. ... This is a sterile environment mirroring the human body's temperature, blood and oxygen supply. ... As the cells take hold and multiply, so the polymer becomes coated. The same methods could be applied to all parts of the face to reconstruct those of people who have had severe facial traumas."


Radical Life Extension at the Melbourne Humanity+ Conference

This weekend sees the Humanity+ 2012 conference in Melbourne, Australia, and you'll find good press on the topic of radical life extension at the Age:

When British gerontologist Aubrey de Grey talks about radical life extension for humans - decades, even centuries more of existence - he is not imagining us slogging by with brain plaque, loose dentures and walking frames. Rather, we would be in rude health, with all the hallmarks of age in abeyance, even retreat. No wrinkles, fraying organs, leaky bladders or aching joints. And not much need for aged care or pensions. ... In a world where life expectancy has already dramatically increased over the past century or two, we now face the likelihood of being able to custom-order fresh organs and body parts on 3D-printers, and to treating the basic causes of ageing with the likes of stem-cell therapy and nanotechnology.

De Grey and [Natasha] Vita-More, in Melbourne for this weekend's Humanity+ conference, are in the vanguard of futurists who believe that looking great or designing our bodies to suit (blue skin and magenta eyes anyone?) will be fringe benefits. That is because, in a fast-approaching era of living longer, healthier lives, it is expected we will have time to enjoy the wisdom and opportunities of getting older - we won't be so focused on all the medical appointments, decrepitude and fragility associated with old age. ... de Grey, who once said some of today's infants might live to 1000 years old, and who not so long ago was viewed sceptically by other scientists for his insistence that ageing is a preventable, treatable medical condition, now sees much broader acceptance of his ideas among scientists.

''Attitudes have changed enormously,'' he says. ''The feasibility of what I have been proposing is now generally accepted. It took a long time, because essentially ... people who were expert in regenerative medicine didn't know about ageing; and people expert in ageing didn't know about regenerative medicine.''

A bigger battle has been with the attitudes of the general population, who view ageing as natural and inevitable and who, asked if they would like to have much longer lifespans, deliver predictable objections, often saying they would get bored (so much for the human imagination). De Grey says these responses are because people don't think of ageing in the same category as other diseases: if they understood they could live much longer without medical problems or signs of ageing, they would be enthusiastic. ''They just don't think of [ageing] as a plausible target for medicine.''

Convincing at least a sizable minority of the public is absolutely necessary for the future growth of funding and the research community. On the large scale and over decades of time, the goals that are accomplished are generally those that are talked about, desired, debated, and looked forward to - the possibilities that are present in the great ongoing cultural conversation to a significant degree, in other words. That has a lot to do with the ease of raising funds and the influence upon career choices for up-and-coming scientists and technologists, amongst other factors. The first phase of producing working rejuvenation medicine by following the SENS approach - to fully rejuvenate mice in the laboratory - is a billion dollar program, something that will require a supportive and vocal community of at least tens of millions of supporters in the wider public.

Aubrey de Grey is right in saying that attitudes have changed enormously over the past decade - it's a whole different world in the scientific community when it comes to talking about aging and longevity, and more importantly when it comes to the respectability of doing something about extending healthy human life. We can hope that over the next decade much the same happens for the public at large, as the newfound respect and interest for longevity science spreads from researchers to be absorbed into the common wisdom.

Making Old Stem Cells Functionally Young

More rejuvenation of stem cell function demonstrated in mice: "Researchers have rejuvenated aged hematopoietic stem cells to be functionally younger, offering intriguing clues into how medicine might one day fend off some ailments of old age. ... The paper brings new perspective to what has been a life science controversy - countering what used to be broad consensus that the aging of hematopoietic stem cells (HSCs) was locked in by nature and not reversible by therapeutic intervention. HSCs are stem cells that originate in the bone marrow and generate all of the body's red and white blood cells and platelets. They are an essential support mechanism of blood cells and the immune system. As humans and other species age, HSCs become more numerous but less effective at regenerating blood cells and immune cells. ... Researchers in the current study determined a protein that regulates cell signaling - Cdc42 - also controls a molecular process that causes HSCs from mice to age. Pharmacologic inhibition of Cdc42 reversed HSC aging and restored function similar to that of younger stem cells. ... We know the aging of HSCs reduces in part the response of the immune system response in older people, which contributes to diseases such as anemia, and may be the cause of tissue attrition in certain systems of the body. ... One reason the research team focused on Cdc42 is that previous studies have reported elevated activity of the protein in various tissue types of older mice - which have a natural life span of around two years. Also, elevated expression of Cdc42 has been found in immune system white blood cells in older humans. In the current study, researchers found elevated activity of Cdc42 in the HSCs of older mice. They also were able to induce premature aging of HSCs in mice by genetically increasing Cdc42 activity in the cells. ... To test the rejuvenated cells, the researchers used a process known as serial competitive transplantation. This included extracting HSCs from young (2-4 months) and aged (20-26 months) mice and processing them in laboratory cultures. Young and rejuvenated cells were then engrafted into recipient mice. This allowed scientists to compare how well young and rejuvenated aged HSCs started to repopulate and transform into different types of blood cells. It also confirmed that HSCs rejuvenated by targeting Cdc42 do function similarly to young stem cells."


Self-Assembling Nanoparticles to Target Unwanted Cells

An example of ongoing work to make targeted cell-killing technologies economically practical: "For more than a decade, researchers have been trying to develop nanoparticles that would deliver drugs more effectively and safely. The idea is that a nanoparticle containing a drug compound could selectively target tumor cells or otherwise diseased cells, and avoid healthy ones. Antibodies or other molecules can be attached to the nanoparticle and used to precisely identify target cells. ... [Researchers] devised a method by which the building blocks of the nanoparticle and the drug self-assemble into a final product. Two types of polymer combine to form the tangled mesh of [a] drug-laden spherical nanoparticle. One of these polymers has two chemically and structurally distinct regions, or 'blocks': a water-insoluble block that forms part of the mesh that encapsulates the drug, and a water-soluble block that gives the final product a stealthy corona to evade the immune system. The other type of polymer has three blocks: the same two as the first, as well as a third region that contains a targeting molecule - the signal that will ensure the final particles attach to the desired cell types. The drug-carrying nanoparticles are formed by simply mixing these polymers together with the drug in the appropriate conditions. The self-assembling polymers can be produced in a repeatable and scalable fashion. But the method has an additional benefit ... The method by which the nanoparticles are built - from individual preparations of the two-block and three-block polymers - would also let researchers use high-throughput screening approaches, akin to how medicinal chemists design and test new drug compounds. Each block could be tweaked - extend one block, change the charge on another - and the relative amounts of each polymer could be varied. With so many parameters for tinkering, [scientists] can screen many combinations."


Plausible, Possible, Expensive, Prohibited

As an idle line of thought, what could you have done to yourself today in the field of cutting edge medicine and biotechnology at a moderate to high cost, setting aside the oppressive prohibition of medical regulation? Absent entities like the FDA - and a million other government employee busybodies who itch to regiment and enforce every aspect of our lives - it would be perfectly possible to get out there and solicit deals with researchers and clinics to try new things. To take your own estimate of risk and benefit, rather than being forced to wait for years or decades longer for medical technologies that might in the end be blocked entirely thanks to regulatory costs.

But what could you do today in world that was more free, and with enough money to pay for a major medical procedure? Here are a few examples with varying risk-reward profiles, pulled from the air:

  • Have your aging immune system wiped out with chemotherapy and replaced from your stem cells. Your wager here would be that undergoing chemotherapy (not a wonderful experience under the best of circumstances) will cause you less harm in the long term than keeping your original, increasingly misconfigured immune system. Alternately, you could wait a decade for targeted cell-killer therapies demonstrated in mice to become a practical concern in humans.
  • Undergo any one of a number of potential enhancing gene therapies. For example, why not pay your way into possessing a myostatin mutation? That boosts muscle mass, increases resistance to a range of age-related conditions, and otherwise seems to be beneficial all-round in mammals.
  • Purchase stem cell infusions of the sort that seem to be at least modestly helpful for any number of degenerative conditions - a better option than traditional pharmaceutical medicines. But of course you can't do that in the US, just like you can't benefit from near all of the most recent advances, locked away in trials for years yet. You'd have to head overseas as a medical tourist to become a customer of the more reliable clinics in Asia or the Middle East.
  • Decide in your healthy old age that the possible benefits outweigh the risks for infusion-based biphosphonate therapy. Of course you can't obtain that legally as a healthy person - those regulators again, deciding that they know better and anyone who disagrees with them will ultimately wind up in jail.
  • Choose to end your own long-lived life in a safe and painless way at the time of your choosing, while attended by cryonics professionals who can provide an immediate and expert preservation - offering absolutely the best chance of later restoration with minimal damage, while keeping the cost to a sensible minimum thanks to scheduling.

I could go on - that just scratches the surface. But of course any group that gathered in the US to try these things, or offer services, or make the process as safe and transparent as possible would quickly find themselves prosecuted and jailed. The land of the free long ago ceased to have much to do with liberty or personal freedom. Freedom is the freedom to take your own risks and pay the costs if you pull a bad card from the deck - and that freedom is exactly what drives progress. Take it away and what results is the regulatory stagnation you see in medicine today.

Replacing Damaged DJ-1 in Parkinson's Disease

It has been a number of years since researchers started to investigate the role of DJ-1 in Parkinson's disease. Here, the work has made it to the stage of a possible therapy: "As we age, we naturally lose dopamine-producing neurons. Parkinson's patients experience a rapid loss of these neurons from the onset of the disease, leading to much more drastic deficiencies in dopamine than the average person. ... Mutations in the gene known as DJ-1 lead to accelerated loss of dopaminergic neurons and result in the onset of Parkinson's symptoms at a young age. The ability to modify the activity of DJ-1 could change the progress of the disease. [Researchers have] now developed a peptide which mimics DJ-1's normal function, thereby protecting dopamine- producing neurons. What's more, the peptide can be easily delivered by daily injections or absorbed into the skin through an adhesive patch. Based on a short protein derived from DJ-1 itself, the peptide has been shown to freeze neurodegeneration in its tracks, reducing problems with mobility and leading to greater protection of neurons and higher dopamine levels in the brain. ... We attached the DJ-1-related peptide to another peptide that would allow it to enter the cells, and be carried to the brain. ... In pre-clinical trials, the treatment was tested on mice ... From both a behavioral and biochemical standpoint, the mice that received the peptide treatment showed remarkable improvement. Symptoms such as mobility dysfunctions were reduced significantly, and researchers noted the preservation of dopamine-producing neurons and higher dopamine levels in the brain. Preliminary tests indicate that the peptide is a viable treatment option. Though many peptides have a short life span and degrade quickly, this peptide does not."


The Power of Moderate Exercise

Moderate exercise improves life expectancy: "Undertaking regular jogging increases the life expectancy of men by 6.2 years and women by 5.6 years, reveals the latest data from the Copenhagen City Heart study ... the study's most recent analysis (unpublished) shows that between one and two-and-a-half hours of jogging per week at a 'slow or average' pace delivers optimum benefits for longevity. ... SThe study, which started 1976, is a prospective cardiovascular population study of around 20,000 men and women aged between 20 to 93 years. The study, which made use of the Copenhagen Population Register, set out to increase knowledge about prevention of cardiovascular disease and stroke. Since then the study, which has resulted in publication of over 750 papers, has expanded to include other diseases ... The investigators have explored the associations for longevity with different forms of exercise and other factors. For the jogging sub study, the mortality of 1,116 male joggers and 762 female joggers was compared to the non joggers in the main study population. All participants were asked to answer questions about the amount of time they spent jogging each week, and to rate their own perceptions of pace (defined as slow, average, and fast). ... The first data was collected between 1976 to 1978, the second from 1981 to 1983, the third from 1991 to 1994, and the fourth from 2001 to 2003. For the analysis participants from all the different data collections were followed using a unique personal identification number in the Danish Central Person Register. ... These numbers have been key to the success of the study since they've allowed us to trace participants wherever they go. ... Results show that in the follow-up period involving a maximum of 35 years, [risk] of death was reduced by 44%."


Cryonics Magazine, March-April 2012

I'm a little late in pointing out the latest issue of Cryonics, the magazine published by cryonics provider Alcor, is presently available as a PDF.

The March-April issue of Cryonics features an extensive treatment of protecting one's cryonics arrangements against inflation through life insurance. Insurance agent and Alcor member Rudi Hoffman makes the case for "superfunding" your cryonics arrangements to keep pace with the rising costs of advanced medical procedures. The author explains the differences between the major forms of life insurance (term life, whole life, universal life, etc.), gives advice on how to evaluate the various bells and whistles insurances companies offer, and provides guidance how to read those long policy illustrations. This issue continues the recent focus on identity-destroying brain disorders by offering an article by Alcor staff member Mike Perry about the latest developments in Alzheimer's Disease diagnosis. Alcor CEO Max More reports on the upcoming Alcor conference and both book reviews deal with the topic of immortality, albeit from a different perspective.

The main topic of the issue ties into the ongoing discussion on maintaining Alcor's reserve of funds at a sufficient level for the long term - which is essentially a battle against the predatory inflation produced by the self-serving actions of politicians and political appointees. The political class can be expected to create ever more money from nothing, continually reducing the value of money in circulation and savings accounts, because it is the most effective way to tax the masses - all other forms of taxation generate far more unrest, resistance, and non-compliance, and are thus much more self-limiting in the revenue they can generate.The battle against the inflation resulting from depreciation of the currency is fought by all entities that must tie contracts inked today to outlays required years from now:

As evidenced by recent exchanges on the Alcor Member Forums, our members have a wide variety of suggestions for how to close the substantial funding gap that has been produced by Alcor's practice to date of not raising cryopreservation minimums for existing members. If there is one area of strong agreement, however, it is that all members who are underfunded for today's cryopreservation minimums and who can afford to change or upgrade their life insurance, should do so. This will not just reduce Alcor's funding shortfall but it will also allow the member to secure new cryopreservation and storage technologies that cannot be offered without charging an additional amount. Surplus funding can also be allocated to a personal revival trust or to Alcor's hardship fund to help members with poor funding and/or challenges to pay annual dues.

The March-April issue of Cryonics magazine features an extensive review of life insurance options by Alcor member and life insurance agent Rudi Hoffman. Rudi introduces the topic by presenting the disturbing long-term effects of (medical) inflation. Not all of Alcor's services may be subject to the kind of cost increases we see in medicine but it is prudent to plan using conservative assumptions. After this sobering introduction, Rudi runs us through the various forms of life insurance, their pros and cons, and how to read those long, intimidating policy illustrations. We at Alcor hope that many of you will make efforts to update your cryonics funding to make it easier to solve the underfunding problem and to assist with the really hard cases.

Alcor has its cultural roots firmly in the non-profit world and mindset, as you can see from the above material. This is admirable, but would produce challenges in any organization that must have continuity over decades of serving the same customers. Prices must change to suit the times, and business models must take that into account.

It has occurred to me once or twice over the years that, setting aside the cultural history, an organization similar to Alcor might be best suited to growth and stability as a for-profit subsidiary of a large insurance company. Many of these challenges could be met by a strong relationship with a group that manages insurance and accounts with customers that span many years. In any case, this is another of the possible business models that has yet to be explored in cryonics - and is unlikely to be explored until such time as the industry grows larger.

More Evidence to Show that Excess Fat Causes Chronic Inflammation

Chronic inflammation is a bad thing - it greatly increases your risk of suffering age-related disease, and may be one of the more important mechanisms linking excess fat tissue to risk of disease and lowered life expectancy. Here is more evidence to show that being overweight exposes a person to greater inflammation: "Postmenopausal women who were overweight or obese and lost at least 5 percent of their body weight had a measurable reduction in markers of inflammation. ... Both obesity and inflammation have been shown to be related to several types of cancer, and this study shows that if you reduce weight, you can reduce inflammation as well. ... Women in the trial who were assigned to a weight loss intervention had a goal of 10 percent weight reduction during the course of one year achieved through a diet intervention with or without aerobic exercise. ... The researchers measured levels of C-reactive protein, serum amyloid A, interleukin-6, leukocyte and neutrophil in 439 women. At the end of one year, C-reactive protein reduced by 36.1 percent in the diet-alone group and by 41.7 percent in the diet and exercise group. Interleukin-6 decreased by 23.1 percent in the diet group and 24.3 percent in the diet and exercise group. ... there were greater reductions in these measures among women who lost at least 5 percent of their body weight. They also found that exercise alone, without a dietary weight loss component, had little effect on inflammation markers."


Telomeres in Disease and Aging

An introduction to what is known of telomeres can be found at the Scientist: "The ends of linear chromosomes have attracted serious scientific study - and Nobel Prizes - since the early 20th century. Called telomeres, these ends serve to protect the coding DNA of the genome. When a cell's telomeres shorten to critical lengths, the cell senesces. Thus, telomeres dictate a cell's life span - unless something goes wrong. Work over the past several decades has revealed an active, though limited, mechanism for the normal enzymatic repair of telomere loss in certain proliferative cells. ... Telomeres shorten as we age. By analogy to the cellular mitotic clock, telomeres have been postulated as a marker of 'genetic age,' and telomere length has been marketed as a simple predictor of longevity. Assays of telomere length have been bundled with recommendations for lifestyle modification and for drug therapy, neither based on appropriate clinical studies. Simple but appealing arguments relating telomeres and aging are currently controversial, likely simplistic, and potentially harmful. Telomere length does indeed reflect a cell's past proliferative history and future propensity for apoptosis, senescence, and transformation. Cellular aging, however, is not equivalent to organ or organismal aging. ... Studies in humans have attempted to relate telomere length to life span. In the provocative initial publication from the University of Utah in 2003, individuals around 60 years of age who had the longest telomeres lived longer than did subjects with the shortest telomeres, but the main cause of death in the latter group was, inexplicably, infectious disease; the persons with shorter telomeres did not have a higher rate of cancer deaths. Moreover, these findings have not been confirmed in other studies of older subjects. In another study evaluating a different population, telomere length failed to predict survival, but interestingly it correlated with years of healthy life. In a Danish study of people aged 73 to 101 years, telomeres correlated with life expectancy in a simple univariate analysis, but only before the researchers corrected for age, suggesting that the correlation was driven simply by the fact that younger subjects had longer telomeres. And a Dutch study of 78-year-old men found that while telomere lengths eroded with age, they failed to correlate with mortality."


Enhancing Lysosomal Function and PADK in the Latest Rejuvenation Research

The April 2012 edition of Rejuvenation Research includes the proceedings of the SENS5 conference, so there's a lot of material you'll have already seen there. The sole open access paper is worth reading as an update on research into the use of Z-Phe-Ala-diazomethylketone (PADK) to boost lysosomal function. The lysosome, you will recall, is a form of roving recycling unit that exists within the cell. Its task is to break down waste and unwanted materials - and that function is vital, as demonstrated by the many ultimately fatal conditions caused by lysosomal dysfunction. Unfortunately for all of us, lysosomal functionality deteriorates with age. This is most likely due in large part to accumulating waste materials, such as lipofuscin, that lysosomes cannot break down. They instead bloat and malfunction.

One body of research aiming to fix this issue is organized and advocated by the SENS Foundation, and focuses on ways to safely break down the waste materials that cannot be handled by lysosomes. For example, through biomedical remediation and the use of tailored bacterial enzymes. Meanwhile, other research groups have worked on boosting lysosomal activity in various ways, which seems to have generated some benefits where successful. For example, reversing decline in liver function, and restoring mental capacity in mice engineered to generate the signs of Alzheimer's disease.

It is that second example that is the subject of this open access paper, showing that enhancing lysosomal activity can potentially help with aggregates of damaging material outside cells, as well as the state of the cell interior:

Positive Lysosomal Modulation As a Unique Strategy to Treat Age-Related Protein Accumulation Diseases

Knowing the link between lysosomal dysfunction and selective pathogenesis, one logical step toward therapeutic intervention is the enhancement of enzymatic activity in lysosomes. [Some age-related diseases] may be slowed or reversed by the positive modulation of the lysosomal system. Many studies suggest that lysosomal activation occurs with age and in diseased brains, but not to the necessary extent that would prevent the gradual loss of neuronal integrity and brain function.

Enhancement of lysosomal function has been proposed as a plausible strategy to reduce protein accumulation events in age-related disorders, including those events in Alzheimer disease, Parkinson disease, and Huntington disease. Several of the studies indicate that induction of protein degradation processes is an attempt to clear amyloid peptides and tau species, as well as α-synuclein and mutant huntingtin. Another potential therapeutic strategy that may involve the endosomal-lysosomal system is the disaggregation of extracellular Aβ peptide, with the idea that the disaggregation would promote uptake of monomers and small oligomers into neurons and microglia where they are trafficked to lysosomes for degradation.


Of the list of lysosomal modulatory agents [provided in the paper] only PADK, diazoacetyl-dl-2-aminohexanoic acid methyl ester, glycyl-phenylalanyl-glycine-aldehyde semicarbazone, and bafilomycin A1 have been reported to elicit protection against protein accumulation pathology under appropriate low-dose conditions.


From the in vitro and in vivo findings, unique lysosomal modulators represent a minimally invasive, pharmacologically controlled strategy against protein accumulation disorders to enhance protein clearance, promote synaptic integrity, and slow the progression of dementia.

Michael Batin's Speech at the 2nd International Conference on the Genetics of Aging and Longevity

Following on from a recent interview with Michael Batin, one of the organizers of the 2nd International Conference on the Genetics of Aging and Longevity, here is a machine translation of his speech to the attendees: "We hope that the conference will identify the most promising points of growth, will contribute to international scientific and research funding [from] international and national foundations, private investors. Let me ask the main question [in biogerontology]. Why [is] aging research funded by the minimum amount? How to change the situation? How to change the attitudes of society and government to seek scientific methods of prolonging life? The first thing that prevents us [is that] aging itself is not considered a disease. Although the aging process fully complies with all common signs of the disease. Aging - a cause of illness and disease. Failure to understand this - [a] deadly mistake. The price of this confusion is very real - [100,000] people die every day from diseases related to aging. Another misconception - aging can be successful and healthy. No, [it] can not! Aging can flow more smoothly. Aging can be slowed down. But you can not make a destructive process or healthy, or successful. As it is impossible to make a decent poverty [or toothache enjoyable]. [This is] the amazing paradox. Nobody disputes the fact that there is nothing more important than human life. All agree that there is nothing more terrible than death. Many suspect that the main cause of death in people [is] aging. But few people make this a logical conclusion. What is the most useful and meaningful activity that has ever engaged [mankind? It is the] struggle with aging. And in particular [the study of] fundamental mechanisms of aging and genetics of longevity. That's what [the scientists in this room do].. And I believe [that they are the] most helpful people on the planet."


Maintenance or Reserve in the Aging Brain?

There are numerous high-level hypotheses that seek to explain why different people suffer neurodegeneration to different levels. Some people remain sharp in old age, whilst others descend into dementia. At the fine-grained level of measuring different types of mental capacity, there are also large variations across an aging population: "Episodic memory and working memory decline with advancing age. Nevertheless, large-scale population-based studies document well-preserved memory functioning in some older individuals. The influential 'reserve' notion holds that individual differences in brain characteristics or in the manner people process tasks allow some individuals to cope better than others with brain pathology and hence show preserved memory performance. Here, we discuss a complementary concept, that of brain maintenance (or relative lack of brain pathology), and argue that it constitutes the primary determinant of successful memory aging. We discuss evidence for brain maintenance at different levels: cellular, neurochemical, gray- and white-matter integrity, and systems-level activation patterns. Various genetic and lifestyle factors support brain maintenance in aging and interventions may be designed to promote maintenance of brain structure and function in late life." It makes more sense for neurodegeneration to be more greatly affected by the impact of regular exercise on long-term tissue health than by the genetics of having a cognitive research.