Amateur Religious Engineering and Longevity Science

There exists a very long history of people starting explicitly religious movements to achieve secular goals in the mundane world. A very broad range of such ventures can be found even in recent history, in this apostate age of comparatively weak and apolitical mainstream religious institutions. For every group who set out to achieve their ends through political advocacy, such as by starting a single issue political party, you'll find another who choose to start a church. Those who do this outside the established religious mainstream are looked at askance, and often deservedly so, but really you're just as likely to be taken for a ride on either side of the fence. The accumulation of worldly wealth and privilege at the expense of a gullible flock is almost a tradition in certain segments of the modern religious landscape.

For the purposes of this post, I want to glance at a very narrow thread of religious ventures, fictional and otherwise, that winds its way from the science fiction of the golden age and later through satire and art of the 70s and 80s and then into the online transhumanist community of the 90s and its present descendant organizations. At all these points in time, someone thought it a plausible idea that a religious movement should exist for the purpose of preserving and propagating secular technological goals, in particular the extension of healthy life spans through progress in medical science.

As an aside, I should mention that when I'm out there talking to people about longevity science and the need for funding, you can be certain that I'm not bringing any sort of religion to the table. In fact I'd be happier if religious movements started for the purpose of promoting the secular goal of life extension didn't exist, and for many of the same reasons that I'd rather the more vocal "anti-aging" supplement sellers and snake-oil salesmen went away. To the extent that these people succeed in gaining attention for themselves, they make life harder for the rest of us. Nonetheless, these initiatives exist, they are a part of the extended community of supporters, there is a fascinating history bubbling behind it all, and therefore this is worthy of at least a short post to note all of the above.

If you are widely read in science fiction, you will have no doubt encountered numerous tales in which the principals are engaged in what might be called religious engineering: attempting to change the world by means of exploiting the religious impulse as a lever, with varying degrees of cynicism and spiritualism involved. Stranger in a Strange Land and Neverness are two works that spring to mind. It is not an uncommon concept in fiction spanning the last decades of the last century, probably helped along by the fact that a former figure in that space was off doing something of the sort in the real world, with results we're all familiar with by now. That aside, science fiction serves a purpose in the evolution of technology and culture by virtue of being an idea hothouse. What exists today in the sciences and technology was usually chewed over speculatively and in increasingly accurate detail by numerous authors of the past century. Ideas don't stay stuck in their books: they take wing when they are found attractive.

Starting a religious movement for reasons that are openly secular, as opposed to keeping your secular goals hidden behind a veneer of faith, has come and gone as a fashion over recently decades. You might look at Discordianism, the Church of the Subgenius, and even Pastafarianism as examples of openly secular religions. The degree to which people do take these things religiously is a matter for debate, but it is hard to argue against their success as cultural movements in their time. These are the children and the siblings of science fictional religious engineering, ideas for advocacy escaped and made real.

So given this promiscuously inventive history, and not even touching on the ever-changing fringes of mainstream Christianity in countries like the US, we shouldn't be entirely surprised to discover small religious movements and proposals for the same associated with the support of longevity science. Any community of a meaningful size will produce such initiatives, and the modern community supportive of radical life extension achieved through advances in medicine is now several generations old, spanning a time of great invention in religious engineering, both inside and outside the mainstream. One of the first examples of this sort of thing that I recall encountering via the transhumanist community was the Church of Virus, a clear descendant of numerous science fiction concepts. That, perhaps appropriately, is little more than an idea:

Virus was created to compete with the traditional (irrational) religions in the human ideosphere with the idea that it would introduce and propagate memes which would ensure the survival and evolution of our species. The main advantage conferred upon adherents is Virus provides a conceptual framework for leading a truly meaningful life and attaining immortality without resorting to mystical delusions.

There are also populated groups, however, such as the Society for Venturism that has been a co-traveler with the cryonics community for some time now:

For those not familiar with it, Venturism is a 'secular religion' in the sense that the Praxis might be considered one, but very minimalistic and targeted specifically to the needs of the cryonics community. One of the things it does is to help cryonicists optimize their suspensions, by giving them "religious" grounds to object to autopsy (which would greatly harm their chances of repair and reanimation). Another thing it has done is fundraising for cases where last-minute funding was needed for a terminal patient who could not obtain life insurance.

Similarly, and of a more recent origin, there is apparently a Church of Perpetual Life which has the sound of Unitarianism for supporters of radical life extension and cryonics:

Perpetual Life is a science-based church that is open to people of all faiths. We are non-denominational and non-judgmental. We are also a central gathering place for Humanists, atheists, agnostics and Transhumanists. We hope that you also will find this church to be welcoming and inspiring. Our Mission is to assist all people in the radical extension of healthy human life, and to provide fellowship for longevity enthusiasts through regular, holiday and memorial services.

As it becomes increasingly known among the public that new approaches to treating aging and extending healthy life spans are on the way, I can only imagine that we'll see more of this. The sphere of religion as it evolves in practice works much like the intersection of politics and business: in particular there is disruption, revolution of ideas, movement of customers, and change. The large mainstream is always slow-moving and conservative, and as a consequence its leaders will find themselves challenged on the topic of extended healthy life spans, just as they have been challenged on medical advances in the past. They will fight a little, and then smaller and more nimble challengers espousing more sympathetic theologies will gain adherents, and ultimately the mainstream will accommodate them or be replaced: the same brand, but different bishops running the show. I'm sure it will be interesting to watch, for all that it has little relevance to presently important goals and challenges in advocacy for longevity science.

The Prospects for Therapies and Enhancements via Magnetic Stimulation of the Brain

Transcranial magnetic stimulation (TMS) is a fascinating field of study in which it is clearly possible to affect the brain, but researchers are still in the comparatively early stages of finding out how to reliably produce and measure useful end results. The research noted here is an example of one of the more positive findings, a way to enhance memory function. It doesn't address underlying causes of dysfunction in aging, unfortunately, rather being a possible methodology to compensate somewhat for losses. This isn't the preferred direction for medicine if we seek true prevention and cure of age-related loss of function, but as for many such things, one has to ask "why not see whether or not this can be applied all the time, for everyone?"

In the past, TMS has been used in a limited way to temporarily change brain function to improve performance during a test, for example, making someone push a button slightly faster while the brain is being stimulated. The study shows that TMS can be used to improve memory for events at least 24 hours after the stimulation is given.

It isn't possible to directly stimulate the hippocampus with TMS because it's too deep in the brain for the magnetic fields to penetrate. So, using an MRI scan, [researchers] identified a superficial brain region a mere centimeter from the surface of the skull with high connectivity to the hippocampus. [They] wanted to see if directing the stimulation to this spot would in turn stimulate the hippocampus. It did. When TMS was used to stimulate this spot, regions in the brain involved with the hippocampus became more synchronized with each other, as indicated by data taken while subjects were inside an MRI machine, which records the blood flow in the brain as an indirect measure of neuronal activity. The more those regions worked together due to the stimulation, the better people were able to learn new information.

Scientists recruited 16 healthy adults ages 21 to 40. Each had a detailed anatomical image taken of his or her brain as well as 10 minutes of recording brain activity while lying quietly inside an MRI scanner. Doing this allowed the researchers to identify each person's network of brain structures that are involved in memory and well connected to the hippocampus. The structures are slightly different in each person and may vary in location by as much as a few centimeters. Each participant then underwent a memory test, consisting of a set of arbitrary associations between faces and words that they were asked to learn and remember. After establishing their baseline ability to perform on this memory task, participants received brain stimulation 20 minutes a day for five consecutive days. Then, at least 24 hours after the final stimulation, they were tested again. Both groups performed better on memory tests as a result of the brain stimulation. It took three days of stimulation before they improved.

In an upcoming trial, [researchers] will study the electrical stimulation's effect on people with early-stage memory loss, [but] cautioned that years of research are needed to determine whether this approach is safe or effective for patients with Alzheimer's disease or similar disorders of memory.


Nasal Cartilage Cells Can Replace Joint Cartilage

Cartilage regeneration and tissue engineering has proven more difficult than initially expected. It is a tissue with a deceptively complex structure, in which important mechanical properties necessary to its load-bearing role are derived from the details of that structure. Simply culturing cartilage cells is far from enough to produce a useful end result, and researchers have only recently made inroads into producing tissue engineered cartilage that is somewhat like the real thing. In this work a novel approach is taken to produce grafts for injured joint cartilage:

Cartilage lesions in joints often appear in older people as a result of degenerative processes. However, they also regularly affect younger people after injuries and accidents. Such defects are difficult to repair and often require complicated surgery and long rehabilitation times. A new treatment option has now been presented by a research team: nasal cartilage cells can replace cartilage cells in joints.

[Scientists] were especially surprised by the fact that in the animal model with goats, the implanted nasal cartilage cells were compatible with the knee joint profile; even though, the two cell types have different origins. During the embryonic development, nasal septum cells develop from the neuroectodermal germ layer, which also forms the nervous system; their self-renewal capacity is attributed to their lack of expression of some homeobox (HOX) genes. In contrast, these HOX genes are expressed in articular cartilage cells that are formed in the mesodermal germ layer of the embryo.

Cartilage cells from the nasal septum (nasal chondrocytes) have a distinct capacity to generate a new cartilage tissue after their expansion in culture. In an ongoing clinical study, the researchers have so far taken small biopsies (6 millimeters in diameter) from the nasal septum from seven out of 25 patients below the age of 55 years and then isolated the cartilage cells. They cultured and multiplied the cells and then applied them to a scaffold in order to engineer a cartilage graft the size of 30 x 40 millimeters. A few weeks later they removed the damaged cartilage tissue of the patients' knees and replaced it with the engineered and tailored tissue from the nose.


João Pedro de Magalhães in Rejuvenation Research

João Pedro de Magalhães is one of the few rising notables in the aging research community who has, from day one of his career, been absolutely and openly in favor of radical life extension through progress in medical science. To his eyes, as mine, the defeat of aging and age-related disease is a goal to strive for, plausible and attainable with the right research strategies. More than ten years ago, de Magalhães penned Winning the War Against Aging, I asked permission to reprint it online, and there is still is:

Imagine that your grandmother looks like a teenager, plays soccer, parties at the clubs all night, and works as a venture capitalist. Or imagine your grandfather teaching you the latest high-tech computer software in his office, which you hate to visit because of the loud heavy metal music. Such a scenario is hard to envision because we are taught to accept aging and the resulting suffering and death as an immutable fact of life. We cannot picture our grandparents in better physical shape than we are. Nonetheless, aging may soon become nothing more than a scary bedtime story, perhaps one your grandfather will tell your grandson after a day of white-water rafting together.

A decade on and my online efforts have become Fight Aging!, while de Magalhães now heads a research group investigating the molecular biology of aging at Liverpool University. He also runs the website and associated databases, which are collectively an excellent resource on the science of aging for laypeople and scientists alike. I in no way suggest equivalence in our efforts: he is doing far more than I to advance this cause. Great things lie ahead in this field, and I have the greatest of admiration for people who plant a flag in the ground, set a target, and then stride forth to do what they say they were going do. The world could use more people of this ilk.

On that note, allow me to draw your attention to a position paper by de Magalhães in the pending publication queue of the Rejuvenation Research journal. In it he recapitulates his long-standing views on aging, radical life extension, and medical science - which is to say that the defeat of aging is possible and plausible, but efforts to that end remain woefully underfunded in comparison to their importance.

The scientific quest for lasting youth: prospects for curing aging

People have always sought eternal life and everlasting youth. Recent technological breakthroughs and our growing understanding of aging have given strength to the idea that a cure for human aging can eventually be developed. As such, it is crucial to debate the long-term goals and potential impact of the field. Here, I discuss the scientific prospect of eradicating human aging. I argue that curing aging is scientifically possible and not even the most challenging enterprise in the biosciences. Developing the means to abolish aging is also an ethical endeavor since the goal of biomedical research is to allow people to be as healthy as possible for as long as possible.

There is no evidence, however, that we are near developing the technologies permitting radical life-extension. One major difficulty in aging research is the time and costs it takes to do experiments and test interventions. I argue that unraveling the functioning of the genome and developing predictive computer models of human biology and disease are essential to increase the accuracy of medical interventions, including in context of life-extension, and exponential growth in informatics and genomics capacity might lead to rapid progress.

Nonetheless, developing the tools for significantly modifying human biology is crucial to intervene in a complex process like aging, yet in spite of advances in areas like regenerative medicine and gene therapy, the development of clinical applications has been slow and this remains a key hurdle for achieving radical life-extension in the foreseeable future.

You'll note from the abstract above, and from the work of his research group, that de Magalhães has a position on the best path forward that is fairly close to that of the present focus on genetics and longevity in the US research and development community. For my part, I ascribe the failure of past efforts to produce progress as being due to the fact that next to no work has been focused on repair of root causes in the SENS model. I predict that we will see significant progress when that state of affairs finally changes, which is something that we can help along by funding SENS or other similar disruptive approaches, pushing them closer to providing ever more convincing results that pull in other researchers as allies and supporters.

A Potential Source of Cardiac Stem Cells

Many research groups in the stem cell field are engaged in a search for sources of useful tissue-specific cells in the body, developing means of identification and isolation. This runs in parallel with efforts to reprogram more easily obtained cells, such as from skin samples, into a range of different types for therapy and research. Both approaches add value in the near term, expanding the range of tissues in which regeneration might be greatly enhanced. The heart is of particular interest as it normally has little capacity for repair, and is of course the cause of a great many fatal problems as we age. Here is an example of progress in identifying existing cell populations that support heart tissue:

Endothelial cells residing in the coronary arteries can function as cardiac stem cells to produce new heart muscle tissue. The findings [offer] insights into how the heart maintains itself and could lead to new strategies for repairing the heart when it fails after a heart attack. The heart has long been considered to be an organ without regenerative potential. Recent findings, however, have demonstrated that new heart muscle cells are generated at a low rate, suggesting the presence of cardiac stem cells. The source of these cells was unknown.

[Researchers] postulated that the endothelial cells that line blood vessels might have the potential to generate new heart cells. They knew that endothelial cells give rise to other cell types, including blood cells, during development. Now, using sophisticated technologies to "track" cells in a mouse model, they have demonstrated that endothelial cells in the coronary arteries generate new cardiac muscle cells in healthy hearts. They found two populations of cardiac stem cells in the coronary arteries - a quiescent population in the media layer and a proliferative population in the adventitia (outer) layer.

The finding that coronary arteries house a cardiac stem cell niche has interesting implications. Coronary artery disease would impact this niche. "Our study suggests that coronary artery disease could lead to heart failure not only by blocking the arteries and causing heart attacks, but also by affecting the way the heart is maintained and regenerated."


The Cost of a Sedentary Lifestyle to Muscle and Bone

A mountain of evidence exists to demonstrate that being sedentary will lead to greater ill health and a shorter life expectancy. As we inch closer towards the implementation of rejuvenation treatments at some uncertain point in the decades ahead, every year of health and life gained counts, raising the odds of living long enough to benefit from proposed ways to repair the damage of aging.

Being physically active may significantly improve musculoskeletal and overall health, and minimize or delay the effects of aging, according to a review of the latest research. It long has been assumed that aging causes an inevitable deterioration of the body and its ability to function, as well as increased rates of related injuries such as sprains, strains and fractures; diseases, such as obesity and diabetes; and osteoarthritis and other bone and joint conditions. However, recent research on senior, elite athletes suggests usage of comprehensive fitness and nutrition routines helps minimize bone and joint health decline and maintain overall physical health.

"An increasing amount of evidence demonstrates that we can modulate age-related decline in the musculoskeletal system. A lot of the deterioration we see with aging can be attributed to a more sedentary lifestyle instead of aging itself." The positive effects of physical activity on maintaining bone density, muscle mass, ligament and tendon function, and cartilage volume are keys to optimal physical function and health. "Regimens must be individualized for older adults according to their baseline level of conditioning and disability, and be instituted gradually and safely, particularly for elderly and poorly conditioned adults." To improve fitness levels and minimize bone and joint health decline, when safely allowable, patients should be encouraged to continually exceed the minimum exercise recommendations.


Liver ATF4 Upregulation Common to Many of the Reliable Means of Slowing Aging in Mice

There are a score or more ways to reliably slow aging in mice, methods that include a few classes of drug, various single gene alterations, and calorie restriction. The most exceptional of these methods extends life by 60% or so, but most are in the much more modest 10-20% range at best. It is suspected that many of these approaches operate on a smaller overlapping set of underlying processes, but at different entry points: metabolism is a very, very complex system of interactions and feedback loops, and it is near impossible to make any change in isolation. Any given portion of our biochemistry distinct enough to be given a name and studied might consist of dozens of proteins at its core, and interact with hundreds more in ways that are important when considering the pace of aging.

To pick one example, increased levels of the cellular housekeeping processes called autophagy show up in many ways of slowing aging in lower animals. Some of the methods of slowing aging may only work at all because they happen to influence cells into taking better care of themselves, but that influence doesn't have to be in any way direct. Some alterations to mitochondria known to extend life in nematode worms slightly raise the generated levels of damaging reactive oxygen species emitted by mitochondrial processes, and that in turn causes cells to react with greater housekeeping vigor for a net gain. Much the same net gain might also be achieved by more direct manipulations that increase levels of autophagy - but from a distance these two approaches look very different, and target quite different proteins.

Thus the challenge facing researchers interested in slowing aging is that they are in no way even close to fully understanding any of the easily replicated and studied methods of slowing aging in various laboratory animals. Decades of work lie ahead to make a serious dent in the great unknowns of how metabolism interacts with aging in detail, even with the expected increases in computing power and new tools in biotechnology. This is why researchers are not generally all that optimistic about progress in the near term via calorie restriction mimetics and other ways of altering metabolism to slow aging. It is why I favor approaches such as SENS that largely bypass expensive attempts to change metabolism in favor of repairing clearly identified age-related changes in tissues, with the expectation that lacking this damage the operation of metabolism will revert back to the known good state that exists in youth, when comparatively little of that damage is present.

Most ongoing work in the aging research community focuses on finding out more about metabolism and aging, however, with some interest in ways to slow aging. It is quite often fascinating stuff, such as the open access paper below, but bear in mind that this really isn't a path to much more than knowledge. From the practical standpoint of whether we are on the road to greatly extend healthy life and reverse aging in the near future, this is not the way forward.

ATF4 activity: a common feature shared by many kinds of slow-aging mice

ATF4 is a transcriptional factor which senses deficits in protein translation, typically related to endoplasmic reticulum stress or amino acid limitation, and in turn activates a group of target genes. The availability of multiple methods to extend mouse maximal lifespan - genetic, dietary, development, or drug-induced - provides an opportunity to test the hypothesis that augmented ATF4 action, necessary for multiple modes of lifespan extension in yeast, is also characteristic of slow aging in mice.

Data in this paper show that ATF4 levels, levels of proteins controlled by ATF4, and levels of three mRNAs regulated directly by ATF4 are elevated in liver of mice exposed to each of five interventions shown elsewhere to increase maximal longevity: the drugs acarbose and rapamycin, diets low in calories or methionine, or transient milk deprivation limited to the suckling period.

Our previous work has shown similar increases in ATF4 protein and downstream indicators of ATF4 function in liver of Snell dwarf mice and PAPP-A knock-out mice, mutations that increase maximal lifespan and health in old age by alteration of endocrine pathways connected to GH and/or IGF-1. The previous study also documented augmented ATF4 responses in fibroblast cell lines derived from skin of adult Snell and PAPP-A KO mice, suggesting that the relevant changes affect more than a single cell type and that the changes include epigenetic modifications preserved during multiple mitotic cycles in tissue culture medium. All of these data are consistent with the idea that elevation of ATF4 function may contribute to the slow aging and extended lifespan in each of these diverse varieties of mice.

You might recall that ATF4 shows up in studies of methionione restriction. It is thought that a fair fraction of the benefits of calorie restriction involve changes in the operation of metabolism triggered by mechanisms that react to low methionine levels. You might look at these past items from the Fight Aging! archives for more context:

A Report from the First International Mini-Symposium on Methionine Restriction and Lifespan

The presentations highlighted the importance of research on cysteine, growth hormone (GH), and ATF4 in the paradigm of aging. In addition, the effects of dietary restriction or MR in the kidneys, liver, bones, and the adipose tissue were discussed.

Methionine Restriction and FGF21 in Mice

Methionine restriction decreased hepatic lipogenic gene expression and caused a remodeling of lipid metabolism in white adipose tissue, alongside increased insulin-induced phosphorylation of the insulin receptor (IR) and Akt in peripheral tissues. Mice restricted of methionine exhibited increased circulating and hepatic gene expression levels of FGF21, phosphorylation of eIF2a, and expression of ATF4. Short-term 48-h MR treatment increased hepatic FGF21 expression/secretion and insulin signaling and improved whole-body glucose homeostasis without affecting body weight.

Identifying Tissue Weakness Before Injury

This is an interesting technology demonstration that suggests an obvious pairing with regenerative treatments based on the use of stem cells or similar means to spur tissue repair. With regular scans it might be possible to preempt many instances of muscle and bone injury caused by use and stress, preventing them from ever developing by repairing tissue weak spots before they develop into injuries.

[Researchers] have developed algorithms to identify weak spots in tendons, muscles and bones prone to tearing or breaking. The technology, which needs to be refined before it is used in patients, one day may help pinpoint minor strains and tiny injuries in the body's tissues long before bigger problems occur. "Tendons are constantly stretching as muscles pull on them, and bones also bend or compress as we carry out everyday activities. Small cracks or tears can result from these loads and lead to major injuries. Understanding how these tears and cracks develop over time therefore is important for diagnosing and tracking injuries."

[The researchers] developed a way to visualize and even predict spots where tissues are weakened. To accomplish this, they stretched tissues and tracked what happened as their shapes changed or became distorted. [They] combined mechanical engineering fundamentals with image-analysis techniques to create the algorithms, which were tested in different materials and in animal models. "The new algorithm allowed us to find the places where the tears were beginning to form and to track them as they extended. Older algorithms are not as good at finding and tracking localized strains as the material stretches."

In fact, one of the two new algorithms is 1,000 times more accurate than older methods at quantifying very large stretches near tiny cracks and tears, the research showed. And a second algorithm has the ability to predict where cracks and failures are likely to form. "This extra accuracy is critical for quantifying large strains. Commercial algorithms that estimate strain often are much less sensitive, and they are prone to detecting noise that can arise from the algorithm itself rather than from the material being examined. The new algorithms can distinguish the noise from true regions of large strains."


Advocating Arterial Destiffening to Treat Cardiovascular Disease

It is always good to see more scientists come around to the SENS viewpoint of damage repair as the best treatment for age-related disease. Addressing root causes is a much better approach than the current prevalent paradigm of trying to adapt failing biological systems to work less poorly when damaged, while failing to make a dent in the damage itself. Tackling the root causes should be much more cost-effective and simply much more effective overall, and in many cases the root causes for specific age-related conditions are known rather than merely surmised.

Cardiovascular risk factors (CVRFs) have been shown to induce end organ damage. Until now, the main approach to reduce CVRF-induced end organ damage was by normalization of CVRFs; this approach was found effective to reduce damage and cardiovascular (CV) events. However, a residual risk always remained even when CVRFs were optimally balanced. An additional risk factor which has an immense effect on the progression of end organ damage is aging. Aging is accompanied by gradual stiffening of the arteries which finally leads to CV events. Until recently, the process of arterial aging was considered as unmodifiable, but this has changed.

Arterial stiffening caused by the aging process is similar to the changes seen as a result of CVRF-induced arterial damage. Actually, the presence of CVRFs causes faster arterial stiffening, and the extent of damage is proportional to the severity of the CVRF, the length of its existence, the patient's genetic factors, etc. Conventional treatments of osteoporosis and of hormonal decline at menopause are potential additional approaches to positively affect progression of arterial stiffening.

The new approach to further decrease progression of arteriosclerosis, thus preventing events, is the prevention of age-associated arterial structural changes. This approach should further decrease age-associated arterial stiffening. A totally new promising approach is to study the possibility of affecting collagen, elastin, and other components of connective tissue that participate in the process of arterial stiffening. Reduction of pulse pressure by intervention in arterial stiffening process by novel methods as breaking collagen cross-links or preventing their formation is an example of future directions in treatment. This field is of enormous potential that might be revolutionary in inducing further significant reduction of cardiovascular events.


Fight Aging! 2014 Fundraiser Poster #2

Following on from yesterday's post and poster, below find the second commissioned piece for the Fight Aging! 2014 Fundraiser starting on October 1st, with all proceeds going to benefit the SENS Research Foundation. The Foundation organizes and funds work on near future rejuvenation treatments, ways to repair the cellular and molecular damage that causes degenerative aging. This research will ultimately lead to cures and prevention for all age-related disease. How soon can this happen? That is up to us, as funding is very much the limiting factor.

One of the exciting aspects of this era of biotechnology is that early stage research has become very cheap indeed. All of that massive expense you constantly hear about in medicine? That is spent on the road to clinical application, long after the basic research is done and finished. The cost of original research leading to a proof of concept is a drop in the bucket compared to the cost of turning that prototype into a tested, trialed, widely available, packaged, manufactured therapy. Funding for clinical application is a lot easier to raise than funding for original research, not least because you can point to something that works. Thus given a group like the SENS Research Foundation with access to existing labs and established researchers, even a few tens of thousands of dollars make the difference between successfully completing one more cutting edge project or postponing it indefinitely.

When the grassroots of this community raises money for biotechnology, it isn't just for show, and isn't just to help create an environment in which wealthier donors and larger donations are more likely to arrive: it gets things done, funds meaningful science, and makes a real difference to the pace of progress in rejuvenation research.

The full size graphics are large enough for 24 x 36 inch posters, but are also suitable for page-sized fliers. The original Photoshop files are available on request, but are a little large to put up here. Make as much use of these as you like: the purpose is to spread the word and encourage support.

Apolipoprotein B Variants and Exceptional Human Longevity

Studies of human longevity-associated genes produce results that tend to be hard to replicate. The effects are individually tiny and vary widely between study populations, indicating a complex web of influences. Only a few genes stand out as having small and consistent rather than tiny and varying associations with longevity, such as APOE variants involved in the operation of cholesterol metabolism among other things. So on the one hand expect the results of this study to be hard to replicate, especially given the small sample size, but on the other hand it is somewhat connected to APOE so we shall see:

Exceptional longevity (EL) is a rare phenotype that can cluster in families, and co-segregation of genetic variation in these families may point to candidate genes that could contribute to extended lifespan. In this study, for the first time, we have sequenced a total of seven exomes from exceptionally long-lived siblings (probands of more than 103 years and at least one sibling of more than 97 years) that come from three separate families. We have focused on rare functional variants (RFVs) which have ≤ 1% minor allele frequency according to databases and that are likely to alter gene product function.

Based on this, we have identified one candidate longevity gene carrying RFVs in all three families, APOB. Interestingly, APOB is a component of lipoprotein particles together with APOE, and variants in the genes encoding these two proteins have been previously associated with human longevity. Analysis of nonfamilial EL cases showed a trend, without reaching statistical significance, toward enrichment of APOB RFVs. We have also identified candidate longevity genes shared between two families (5 - 13) or within individual families (66 - 156 genes). Some of these genes have been previously linked to longevity in model organisms, such as PPARGC1A, NRG1, RAD52, RAD51, NCOR1, and ADCY5 genes. This work provides an initial catalog of genes that could contribute to exceptional familial longevity.


Everything Looks the Same in the Distance

One of the challenges we face in directing fund and attention to the most promising research into human longevity, rather than efforts that are doomed from the start to achieve no meaningful near term gains, is that from the distance of unfamiliarity everything looks the same. The average journalist or person in the street can't tell the difference between SENS rejuvenation research, metabolic alterations with a poor chance of slightly slowing aging after the Longevity Dividend model, research into genetics of longevity and personalized medicine, and opportunists who cloak their old-fashioned health businesses with the mere appearance of modern longevity science. From the perspective of people at a distance it all looks the same, equally valid. Which is far from being the case.

This article is an example of the phenomenon, in which it is a matter of accident and publicity as to whom the author discusses, rather than whether or not their efforts are relevant or effective. Thus what is intended to be a discussion of Silicon Valley initiatives targeting aging and longevity manages to omit the SENS Research Foundation, despite the organization being headquartered there, and spends many of its words on the next generation of self-deluding snake oil salespeople, pushing the quantified self rather than pills this time around.

Asprey is trying to stop individual bodies from aging - starting with his own - and investment is pouring into a growing number of companies whose stated goal is to increase human longevity and, in some cases, even cure death. Asprey freely admits that these are grandiose, quixotic endeavors. But in a place where geeks have changed the world with previously unthinkable breakthroughs in science, nothing seems impossible. "When you're young and you've just created something amazing that makes you a ton of a money, you do egotistical things. And I'm not saying that's a bad thing: I want to swing for the fences. What is all of this cool technology we're creating compared to getting an extra hundred years of life?"

He's far from the only one dreaming of a home run. Last year Google launched Calico Labs, a medical company whose goal is to tackle aging and illness. While so far Calico is remaining fairly secretive about its projects (my requests for an interview were politely declined), experts believe its objective is to go beyond solving individual diseases the way most medical researchers have done until now. Earlier this year, Calico hired Cynthia Kenyon [who] has been experimenting with tweaking genes in animals to slow aging. By disabling a gene called daf-2, she has doubled the life-span of roundworms, fruit flies, and mice. In her new role as VP of aging research at Calico, she will ostensibly be attempting to re-create these results in humans.

This year, another company, Human Longevity, joined the anti-aging quest. Founded by J. Craig Venter, another millionaire entrepreneur, it's central goal involves understanding DNA. [In] some ways, the goals of Human Longevity are in line with what medicine has been trying to do all along: cure illness, improve life quality, and extend the human life-span. The difference is that his company applies big-data tools to process vast quantities of information we now have about the human body. The organization will sequence 2 million human genomes in five years, gathering unparalleled insights into the causes of disease. Rather than tackling problems incrementally, he says it is possible to work on a bigger scale, yielding more dramatic results. One of them could be cheating death.

I brought many of these questions to Laura Deming, one of the youngest people in the anti-aging movement. She's just 20, but she's already been working on the problem for close to a decade. "I was taken by this idea that if you have a vision of what you want to make, you can just build it," she tells me. Deming immediately began trying to fix the problem. At 12 she started work at a lab and enrolled at MIT at the age of 14. Three years later, she dropped out to become a Thiel fellow to continue her research. She has recently started the Longevity Fund, a company that seeks to attract investors to startups working on aging and life extension. Deming points out that people's views tend to change when they move away from big existential questions to imagining individual people instead. While ending death is one part of the story, a more tangible part is curing the diseases that cause death. She believes almost everyone would cure cancer or arthritis or dementia if they could.


Fight Aging! 2014 Fundraiser Poster #1

October 1st is the start date for the Fight Aging! 2014 Fundraiser to benefit ongoing programs at the SENS Research Foundation, and the event will run through to the end of the year. While new attention and funding is swelling the longevity science community these days, it remains the case that the SENS Research Foundation is the only scientific network that meets all of my criteria for support: work is directed towards repair-based approaches to human rejuvenation rather than merely tinkering with metabolism to slow aging; there is an established non-profit organization so that average folk like you and I can make tax-deductible donations in the US and EU; and funds are spent effectively to advance the state of the art. It is a short list, but hard to fill, and it matters greatly which scientific programs we support.

In the past few months, generous donors have assembled a $100,000 Fight Aging! matching fund to encourage us all to help speed progress in rejuvenation research. Starting on October 1st we seek to raise $50,000 from the community, drawing a match of $2 from the fund for every $1 donated. Don't miss out on the chance to make every dollar you give count for three times as much! More than just a matter of donating, however, help in organization and outreach is also essential. You all know scores of people who don't read Fight Aging! and don't participate in the community, and some of them might if asked. Can you help to make this fundraiser a success by putting up flyers, organizing local events, or reaching out in your community to find new supporters? Here is the first of two posters commissioned for the fundraiser:

The full size graphics are large enough for 24 x 36 inch posters, but are also suitable for page-sized fliers. The original Photoshop files are available on request, but are a little large to put up here. Make as much use of these as you like: the purpose is to spread the word and encourage support.

Inhibiting P38 MAPK Restores Proliferation in Senescent T Cells

Senescent non-dividing cells of all types accumulate in various tissues. This is probably an adaptation that acts to suppress cancer risk, but these cells secrete damaging compounds that degrade nearby tissue function and cause surrounding cells to also tend towards senescence. The most straightforward approach to removing this contribution to degenerative aging is some form of targeted destruction of senescent cells, perhaps via adaptation of any one of the numerous cell killer technologies under development in the cancer research community.

In recent years some progress has been made in another direction, that of reversing the senescent state of cells. Ultimately the research community will be able to reprogram any cell into any desired state, but that lies a way into the future yet. Reversing senescence will undoubtedly prove complicated and tissue-specific, and there is the open question of whether this will increase cancer risk. Here is an example of one small step on this road, but note that it is only restoring the ability of one type of senescent cell to divide once more. It may or may not be adequately addressing the other undesirable behaviors of the cells, and may or may not turn out to be the best approach.

As we age our immune systems decline. Older people suffer from increased incidence and severity of both infections and cancer. In addition, vaccination becomes less efficient with age. In previous [work, researchers] showed that ageing in immune system cells known as T lymphocytes was controlled by a molecule called p38 MAPK that acts as a brake to prevent certain cellular functions. They found that this braking action could be reversed by using a p38 MAPK inhibitor, suggesting the possibility of rejuvenating old T cells using drug treatment.

In a new study [the] group shows that p38 MAPK is activated by low nutrient levels, coupled with signals associated with age, or senescence, within the cell. It has been suspected for a long time that nutrition, metabolism and immunity are linked and this paper provides a prototype mechanism of how nutrient and senescence signals converge to regulate the function of T lymphocytes. The study also suggests that the function of old T lymphocytes could be reconstituted by blocking one of several molecules involved in the process.

"Our life expectancy at birth is now twice as long as it was 150 years ago and our lifespans are on the increase. Healthcare costs associated with ageing are immense and there will be an increasing number of older people in our population who will have a lower quality of life due in part to immune decline. It is therefore essential to understand reasons why immunity decreases and whether it is possible to counteract some of these changes. An important question is whether this knowledge can be used to enhance immunity during ageing. Many drug companies have already developed p38 inhibitors in attempts to treat inflammatory diseases. One new possibility for their use is that these compounds could be used to enhance immunity in older subjects. Another possibility is that dietary instead of drug intervention could be used to enhance immunity since metabolism and senescence are two sides of the same coin."


Growing a New Thymus From Engineered Cells

The thymus is vital to generation of new immune cells, and the fact that it atrophies early in life, turning a river of new cells into a trickle, is one of the factors placing an effective cap on the adult immune cell population. In part because of this limit in later life competent immune cells capable of dealing with new threats are crowded out by other immune cell types. Solutions to this issue include restoration of a larger supply of new cells by restoring the thymus or targeted destruction of the excess cells to free up space and spur the body to generate replacement immune cells that are capable of doing their jobs.

Earlier this year researchers published a demonstration of a short cut to rejuvenate the aged thymus simply by manipulating levels of FOXN1 to boost the population of certain important progenitor cells responsible for maintaining the thymus. It is rare to find such short cuts in tissue engineering, and this one most likely only exists for the thymus because of its unusual early decline in adults - a course very different from most organs, and which may have a comparatively simple set of triggers. Here the same research group shows off the next stage in their work, which is the generation of a complete new thymus in vivo by much the same set of mechanisms:

[Scientists] started with cells from a mouse embryo. These cells were genetically "reprogrammed" and started to transform into a type of cell found in the thymus. These were mixed with other support-role cells and placed inside mice. Once inside, the bunch of cells developed into a functional thymus. Structurally it contained the two main regions - the cortex and medulla - and it also produced T-cells. "This was a complete surprise to us, that we were really being able to generate a fully functional and fully organised organ starting with reprogrammed cells in really a very straightforward way. This is a very exciting advance and it's also very tantalising in terms of the wider field of regenerative medicine."

Here, we show that enforced ​Foxn1 expression is sufficient to reprogramme fibroblasts into functional thymic epithelial cells (TECs), an unrelated cell type across a germ-layer boundary. On transplantation, iTECs established a complete, fully organized and functional thymus, that contained all of the TEC subtypes required to support T-cell differentiation and populated the recipient immune system with T cells. iTECs thus demonstrate that cellular reprogramming approaches can be used to generate an entire organ, and open the possibility of widespread use of thymus transplantation to boost immune function in patients.

Patients who need a bone marrow transplant and children who are born without a functioning thymus could all benefit. Ways of boosting the thymus could also help elderly people. The organ shrinks with age and leads to a weaker immune system. However, there are a number of obstacles to overcome before this research moves from animal studies to hospital therapies. The current technique uses embryos. This means the developing thymus would not be a tissue match for the patient. Researchers also need to be sure that the transplant cells do not pose a cancer risk by growing uncontrollably.


Reports from Rejuvenation Biotechnology 2014

If things are comparatively quiet at the moment, it is because a lot of people are attending Rejuvenation Biotechnology 2014 in California. The event is hosted by the SENS Research Foundation in an effort to hasten some of the organization and relationship building needed to speed the clinical development of near future rejuvenation treatments. The basic science for those treatments is in some cases just a few years away from practical utility if funding continues to grow, so some foresight and preparation is called for with regard to the long path ahead. There are many steps on the road leading from limited technology demonstration in the laboratory to widely available therapy in the clinic, and while not all of them need planning at this stage, it is certainly the case that a smooth transition from laboratory research to clinical development doesn't happen without planning and effort.

Some of the folk attending the Rejuvenation Biotechnology 2014 conference are posting on the topic, and many thanks to them for doing so. You might browse the links below:

Live from SENS Rejuvenation Biotechnology Conference

Opening remarks by Mike Kope, CEO of SENS Research Foundation, remind us of how much progress has been made in the field in the last several years, yet also reminds us we still have a way to go. Jerri Riley, VP of Outreach, outlines the agenda for the day, and thanks the audience, sponsors and exhibitors before introducing the keynote speaker, Dr. George Church, a pioneer in genomics and synthetic biology.

Molecular and Cellular Damage as the Cause of the Diseases of Aging

On the stage sits an all-star panel including Aubrey de Grey, Jeff Karp, Caleb Finch, Stephen Minger and Richard Baker, discussing the idea that diseases of aging may stem from molecular and cellular damage that accrues with age. I am trying to not think about the sheer brainpower and knowledge that sits just a few feet away.

SENS Rejuvenation Biotechnology Conference - Toward a New Investment Paradigm

Jim O'Neil is a partner at Mithril Capital Management, which invests in transformative and durable technologies. With a background in as a Regulator at DHHS, he quickly realized that too much regulation is counterproductive. Jim talks about Breakout Labs, which funds emerging technology start ups. He states Mithril wants to right "backwards industries," those which desperately need to be examined and changed to become more efficient. One example he uses is health care, which I can certainly attest to, having worked and consulted in the field for over 20 years.

SENS Rejuvenation Biotechnology - Economic Impact of an Aging Population on the Healthcare System

If this helps people live longer, albeit not necessarily without disease, what are the economic effects we can expect to see? Enter Peter Nakada. Well, if you can model it, you can insure it, right? With a background in Risk Management, Peter tell us that statistical models are not the way to go, as they do not capture "regime shifts", such as advancing technology. For example, mortality rates went up during the Industrial Revolution, due to more dangerous jobs using machinery, increased pollution, etc. These are examples of the "regime shifts" that are not accounted for in statistical models. Yet another reason how you measure is just as important as what you measure.

Studying regenerative medicine, amount of improvement was calculated, along with types of diseases that can be treated by stem cell therapy. It is up to this community to probabalize the benefits of developments such as new organ growth and stem cell treatments. In essence, we need to start thinking about the implications of longevity now, to ensure a better future tomorrow.

SENS Rejuvenation Biotechnology Conference - Cancer Session

We learn that senescent cells drive aging and age related diseases, but why? Apparently, these cells secrete molecules that can act at a distance, affecting multiple neighboring cells, which causes failure of tissue function. [This is] noted to increase inflammation, which is single factor common in all diseases, including cancer. Senescent cells disrupt normal cellular function and structure. For example, premalignant cells injected into mice are activated and turn cancerous with the addition of senescent cells, while injection of non-senescent cells did not result in development of cancerous tumors. How can we fix this? One strategy includes medication which stop cells from secreting [these molecules] yet it needs to be present at all times.

Cryopreservation at Alcor

Cryonics is the process of vitrifying the body and brain at death, preserving as much of the fine tissue structure as possible to enable the possibility of future restoration to life. There's no fundamental barrier to achieving that revival other than the fact that the necessary technology doesn't yet exist, and subject to the continuation of storage facilities the vitrified cryopreservees can wait for that time to arrive. A small cryonics industry has existed for some four decades now, with the most established non-profit groups being Alcor and the Cryonics Institute in the US. Several hundred people are presently preserved. It is an undertaking with an unknown timeline and chance of success, but these are the best odds offered to those who will age to death prior to the development of rejuvenation treatments.

Like most popular press articles on cryonics, the piece quoted below confuses low-temperature vitrification with freezing. They are in fact two very different things with very different outcomes on tissue viability: vitrification minimizes ice crystal formation, for example, which is the cause of much of the damage to frozen tissues.

Cryopreservation is a darling of the futurist community. The general premise is simple: medicine is continually getting better. Those who die today could be cured tomorrow. Cryonics is a way to bridge the gap between today's medicine and tomorrow's. "We see it as an extension of emergency medicine. We're just taking over when today's medicine gives up on a patient. Think of it this way: 50 years ago if you were walking along the street and someone keeled over in front of you and stopped breathing you would have checked them out and said they were dead and disposed of them. Today we don't do that, instead we do CPR and all kinds of things. People we thought were dead 50 years ago we now know were not. Cryonics is the same thing, we just have to stop them from getting worse and let a more advanced technology in the future fix that problem."

Alcor's members come from all over the world. Ideally the company will have an idea of when their members are going to die. Alcor maintains a watch list of members in failing health, and when it seems as though the time has come they send what they call a "standby team" to do just that - stand by the person's bed until they die. "It could be hours, days, we've gone as long as three weeks on standby." Once the person in question is declared legally dead, the process of preserving them can begin, and it's an intense one. First, the standby team transfers the patient from the hospital bed into an ice bed and covers them with an icy slurry. Then Alcor uses a "heart-lung resuscitator" to get the blood moving through the body again. They then administer 16 different medications meant to protect the cells from deteriorating after death. Once the patient is iced up and medicated, they move them to a place for surgery.

The next step includes draining as much blood and bodily fluids as possible from the person, replacing them with a solution that won't form ice crystals - essentially the same kind of antifreeze solution used in organ preservation during transplants. Once the patient's veins are full of this antifreeze, Alcor can begin to cool them down by about one degree Celsius every hour, eventually bringing the body down to -196C after about two weeks. Eventually the body finds its final home for the foreseeable future: upside down in a freezer, often alongside three others.

Most members are somewhat squeamish about the actual process of cryopreservation - but they see it as a means to an end. "We don't want to be cryopreserved - we hate the idea in fact. The idea of sitting in a tank of liquid nitrogen not able to control our own destinies is not appealing. But it's a lot more appealing than the alternative, to be digested by worms or incinerated - that doesn't appeal to us at all."


Supporting Evidence for Mitochondrial Transfer as Therapy

Bacteria-like mitochondria are the cell's power plants, and they become damaged with age. This damage spirals out to create a small but significant population of cells that export harmful reactive compounds into surrounding tissues and the circulatory system, contributing to a range of age-related conditions. One possible approach to address this issue involves destroying existing damaged mitochondria and replacing them with undamaged versions. Simply introducing new undamaged mitochondria is an easier proposition but probably not sufficient, as the damaged versions overtake cells because they have an advantage in replication: diluting their numbers won't last very long.

Here researchers provide more evidence to show that simply introducing new mitochondria into a tissue environment is probably sufficient to see them taken up into cells and used. This is great news for work on inherited genetic mitochondrial disorders, where supplying new unmutated mitochondria should be a cure, but it is only a part of any potential treatment for the mitochondrial damage of aging based on mitochondrial replacement:

Mitochondria play an essential role in eukaryotes, and mitochondrial dysfunction is implicated in several diseases. Therefore, intercellular mitochondrial transfer has been proposed as a mechanism for cell-based therapy. In addition, internalization of isolated mitochondria cells by simple coincubation was reported to improve mitochondrial function in the recipient cells. However, substantial evidence for internalization of isolated mitochondria is still lacking, and its precise mechanism remains elusive.

We tested whether enriched mitochondria can be internalized into cultured human cells by simple coincubation using fluorescence microscopy and flow cytometry. Mitochondria were isolated from endometrial gland-derived mesenchymal cells (EMCs) or EMCs stably expressing mitochondrial-targeted red fluorescent protein (EMCs-DsRed-mito), and enriched by anti-mitochondrial antibody-conjugated microbeads. They were coincubated with isogeneic EMCs stably expressing green fluorescent protein (GFP).

Live fluorescence imaging clearly showed that DsRed-labeled mitochondria accumulated in the cytoplasm of EMCs stably expressing GFP around the nucleus. Flow cytometry confirmed the presence of a distinct population of GFP and DsRed double-positive cells within the recipient cells. In addition, transfer efficiency depended on mitochondrial concentration, indicating that human cells may possess the inherent ability to internalize mitochondria. Therefore, this study supports the application of direct transfer of isogeneic mitochondria as a novel approach for the treatment of diseases associated with mitochondrial dysfunction.


Without New Medical Technologies Your Odds of Living to 100 are Extremely Poor

Very few people become centenarians, making it to the old age of 100 years. As you pass 80 and 90 years of age your past and current lifestyle choices start to diminish in significance, while genetic variations gain a growing influence on your survival as an increasingly damaged and frail individual. At age 90 something like 75% of your age-matched peers are dead, and that includes a majority of everyone who made the best choices throughout life in health and lifestyle. You can't reliably exercise your way to living to 100, as illustrated by the numbers quoted below: between age 90 and age 100 there is a precipitous fall in survival.

Becoming Centenarians: Disease and Functioning Trajectories of Older U.S. Adults as They Survive to 100

Little is known about the health and functioning of individuals who become centenarians in the years prior to reaching age 100. We examined long-term trajectories of disease, disability, and cognitive function in a sample of U.S. centenarians to determine how their aging experience differs from their nonsurviving cohort counterparts, and if there is heterogeneity in the aging experience of centenarians.

Data are from the 1993-2010 waves of the nationally representative Health and Retirement Study. Among those who had the potential to become centenarians, we identified 1,045 respondents who died before reaching age 100 and 96 who survived to their 100th birthday. Respondents, or their proxies, reported on diagnosis of six major diseases (hypertension, heart disease, lung disease, stroke, cancer, and diabetes), limitations in activities of daily living, and cognitive function.

As they age to 100, centenarians are generally healthier than nonsurviving members of their cohort, and a number of individuals who become centenarians reach 100 with no self-reported diseases or functional impairments. About 23% of centenarians reached age 100 with no major chronic disease and approximately the same number had no disability (18%). Over half (55%) reached 100 without cognitive impairment. Disease and functioning trajectories of centenarians differ by sex, education, and marital status.

It's a great idea to exercise regularly and practice calorie restriction. Research demonstrates that it will make your later life much more tolerable, healthy, and likely a few years longer besides. But don't think that this will produce enormous changes in the end result in and of itself: don't buy into that story. If medical technology fails to advance significantly by the time you are old, then regardless of what you do and have done then you will die on roughly the same schedule as your parents and grandparents. Similarly, your later life will see you much reduced: sick, frail, and in pain, no matter what path you took to get there. You can tilt the scales to make it less terrible, but it is still going to be terrible.

There is only one way to break out of this box, and that is for today's body of medicine to expand and progress to include rejuvenation treatments. The nature of these treatments can presently be envisaged in great detail, such as in the SENS research programs or the noted Hallmarks of Aging paper. There is a short laundry list of forms of damage that accumulate in and around cells, and to reverse and prevent the ravages of age-related disease and frailty all that has to be accomplished is to repair this damage.

I say "all" and of course it is a tall order, but this goal is nonetheless a lot less challenging than continuing along the present path in which researchers try to intervene in the enormously complex late stages of aging. Aging is like rust: simple root causes spiral out into very complex patterns based on the details of random chance and because their surroundings are very complex. Yet much of the research community focuses on proximate causes in age-related disease, trying to decipher details of a process at the very point at which it is most complicated and hardest to understand. The treatments they produce ignoring root causes, and are in essence attempts to adapt a very complicated system to work less poorly when it is damaged. Can you imagine doing this with a car? Rebuilding it to work slightly less poorly while dangerously rusted rather than fixing the rust problem at the source? This approach guarantees that the work of most medical researchers will produce at best marginal, expensive results that do little more than delay the inevitable.

We want to do better than that, and produce meaningful cures for aging - to bring aging under medical control by directly and effectively addressing its causes. That is the only way that most of us will see a hundredth birthday. But if it does happen, if sufficient funding and support arrives, then we will be in far better health at age 100 than any centenarian in history has been, as the causes of aging will be stripped from us, leaving vigor and health in their place.

Media Babble on Greatly Extended Human Longevity is Drifting in a Positive Direction

Radical life extension is the now somewhat dated term for the process of adding decades and then centuries to healthy life spans through near future rejuvenation therapies. The media has a quota system, I think, for turning out articles on this topic that are little better than babble. A stream of consciousness is committed to the page and sent forth into the world. In past years this typically consisted entirely of knee-jerk objections and assertions that death by aging was a wonderful thing: that we live in the best of all worlds in which we are privileged to suffer and die to a schedule not our own, and besides the whole idea of living longer is impossible, as any sensible individual should see, and now let us stop dwelling upon fantasies of a world in which medicine improves and get back to something important, such as the latest celebrity gossip.

It is hopefully not just an illusion in my eyes, but I do believe I see some drift in a positive direction in the babble of late. Babble it may be, but it is still a signal of sorts. There is more of an acceptance of radical life extension as an inevitability, and something of a balancing of views. The same old knee-jerk objections remain in force, but there are also wistful glances at the possibility of a life that is longer and better in all aspects. The times are changing, and the average media figure bends with the wind when it comes to any field in which large and very public investments are now happening. Take this piece from NPR, for example:

Even if we don't spend the day thinking about it (and who could bear it?), pretty much most of what we do is connected in one way or another with the certainty of death. To lose this certainty, to have a vast, unchallenged expanse of time ahead, would certainly change our psyche in very essential ways. The word "legacy" would need to be redefined. Immortality could be quite boring, a life without a sense of pace. An immortal being would be an aberration, opposite to everything that we see around us, a world where transformation and decay is the rule.

Thomas Nagel, [counters] by arguing that, perhaps, an immortal life could still be "composed of an endless sequence of quests, undertakings and discoveries, including successes and failures. ... I am not convinced that the essential role of mortality in shaping the meaning we find in our actual lives implies that earthly immortality would not be a good thing."

Is immortality scientifically viable? We don't know, although many researchers think of aging as an illness that can be treated. It's hard to imagine that science will not be going that way. But here is the key question: If you could extend your life by another 50 or 100 healthy years, would you? Quite possibly, we will be moving toward a "soft immortality" in the next decades. The question of how a very long life will affect our minds will then become an experiment.

Whatever the many debates the topic incites, there is one good consequence of it, as Ed Regis and George Church noted in an essay from 2012: A race of soft immortals would have plenty of motivation to preserve the planet. After all, without Earth, what's the point of pursuing a long life?


Human Trials of Young Blood Transfused into Old Individuals

Studies of parabiosis, in which a young and an old mouse have their blood systems joined, show that altering the balance of circulating proteins in old tissue can restore stem cells to action and revert a range of measures that change with age. It is thought that frequent blood transfusions should capture at least some of this outcome, although it is unclear as to the degree to which the relevant proteins are short-lived in circulation, and transfusions are really just a stand-in for some yet to be established but more effective way of directly altering levels of the proteins of interest.

Stem cells decline and protein levels change as a reaction to rising levels of cellular damage, or at least that is the dominant view of aging as a process in the research community. In the case of stem cells this may be an evolved mechanism to suppress cancer risk, a balance between death by failing tissue maintenance versus death due to damaged cells running amok. Thus there is some concern that crude changes intended to bring stem cells back into a youthful mode of activity will produce high rates of cancer, but it is entirely possible that this can be avoided while still retaining benefits. First generation stem cell treatments came attached to much the same concern, and where that concern was professionally addressed these therapies are clearly producing meaningful benefits in older people.

In both mice and humans, GDF11 falls with age. We don't know why it declines, but we know it is involved in several mechanisms that control growth. It is also thought to mediate some age-related effects on the brain, in part by activation of another protein that is involved in neuronal growth and long-term memory. So the billion-dollar question is: would a GDF11 boost have the same effect in humans? [Researchers think] it will, having taken the next step of injecting young human blood plasma into old mice. His preliminary results suggest that human blood has similar rejuvenating benefits for old mice as young mouse blood does. "We saw these astounding effects. The human blood had beneficial effects on every organ we've studied so far."

Now, the final step - giving young human blood plasma to older people with a medical condition - is about to begin. Getting approval to perform the experiment in humans has been relatively simple, thanks to the long safety record of blood transfusions. So in early October, a [team] will give a transfusion of blood plasma donated by people under 30 to older volunteers with mild to moderate Alzheimer's. Following the impressive results in animal experiments, the team hopes to see immediate improvements in cognition, [but] cautions that it is still very experimental. "We will assess cognitive function immediately before and for several days after the transfusion, as well as tracking each person for a few months to see if any of their family or carers report any positive effects. The effects might be transient, but even if it's just for a day it is a proof of concept that is worth pursuing."

All researchers involved in the work agree that GDF11 is unlikely to be the only factor that keeps organs youthful. "It's too optimistic to think there would be just one factor. It's much more likely to be several factors that exert these effects in combination."


Digging Into the Biochemistry of Lizard Tail Regeneration

Many lower species are far more proficient at regeneration than mammals. Some tiny creatures like hydra are enormously capable regenerators, and may even be so good at it that they are effectively ageless. But the simple strategy of "regenerate and replace everything, all the time" is most likely inapplicable to higher organisms that need to maintain the complex fine structure of the brain and central nervous system: a sweeping regeneration of much of the brain would most likely be equivalent to death for mammals, erasing the data of the mind and disrupting other structures and relationships necessary for moment to moment survival.

The ability of species such as salamanders, zebrafish, and lizards to regenerate inner organs, tails, fins, and limbs is much more interesting however. These animals have complex central nervous systems, yet can rebuild portions of themselves and recover from injuries that would permanently cripple or kill most mammals. A fair amount of research in recent years has focused on salamander regeneration, but at this point it is still too early to say whether it will be practical to take any of what is learned and produce a way for mammals to regenerate in the same way. Perhaps the necessary biochemical tools lie buried in the mammalian metabolism, turned off at some point in the deep evolutionary past, or perhaps they have been lost entirely.

It is clearly the case, based upon the fortuitous discovery of MRL mice capable of healing small wounds without scarring, that there are potential improvements to be made. But it is unlikely that there is much shared biochemistry to be found in the mechanisms involved in regeneration in MRL mice, salamanders, and zebrafish. Biology is complex and it is often the case that any two species found to have evolved similar capabilities actually use completely different mechanisms under the hood.

So to the green anole lizard, which like the salamander is capable of tail regeneration. As it turns out, the way in which that regeneration happens is very different in these two species. This somewhat strengthens the case for tempering any optimism regarding limb and organ regeneration in humans achieved via this means. If researchers are in fact examining a range of independently evolved mechanisms in these various species, it renders it less likely that there is a shared heritage dormant in mammals, and more likely that it will be very hard to recreate these forms of regeneration in humans - no shortcuts here. But again, it really is far too early to have more than suspicions about where this will all go. This group of researchers seem optimistic about the study of lizard regeneration, however:

How lizards regenerate their tails: researchers discover genetic 'recipe'

"Lizards basically share the same toolbox of genes as humans. Lizards are the most closely-related animals to humans that can regenerate entire appendages. We discovered that they turn on at least 326 genes in specific regions of the regenerating tail, including genes involved in embryonic development, response to hormonal signals and wound healing. Regeneration is not an instant process. In fact, it takes lizards more than 60 days to regenerate a functional tail. Lizards form a complex regenerating structure with cells growing into tissues at a number of sites along the tail."

Other animals, such as salamanders, frog tadpoles and fish, can also regenerate their tails, with growth mostly at the tip. During tail regeneration, they all turn on genes in what is called the 'Wnt pathway' - a process that is required to control stem cells in many organs, such as the brain, hair follicles and blood vessels. However, lizards have a unique pattern of tissue growth that is distributed throughout the tail.

"We have identified one type of cell that is important for tissue regeneration. Just like in mice and humans, lizards have satellite cells that can grow and develop into skeletal muscle and other tissues. Using next-generation technologies to sequence all the genes expressed during regeneration, we have unlocked the mystery of what genes are needed to regrow the lizard tail. By following the genetic recipe for regeneration that is found in lizards, and then harnessing those same genes in human cells, it may be possible to regrow new cartilage, muscle or even spinal cord in the future."

Transcriptomic Analysis of Tail Regeneration in the Lizard Anolis carolinensis Reveals Activation of Conserved Vertebrate Developmental and Repair Mechanisms

We have carried out the first transcriptomic analysis of tail regeneration in a lizard, the green anole Anolis carolinensis, which revealed 326 differentially expressed genes activating multiple developmental and repair mechanisms. Specifically, genes involved in wound response, hormonal regulation, musculoskeletal development, and the Wnt and MAPK/FGF pathways were differentially expressed along the regenerating tail axis.

However, high levels of progenitor/stem cell markers were not observed in any region of the regenerating tail. Furthermore, we observed multiple tissue-type specific clusters of proliferating cells along the regenerating tail, not localized to the tail tip. These findings predict a different mechanism of regeneration in the lizard than the blastema model described in the salamander and the zebrafish. Thus, lizard tail regrowth involves the activation of conserved developmental and wound response pathways, which are potential targets for regenerative medical therapies.

Mapping Blood Vessel Elasticity in the Brain

Loss of elasticity in blood vessels occurs for a number of reasons, including the rising level of persistent cross-links that glue together important structural proteins, effects of chronic inflammation on mechanisms needed for blood vessel elasticity, and so forth. This form of structural failure has material consequences, raising the risk of life-threatening events such as stroke.

Exercise has been shown to slow the progression of blood vessel stiffening, and here a new technique for assessing blood vessel stiffness in the brain adds more data in support of that view. More importantly, this sort of technology will be very useful as a means of rapidly assessing the effectiveness of near future rejuvenation treatments, such as means to break glucosepane cross-links presently funded by the SENS Research Foundation:

[Researchers] have developed a new technique that can noninvasively image the pulse pressure and elasticity of the arteries of the brain, revealing correlations between arterial health and aging. The [researchers] routinely record optical imaging data by shining near-infrared light into the brain to measure neural activity. Their idea to measure pulse pressure through optical imaging came from observing in previous studies that the arterial pulse produced strong signals in the optical data, which they normally do not use to study brain function. Realizing the value in this overlooked data, they launched a new study that focused on data from 53 participants aged 55-87 years.

"When we image the brain using our optical methods, we usually remove the pulse as an artifact - we take it out in order to get to other signals from the brain. But we are interested in aging and how the brain changes with other bodily systems, like the cardiovascular system. When thinking about this, we realized it would be useful to measure the cerebrovascular system as we worry about cognition and brain physiology."

The initial results using this new technique find that arterial stiffness is directly correlated with cardiorespiratory fitness: the more fit people are, the more elastic their arteries. Because arterial stiffening is a cause of reduced brain blood flow, stiff arteries can lead to a faster rate of cognitive decline and an increased chance of stroke, especially in older adults. "Noninvasive optical methods can provide estimates of arterial elasticity and brain pulse pressure in different regions of the brain, which can give us clues about the how different regions of the brain contribute to our overall health. For example, if we found that a particular artery was stiff and causing decreased blood flow to and loss of brain cells in a specific area, we might find that the damage to this area is also associated with an increased likelihood of certain psychological and cognitive issues."


Elite Athletes Live Longer

It remains an open question as to why top-level athletes live notably longer than the rest of us. The point of interest is to what degree the longevity difference is produced by exercise and training versus a population bias among successful athletes to more robust individuals who would live longer regardless of their profession. That's hard to answer at this point, and is a part of broader research regarding exercise, in that while moderate regular exercise is clearly beneficial, it is unknown as to whether anything more than merely moderate regular exercise is more beneficial over the long term.

To determine whether the health benefits of exercise are actually confined (or not) to noncompetitive, moderate (or recreational) practice is of broad medical interest and might help clinicians have more evidence-based data on exercise benefits. Thus, we conducted a meta-analysis of cohort studies comparing mortality in elite athletes with mortality in the general population. We hypothesized that the overall health benefits of competitive exercise would counteract any potential detrimental effect, resulting in higher longevity and lower disease risk in elite athletes than in the general population.

Ten studies, including data from a total of 42,807 athletes (707 women), met all inclusion criteria. The all-cause pooled standard mortality ratio (SMR) was 0.67 with no evidence of publication bias but with significant heterogeneity among studies. Six studies provided data on cardiovascular disease (CVD) and 5 on cancer (in a total of 35,920 and 12,119 athletes, respectively). When only CVD was considered as a cause of mortality, the pooled SMR was 0.73 with no evidence of bias or heterogenity among studies. The SMR for cancer was 0.60 with no evidence of bias despite a significant heterogeneity.

The evidence available indicates that top-level athletes live longer than the general population and have a lower risk of 2 major causes of mortality, namely, CVD and cancer. [This] suggests that the beneficial health effects of exercise, particularly in decreasing CVD and cancer risk, are not necessarily confined to moderate doses. Future studies might elucidate whether the present high demands of professional sports participation also translate into an actual longevity and health benefit.


An Interesting Paper on Calorie Restriction

There is a little debate over mortality and body mass index in humans. The overwhelming majority of epidemiological evidence coupled with animal studies and what is known of the underlying biochemistry shows that being fat is bad for you on a sliding scale: the more fat, the worse off you are. The occasional study turns up to claim the opposite, which is the way things go in science. It doesn't matter how overwhelming the evidence or solid the theories, it is still possible for professional teams to generate contrary data in good faith, by accident or simply via the whims of statistical chance. So last year a study was published suggesting that the moderately overweight do best in old age, having the lowest mortality rates. This was widely debated at the time and, I think, largely successfully dismantled and shown to be a poor result.

Nonetheless, the wheels of scientific publication move slowly, and that published data is referenced in the interesting paper on calorie restriction linked below, which was probably written before last year's debate wound to a close. Regardless, the general thrust of the paper remains worth reading, which is how to reconcile various short and long term data obtained from the study of calorie restriction, some of which appears at first glance to be contradictory. The practice of calorie restriction greatly improves health and extends healthy life spans in animal studies. In human studies it is shown to greatly improve short term measures of health. As to the few primate studies, there is a great deal of debate over what exactly the results of twenty years of data are in fact showing us, and whether that research was carried out in a way that allows all of the useful conclusions we'd like to see. Under the hood, there are many theories and much evidence on how calorie restriction alters biochemistry to slow aging, but no unified theory as of yet. It is probably very complex. Calorie restriction is a jigsaw with many missing pieces at every level, from the biochemistry all the way up to drawing lines between the results in different species.

Still, calorie restriction is well supported as a beneficial thing to be doing as a human. Eat less and benefit. The big question is whether this is "just" the best thing you can presently do for your long-term health while paradoxically having little effect on your life expectancy, or whether it can add additional years. The present scientific consensus is that it probably won't add more than five to seven years to life, but is just as good as regular moderate exercise in many ways and considerably better in others.

As this paper shows, there are those who don't really look too far beyond simple measures over populations, such as BMI and mortality. I think they are doomed to see only paradox, and whatever resolutions exist are to be found in the lower level details. At some point there has to be a good resolution between detailed observations that show large benefits from calorie restriction, a mountain of statistical population data telling us that being overweight is bad, and a much lesser collection of statistical population data telling us that being overweight isn't bad. Meanwhile, I'll still with the compelling evidence for not eating so much and keeping the fat tissue to a minimum.

How much should we weigh for a long and healthy life span? The need to reconcile caloric restriction versus longevity with body mass index versus mortality data

A recent, very large meta-analysis has shaken the epidemiological community by showing that the lowest inflection point for the BMI-mortality curve (its nadir) lays in the overweight range. Discussion is ongoing among epidemiologists on this topic, some time referred to as the "obesity-mortality paradox." There are several confounding factors, in fact, to consider: for example, smokers tend to weigh less but have higher mortality; some chronic diseases may induce weight loss; the frail elderly with higher risk of death may also experience weight loss, etc.

An important question that gerontologists and epidemiologists should try to answer together is the following: "people who voluntarily choose a CR regimen and are already within a normal BMI range, let us say its upper half, are increasing their longevity or their mortality?" Indeed, when glancing on reports about members of the Calorie Restriction Society, or CRONies (Calorie Restriction with Optimal Nutrition) as they call themselves, we should consider their BMI. In one of the longest studies available, for example, where subject were monitored for a period of 6 years, 28 weight-stable CRONies had an average BMI of 19.7, and they were compared with 28 age-matched subjects on a typical western diet who had an average BMI of 25.6 and served as the control group. These two groups, for example, had BMI values that quite precisely spanned the normal BMI range. If these two groups of persons will keep their body weight constant for the future, what could we predict regarding their longevity? Using as guidance studies like the [the meta-analysis noted above], we should conclude that the control group should experience a lower mortality. Instead, using as guidance the generally accepted idea that CR extend laboratory animals life span together with the few available prospective studies where persons who were leaner in youth or in midlife resulted longer lived, we should conclude that the CRONies will actually experience decrease mortality and extended longevity.

Which somewhat skips over the point that the calorie restriction practitioners in that study had a longevity-associated measurement of biochemistry that was much better than the control group members. To me this is the interesting paradox regarding calorie restriction: why is it that the shifts in biochemistry are so similar between humans and mice, and yet only the mice experience a sizable extension of life as a result?

An Example of a Targeted Viral Cancer Therapy

The present standards for cancer treatment are poorly targeted in comparison to prototype work taking place in the labs and clinical trials. Chemotherapy, radiotherapy, and the like have a detrimental impact on the rest of the body, and their effectiveness is limited by the degree to which they hurt the patient in the process of impacting cancer cells. Their days are numbered, however. A broad range of next generation targeted treatments have been demonstrated in recent years, with few side-effects because they affect only cancer cells and their nearest neighbors. A number of these therapies use existing biological systems as a means of targeting cancer cells, such as viruses:

The patient suffered from multiple myeloma, a cancer of the bone marrow. Last June, [doctors] injected her bloodstream with a form of measles that was genetically re-engineered to attack myeloma cells. The measles therapy followed a decade of unsuccessful treatments from numerous courses of chemotherapy to two stem cell transplants. But the cancer returned time and time again - until now. A year after the measles injections, she's still cancer-free. The idea of using viruses to defeat cancer - called oncolytic virotherapy - is not a new idea. [But] her case is the "first well-documented instance of a patient who has received an intravenously administered virus that has caused complete remission of disseminating cancer. We've known for a long time that this is possible in mice, but we had not known that it's possible in people. We now know it's possible and this should energize the field - but we have a lot of work to do."

Oncolytic virotherapy works by exploiting the fact that cancer cells usually have weak ability to fight off infections. Viruses can infect normal cells, but it's a self-limiting infection, so normal cells can easily overpower these viruses and get rid of the infection. But in the weakened cancer cells, the virus can replicate, destroy cancer cells [and] make more new virus, which can then go and kill more cancer cells around it. [The] treatment is different from a vaccine. "When you administer a vaccine, you give the minimum dose you can give in order to alert the immune system. We are using the virus as a weapon. We give it into a vein and we ask those viruses to seek and destroy the cancer cells. There are a large number of cancer cells in the body, so you need to give a massive dose of virus."

The [researchers] used a strain of the measles virus that has been used in vaccinations since 1954 and "taught it to grow on human cancer cells ... That's how it became specific for cancer." [Researchers] have given this treatment to six patients, but only one of them had a complete response to the treatment. One had a partial response and the others no response at all. One of the barriers to successful virotherapy treatment is the body's own immune system. If an antibody to a virus is present in the patient's blood stream, it will negate the benefit of giving the virus. [The] hope is to have a variety of viruses to use so that doctors can always find ones patients aren't already immune to.


Incremental Progress Towards Xenotransplantation

In between today and a future in which cell therapies are advanced enough to repair organs in situ a range of sophisticated transplant treatments will emerge to address organ failure. Among the present contenders are decellularization of donor organs, artificial organs of various types, including bioprinted tissues, and xenotransplantation, the use of animal organs. The latter is moving towards practicality, step by step:

[Researchers] have successfully transplanted hearts from genetically engineered piglets into baboons' abdomens and had the hearts survive for more than one year, twice as long as previously reported. This was achieved by using genetically engineered porcine donors and a more focused immunosuppression regimen in the baboon recipients. "Until we learn to grow organs via tissue engineering, which is unlikely in the near future, xenotransplantation seems to be a valid approach to supplement human organ availability. Despite many setbacks over the years, recent genetic and immunologic advancements have helped revitalized progress in the xenotransplantation field."

[Reseachers] developed techniques on two fronts to overcome some of the roadblocks that previously hindered successful xenotransplantation. The first advance was the ability to produce genetically engineered pigs as a source of donor organs. The pigs had the genes that cause adverse immunologic reactions in humans "knocked out" and human genes that make the organ more compatible with human physiology were inserted. The second advance was the use of target-specific immunosuppression, which limits rejection of the transplanted organ rather than the usual generalized immunosuppression, which is more toxic.

In this study, researchers compared the survival of hearts from genetically engineered piglets that were organized into different experimental groups based on the genetic modifications introduced. The gene that synthesizes the enzyme alpha 1-3 galactosidase transferase was "knocked out" in all piglets, thus eliminating one immunologic rejection target. The pig hearts also expressed one or two human transgenes to prevent blood from clotting. This longest-surviving group was the only one that had the human thrombomodulin gene added to the pigs' genome. Thrombomodulin expression helps avoid some of the microvascular clotting problems that were previously associated with organ transplantation.


A Brief Letter to the Long Retired

Life isn't fair, but you've probably figured that out by now. Your body is corroding, and there's nothing great about that. I guess I'm not telling you anything you don't know here.

So try this on for size: in among all of the modern wonders of medicine, many of which you have become familiar with, some few scientists are working on ways to control the causes of aging and thus put a halt to all age-related disease.

"All?" you might well ask. Well, aging is just another medical condition, so why not? We didn't put up with tuberculosis once we could do something about it. Coughing up your lungs just because everyone else up until that point did as much? That would have been silly.

The good news then is that people are working to make the world a better place. The march of medicine continues. The bad news is that control of aging isn't going to happen soon enough for today's oldest, not even in the best of worlds. There is just too much to do, too little money, and too few people working on it.

Wherever there is progress, someone is the last to miss out. Life isn't fair, as you know. But control over aging could happen in time for the children and grandchildren of today's oldest - if there were more funding and more workers.

You could be a curmudgeon and say "to hell with them, let them take their chances on suffering everything I have." I've known some folk who dug themselves into that mindset; pain is an unpleasant companion.

There are more gracious legacies to leave behind, such as doing something to make the world a lasting better place. So why not fund the daylights out of those scientists working on aging? There is a lot to be said for helping to ensure that your children and grandchildren won't have to suffer your pains and indignities.

The short truth of it is that old age is a blessing, but marred by the unwanted failures of the the flesh. Being old used to be a lot worse than it is today, and one day it will be a lot better than it is now. That is all down to the march of medicine, and a few brave souls deciding to improve the world for their descendants.

Will control over the causes of aging arrive in time for your children and grandchildren? That's a question only you can answer. Fund the daylights out of those scientists, I say. You can find most of them at the SENS Research Foundation, and here's a link were you inclined to think about donating:

Death is Wrong, Free PDF Version

Fresh from the success of a fundraiser to distribute copies of the children's book Death is Wrong, the PDF version is now freely available. Grassroots advocacy for longevity science is made up of many such small projects, all of which are collectively necessary as a foundation for attracting greater support from more conservative institutions and high net worth individuals. Large donations only reliably arrive for fields in which public support is active and involved in this way:

At least 1,029 children in at least 14 countries will be taught that death is wrong as a result of the successful provision of Death is Wrong books to 50 longevity activists throughout the world. On August 7, 2014, the last book shipment, free for all recipients, was made, paid for by the funds raised through the Indiegogo campaign I ran in coordination with the Movement for Indefinite Life Extension (MILE). (Read Eric Schulke's earlier article about the success of the fundraiser and the tremendous efforts and publicity that made it possible.) While some of my critics, such as Slate's Joelle Renstrom, preemptively proclaimed that the funds raised would fall well short of the goal, we actually not only reached the goal in time but even exceeded it - and we have already spent all the money raised on providing free books to children.

Now that my campaign to spread over 1,000 Death is Wrong books to children has succeeded, I have asked myself what I could do to spread the book and its message even further. In an effort to increase the readership of the book, I have made the Second Edition available for free download as a PDF file. Perhaps, in this way, the book could reach tens or even hundreds of thousands of readers. Thus far, PDF versions are available in English, Russian, and Spanish.


We Justify What We Have No Choice In, To Our Detriment

People are good at building a belief that whatever cannot be changed in life is in fact a good situation. It is a lie, but it helps keep us sane in the face of miserable situations that we can do nothing about. So while matters are improving with the advance of technology, the world remains packed wall to wall with pain and suffering, and with people who tell us that it is all good. The pain and suffering of aging is the focus here at Fight Aging!, as it is the greatest cause of death and disease. Even here where the cost is so clear and so high positive change driven by progress in medical science is resisted by those who tell us that aging, a terrible degenerative condition that ends in death, is in fact a good thing:

Buddha believed the way to end human suffering was the regular practice of meditation and introspection. But Buddha didn't have biotech. As far as we know, humans are the only species conscious of their own mortality. The theme has dominated human thought for ages untold. Philosophy and religion, built brick by brick over millennia, aim to ease our anxiety over death and impermanence.

Much of our musing has focused on how best to deal with or justify death and suffering because, of all our problems, they look the most unassailable, the least likely to yield to technology. Our mortality motivates us to do great works, we say. Suffering informs deep insights about ourselves. Pleasure is only pleasurable relative to pain.

Above all, it's often said that because death and suffering are a natural part of life, we should resign ourselves to them. In Meditations, Roman emperor and stoic philosopher Marcus Aurelius said, "Despise not death, but welcome it, for nature wills it like all else." But biotechnology wasn't even the hint of a mote in the eye of Marcus Aurelius. And it's fascinating that the modern mind simultaneously rebels against its own mortality and at the thought of abolishing death and suffering.


LabCures: Crowdfunding by Laboratory Rather than by Project

Current efforts to build a science crowdfunding community akin to the technology crowdfunding of KickStarter are largely a cut and paste of what works in for-profit space: similar presentation of projects, similar flow for donors and project managers, and so on. I remain dubious that this will work well, as the motivations for all parties are very different when comparing research funding to purchasing a new gizmo or comic, but I am nonetheless hopeful that among all of the experimentation someone will hit upon the magic recipe in the years ahead. Some fraction of people do meaningfully support science, after all, and this is demonstrated by the success of middle man organizations such as the big per-disease charities for various cancers, Parkinson's, Alzheimer's, and so on. These groups serve as intermediaries that process the incoherent desire to help and pipe money from donors to specific projects where it can do some good - or at least that is the way things work in the ideal world. This modern information age is all about disintermediation, however: making it so easy to find out how to donate to specific research projects within a donor's field of interest that much of the present function of the intermediary charities will ultimately fade away. The degree to which this will happen and the role played by present methods of crowdsourcing remain to be seen.

A recent post from Maria Konovalenko notes the existence of the very newly created venture LabCures. This is a research crowdfunding platform that focuses on the laboratory group as the fundamental unit to follow and fund rather than a per-project layout. This creates a very different dynamic to the fundraising process, and given what I've seen so far of online research crowdfunding I think that this is an approach well worth trying. The most success I have when fundraising is when doing so for a known organization, rather than for any specific project at that organization. People support teams, not games, and the level of knowledge needed jumps precipitously if you are asking someone to pick and choose research projects.

So you might consider this in the context of the potential for disintermediation noted above; after a certain point, people don't want to do the digging for information, but rather just donate and trust a reputable broker to direct the funds to where they can best be used. It is a big leap in and of itself to go from a general position of supporting research to cure a specific disease all the way to knowing enough to back specific laboratory groups: to know that you could be rooting for Wake Forest rather than just regenerative medicine in general. For most people that doesn't happen until they are suffering from the disease in question. Supporting teams in medical research might be all we should expect from busy, distracted people with access to the libraries of the internet, and thus the target that crowdfunding groups should aim for: building brand awareness for the competing teams, as it were. That goal intersects well with what the laboratories themselves are interested in achieving, as brand and public awareness have large impacts on all areas of their fundraising. So perhaps it should not be surprising to find that LabCures is a spin-off venture from one of these laboratories:

New Buck Institute spinoff will use Internet to solicit donations for medical research

LabCures, a new for-profit spinoff from the Buck Institute for Research on Aging in Novato, hopes to generate money for new research in the life sciences by using the Internet to attract lots of smaller donations. "The projects on our platform are not coming from the crowd, they are coming from a very unique, irreplaceable group of researchers. We're inviting all life science research labs in the United States, from institutes to universities to nonprofits, onto one platform and organizing the labs in ways that matter to the donor."

Why LabCures

Unique to LabCures, all labs on our platform come from verified University and Institute non-profit research facilities. Recognized scientists and open accountability means a new and direct method for contributing to medical research. Contributions made in the US are 100% tax deductible.

Researchers focus on science. LabCures is designed for individuals to find and support medical research that matters to them. By hosting labs in the life sciences we are able to focus on the unique characteristics of funding medical and biological research in ways that are meaningful. The reward is knowing, celebrating and empowering the research community.

LabCures does not set a time limit on lab profiles. Verified labs share current projects and associated budgets on an ongoing basis. Once a lab reaches its fundraising goal for a particular project it will update its followers on that project. This helps facilitate ongoing partnerships between contributors and researchers.

Labs keep what they raise. Research is not all or nothing and neither is LabCures. We understand contributions to research can be highly personal acts for which a lab will always benefit. We are worldwide. LabCures enables participation between the research community and any individual from anywhere in the world.

We make funding research easy. Users can reference their contributions made on LabCures and preference a debit or credit card to support a lab on a monthly basis. Users will also receive tax deductible receipts via email. Users will also stay current to research via update notifications from the lab.

You'll note that the initial groups populating the LabCures system are all aging research laboratories, which is understandable given the folk involved. This is a venture I'd like to see succeed in making it over the initial hurdle of attracting users and traffic, perhaps by engaging in an effort to present feeds of lab news, ranking labs, and providing review articles on what exactly these specific labs are up to. All of these are functions carried out by successful sites elsewhere, and there is no reason why they couldn't be mixed in with crowdfunding for philanthropic fundraising. At the very least, success here is measured in the degree to which other science crowdfunding sites such as Experiment grasp the point of the per-laboratory approach and work to adapt it into their systems.

Daumone as Calorie Restriction Mimetic

In this open access paper researchers present the evidence for daumone to be a calorie restriction mimetic in mammals:

The liver is one of the most susceptible organs to aging, and hepatic inflammation and fibrosis increase with age. Chronic inflammation has been proposed as the major molecular mechanism underlying aging and age-related diseases, whereas calorie restriction has been shown to be the most effective in extending mammalian lifespan and to have anti-aging effects through its anti-inflammatory action. Thus, it is necessary to develop effective calorie restriction mimetics.

Daumone, a pheromone secreted by Caenorhabditis elegans, forces them to enter the dauer stage when facing inadequate conditions. Because Caenorhabditis elegans live longer during the dauer stage under energy deprivation, it was hypothesized that daumone may improve survival in mammals by mimicking calorie restriction.

Daumone (2 mg/kg/day) was administered orally for 5 months to 24-month-old male insulin normally presented in old mice was significantly reduced by daumone. The increased hepatic hypertrophy, senescence-associated β-galactosidase activity, insulin resistance, lipid accumulation, inflammation, oxidative stress, and fibrosis in old mice were significantly attenuated by daumone. Oral administration of daumone improves survival in mice and delivers anti-aging effects to the aged liver by modulating chronic inflammation, indicating that daumone could be developed as an anti-aging compound.


12-Lipoxygenase is Critical in Type 2 Diabetes

For the overwhelming majority of sufferers, type 2 diabetes is a lifestyle disease. It is something that they did to themselves, and which could be turned back at near any point with a suitable (albeit increasingly drastic) change in diet and lifestyle. Giving yourself the highest chance of avoiding type 2 diabetes is easy: stay active and stay thin. Nonetheless, the medical research community spends a lot of time and effort on finding ways for people to remain fat and indolent while still avoiding diabetes - though of course these efforts also apply to the much smaller population unfortunate enough suffer the condition regardless.

Here researchers find a way to protect the small population of insulin generating beta cells impacted by the mechanisms of type 2 diabetes, but by the sounds of it this will not affect any of the numerous other consequences of becoming fat, such as a raised risk of suffering all of the other common age-related conditions.

An enzyme called 12-LO promotes the obesity-induced oxidative stress in the pancreatic cells that leads to pre-diabetes, and diabetes. 12-LO's enzymatic action is the last step in the production of certain small molecules that harm the cell. The findings will enable the development of drugs that can interfere with this enzyme, preventing or even reversing diabetes. In earlier studies, these [researchers] showed that 12-LO (which stands for 12-lipoxygenase) is present in these cells only in people who become overweight.

The harmful small molecules resulting from 12-LO's enzymatic action are known as HETEs, short for hydroxyeicosatetraenoic acid. HETEs harm the mitochondria, which then fail to produce sufficient energy to enable the pancreatic cells to manufacture the necessary quantities of insulin.

For the study, the investigators genetically engineered mice that lacked the gene for 12-LO exclusively in their pancreas cells. Mice were either fed a low-fat or high-fat diet. Both the control mice and the knockout mice on the high fat diet developed obesity and insulin resistance. The investigators also examined the pancreatic beta cells of both knockout and control mice, using both microscopic studies and molecular analysis. Those from the knockout mice were intact and healthy, while those from the control mice showed oxidative damage, demonstrating that 12-LO and the resulting HETEs caused the beta cell failure. "Our research is the first to show that 12-LO in the beta cell is the culprit in the development of pre-diabetes, following high fat diets. Our work also lends important credence to the notion that the beta cell is the primary defective cell in virtually all forms of diabetes and pre-diabetes."


A Cross-Section of Recent Results in the Study of Aging

It is important to remember that much of the study of aging is just that - study of aging, no more. Most of the researchers involved in the field are not working on ways to enhance healthy longevity, or ways to treat aging as a medical condition. They are merely studying aging: collecting data and establishing theories about how aging proceeds. Aging science remains a strange field in that respect. If you look at cancer research, to pick one example, a much higher proportion of research is aimed at producing treatments or carried out in direct support of producing treatments, and you certainly won't find the same phenomenon of researchers quick to deny that any of their work would be used to actually treat the medical condition they focus on. While things have changed for the better in the aging research community, as illustrated by the fact that many noted researchers now advocate working towards greater human longevity, there remains a sizable contingent of researchers who do not talk about treating aging and who would avow that goal if asked in public.

Bear in mind that for every interesting item I point out here at Fight Aging! there are a dozen more papers that report on gathering data on aging and nothing more. The majority of funding goes towards a mix of epidemiological work that arguably has absolutely no impact whatsoever on the prospects for defeating age-related disease, and an endless cataloging of the changing biology of aging in ever-greater detail, which has only a minor impact. The small segment of research that might actually produce meaningful results, involving repair of the causes of aging, presently makes up a tiny fraction of a tiny fraction of the overall resources devoted to aging science. That whole field in and of itself is a small fraction of overall medical research, very much underfunded for its importance. Stepping up another level, medical research in general is a forgotten child in our culture, largely ignored and also poorly funded for its importance. People would rather have war, celebrity, and circuses. Much must change in the years ahead, and the past decade of growth and change in the culture of aging research has been but start. A good start, yes, but there is much to be done yet.

Here is a selection of papers that represent the sort of work that makes up much of aging research at the moment.

Declining intelligence in old age linked to visual processing

Age-related declines in intelligence are strongly related to declines on a very simple task of visual perception speed. The evidence comes from experiments in which researchers showed 600 healthy older people very brief flashes of one of two shapes on a screen and measured the time it took each of them to reliably tell one from the other. Participants repeated the test at ages 70, 73, and 76. The longitudinal study is among the first to test the hypothesis that the changes they observed in the measure known as "inspection time" might be related to changes in intelligence in old age. "The results suggest that the brain's ability to make correct decisions based on brief visual impressions limits the efficiency of more complex mental functions. As this basic ability declines with age, so too does intelligence. The typical person who has better-preserved complex thinking skills in older age tends to be someone who can accumulate information quickly from a fleeting glance."

Study examines midlife hypertension, cognitive change over 20-year period

Authors used the Atherosclerosis Risk in Communities (ARIC) study to examine the effects of hypertension by analyzing the results of three cognitive tests over time. Data from 13,476 participants were used and the maximum follow up was 23.5 years. The decline in global cognitive scores for participants with hypertension was 6.5 percent greater than for individuals with normal blood pressure. An average ARIC participant with normal blood pressure at baseline had a decline of 0.840 global cognitive z score points during the 20-year period compared with 0.880 points for participants with prehypertension and 0.896 points for patients with hypertension. Individuals with high blood pressure who used medication had less cognitive decline during the 20 period than participants with high blood pressure who were untreated.

Exercise, Sedentary Pastimes, and Cognitive Performance in Healthy Older Adults

Moderately vigorous physical activity (MVPA) provides a protective affect against cognitive decline and cardiovascular risk factors. Less is known about sedentary pastimes or non exercise physical activity (NEPA) and cognitive performance. 125 healthy adults 65 or older with no clinical evidence of cognitive impairment were enrolled. Sedentary pastimes were associated with executive dysfunction; MVPA with high memory scores and NEPA with improved working memory. Only sedentary pastimes and executive dysfunction retained significance after correction for multiple comparisons. Smoking and alcohol confounded the association of memory with sedentary pastimes and MVPA.

Incidence and Predictors of Multimorbidity in the Elderly: A Population-Based Longitudinal Study

We aimed to calculate 3-year incidence of multimorbidity, defined as the development of two or more chronic diseases in a population of older people free from multimorbidity at baseline. Data were gathered from 418 participants in the first follow up of the Kungsholmen Project (Stockholm, Sweden, 1991-1993, 78+ years old) who were not affected by multimorbidity (149 had none disease and 269 one disease). After 3 years, 33.6% of participants who were without disease and 66.4% of those with one disease at baseline, developed multimorbidity. After adjustments, worse cognitive function was associated with increased risk of multimorbidity among subjects with no disease at baseline. Higher age was the only predictor of multimorbidity in persons with one disease at baseline.

The contribution of personality to longevity: Findings from the Australian Centenarian Study

Centenarians were currently low in Openness and Extraversion and high in Neuroticism, but were low in Openness and high in Neuroticism, Conscientiousness and Extraversion when reflecting on past traits. Currently, centenarians in high care facilities reported higher levels of Neuroticism, as did centenarians who did not socialize. Cognitively intact centenarians reported higher levels of Agreeableness; and males reported lower Neuroticism compared to females when reflecting on past experiences. Centenarians were characterized by several personality traits, which facilitated positive health behaviors and thus contributed to their longevity. It is possible that personality may not be static across the lifespan, but instead, reflect advancing age, psychosocial factors and changes in life circumstances.

Working Towards a Way to Clear Cytomegalovirus

Like other herpesviruses, cytomegalovirus (CMV) cannot be effectively naturally cleared from the body as it has evolved the means to hide from the immune system. It is harmless for most people in the short term, but over the long term it causes ever more of the limited supply of immune cells to become uselessly devoted to fighting it. Since near everyone is exposed to CMV by the time they are old, this appears to be an important contribution to the age-related decline of the immune system.

One possible approach to dealing with this issue is to selectively destroy CMV-specialized immune cells. They will be replaced naturally and fairly quickly, or that replacement can be hurried along with an infusion of immune cells grown from a sample of the patient's tissues. The cancer research community is a fair way along in the development of highly selective cell destruction technologies that identify targets based on their distinctive surface chemistry, and this work can be adapted for use in winnowing the immune system.

Another approach is to find ways to clear out CMV, but that isn't so helpful for people who have lived with it for a long time and are therefore already suffering the consequences in the form of a distorted balance of immune cells. Nonetheless, here is a look at research into how CMV hides from the immune system. This is a starting point on the path towards disabling these molecular mechanisms to enable immune cells to clear CMV from the body:

Human cytomegalovirus (HCMV) is a herpesvirus that infects most people in the world, usually without producing symptoms. However, infection is life-long and must be kept in check by the immune system. When the immune system is weakened, the outcome of HCMV infection can be very serious. Thus, HCMV is the major cause of birth defects resulting from infection of the fetus during pregnancy, and it can cause severe disease in people with a weakened immune system, especially transplant recipients and HIV/AIDS patients. One type of immune cell, the natural killer (NK) cell, is crucial in controlling cells in the body that are abnormal. They do this by recognizing cells, which have special stress proteins on their surface, and killing them. When cells are infected with HCMV, they start to make these stress proteins. However, the virus has evolved ways to stop NK cells from killing infected cells by quickly stopping the stress proteins from reaching the surface. We have now identified two HCMV genes that target a major stress protein (called MICA) and cause its rapid destruction. Removing these two genes from HCMV renders infected cells very susceptible to killing by NK cells. This discovery might help the development of new ways to fight HCMV.

NKG2D plays a major role in controlling immune responses through the regulation of natural killer (NK) cells. Despite [activation], HCMV effectively suppressed cell surface expression of NKG2D ligands through both the early and late phases of infection. The immune evasion functions UL16, UL142, and microRNA(miR)-UL112 are known to target NKG2D ligands. While infection with a UL16 deletion mutant caused the expected increase [in NKG2D ligand] cell surface expression, deletion of UL142 did not have a similar impact on its target, MICA. We therefore performed a systematic screen of the viral genome to search of addition functions that targeted MICA. US18 and US20 were identified as novel NK cell evasion functions capable of acting independently to promote MICA degradation by lysosomal degradation. The most dramatic effect on MICA expression was achieved when US18 and US20 acted in concert.


Being Overweight or Obese Raises the Risk of Cancer

This recent study provides yet another reason to make lifestyle choices that better manage your weight. If nothing else cancers thrive in an inflammatory environment, and metabolically active visceral fat tissue generates chronic inflammation. More of it is definitely worse for your long-term health in a range of ways:

Using data from general practitioner records in the UK's Clinical Practice Research Datalink (CPRD), the researchers identified 5.24 million individuals aged 16 and older who were cancer-free and had been followed for an average of 7.5 years. The risk of developing 22 of the most common cancers, which represent 90% of the cancers diagnosed in the UK, was measured according to BMI after adjusting for individual factors such as age, sex, smoking status, and socioeconomic status. A total of 166,955 people developed one of the 22 cancers studied over the follow-up period. BMI was associated with 17 out of the 22 specific types of cancer examined.

Each 5 kg/m² increase in BMI was clearly linked with higher risk of cancers of the uterus (62% increase), gallbladder (31%), kidney (25%), cervix (10%), thyroid (9%), and leukaemia (9%). Higher BMI also increased the overall risk of liver (19% increase), colon (10%), ovarian (9%), and breast cancers (5%), but the effects on these cancers varied by underlying BMI and by individual-level factors such as sex and menopausal status. Even within normal BMI ranges, higher BMI was associated with increased risk of some cancers.

Based on the results, the researchers estimate that excess weight could account for 41% of uterine and 10% or more of gallbladder, kidney, liver, and colon cancers in the UK. They also estimate that a population-wide 1 kg/m² increase in average BMI (roughly an extra 3 to 4 kg, or 8 to 10 pounds, per adult), which would occur every 12 years or so based on recent trends, would result in an additional 3790 cases of these 10 cancers in the UK each year.


Reminder: Rejuvenation Biotechnology 2014 is Next Week

The SENS Research Foundation is hosting Rejuvenation Biotechnology 2014 on August 21st in Santa Clara, California. The theme for this conference is bringing together business and science to pave the way for later clinical applications of the results of research programs that are still in progress.

SENS Research Foundation is proud to present the Rejuvenation Biotechnology Conference: Emerging Regenerative Medicine Solutions for the Diseases of Aging. This conference will bring together leaders from the Alzheimer's, cardiovascular, cancer, and other age-related disease communities to discuss preventative and combinatorial strategies to address the diseases of old age.

The Rejuvenation Biotechnology Conference builds upon novel strategies being pioneered by the Alzheimer's and cancer communities. By convening the foremost leaders from academia, industry, investment, policy, and disease advocacy, SRF seeks to inspire consideration of the wider potential of these strategies and evaluate the feasibility of preventative and combinatorial medicine applications to treat all aging-related diseases. Through a series of presentations and panel discussions, Alzheimer's disease, cancer, cardiovascular disease, diabetes, macular degeneration, musculoskeletal disease and Parkinson's disease will be examined with scientific, economic, regulatory and other considerations in mind.

In the years ahead novel forms of medicine will emerge that are a long way removed from the sort of drugs that today's regulatory process is intended to handle: gene therapies to move mitochondrial DNA into the cell nucleus, for example. Moreover, this new medicine will target the causes of aging, and thus be intended for more than just the sick among the elderly. Patients will include everyone that present regulations declare to be healthy, even through they are old and damaged. If you are sixty years old and have no defined medical condition, then congratulations - but you are not healthy by any measure. Your risk of death and disease is much higher than it was three decades ago, and this is precisely because of the cellular and molecular damage that has gnawed away at every part of your biology. Present regulation and institutional views on aging and health are outmoded, an obstacle to a future in which the causes of aging can be treated. Much that is currently encoded as tradition or law in the medical research and development community must change.

Thus when considering a timeline of decades between today and the advent of functional rejuvenation biotechnologies, it is important to lay the groundwork. As public awareness and support grows, it helps to have influential individuals and organizations who are already willing to move forward and change. It always moves more slowly than we'd like it to, but the work has to be done: it is all a part of the broader spectrum of advocacy.

The list of speakers at the Rejuvenation Biotechnology conference is well worth a look, and there's a glossy PDF brochure as well. One portion of the conference agenda is a focus on how the existing obstructive regulatory system can be changed rather than how it can be worked around, which is what you'll get as a view from the community of those who must shape their careers within the bounds of what is permitted by the FDA. They can't talk about working around the system or (better) tearing it down as that has material consequences when it comes to the ability to lead research and development programs. Talking about change and expansion of regulation is permitted dissidence, while everything else is likely to cause issues for any program that a noteworthy dissident is involved in:

Escalating societal healthcare needs have driven an unprecedented era of biomedical innovation. However, the development of candidate technologies without consideration of a robust regulatory strategy is likely to contribute to stymied patient access and commercial viability. Therefore, this session will consider worldwide efforts to rapidly and proportionally develop international regulatory processes to accommodate increasingly heterogeneous and unfamiliar healthcare technologies and their swift translation from lab to bedside.

So everyone recognizes that there is a problem, in that regulation blocks progress and makes it far more expensive than it should be, but the usual reaction is some variant of "we need more and better regulation." Which is pretty much how we arrived at the ridiculous system of medical regulation that presently exists, in which it is illegal to treat aging, near everything that isn't explicitly permitted is forbidden, and it requires a decade of therapies widely available via medical tourism to embarrass politically sensitive regulators into allowing treatments to move forward. Absent that regional competition you can be certain that stem cell medicine would still be stuck in the labs, faced with ever-steeper demands for trials and data. At every step of the way people involved with medical regulation said "this isn't working," and yet the next regulatory iteration is always worse, more invasive, more costly, and more harmful than the last.

Aging is the Cost of Species Adaption and Survival

A small number of species have exceedingly long life spans and show few signs of degenerative aging, so clearly biology is up to the task of continual repair and vigor. Yet the vast majority of species consist of individuals who age, and who will die because of aging should they survive the many other causes of mortality in the wild. Why do we age to death? The present consensus is that the prevalence of aging is the result of an evolutionary arms race to the bottom. Species that age better adapt to changing conditions and thus will take over most evolutionary niches. In effect we age because the world changes. Some thoughts here from a researcher in the field:

In the long run, the ability of a species to evolve is more important than anything else in determining its competitive success. This is true almost by definition: given enough time, the ability to adapt and improve will overtake any initial disadvantage. But evolutionary theory these last 50 years has been quite skeptical of "in the long run". If it is driven to extinction because of a competitive disadvantage in the short run, then what matters if it has the potential to improve, eventually?

This has everything to do with aging. A population with aging has more diversity and a faster turnover compared to a similar population in which death is only due to famine, predators, disease, etc. So - in theory - a population with aging evolves more rapidly than a population that doesn't age. But "the long run" can be thousands of lifetimes, and in the meantime those individuals that die early (of aging) are at a competitive disadvantage compared to those who continue to live, and have that much more time in which to produce offspring.

Can an aging population resist invasion (by longer-lived competitors) and cohere long enough that its superior rate of adaptation turns into a decisive advantage? This is the question that has been at the center of my research the last dozen years. On the one hand, there is abundant evidence that aging is no accident, that it has evolved via natural selection that explicitly favors aging. On the other hand, the theoretical argument casts doubt on the scenario where aging is selected on this basis.

The best resolution I have been able to find for this paradox is that aging has been able to evolve on this basis, and it is because the short-term advantage of unrestrained reproduction has been held in check by a different, faster-acting evolutionary principle than evolvability. Unrestrained reproduction leads to population overshoot, population crash, and extinction. This is a powerful, fast-acting evolutionary force, and populations have had to adapt by tempering individual competitiveness. This has created an environment in which the long-term advantage of aging is relevant, and aging as a population-level adaptation can thrive on this basis.


A Twist in the Progression of Atherosclerosis

Atherosclerosis is a dangerous condition caused by molecular damage to certain proteins circulating in the blood and then spurred on by growing chronic inflammation in aging. Where it takes root, the walls of your arteries corrode, malform, and expand inward into soft plaques of degenerative material. This is largely formed of macrophage cells attracted to the area by dysfunctional signaling and then choked by the debris. Ultimately this leads to serious vascular dysfunction, but more importantly if a large enough chunk of plaque material breaks away it will cause a heart attack or stroke.

Here researchers suggest that the immune system is not the dominant origin for the macrophages that make up plaque debris, and a more important and unusual source is actually closer at hand:

Scientists [have identified] a long-overlooked function of vascular smooth muscle cells in atherosclerosis. Atherosclerosis [is] a chronic inflammatory disease of the arteries arising from interactions of modified lipoproteins and various cell types including monocyte-derived macrophages from the blood and smooth muscle cells (SMCs) in the vessel wall. "It is unclear, however, how each particular cell type contributes to the development of an atherosclerotic lesion. One highly controversial issue is the contribution of vascular SMCs to plaque growth."

[The] researchers performed lineage tracing experiments in mice, in which they have genetically labeled mature SMCs in the vessel wall of young mice before the onset of the disease and then monitored their fate in older atherosclerotic animals. "Surprisingly, we found that SMCs in the arterial wall can undergo clonal expansion during disease progression and convert into macrophage-like cells that have lost the classical SMC marker, α-smooth muscle actin. It seems that certain atherosclerotic lesions contain even more SMC-derived macrophages than traditional monocyte-derived macrophages."

These findings indicate that previous studies based on immunostaining of plaque cells for smooth muscle and macrophage markers have vastly underestimated the role of SMCs and overestimated the role of monocyte-derived macrophages in atherosclerosis. "Targeting SMC-to-macrophage transdifferentiation could be a novel therapeutic strategy to treat atherosclerotic heart disease and perhaps many other diseases with a smooth muscle component."


When You Are Damaged, You Break More Readily

It is about as proven as it gets in human studies that moderate exercise is good for you and a sedentary lifestyle is bad for you. The difference in life expectancy is probably somewhere in the low end of the five to ten year range, though it is very challenging to pin down how much of that is due to more direct mechanisms of exercise versus indirectly related items such as the amount of visceral fat tissue present in the body. Human studies turn out correlations only: it isn't as though you can structure your study population up front to determine cause and effect. That is possible in animal studies, however, and those robustly demonstrate that moderate exercise is good for you while lazing around being fat isn't. It is entirely reasonable, I believe, to live life under the assumption that the causation for exercise and health shown in animal studies is the reason for the correlation shown in human studies.

Things become somewhat more challenging when you move beyond moderate exercise in humans, however. Whether twice as much exercise is better and why it is that professional athletes live longer than the general population are harder questions to answer. The athlete correlation may well exist because people who are capable of success in that field of endeavor are simply more robust than the rest of us, and would have lived longer than their peers regardless of career. Similar issues exist with most past data on levels of exercise beyond merely moderate and the resulting benefits.

Here is another interesting question: is there such a thing as too much exercise? Is exercise like any drug in that the dose-response curve is most favorable in the middle, and going too far in either direction means losing the benefits? This becomes a more pressing issue in later life, when an individual is damaged by aging and suffering the consequences of a lifetime's accumulation of cellular and molecular defects. We are machines, and a damaged machine is more prone to breakage at any given level of activity. So when we learn that people who are old and damaged tend to have a raised rate of cardiovascular failure at greater levels of exercise, that is the lesson we should take away: damaged machines break. We shouldn't accept this fate for ourselves and restrict our activities, but rather eagerly support research into ways to repair the damage that so greatly impacts health and survival in later life.

Contrary to Popular Belief, More Exercise Is Not Always Better

There is strong epidemiological evidence of the importance of regular physical activity, such as brisk walking and jogging, in the management and rehabilitation of cardiovascular disease and in lowering the risk of death from other diseases such as hypertension, stroke, and type 2 diabetes. The Physical Activity Guidelines for Americans recommends about 150 minutes per week of moderate-intensity exercise or about 75 minutes of vigorous-intensity exercise. But there is clear evidence of an increase in cardiovascular deaths in heart attack survivors who exercise to excess, according to a new study.

[Researchers] studied the relationship between exercise and cardiovascular disease-related deaths in about 2,400 physically active heart attack survivors. They conducted a prospective long-term study using the National Walkers' and Runners' Health Studies databases. This study confirmed previous reports indicating that the cardiovascular benefits for walking and running were equivalent, as long as the energy expenditures were the same (although when walking, as compared to running, it will take about twice as long to burn the same number of calories). Remarkable dose-dependent reductions in deaths from cardiovascular events of up to 65% were seen among patients who were running less than 30 miles or walking less than 46 miles per week. Beyond this point however much of the benefit of exercise was lost, in what is described as a reverse J-curve pattern.

"These analyses provide what is to our knowledge the first data in humans demonstrating a statistically significant increase in cardiovascular risk with the highest levels of exercise. Results suggest that the benefits of running or walking do not accrue indefinitely and that above some level, perhaps 30 miles per week of running, there is a significant increase in risk. Competitive running events also appear to increase the risk of an acute event. However, our study population consisted of heart attack survivors and so the findings cannot be readily generalized to the entire population of heavy exercisers."

Increased Cardiovascular Disease Mortality Associated With Excessive Exercise in Heart Attack Survivors

Habitual physical activity and exercise have repetitively been shown to reduce the risk of sudden cardiac death and acute myocardial infarction. Several articles suggest that there is a U-shaped relationship between running dose and reduced all-cause mortality, but these studies lack the statistical power to formally test for a nonlinear dose-response relationship. We therefore used the National Walkers' and Runners' Health studies to examine the dose-response relationship between exercise energy expenditure and cardiovascular disease (CVD)-related mortality in heart attack survivors. The large number of highly active subjects, and the high risk for CVD mortality in persons having had a previous heart attack, provides the statistical power required for testing whether there is an increased CVD risk in the most active heart attack survivors.

Exercising for Health and Longevity vs Peak Performance: Different Regimens for Different Goals

Accumulating evidence suggests that exercise practices that are ideal for promoting health and longevity may differ from the high-volume, high-intensity endurance training programs used for developing peak cardiac performance and superb cardiorespiratory fitness (CRF). Studies consistently show that regular moderate-intensity physical activity (PA) is highly beneficial for long-term cardiovascular (CV) health. Improving the CRF from low to moderate to high will progressively improve CV prognosis and overall survival. However, the survival benefits from improvements in the CRF plateau at about 10 metabolic equivalents (with 1 metabolic equivalent equal to an oxygen consumption of 3.5 mL O2/kg body weight per minute), with no additional survival benefit accruing from higher CRF levels. Clearly, 30 minutes of regular vigorous PA enhances health and well-being, but performing 3-hour bouts of strenuous PA does not multiply the health benefits.

Building Brain Tissue for Research and Testing

A lot of the early applications of tissue engineering are focused on aiding research: the small amounts of tissue created are using for testing and investigation. That is a stepping stone for the various companies and labs involved, a way to generate revenue and interest while steadily improving their capabilities. It is worth keeping an eye on these efforts, because it is from here that later applications in clinical medicine will arise.

Currently, scientists grow neurons in petri dishes to study their behavior in a controllable environment. Yet neurons grown in two dimensions are unable to replicate the complex structural organization of brain tissue, which consists of segregated regions of grey and white matter. Recently, tissue engineers have attempted to grow neurons in 3D gel environments, where they can freely establish connections in all directions. Yet these gel-based tissue models don't live long and fail to yield robust, tissue-level function.

Now [a] group of bioengineers report that they have successfully created functional 3D brain-like tissue that exhibits grey-white matter compartmentalization and can survive in the lab for more than two months. As a first demonstration of its potential, researchers used the brain-like tissue to study chemical and electrical changes that occur immediately following traumatic brain injury and, in a separate experiment, changes that occur in response to a drug. The tissue could provide a superior model for studying normal brain function as well as injury and disease, and could assist in the development of new treatments for brain dysfunction.

The key to generating the brain-like tissue was the creation of a novel composite structure that consisted of two biomaterials with different physical properties: a spongy scaffold made out of silk protein and a softer, collagen-based gel. The scaffold served as a structure onto which neurons could anchor themselves, and the gel encouraged axons to grow through it. To achieve grey-white matter compartmentalization, the researchers cut the spongy scaffold into a donut shape and populated it with rat neurons. They then filled the middle of the donut with the collagen-based gel, which subsequently permeated the scaffold. In just a few days, the neurons formed functional networks around the pores of the scaffold, and sent longer axon projections through the center gel to connect with neurons on the opposite side of the donut. The result was a distinct white matter region (containing mostly cellular projections, the axons) formed in the center of the donut that was separate from the surrounding grey matter (where the cell bodies were concentrated).


Studying Calorie Restriction and Rapamycin

Here is an example of the sort of work presently taking place in many of the labs interested in aging and longevity, consisting of exploration of existing drugs shown to have some effect on life span in animal studies, alongside continued research into the details of the calorie restriction response:

"Research has shown that consuming fewer calories, while maintaining sufficient nutrients, extends lifespan, and there are ongoing clinical studies in humans. However, aging also is associated with increased susceptibility to diseases. Remarkable extension of lifespan has been achieved in organisms by lowering calorie intake or tricking cells into thinking that there is not enough food. These manipulations are being considered for potentially increasing lifespan in humans. It is critical to understand the effects of these interventions upon physiological function of older organisms, as any increase in longevity must be accompanied by improved quality of life."

Rapamycin, or Rapa, a drug used to keep the body from rejecting organ and bone marrow transplants, blocks an enzyme that controls cellular division. Rapa has been shown to extend lifespan in mice; however, the effects of chronic low-dose Rapa-mediated treatment on resistance to infection remain unknown.

"Our study will test whether life-extending dietary interventions may improve or impair survival from, and immunity to, infection, allowing us to evaluate whether manipulations of nutrient pathways may be safe and desirable to achieve optimal healthy longevity. While calorie restriction appears to improve immune function and homeostasis in old animals, the few infectious challenge experiments suggest increased susceptibility to infection. Our exploratory proposal aims to test the hypothesis that calorie restriction and drugs that trick the cells into thinking that there is not enough food, such as Rapa, could be deleterious for protective immunity, because they may curtail full development of immune responses. We aim to dissect possible defects and discover whether we may use Rapa as is or whether we may need to seek for similar compounds with beneficial effects in healthy aging across different tissues."


Chronic Inflammation Chews Up Your Blood Vessels

A number of the most serious age-related conditions involve the progressive structural and functional decay of your blood vessels. A number of different forms of cellular and molecular damage conspire to clog, weaken, and stiffen blood vessels until one of these small but vital pieces of the body's infrastructure fails catastrophically, and then a blockage or a bleed causes death or crippling injury in a matter of moments. The older you are the more extensive the damage and the worse the odds, but poor lifestyle choices will generally put you in a poorer position than would otherwise be the case.

Chronic inflammation is a noteworthy contribution to many issues associated with aging, and it is one of the contributing causes that most of us have a fair level of control over throughout most of our lives. By taking basic good care of health matters, exercising, and eating a diet low enough in calories to stay slim, the average individual will have a lower level of inflammation as a result. Inflammation is probably a primary mechanism in the link between excess fat tissue and raised risk of suffering from all of the common age-related disease. Visceral fat tissue is metabolically active in ways that promote inflammation, and the more of it you have the worse off you are. You can't escape chronic inflammation in aging entirely by staying thin and active, however, as significant raised inflammation levels also result from the characteristic age-related failure of the immune system. As a result of the damage of aging, the immune system becomes both ineffective and constantly overactive at the same time.

Why exactly is chronic inflammation bad? What does it do under the hood? There are many distinct mechanisms, but here are some papers to illustrate a couple that involve your blood vessels. In effect you might think of inflammatory processes as gnawing away at the structural integrity of these important tissues, at an insignificant pace in youth, but accelerating over the years. There is always repair taking place as well, of course, but ultimately the inflammation wins - or at least that will be the case until the research community is given enough support and funding to produce the means to reverse these mechanisms.

A Crucial Role for CDC42 in Senescence-Associated Inflammation and Atherosclerosis

Chronic inflammation is characterized by the long-term presence of immune cells in affected tissues and is associated with age-related diseases such as cancer, neurodegenerative disorders, and cardiovascular disease. Interestingly, levels of pro-inflammatory cytokines are elevated in the endothelial cells and serum of older persons in the absence of disease. Thus, inflammation that accompanies the natural aging process may contribute to the onset of age-related diseases, which are responsible for most of the mortality in modern societies.

Atherosclerosis is an age-related chronic inflammatory disease. In persons with atherosclerosis, chronic inflammation is mainly induced by sterile stimuli and it accelerates disease progression. The initial step of the atherosclerotic process involves recruitment of inflammatory monocytes to dysfunctional endothelial cells. Senescent endothelial cells have been suggested to represent "dysfunctional endothelial cells" since they are specifically localized in the atherosclerotic lesions of patients and share many common features, including the pro-inflammatory phenotype that can induce sterile inflammation related to atherosclerosis. Although senescence of endothelial cells has been implicated in the process of atherogenesis, a specific role of senescent endothelial cells in chronic inflammation associated with atherosclerosis remains uncertain due to the lack of in vivo models. The molecular mechanisms underlying the pro-inflammatory phenotype in senescent endothelial cells also remain unclear [but we] identified CDC42 signaling as a mediator of chronic inflammation associated with endothelial senescence.

Mesenchymal stem cells for treatment of aortic aneurysms

An aortic aneurysm (AA) is a silent but life-threatening disease that involves rupture. It occurs mainly in aging and severe atherosclerotic damage of the aortic wall. Even though surgical intervention is effective to prevent rupture, surgery for the thoracic and thoraco-abdominal aorta is an invasive procedure with high mortality. Therefore, an alternative strategy for treatment of AA is required. Recently, the molecular pathology of AA has been clarified. AA is caused by an imbalance between the synthesis and degradation of extracellular matrices in the aortic wall. Chronic inflammation enhances the degradation of matrices directly and indirectly, making control of the chronic inflammation crucial for aneurysmal development.

Meanwhile, mesenchymal stem cells (MSCs) are known to be obtained from an adult population and to differentiate into various types of cells. In addition, MSCs have not only the potential anti-inflammatory and immunosuppressive properties but also can be recruited into damaged tissue. MSCs have been widely used as a source for cell therapy to treat various diseases involving graft-versus-host disease, stroke, myocardial infarction, and chronic inflammatory disease such as Crohn's disease clinically. Therefore, administration of MSCs might be available to treat AA using anti-inflammatory and immnosuppressive properties.

Genetic Studies of Longevity Leading to Drug Development

The research linked below is an example of work in the Longevity Dividend model: study the comparative genetics of longevity in humans to find epigenetic patterns and genetic variants that correlate with membership of long-lived families. From there proceed to identify underlying mechanisms and undertake drug development to find ways to recreate those differences. This mainstream, well-supported research is absolutely the wrong path to take if the aim is to producing meaningful extension of healthy life, however. Aging occurs because we accumulate damage as a side-effect of metabolism within and around our cells. Outside of a few rare and devastating genetic mutations, we all suffer exactly the same types of damage for exactly the same reasons. Genetic and epigenetic variants have a limited effect on our interaction with this growing damage until very old age, so we should ignore them: researchers should focus instead on repairing and reverting these known forms of damage that cause aging. The resulting treatments built for this purpose will be applicable to everyone, and thus can be mass produced cheaply.

Given a choice between spending vast sums on building age-slowing drugs that help maintain people for longer in a state of being old and damaged, or building repair biotechnologies that help maintain people in a youthful, undamaged state, I know in which direction my money is heading. Drugs to slow aging will never be particularly helpful for those already old and damaged, while repair biotechnologies will aid those in greatest need of repair. It seems fairly self-evident to me where the focus should be. Yet the vast majority of research funding for the comparatively young field of longevity science is aimed at the inferior goal of slowing aging. This must change.

Frailty is a common condition associated with old age, characterized by weight loss, weakness, decreased activity level and reduced mobility, which together increase the risk of injury and death. Yet, not all elderly people become frail; some remain vigorous and robust well into old-age. The question remains: why? "People who are frail are more vulnerable to serious complications from falls or surgery and more susceptible to infection. Understanding why some elderly people do not experience a loss of balance or strength and do not suffer from abnormal gait may help us prevent and treat such physical decline."

The new project taps into the resources of [the] LonGenity Research Study, which builds upon the Longevity Genes Project, an ongoing 15-year study with more than 500 Ashkenazi Jews over the age of 95. LonGenity compares the genetics of the centenarians and their children with those with usual survival. Over the past 10 years, [researchers have] identified several biological markers that may explain their extreme longevity. "We have shown that our centenarian participants have a significant genetic advantage over the general population. Their rare genetic variants have allowed them to live longer, healthier lives and avoid or significantly delay age-related diseases, such as Alzheimer's and type 2 diabetes. We now want to know if a family history of those same 'longevity genes' reduces the risk for frailty."

The researchers will build on a pilot study funded by the American Federation for Aging Research that linked exceptional longevity to improved physical function and reduced risk of frailty. [The] team plans to further those initial efforts to identify gene variants that keep frailty at bay, explore biological pathways that may lead to frailty, and develop drugs that mimic the effect of those frailty-preventing genes.


Calico Website Launched

Google's California Life Company has launched a stub website. The sparse information presented there is supportive of the view that Calico will be taking the Longevity Dividend path of focusing on genetics, metabolic manipulation, and standard issue drug discovery. This will look a lot like a continuation of sirtuin research, which is to say that they will spend a lot of money, generate a lot of data, and utterly fail to produce ways to meaningfully extend healthy human life. That is a fairly safe prediction for the outcome of any well-funded project that is not trying to build repair-based technologies to revert the causes of aging, but rather intends to alter the operation of metabolism to gently slow aging. Metabolism is immensely complex and poorly understood, and there is no well-defined course towards results that is analogous to the SENS plans for repair-based approach. A billion dollars and fifteen years has been spent on simply trying to reproduce a fraction of the most understood form of natural metabolic alteration that enhances longevity, the response to calorie restriction, with no good results. For that time and money we could have a demonstration of rejuvenation in mice via SENS therapies already.

Genetics is hot and drug discovery is safe and understood by investors. So as interest in treating aging is rising, we see funds raised and ventures started for groups trying to perform drug development based on genetic studies of aging and longevity. This is not because it has a hope of meaningful results, but because it is where funds can be raised, and where money can be made in the traditional Big Pharma fashion even without achieving any great extension of human longevity. In the Longevity Dividend viewpoint an ambitious goal is to add seven years of life expectancy over the next two decades through new drugs that alter metabolism - which is a miserable failure and a grand missed opportunity when compared to the indefinite extension of healthy life that might be attained by realizing comprehensive repair therapies for the damage that causes aging.

This is all disappointing, but that has been the signal all along as to where things were going with Calico: it is a project that may turn out to look a lot like a more highly publicized version of the Ellison Medical Foundation, in that it is simply adding more of the work already taking place at the NIA and elsewhere that is destined from the start to fail to advance human longevity. Its existence helps those elsewhere who are trying to raise funds to tackle aging, as it shifts conservative funding institutions in a direction of supporting such work, but that is about it.

To my eyes all of this reinforces the need to demonstrate beyond a doubt that repair approaches to reverse aging do in fact work, and work very much better and for far less cost of development than metabolic alteration. The way in which repair-based approaches will take over the mainstream of research is by showing that they produce compelling results at a time in which the other approaches are failing to do anything other than generate data and consume resources. The nearest approach to that point for the purposes of convincing people who support slowing aging but are not on board with aiming for rejuvenation is probably the targeted destruction of senescent cells, but even there it has been hard to raise funding for continued work and the reliance is on philanthropy to run the present study in normal rather than accelerated aging mice.

We're tackling aging, one of life's greatest mysteries.

Calico is a research and development company whose mission is to harness advanced technologies to increase our understanding of the biology that controls lifespan. We will use that knowledge to devise interventions that enable people to lead longer and healthier lives. Executing on this mission will require an unprecedented level of interdisciplinary effort and a long-term focus for which funding is already in place.

We are scientists from the fields of medicine, drug development, molecular biology, and genetics. Through our research we're aiming to devise interventions that slow aging and counteract age‑related diseases. Understanding the fundamental science underlying aging and finding cures for the intractable diseases associated with aging require time, deep technical expertise, research and partnerships. We're just getting started and will post career opportunities here when they become available.


Recent News in Stem Cell Research

The rejuvenation toolkit of the near future must include ways to replace some populations of cells. The ones you might be familiar with are immune cells and some populations of long-lived cells that tend to diminish over time such as the dopamine generating neurons whose loss leads to Parkinson's disease and certain cells in the retina essential to vision. The situation for stem cell research is somewhat different to that of much of the rest of the scientific effort needed to bring degenerative aging under medical control and prevent all age-related disease. There is no real lack of funding for one: it is a very energetic, well-supported field that is making good progress towards the goal of fine control over cell operation and fate. The challenge here is more one of steering at least some of this research in the right direction, which is aided by the existing incentives: most of the conditions that will most benefit from stem cell therapies are age-related, and thus researchers must engage with stem cell aging in order to produce treatments that are effective.

Along the way the research community will probably wind up producing useful transitional technologies, ways to revert the decline in stem cell activity with aging that produce meaningful benefits without addressing the underlying damage of aging. It is most likely the case that stem cell populations become less active as a reaction to damage, but since this largely seems to key from circulating levels of specific proteins it is a reaction that can in principle be overridden. This is not a solution for the long term as it doesn't address the underlying causes. It is a patch, but a better class of patch: I think that it is fairly evident from the state of first generation stem cell therapies today that there are worthwhile gains to be obtained.

Here are a few recent snippets of news from the stem cell research community, illustrative of progress well underway. You'll notice there's a lot of focus on repair after the fact and less on the use of cell treatments in a preventative manner. This is one of the things that must change in today's research community, leading to a growing willingness to build therapies for people who are aging but classed as "healthy" so that they do not become damaged and stricken. Prevention trumps cure.

Dramatic Growth of Grafted Stem Cells in Rat Spinal Cord Injuries

Neurons derived from human induced pluripotent stem cells (iPSC) and grafted into rats after a spinal cord injury produced cells with tens of thousands of axons extending virtually the entire length of the animals' central nervous system. The iPSCs used were developed from a healthy 86-year-old human male. "These findings indicate that intrinsic neuronal mechanisms readily overcome the barriers created by a spinal cord injury to extend many axons over very long distances, and that these capabilities persist even in neurons reprogrammed from very aged human cells."

While numerous connections were formed between the implanted human cells and rat cells, functional recovery was not found. [The researchers] are attempting to identify the most promising neural stem cell type for repairing spinal cord injuries. They are testing iPSCs, embryonic stem cell-derived cells and other stem cell types. "Ninety-five percent of human clinical trials fail. We are trying to do as much as we possibly can to identify the best way of translating neural stem cell therapies for spinal cord injury to patients. It's easy to forge ahead with incomplete information, but the risk of doing so is greater likelihood of another failed clinical trial. We want to determine as best we can the optimal cell type and best method for human translation so that we can move ahead rationally and, with some luck, successfully."

Stem cells show promise for stroke in pilot study

A stroke therapy using stem cells extracted from patients' bone marrow has shown promising results in the first trial of its kind in humans. Five patients received the treatment in a pilot study. The therapy was found to be safe, and all the patients showed improvements in clinical measures of disability. The therapy uses a type of cell called CD34+ cells, a set of stem cells in the bone marrow that give rise to blood cells and blood vessel lining cells. Previous research has shown that treatment using these cells can significantly improve recovery from stroke in animals. Rather than developing into brain cells themselves, the cells are thought to release chemicals that trigger the growth of new brain tissue and new blood vessels in the area damaged by stroke.

Stem Cell Advance May Increase Efficiency of Tissue Regeneration

A new stem-cell discovery might one day lead to a more streamlined process for obtaining stem cells, which in turn could be used in the development of replacement tissue for failing body parts. The work builds on a strategy that involves reprogramming adult cells back to an embryonic state in which they again have the potential to become any type of cell. The efficiency of this process may soon increase thanks to the scientists' identification of biochemical pathways that can inhibit the necessary reprogramming of gene activity in adult human cells. Removing these barriers increased the efficiency of stem-cell production, the researchers found.

Teeth Sprout from Glia-Derived Stem Cells

The researchers discovered that young cells, which at first are part of the neural support cells, or the glial cells, leave the nerves at an early stage of the fetal development. The cells change their identity and become both connective tissues in the tooth pulp and odontoblasts - that is, the cells that produce the hard dentin underneath the enamel. "The fact that stem cells are available inside the nerves is highly significant, and this is in no way unique for the tooth. Our results indicate that peripheral nerves, which are found basically everywhere, may function as important stem cell reserves. From such reserves, multipotent stem cells can depart from the nerves and contribute to the healing and reformation of tissues in different parts of the body."

Compensating for Cognitive Decline in Alzheimer's Disease

In this open access paper researchers report on a way to somewhat compensate for the measurable cognitive dsyfunction resulting from Alzheimer's disease by boosting synaptic activity. This is characteristic of much of what emerges from the medical research community in that it makes no attempt to engage with the causes of the condition, but rather adjusts biological processes so as to better force continued operation despite the underlying disease pathology:

A series of recent studies have found that the levels of the enzyme striatal-enriched protein tyrosine phosphatase (STEP) are raised in several different neuropsychiatric and neurodegenerative disorders, including Alzheimer's disease, fragile X syndrome, and schizophrenia. STEP normally opposes the development of synaptic strengthening, and these abnormally high levels of active STEP disrupt synaptic function by removing phosphate groups from a number of proteins, including several glutamate receptors and kinases. Dephosphorylation results in internalization of the glutamate receptors and inactivation of the kinases - events that disrupt the consolidation of memories.

The increase in STEP activity [likely] contributes to the cognitive deficits in AD. AD mice lacking STEP have restored levels of glutamate receptors on synaptosomal membranes and improved cognitive function, results that suggest STEP as a novel therapeutic target for AD. Here we identify the benzopentathiepin 8-(trifluoromethyl)-1,2,3,4,5-benzopenta​thiepin-6-aminehydrochloride (known as TC-2153) as a novel inhibitor of STEP, and we demonstrate the activity of TC-2153 both in vitro and in vivo. TC-2153 shows specificity towards STEP compared to several other tyrosine phosphatases and shows no toxicity to cultured neurons. Importantly, the compound reversed cognitive deficits in a mouse model of Alzheimer's disease in a way that did not involve changes in the usual pathological signs (p-tau and beta-amyloid).


Considering Cerebrospinal Fluid Flow Disruption as a Contributing Cause of Alzheimer's Disease

Alzheimer's disease is associated with buildup of amyloid-β in the brain, aggregates formed of misfolded proteins. The amount of amyloid present at any given time is dynamic, however, which has long suggested that Alzheimer's is in part caused by a slow decline in the mechanisms responsible for clearing amyloid from the cerebrospinal fluid. You might look at investigations of the choroid plexus, for example, which acts as a filtration mechanism for cerebrospinal fluid. Here a researcher theorizes on the possible role of disruptions in the flow of cerebrospinal fluid in Alzheimer's disease, another way in which clearance of amyloid might be impacted with the progression of aging:

Plaques and tangles may be manifestations of a more substantial underlying cause of Alzheimer's disease (AD). Disease-related changes in the clearance of amyloid-β (Aβ) and other metabolites suggest this cause may involve cerebrospinal fluid (CSF) flow through the interstitial spaces of the brain, including an archaic route through the olfactory system that predates neocortical expansion by three hundred million years. This olfactory CSF conduit (OCC) runs from the medial temporal lobe (MTL) along the lateral olfactory stria, through the olfactory trigone, and down the olfactory tract to the olfactory bulb, where CSF seeps through the cribriform plate to the nasal submucosa.

Olfactory dysfunction is common in AD and could be related to alterations in CSF flow along the OCC. Further, reductions in OCC flow may impact CSF hydrodynamics upstream in the MTL and basal forebrain, resulting in less efficient Aβ removal from those areas - among the first affected by neuritic plaques in AD. Factors that reduce CSF drainage across the cribriform plate and slow the clearance of metabolite-laden CSF could include aging-related bone changes, head trauma, inflammation of the nasal epithelium, and toxins that affect olfactory neuron survival and renewal, as well as vascular effects related to diabetes, obesity, and atherosclerosis - all of which have been linked to AD risk. Problems with CSF-mediated clearance could also provide a link between these seemingly disparate factors and familial AD mutations that induce plaque and tangle formation. I hypothesize that disruptions of CSF flow across the cribriform plate are important early events in AD, and I propose that restoring this flow will enhance the drainage of Aβ oligomers and other metabolites from the MTL.


Preventing Damage from Mitochondrial Mutations

SENS, the Strategies for Engineered Negligible Senescence, is an ongoing research and advocacy program that aims to bring aging under medical control. One day aging will be in exactly the same bucket as tuberculosis: it exists, it is a threat if you somehow lose access to modern medicine, but most people are never troubled by it. After watching the research community for more than a decade, I firmly believe SENS is the best path towards this goal, offering a shot at real working rejuvenation within our lifetimes if funded sufficiently. Aging is a matter of cellular and molecular damage, and SENS is in essence a repair program, outlining the shortest likely paths towards therapies that can revert the full list of known fundamental forms of damage that distinguish old tissue from young tissue.

SENS has been running as a research program for some years, albeit with far less funding that we'd like to see. A lesser known aspect of modern medical research is that near all early stage, proof of concept, high-risk work is funded by philanthropy. The better known institutional and for-profit sources of funding are risk averse and don't become involved until researchers already have demonstrations and prototypes. It's a wonder anything is ever accomplished, frankly. Thus SENS is funded near entirely by philanthropic donations. It has been since the days when research started under the auspices of the Methuselah Foundation, and this is still the case as it continues at the SENS Research Foundation.

One of the longer running SENS research programs is focused on mitochondrial DNA damage in aging, and an innovative way of dealing with this problem that was first pioneered by researchers working on inherited mitochondrial diseases. These conditions are very different from aging: in a genetic disease such as Leber's hereditary optic neuropathy a large fraction of a patient's mitochondria are dysfunctional from birth due to one or more damaged genes, whereas in a normal individual damage to mitochondrial genes accumulates over time as a side-effect of the operation of ordinary metabolic processes. Nonetheless, in both cases the damage is essentially similar and the same types of treatment will work. Genes encode protein machinery, and it is the proteins that are important. If the missing proteins can be supplied somehow, then it no longer matters that the genes are damaged. Thus the SENS plan, and the plan of researchers aiming to cure inherited mitochondrial diseases, is to place a copy of the crucial mitochondrial genes into the cellular nucleus.

Here is the latest in a series of articles from philanthropist Jason Hope on the nuts and bolts of the SENS research programs. This discusses work on mitochondrial damage in aging and how to make it no longer matter:

MitoSENS: Preventing Damage from Mitochondrial Mutations

Various structures inside the cell read DNA like a set of instructions on how to do their jobs. A body cell keeps most of its DNA safely tucked away in its nucleus. Mitochondria are different in that they have their own DNA, known as mtDNA, that they use as an instruction booklet to make the proteins that make up the machinery they use to harvest energy from our food and convert it to ATP. Mitochondria are also different from other cell structures because they keep this mtDNA nearby instead of storing the set of instructions in remote location inside the nucleus.

Just like municipal power plants, mitochondria create toxic waste as a byproduct. This toxic waste can pollute the surrounding cellular community and cause damage to structures within the cell. Mitochondria power plants spew out free radicals that impart particular damage to cellular structures. Because of proximity to the power plant, mtDNA is at special risk for exposure to toxic waste. Free radicals can assault vulnerable mtDNA and delete large chunks of genetic code. This can render the mitochondria incapable of reading the instructions for making the critical components these little power stations need to create energy.

To make matters worse, cells tend to hang on to mutant mitochondria while destroying healthy ones. As a result, once even one mitochondrion with these large deletions appears, its progeny quickly take over a healthy cell. In a perfect world, scientists would simply prevent deletions in mitochondrial DNA or repair deletions before they cause harm. Unfortunately, science is nowhere near ready to prevent or repair mtDNA deletions. For now, the most reasonable approach is to engineer a system that protects cells from damage caused by mutant mitochondria. One way of doing this is to create backup copies of mtDNA and safely tuck them away in the cell's nucleus, where free radicals cannot harm the information contained within the mitochondrial genes.

This approach of making backup copies is not new - evolution has already moved thousands of genes that were originally part of the mtDNA into the protective confines of the nucleus. Today, the mtDNA that mitochondria keep near the power plant contains instructions to build only the 13 different proteins it needs on a day-to-day basis, even though it originally contained over a thousand. The others are now safely ensconced in the nucleus. When accessed, these genes create proteins in the main body of the cell, outside the mitochondria. The cell then imports the newly created proteins into the mitochondria through specialized transport docks in the mitochondria membranes.

The greatest challenge to importing the 13 remaining proteins is that they tend to fold up on themselves while in the main body of the cell, creating folded structures too large to fit through the transport docks. Scientists at the SENS Research Foundation Research Center are working [on] ways to allow decoding the "working copies" of backup copies of genes whose proteins are destined for the mitochondria to occur near mitochondria rather than far away in the cell body. Because they do not have so far to travel, proteins may pass through transport docks before they fold up.

This new approach was pioneered by Professor Marisol Corral-Debrinski at the Institut de la Vision at Pierre and Marie Curie University, Paris. SENS Research Foundation funding helped Dr. Corral-Debrinski's team introduce into the eyes of a rat a mutated mitochondrial gene associated with an inherited form of blindness to cause vision loss in the lab animal. Using the same technique, the team then restored the rat's vision.

AGEs Contribute to the Development of Osteoporosis

Osteoporosis is the characteristic loss of bone mass and strength that occurs with aging, with proximate causes that include an imbalance in the distinct populations of cells responsible for bone creation and destruction, as well as the general decline in stem cell maintenance activities that occurs for every tissue in the body. For root causes you have to look to cellular and molecular damage of the sort listed in the SENS research programs, which include an accumulation of sugar-based metabolic waste molecules called advanced glycation endproducts (AGEs). These gum together important proteins in the extracellular matrix between cells and degrade tissue elasticity, but they also trigger increased levels of chronic inflammation through reacting with RAGE, the receptor for AGEs. Chronic inflammation is an unpleasant thing, a source of damage and dysfunction in and of itself, and it contributes meaningfully to many age-related conditions - such as osteoporosis.

Among the wide spectrum of bone disorders, osteoporosis has emerged as a medical and socioeconomic threat. Although it is accepted that more than 8.9 million fractures annually worldwide are caused by osteoporosis, they are often diagnosed only after the first clinical fracture has occurred because bone loss arises insidiously and is initially asymptomatic. The lifetime fracture risk of a patient with osteoporosis has been estimated to be in the order of 30-40%, which is very close to the risk for coronary heart disease. Moreover, in addition to pathologic fractures, osteoporosis carries a considerable risk of disability due to serious medical complications. With the aging of the population, the prevalence of osteoporosis is expected to further increase.

In the last twenty years, advanced glycation end products (AGEs) have been shown to be critical mediators both in the pathogenesis and development of osteoporosis and other chronic degenerative diseases related to aging. The accumulation of AGEs within the bone induces the formation of covalent cross-links with collagen and other bone proteins which affects the mechanical properties of tissue and disturbs bone remodelling and deterioration, underlying osteoporosis. On the other hand, the gradual deterioration of the immune system during aging (defined as immunosenescence) is also characterized by the generation of a high level of oxidants and AGEs. The synthesis and accumulation of AGEs (both localized within the bone or in the systemic circulation) might trigger a vicious circle (in which inflammation and aging merged in the word "Inflammaging") which can establish and sustain the development of osteoporosis.


Claiming a Cure for Rheumatoid Arthritis in Mice

Autoimmunity is one of the remaining dark frontiers of human disease, and the collection of medical conditions in which the immune system starts to attack a patient's own tissues are largely poorly understood. In the case of rheumatoid arthritis, for example, there is no real consensus on root cause or how the disease mechanisms work in detail, and it even may be a collection of several distinct issues lumped under one heading because the outcome looks the same. The effectiveness of treatments has been improving, but some patients just don't respond to the standard approach of trying to suppress the unwanted immune responses via TNF inhibitors.

Here researchers are making the bold claim of an effective cure for rheumatoid arthritis in mice, with a method that sounds like a more targeted way of suppressing unwanted immune activity rather an advance towards addressing root causes, and are heading for clinical trials:

Researchers have developed a therapy that takes the treatment of rheumatoid arthritis in mice to a new level: after receiving the medication, researchers consider the animals to be fully cured. The drug is a biotechnologically produced active substance consisting of two fused components. One component is the body's own immune messenger interleukin 4 (IL-4); previous studies have shown that this messenger protects mice with rheumatoid arthritis against cartilage and bone damage. [The] scientists have coupled an antibody to IL-4 that, based on the key-lock principle, binds to a form of a protein that is found only in inflamed tissue in certain diseases (and in tumour tissue).

"As a result of combination with the antibody, IL-4 reaches the site of the disease when the fusion molecule is injected into the body.It allows us to concentrate the active substance at the site of the disease. The concentration in the rest of the body is minimal, which reduces side-effects." The researchers tested the new fusion molecule [in] a mouse model in which the animals developed swollen, inflamed toes and paws within a few days. Among other things, the researchers studied the fusion molecule in combination with dexamethasone, a cortisone-like anti-inflammatory drug that is already used to treat rheumatoid arthritis in humans.

When used separately, the new fusion molecule and dexamethasone managed only to slow the progression of the disease in the affected animals. In contrast, the typical signs of arthritis, such as swollen toes and paws, disappeared completely within a few days when both medications were administered at the same time. Concentrations of a whole range of immune messengers in blood and inflamed tissue, which are changed in rheumatoid arthritis, returned to their normal levels. "In our mouse model, this combined treatment creates a long-term cure."


Until, a Short Film from the Wellcome Trust

The Wellcome Trust is a biomedical research foundation of some size and influence. A fellow from their publicity group recently pointed me to a short film published by their house magazine, Mosaic. To my eyes the noteworthy item here is not the film in and of itself, nor the fact that the Trust has aging and longevity on its agenda, but rather that this organization, which is far and away large enough to be very sober and conservative, is comfortable publishing serious discussions of radical life extension and the prospects for unlimited life spans achieved through future advances in medical science.

If you're interested in reading the tea leaves, you might take a look at the Wellcome Trust's strategic plan for 2010-2020. About a quarter of their grants, around $250 million each year, go towards research into aging and the diseases of aging:

This challenge encompasses a broad spectrum of research to understand the cellular and physiological processes underlying normal development and ageing, and the mechanisms that underpin the onset of non-communicable diseases. Looking ahead, we will continue to work with the research community to stimulate research applications in this challenge area. We will hold a Frontiers Meeting to examine the topic of healthy ageing, and we will also examine the topic of disease prevention as a potential future area of focus. We will take forward discussions to examine the potential to use human induced pluripotent stem cells for large-scale studies on how genomic variation affects cellular phenotype and disease mechanisms.

Funded work is all very mainstream, and the Trust appears to follow the safe philanthropic playbook of reinforcing successful, established fields that already have a great deal of attention and support. Here that includes regenerative medicine and investigations into the genetics of aging. That makes the film below somewhat more interesting in the context of this organization's recent history and stated goals. One might hope that it is a sign that the veneer of conservatism in large funding institutions is cracking a little in the face of what might be achieved in the near future if only the right research programs are funded.

Until: Who wants to live for ever?

Do you want to live to 100? 1,000? What about for ever? Meet a man seeking immortality, leading age-research scientists, the very young and the very old as they grapple with deciding what is the right age to die in Until, a journey of the lifetime.

The human lifespan is increasing by five hours a day - every day. But how much life is enough? What if society reached a point where individuals could essentially choose how long they lived? At what age would people decide to call it a day, meet their maker and embrace death? And, for those reaching towards immortality, what would they do with their infinite time?

These are the profound questions explored in Until. Part science, part philosophy, this film invites us all to ask just one question: would I want to live for ever?

Testing PTB as an AGE-Breaker in Bone

Advanced glycation endproducts, AGES, are a class of undesirable sugary metabolic waste that accumulate in tissues over time. They gum together important protein structures and cause cells to react to their presence in ways that are damaging and raise levels of chronic inflammation. There are many different types of AGE, but most are not all that relevant to the aging process in healthy people, being short-lived and well controlled by our biochemistry. More hardy types of AGE that cannot be effectively cleared are a fundamental difference between old and young tissues, and a contribution to degenerative aging. Of these glucosepane is the most important in human tissues.

Much of the limited work of past decades that aimed to produce AGE-breaker drugs capable of clearing out AGEs went nowhere, as drug candidates established in animal studies performed very poorly in people. It turned out that the types of AGE important in mice and rats are quite different from those that are important in humans. So researchers now realize that they have to work with human tissues to draw any reasonable conclusions, such as in this study. Note that the drug candidate PTB has been known as a potential AGE-breaker on the basis of animal studies for some years now, but it remains unclear as to its utility as a treatment for people:

Nonenzymatic glycation (NEG) describes a series of post-translational modifications in the collagenous matrices of human tissues. These modifications, known as advanced glycation end-products (AGEs), result in an altered collagen crosslink profile which impacts the mechanical behavior of their constituent tissues. Bone, which has an organic phase consisting primarily of type I collagen, is significantly affected by NEG. Through constant remodeling by chemical resorption, deposition and mineralization, healthy bone naturally eliminates these impurities. Because bone remodeling slows with age, AGEs accumulate at a greater rate. An inverse correlation between AGE content and material-level properties, particularly in the post-yield region of deformation, has been observed and verified.

Interested in reversing the negative effects of NEG, here we evaluate the ability of n-phenacylthiazolium bromide (PTB) to cleave AGE crosslinks in human cancellous bone. Cancellous bone cylinders were obtained from nine male donors, ages nineteen to eighty, and subjected to one of six PTB treatments. Following treatment, each specimen was mechanically tested under physiological conditions to failure and AGEs were quantified by fluorescence. Treatment with PTB showed a significant decrease in AGE content versus control NEG groups as well as a significant rebound in the post-yield material level properties. The data suggest that treatment with PTB could be an effective means to reduce AGE content and decrease bone fragility caused by NEG in human bone.


Most Gains in Life Expectancy are Now Realized Late in Life

Much of the gain in life expectancy at birth over the past two centuries was realized through reductions in early mortality. This was achieved through sanitation, increased wealth, and control of infectious disease. As this paper notes, that trend is largely done with now, and the gains in life expectancy overwhelmingly arrive in later life due to advances in medical technologies aimed at treating the diseases of aging. The authors, economists rather than biogerontologists, see this as a potential problem because of increased length of retirement. In reality retirement is just a tradition, however, already unjust where it is enforced by law, and removed from the reality that individuals who remain healthy for longer thanks to modern medicine can just carry on being productive and working for a living. Do people serve laws or do laws serve people?

As life spans lengthen, retirement as an institution will change, as the reason for its existence - the ill health and incapacity that accompanies aging - will ultimately vanish. Similarly the culture of government-enforced entitlement in which resources are transferred from comparatively poor and disempowered young people to comparatively wealthy and empowered old people must also be dismantled in the years ahead: it is unsustainable and morally bankrupt besides. All of the financial problems that the political chattering classes fret about with respect to increasing longevity are created by the present system of governance and its entitlements and rules, which together threaten to make a grand and damaging economic ruin out of what would otherwise be a great benefit.

The original "demographic transition" describes a process that began in Europe by the early 1800s with decreases in mortality followed, usually after a lag, by decreases in fertility. This historical process ranks as one of the most important changes affecting human society in the past half millennium. The increase in life expectancy associated with this demographic transition has been accompanied by rising levels of per capita output, which have in turn spurred further improvements in population health.

Now, the United States and many other countries are experiencing a new kind of demographic transition. Instead of additional years of life being realized early in the lifecycle, they are now being realized late in life. At the beginning of the twentieth century, in the United States and other countries at comparable stages of development, most of the additional years of life were realized in youth and working ages; and less than 20 percent was realized after age 65. Now, more than 75 percent of the gains in life expectancy are realized after 65 - and that share is approaching 100 percent asymptotically. The choice of age 65 to illustrate this new demographic transition is somewhat arbitrary, but if we used 60 or 70 instead, the results would be qualitatively similar.

The new demographic transition is a longevity transition: how will individuals and societies respond to mortality decline when almost all of the decline will occur late in life? This issue is broader and more far-reaching than the issue of cohort size in each age group, with its focus on the prospective retirement of the unusually large "baby boomer" cohort, and has important socio-economic implications independent of patterns of fertility.

When the gains in life expectancy occur mainly towards the end of life, they contribute more to the age bracket that is traditionally mostly retired rather than to the age bracket in prime working years. Retirees are highly dependent on transfers from the working population for living expenses, including large consumption of medical care. Thus, gains in life expectancy concentrated at the end of life can unsettle an economy's balance between production and consumption in ways that pose a long-run challenge for public policy. The obvious changes that are needed (at least "obvious" to many economists") would be to raise productivity, to raise the savings rate, and to raise the age of retirement, but how to accomplish such goals is controversial and uncertain.


Video: Aubrey de Grey Presenting at Google London

In any given year Aubrey de Grey, cofounder of the SENS Research Foundation, gives a great many presentations on his vision for the successful treatment and reversal of aging: at scientific conferences, for life insurance companies, in front of advocacy group meetups, and more. A sizable fraction of his work and the work of many of the staff at the Foundation is in essence persuasion. After all, the only reason we are not well on our way towards the robust demonstration of rejuvenation in old mice is that most people don't care about building new medical technologies to treat aging, and don't give much thought to the prospects for defeating age-related disease. There is consequently very little funding for the relevant research programs; you can compare and contrast the present state of aging research and its lack of support with the way society at large thinks about cancer and the size of the cancer research establishment. Two very different mindsets and very different research communities as a result.

Here is video of a presentation given last week to Google employees in London. It includes some implementation progress reports from the past few years that may or may not be news to you, depending on how closely you've been keeping track of the field. When you spend your time following along with your nose to the news feed, sometimes it is pleasant to step back and note that SENS has moved a fair way down the path from "here is a plan, and this is what we should do," and well into the realm of "this is what we're doing, and here is where we are now." A lot of people worked hard and donated generously to make that progress happen, and beyond that it is a testament to just how much you can do with a few million dollars in early stage biotechnology research these days: prices are falling even as capabilities improve dramatically.

Google brings in a lot of noted people to present to company employees, so don't read anything into this. I believe de Grey has presented there in the past, long before the California Life Company, Google's new venture into longevity science, came into being. He will probably present again in the future, regardless of whether Calico heads off into the wilderness of the genetics of human longevity or the leadership there choose to fund something more likely to produce meaningful results and treatments for aging, such as SENS-like repair biotechnologies.

Towards Cell Therapy to Treat Neurodegeneration

A range of neurodegenerative conditions that primarily involve cell loss, such as Parkinson's disease, might be treated with transplants of neural stem cells or more specialized differentiated cells. Replacing the cells doesn't address the underlying causes that led to their loss, the rising toll of molecular damage that accompanies aging, but it may be a far more effective patch treatment than those presently available. Perhaps more importantly, it is expected that any more general rejuvenation toolkit that does address underlying causes will still need some way of making up the numbers in various small populations of long-lived nerve cells of the brain and central nervous system that have diminished over time. Progress towards this goal is to be welcomed:

[Researchers] have grafted neurons reprogrammed from skin cells into the brains of mice for the first time with long-term stability. Six months after implantation, the neurons had become fully functionally integrated into the brain. This successful, because lastingly stable, implantation of neurons raises hope for future therapies that will replace sick neurons with healthy ones in the brains of Parkinson's disease patients, for example. "Successes in human therapy are still a long way off, but I am sure successful cell replacement therapies will exist in future. Our research results have taken us a step further in this direction."

The stem cell researchers' technique of producing neurons, or more specifically induced neuronal stem cells (iNSC), in a petri dish from the host's own skin cells considerably improves the compatibility of the implanted cells. The treated mice showed no adverse side effects even six months after implantation into the hippocampus and cortex regions of the brain. In fact it was quite the opposite - the implanted neurons were fully integrated into the complex network of the brain. The neurons exhibited normal activity and were connected to the original brain cells via newly formed synapses, the contact points between nerve cells. "Building upon the current insights, we will now be looking specifically at the type of neurons that die off in the brain of Parkinson's patients - namely the dopamine-producing neurons." In future, implanted neurons could produce the lacking dopamine directly in the patient's brain and transport it to the appropriate sites.


A Mainstream Press Article on Longevity Science

These days the mainstream press is giving a larger sliver of attention to various ongoing efforts to treat aging as a medical condition and thereby extend healthy life. We should expect to see an increasing number of articles similar to this one as funding for proactive aging research grows and more large institutions with publicity teams become involved:

There are a number of biological components involved in the process of ageing. These cause the body to slowly degrade at the cellular level. Old age is also a leading risk factor for many common illnesses, such as cancer and heart disease. Tackling ageing, therefore, is seen as a way to combat many diseases at once. This is the motivation behind Google's anti-ageing startup called Calico, which was founded last year and is led by Art Levinson, the former head of Genentech, a pioneer of the biotechnology industry. Craig Venter, a geneticist who was instrumental in the sequencing of the human genome, created a similar company earlier this year. The primary goal of these and other efforts is not necessarily to extend humans' lifespan, but rather their healthspan, or the number of years lived in good health. Many scientists, though, believe that any effort to slow or stop the progression of age-related diseases must deal with the cellular damage involved in ageing - so longer life is an inevitable and welcome byproduct.

These newer outfits and much anti-ageing research over the past decade have focused on genes. The chances of a person living to 80 are based mostly on behaviour - don't smoke, eat well and exercise - but the chances of living beyond that are based largely on genetics. So scientists are looking for the "protective genes" that slow cellular decline and ward off diseases in [long lived individuals]. If researchers can find them it is hoped that pharmaceutical firms might create drugs that mimic their effects in people otherwise likely to achieve normal lifespans. Others think that to go further the body must be treated like a machine in need of regular repair and replacement parts. Regenerative medicine offers some hope in this regard. Scientists are using stem cells to grow human replacement parts, like tissues and organs. In theory, a person could keep going back to the shop for new parts, so long as his brain remained intact. Scientists even talk about treating diseases that ravage the brain, like Alzheimer's and Parkinson's, with replacement nerve cells.

Optimists, like Aubrey de Grey, a provocative anti-ageing researcher in England, believe that technology will allow people alive today to live well beyond [the present limits of old age]. Most others believe that such progress is some way off. A more realistic hope is that anti-ageing research will lead to lower health-care costs. One of the characteristics of the very old is that they tend to be healthy right up until their deaths. They therefore cost health-care systems less than most old people, especially those suffering from chronic diseases. Scientists talk of a "longevity dividend" that might be achieved by compressing the period of ill health at the end of life for everyone. This would at least address the paradox of the quest for eternal life: people want to live for ever, but they don't want to grow old.


A Gameplan to End Age-Related Disease

SENS, the Strategies for Engineered Negligible Senescence, is the only presently plausible road to the prevention and cure of all age-related disease that could be accomplished in a short enough period of time to save most of those reading this today. It is a repair-based approach to treating the causes of aging, taking the present scientific consensus on the fundamental cellular and molecular differences between old and young tissue, and providing detailed plans to produce treatments capable of reverting or working around all of them. Given funding of a hundred million dollars a year, functional rejuvenation treatments following the SENS proposals could be demonstrated in mice a mere decade from now. The chief problem at this time is that we stand a long way away from that level of funding.

This is not to point out a lack of success: far from it. The existence of the SENS Research Foundation and its present $5 million yearly budget is just one of the visible signs of fifteen years of hard work and advocacy to bring a vision into reality. Fifteen years ago there was no SENS research and the scientific community was largely unwilling to talk about treating aging in public, for fear of endangering their ability to obtain grants. Yet today this is a line of research now widely supported within the scientific community, and researchers are far more willing now to talk about treating aging. Progress towards meaningful rejuvenation treatments is progressing more rapidly today than it ever has. These are still the early years in a longer process of decades, however, and we have barely started to climb the funding mountain, and barely started to build the aging research community of tomorrow.

Large-scale funding for rejuvenation research in the SENS model will happen eventually. No other faction in the research community is proposing or working on anything that can possibly be as effective as repair of damage in aging tissue. So over the course of time SENS will inevitably take over the research community mainstream simply by virtue of the fact that it will produce meaningful results in early stage work while other approaches to treating aging will continue to fail miserably on that count. The pressing question is how long it will take, give that the clock is ticking for all of us. In helping SENS move faster we are quite literally running for our lives.

Here is a recent article on the work of the SENS Research Foundation, and while all publicity is good publicity, I'm forced to note that is somewhat annoying to see the 2005 SENS challenge given so much of a focus, while only passing mention is given to the fact that the SENS Research Foundation is now an organization with scientific programs running in numerous noted laboratories in the US and Europe, as well as a scientific advisory board that includes well-known luminaries in the fields of genetics, tissue engineering, and other fields relevant to aging research. The decade old debate as to whether or not SENS is serious science was had and done and the skeptics lost because they were wrong. End of story, and way past time to move on.

Against the Biological Clock - A Gameplan to End Age-Related Diseases

To Aubrey de Grey, the body is a machine. Just as a restored classic car can celebrate its hundredth birthday in peak condition, in the future, we'll maintain our bodies' cellular components to stave off the diseases of old age and live longer, healthier lives.

Dr. de Grey is cofounder and Chief Science Officer of the SENS Research Foundation and faculty at Singularity University's November Exponential Medicine conference - an event exploring the healthcare impact of technologies like low-cost genomic sequencing, artificial intelligence, synthetic biology, gene therapy, and more. Recently speaking to participants in Singularity University's graduate studies program, de Grey said the greatest challenge in aging research today is less of a technical nature, more a misguided focus in the mainstream.

Most approaches to age-related disease aim to manage symptoms. They have contributed to longer life expectancy and eased complications, but because treatments interfere with the body's finely tuned systems, they can have nasty side effects and are ultimately powerless (even with advances) to reverse age-related illness. Why? "Aging is a side effect of being alive in the first place," says de Grey.

Metabolic processes drive the day-to-day business of living, but they also inevitably cause cellular damage. The body's range of self-repair mechanisms don't take care of everything. Eventually, a lifetime of accumulated damage causes the familiar signs of aging like "thinning skin, cloudy eyes, muscles sapped of strength, heart disease, and cognitive decline." Negligible senescence is a term used to describe certain animals that don't display symptoms of aging. De Grey believes we can use biotechnology to engineer negligible senescence in humans, and he cofounded the SENS Research Foundation to lead the way.

An Example of Continuing Legal Opposition to Cryonics

The small four decades old cryonics industry provides low-temperature storage at the end of life, an attempt to preserve the fine structure of the brain until future technologies can restore a preserved individual to life. This is not beyond the realm of the possible: it will require at the very least mature molecular nanotechnology and near complete control over cells, but both of these are expected to come to pass over the next century.

Cryonics has long faced legal opposition, and it remains illegal in many regions for reasons that have less to do with actual directed opposition and more to do with a state of bureaucracy surrounding death and funerary arrangements in which everything not explicitly permitted is forbidden. The tiny size of the cryonics community makes effective lobbying a challenge at this level; its membership can oppose local government and win, as happened in the US some years back, but that is about it at this time. This post outlines another similar situation in Canada, but here the legislative opposition to cryonics is more deliberate:

The Cryonics Society of Canada was created by Douglas Quinn in 1987. ​In 1990, British Columbia, our westernmost province passed a law prohibiting the marketing of cryonics, and the early 1990's were spent by the CSC unsuccessfully attempting to overturn it. Similar legislation was considered in Alberta, but it was not passed into law. Even though it is fortunate that no other state or province has passed such a law, it still remains in force to this date. Technically, a resident of British Columbia can have cryonics arrangements made, but as one can imagine, a law written in such a manner makes it difficult to find funeral directors and medical professionals that are comfortable assisting these efforts.

Cryonicists in BC have been trying to have that prejudicial law overturned for many years now. This is a very important issue, not only for the people of BC, but also for cryonicists in other regions. Having an anti-cryonics law on the books creates the potential for others to be influenced by that established precedent. It is in everyone's best interest to overturn it, lest another zealous lawmaker sees that as an opportunity to create similar rules. In consultation with a civil rights attorney, BC cryonicists have proposed that the best way to challenge the law is to create a business that would be directly affected by it and appeal on the grounds that it is discriminatory. This creates an opportunity to formally start an organization with a similar purpose that Suspended Animation Inc has in the USA, and it falls beautifully in line with the above mentioned goals of the CSC.


A Press Article on the Cryonics Institute

This press article on the history of cryonics and the work of the Cryonics Institute skips over a lot of the important technical details, such as the fact that patients are vitrified these days rather than frozen, a technique that minimizes ice crystal formation in tissues, but is still worth reading:

Inside the brick-fronted warehouse in Clinton Township, the body count has topped 100. Nestled inside Wal-Mart sleeping bags, the bodies stand upside-down within 10-foot-high tanks resembling immense white thermos bottles. This is the Cryonics Institute, and the people in those tanks - "cryostats," they're called - after being declared dead, have had their bodies frozen in perpetuity in the belief that future science may be able to thaw them, cure their ills, and, just maybe, return them to youthful vigor. They've made a bet: that in a time yet to come, they'll rise again, with "death" only a temporary and reversible embarrassment easily remedied by medical know-how.

Death is a gray line and it's always moving. What might have been terminal 150, 15, even five years ago is treatable today. Something as simple as CPR has saved countless lives; cardiac defibrillation - the "shock paddles" used to jump-start a stopped heart - has revived patients previously considered dead. What's "dead" mean to medicine, other than a challenge? From that perspective a storehouse of frozen bodies is no more macabre than a heart transplant, a now-common medical procedure once considered grotesque.

Right now, though, cryonics is more like an in-progress medical trial. Advances in stem-cell research, nanotechnology, and therapeutic cloning give cryonicists hope, but there are no guarantees. Today's frozen people are already dead, or "deanimated," as some prefer; tomorrow's helpful scientists will not only have to successfully thaw their "patients," but return them to life. That's assuming, fingers crossed, that they've been frozen in a recoverable way, without too much tissue damage, and that they've been carefully maintained. Once thawed, they'll have to be treated for being "dead," by whatever methods would make that possible. And who wants to wake up alone in the future in a body already ravaged by time? Better to hope that a new, youthful body is waiting for you.


Replication Stress Explains Some of Blood Stem Cell Aging

The stem cells responsible for generating blood, hematopoietic stem cells, are of considerable importance because they are the origination point for new immune cells. Much of the ongoing investigation into mechanisms that cause the age-related decline of the immune system focus on the thymus, where T cells develop, and on structural deficiencies in the immune system's operation that lead to memory T cells crowding out the naive T cells needed to destroy pathogens. There is a great deal in those two areas that might be done to restore the old immune system to former strength: rejuvenate the thymus to boost the pace at which immune cells come to readiness after creation, or selectively destroy excess memory T cells to prompt the generation of fresh replacement naive T cells.

Here, however, is another line of thinking and another contribution to the reduced influx of new immune cells. It is based on a form of damage to hematopoietic stem cells, though as for many of these things it is unclear at this point as where the observed changes stand in the hierarchy of damage and reactions to damage. Most stem cell populations have evolved to decline in function with age, most likely because this reduces the risk of cancer: the longer human life span in comparison to other primates is somewhat linked with this balance between failing tissue maintenance and lowered cancer risk. Different populations of stem cells may have achieved this decline in wildly divergent ways, however, and so a whole range of entirely different mechanisms are probably involved. Investigations of muscle stem cells strongly suggest that these mechanisms are largely reactions to damage and can be reversed by suitable signals or epigenetic changes - or in theory by repairing the damage, such as via SENS rejuvenation therapies. Again, however, this isn't necessarily the case for every stem cell population in the body. Biology is enormously complex, and finding similarities should be the more surprising outcome, not finding differences.

Key to Aging Immune System Is Discovered

Blood and immune cells are short-lived, and unlike most tissues, must be constantly replenished. The cells that must keep producing them throughout a lifetime are called "hematopoietic stem cells." Through cycles of cell division these stem cells preserve their own numbers and generate the daughter cells that give rise to replacement blood and immune cells. But the hematopoietic stem cells falter with age, because they lose the ability to replicate their DNA accurately and efficiently during cell division.

In old blood-forming stem cells, the researchers found a scarcity of specific protein components needed to form a molecular machine called the mini-chromosome maintenance helicase, which unwinds double-stranded DNA so that the cell's genetic material can be duplicated and allocated to daughter cells later in cell division. In their study the stem cells were stressed by the loss of activity of this machine and as a result were at heightened risk for DNA damage and death when forced to divide.

The researchers discovered that even after the stress associated with DNA replication, surviving, non-dividing, resting, old stem cells retained molecular tags on DNA-wrapping histone proteins, a feature often associated with DNA damage. However, the researchers determined that these old survivors could repair induced DNA damage as efficiently as young stem cells. "Old stem cells are not just sitting there with damaged DNA ready to develop cancer, as it has long been postulated. Everybody talks about healthier aging. The decline of stem-cell function is a big part of age-related problems. Achieving longer lives relies in part on achieving a better understanding of why stem cells are not able to maintain optimal functioning."

Replication stress is a potent driver of functional decline in ageing haematopoietic stem cells

Haematopoietic stem cells (HSCs) self-renew for life, thereby making them one of the few blood cells that truly age. Paradoxically, although HSCs numerically expand with age, their functional activity declines over time, resulting in degraded blood production and impaired engraftment following transplantation. While many drivers of HSC ageing have been proposed, the reason why HSC function degrades with age remains unknown.

Here we show that cycling old HSCs in mice have heightened levels of replication stress associated with cell cycle defects and chromosome gaps or breaks, which are due to decreased expression of mini-chromosome maintenance (MCM) helicase components and altered dynamics of DNA replication forks. Nonetheless, old HSCs survive replication unless confronted with a strong replication challenge, such as transplantation. Our results identify replication stress as a potent driver of functional decline in old HSCs, and highlight the MCM DNA helicase as a potential molecular target for rejuvenation therapies.

Healthier, Wealthier, and Wiser

It is known that greater health throughout life, greater wealth, greater social status, and greater intelligence are all associated with greater life expectancy. Untangling the nature of these linked correlations is ever a challenge, however, since they all associate with one another as well. There are any number of plausible explanations as to why the wealthy or the more intelligent live longer, and some interesting speculation besides, such as the association of intelligence with physical robustness, but rarely is there any way to prove these explanations true in the data obtained from population studies. Correlations are what is obtained, and it is then usually a matter of retreating to animal studies where it is possible to structure the work to prove causation - but of course this is somewhere between hard and impossible to achieve for intelligence and social status.

This paper reminds us of the tendency for age-matched cohorts to become on average healthier, wealthier, and wiser over time. This isn't a matter of self-improvement, though any of us can work on that, but occurs because those who were not comparatively healthy, wealthy, and wise are more likely to be dead already:

The gradual changes in cohort composition that occur as a result of selective mortality processes are of interest to all aging research. We present the first illustration of changes in the distribution of specific cohort characteristics that arise purely as a result of selective mortality. We use data on health, wealth, education, and other covariates from two cohorts (the AHEAD cohort, born 1900-23 and the HRS cohort, born 1931-41) included in the Health and Retirement Survey, a nationally representative panel study of older Americans spanning nearly two decades (N=14,466). We calculate sample statistics for the surviving cohort at each wave. Repeatedly using only baseline information for these calculations so that there are no changes at the individual level (what changes is the set of surviving respondents at each specific wave), we obtain a demonstration of the impact of mortality selection on the cohort characteristics.

We find substantial changes in the distribution of all examined characteristics across the nine survey waves. For instance, the median wealth increases from about $90,000 to $130,000 and the number of chronic conditions declines from 1.5 to 1 in the AHEAD cohort. The mortality selection process changes the composition of older cohorts considerably, such that researchers focusing on the oldest old need to be aware of the highly select groups they are observing, and interpret their conclusions accordingly.


TRAP-1 Knockout Improves Health and Extends Life in Mice

Cancer researchers here stumble upon a way to alter mitochondrial function to improve health and extend life in mice. A range of the known ways to slow aging through genetic alteration work through similar mechanisms to those shown here, creating somewhat dysfunctional mitochondria that can still perform their necessary functions but which generate a raised level of damaging oxidative molecules in the process. This spurs cells to increase cellular housekeeping activities in response, which in turn leads to a net gain in cellular health and function. Over the lifespan of an organism these small differences in every cell add up.

The mice, which lack the TRAP-1 protein, demonstrated less age-related tissue degeneration, obesity, and spontaneous tumor formation when compared with normal mice. TRAP-1 is a member of the heat shock protein 90 (HSP90) family, which are "chaperone" proteins that guide the physical formation of other proteins and serve a regulatory function within mitochondria.

The researchers found that in their knockout mice, the loss of TRAP-1 causes mitochondrial proteins to misfold, which then triggers a compensatory response that causes cells to consume more oxygen and metabolize more sugar. This causes mitochondria in knockout mice to produce deregulated levels of ATP, the chemical used as an energy source to power all the everyday molecular reactions that allow a cell to function.

This increased mitochondrial activity actually creates a moderate boost in oxidative stress ("free radical damage") and the associated DNA damage. While DNA damage may seem counterproductive to longevity and good health, the low level of DNA damage actually reduces cell proliferation - slowing growth down to allow the cell's natural repair mechanisms to take effect. "Our findings strengthen the case for targeting HSP90 in tumor cells, but they also open up a fascinating array of questions that may have implications for metabolism and longevity. I predict that the TRAP-1 knockout mouse will be a valuable tool for answering these questions."