Fight Aging!

Another year passes us by, and change is always in the air. As was the case in 2013 more people are working on fundraising, and this is a comparatively recent development. It is taking place at both ends of the funding spectrum: we held a successful $150,000 grassroots fundraiser for early stage rejuvenation research coordinated by the SENS Research Foundation, while Google Ventures is working to pour hundreds of millions of dollars into much more mainstream Big Pharma approaches to aging research. This has also been a year of continued efforts and growth in crowdfunding as it applies to science. Microryza garnered more attention and changed their name to become Experiment, while the Buck Institute has been working on an interesting approach called LabCures. In general I am optimistic that we will see movement beyond a simple cut and paste of Kickstarter towards models more likely to work in research fundraising for modestly sized projects at a large scale.

There have been other funding developments relevant to longevity science around the world also, such as the greater prominence of the UMA Foundation, and a growing confidence in the research community when it comes to talking about treating aging and seeking funding for the same. From the point of view of developing advocacy and conversation this is a whole different world in comparison to just a few years back. Even the large and exceedingly conservative Wellcome Trust research foundation has things to say about longevity and medicine, which hopefully portends more of an investment in the space in the years ahead.

Research prizes of relevance have also emerged as another way for people to attempt to guide significant funding into the scientific projects most useful to a given field - though there are far too few of them given their effectiveness. The New Organ liver prize gained contending teams this year, and the Palo Alto Longevity Prize launched just a few months ago.

In hindsight some years hence it is likely that the Google investment in longevity science, for all that I see it achieving little of immediate practical relevance to human longevity because of its focus on pharmaceutical development, is the sort of landmark that people point to when noting that "this is where things changed." It is hard to pick out the exact point of a pivotal shift in a field of science and technology, because in truth these things are always slow and hard-fought incremental changes at the time, but we are in the midst of one now. Aging research is changing from a field of look-but-don't-touch to a field of clinical intervention, developing the means to slow, repair, or otherwise alter the aging process rather than merely cataloging what is taking place when we decline with age.

Thus I think that the long period of persuading the research community to talk about, support, and work on treatments for the causes of aging is nearly over. Now the efforts move to persuading people to fund the work, persuading researchers to work on projects that are likely to produce actual results in the near future rather than just data, and persuading the public to support the idea of curing all age-related disease - something that a surprisingly large majority oppose at this time.

So the market is up, investing is hot, and Google's California Life Company is far from the only longevity-related venture that received significant funding this year. Reinforcing the view of the mainstream that genetics is an important part of any attempt to intervene in aging to enhance healthy longevity, Human Longevity, Inc. raised tens of millions this year also. Sadly, again, I really think this is one of those initiatives that can improve medicine and the state of knowledge considerably without having much of a hope of moving the needle on practical treatments to extend life. Another similar venture closer to our community that launched this year was In Silico Medicine.

This tendency for the mainstream to pursue courses that are natural extensions of the research imperative to map all genetics and metabolism, but which are very unlikely to produce rejuvenation treatments that can help the old, is exactly why we need more grassroots advocacy and fundraising to draw attention to SENS and similar repair-based strategies. The deciphering and manipulation of metabolism will be slow, exceedingly expensive, and no-one has a concrete plan at this point as to how to produce meaningful results. The most likely outcome for the next two decades is a few drugs that might slightly slow aging - adding perhaps five years to human life span if someone can recapture almost all of the natural calorie restriction response. If that is all that happens, it will be a grand missed opportunity. The whole point of SENS as a research strategy is that we don't have to strive to understand the whole of aging and manipulate highly complex metabolic states in this way: researchers can instead try to repair the known fundamental differences between old and young tissues. These differences are well-described and well-known to a point sufficient for detailed plans for repair therapies to exist. The development of these therapies will thus cost a fraction of the exploration of metabolism needed for the slowing aging approach, and since repair will induce rejuvenation the expected outcome is far better: adding decades to healthy life spans, not merely a few years.

But much of the research community remains to be convinced. There is an enormous inertia in the Big Pharma, drug discovery, work backwards from the end state of aging approach that has consumed billions over the past decade in search of age-slowing drugs with nothing to show for it but data and an increased appreciation for the complexity of our biology. If that funding had gone to SENS, there are good odds we'd have the answer today as to whether many of its repair modes can create rejuvenation in old mice. Thus much advocacy lies ahead: we still have to make this happen if we want a good shot at living to see human rejuvenation.

Speaking of advocacy, this past year the SENS Research Foundation launched a new conference series, Rejuvenation Biotechnology, that is intended to build the relationships between science and industry needed for faster commercial hand-off and support of the sort of repair biotechnologies that the Foundation works on. By all accounts the first conference went pretty well. The second in the series is coming in 2015, so stay tuned. Other interesting conference series going strong include the Genetics of Aging and Longevity Conference organized by groups within the active Russian gerontology community. Of course there is a near endless parade of conferences devoted to individual fields that are relevant to longevity science: those for the large and still growing fields of tissue engineering and regenerative medicine alone would be quite a long list.

On a sad note, this past year saw the death of several vocal and productive members of the advocacy community. As our community grows, the consequences of aging become ever more apparent. The one closest to my network was Stephen Coles of the Gerontology Research Group, whom you might recall as one of the researchers involved in uncovering the predominant cause of death in supercentenarians, but he was by no means the only one. This should be a continued and painful reminder for all of us as to why we do this: why persuade the world, why raise funds, why keep working on the science. It is perhaps unfortunate that it is only human to feel little to nothing for the hundreds of people who will die due to aging while you read this post, and to only be affected by the comparatively few deaths among those people you happen to have exchanged emails with here and there.

But on to the science, which does not suffer as we do, and it is, I think, why most of you peruse this modest website, after all. This year has seen something of great interest every month, usually several advances if you are particularly enmeshed in the field. There are scores of very interesting items buried in the posts here from the past year, and I couldn't possibly mention them all. I'd say that the theme of the year was stem cell research and tissue engineering, but that is the theme for every year. This is the age of cell control with all that implies, and the advances in regrowth and regeneration are going to continue apace for decades yet: every few weeks a research group somewhere in the world is discovering a new way to make cells perform desired tasks, or coming that little bit closer to building an organ from scratch.

If there was a theme unique to the year, than it is probably that genetics has reached the sort of critical mass that stem cell research did a decade ago. Unlike stem cell research this is of less direct relevance to the path to human rejuvenation, however, although all improvements in the tools of biotechnology are welcome. The variations in human genetics that influence variations in natural longevity are fascinating, but we all age for the same root causes. Any repair technology that successfully treats aging will be exactly the same for everyone: the subtle genetic variants in our responses to the cellular and molecular damage that cause aging simply don't matter if we can repair that damage.

Another important theme in the past year of research has been the parabiosis experiments in which old and young mice have their circulatory systems linked. Results are, as usual, mixed. Researchers are showing benefits from manipulation of levels of GDF-11, but also finding that replicating the effects of parabiosis via blood transfusion isn't straightforward and doesn't seem to have the same outcome. There are human transfusion trials underway, but based on the results in mice I'm not expecting much to result from that effort.

For research directly relevant to rejuvenation after the SENS model, you might look at the 2014 annual report from the SENS Research Foundation, which is a glossy overview of advances made in the last twelve months. One of the items the Foundation leadership is particularly pleased with is progress in the comparatively high-profile work on catabody methodologies to treat senile systemic amyloidosis, the condition thought to kill the very oldest people who survive everything else that old age throws at them. The Foundation staff are doing a lot to change the nature of aging research, and not just through the scientific projects that they sponsor. It is also a matter of changing minds, persuading more people to move from the less effective old Big Pharma model of medical research via drug discovery to work on new and more exciting technologies that can lead to rejuvenation.

To wind up this post, I'll note that I have been slacking when it comes writing my own short essays from scratch rather than commenting at length in reaction to events and publications. So the following is a short list this year, but I hope that you find some of them interesting if you missed them the first time around:

• The 2010s in Biotechnology Reflect the 1960s in Computing
• It Comes Time for the Next Wave of Advocacy and Initiatives in Longevity Science
• The Decade to Come in Which Treatments for Aging Exist, But Are Largely Illegal
• What is Robust Mouse Rejuvenation, and Why Should We Care?
• The Strategic Future of the SENS Research Foundation
• Reaching the Larger Audience
• A Brief Letter to the Long Retired
• Why Do We Advocate for Rejuvenation Research?

Our 2014 fundraiser to benefit the work of the SENS Research Foundation on rejuvenation biotechnology came to a successful completion two weeks ago. At the time I noted that a new $10,000 matching fund was put in place by a generous supporter, and all donations for the remainder of the year are matched. It is now the last day of the year and a little under $2,000 remains in order to meet this goal. So donate!

We are excited to note that a new challenge grant has been received from Ronny Hatteland, AutoStore - Software Developer. For every dollar we receive from now until the end of the year (December 15 - 31st), the first $10,000 will be matched by Ronny's generous gift. Ronny tells us that "The work of the SENS Research Foundation gives us all a chance to secure ourselves a healthy future and an extended lifetime to continue to embrace all that life has to offer us. I am very pleased to support SENS Research Foundation and I encourage all of you to join me."

Link: http://sens.org/donate

The use of scaffolding in regenerative medicine is becoming more sophisticated, with researchers developing a wider range of approaches that offer a variety of different structural characteristics. This allows for attempts to repair load bearing or supporting tissues such as ligaments and tendons:

Not only is the anterior cruciate ligament (ACL) inelastic and prone to popping, it is incapable of healing itself, causing surgeons to rely on autografts for reconstruction. Most common is the bone-patellar tendon-bone (BPTB) graft, in which the surgeon removes part of the patellar tendon to replace the damaged ACL. "BPTB autografts have a high incidence of knee pain and discomfort that does not go away. By saving the patient's patellar tendon and using an off-the-shelf product, one may have a better chance of preserving the natural biomechanics of the knee."

[Researchers] are working to engineer such a product by combining three components: polyester fibers that are braided to increase strength and toughness, an inherently antioxidant and porous biomaterial, and calcium nanocrystals, a mineral naturally found in human teeth and bones. During ACL reconstruction surgeries, tunnels are drilled into the femur and tibia bones to hold the new ligament in a fixed position. [The researchers] created a bone-like material by combining antioxidant biomaterials with the calcium nanocrystals and then embedded braided polyester fibers into it. The artificial ligament's bone-like ends healed to the native bone in the drilled tunnels, anchoring the ligament into place.

By studying an animal model, the team noticed that the animal's natural bone and tissue cells migrated into the pores of the artificial ligament, populating it throughout and integrating with the bone tunnels. "The engineered ligament is biocompatible and can stabilize the knee, allowing the animal to function. Most importantly, we may have found a way to integrate an artificial ligament with native bone."

Link: http://www.eurekalert.org/pub_releases/2014-12/nu-run123014.php

Telomeres are caps of repeated DNA sequences at the end of chromosomes. A little telomere length is lost every time a cell divides and its DNA is replicated, and this is one portion of the limiting mechanism that causes the somatic cells that make up the overwhelming majority of tissues to divide only a set number of times and then destroy themselves. Stem cells on the other hand make use of the enzyme telomerase to add repeated DNA sections to the ends of their telomeres as needed. They must maintain lengthy telomeres as it is their job is to continually spin off new long-telomere somatic cells to keep tissues running smoothly. This is a considerable simplification of the actual situation, but it is good enough for this discussion. The important point here is that if you measure average telomere length in a given tissue, and immune cells from blood are the most commonly used for this purpose at the moment, what you are in fact measuring is a some combination of present cell replication rates, cell replenishment rates, and telomerase activity.

There is a statistically significant correlation between average telomere lengths in immune cells and age and illness across a population. This isn't so useful for any given individual looking at a number and trying to figure out whether or not it means anything for future health, but it is true that the older and more ill a person is, the more likely it is for average telomere length in immune cells to be comparatively short. Is this meaningful to efforts to extend life? That is a question worth asking twice, given that telomere length measures look very much like a secondary marker resulting from the characteristic decline of stem cell activity and tissue maintenance with advancing age, and we really want to aim at primary causes rather then secondary and later mechanisms.

Nonetheless, a fair number of researchers are interested in trying to lengthen telomeres as a potential way to treat illness or lengthen life, and in recent years one research group has used gene therapy to raise levels of telomerase in mice. This turns out to extend mouse life span, with the caveats that (a) short-lived mammals like mice actually have quite different telomere dynamics from long-lived mammals such as we humans, so it is far from clear as to what the same thing would do in people, and (b) it is by no means certain what exactly is going on under the hood here. Is telomerase keeping somatic cells alive for longer, it is increasing stem cell activity, is it perhaps interacting with mitochondria in some way to reduce their contribution to aging, or is some other as yet undiscovered mechanism is at work?

Researchers will come to a conclusion at some point, as there seems to be slow but steady progress towards further investigations of telomerase gene therapy in mice. The same group that pioneered this approach is now heading down the traditional path of attempts to apply this treatment as a late stage intervention for age-related disease and dysfunction. They do this because it is still the only practical way to bring treatments to the clinic these days: approaches are inevitably sidelined into marginal applications intended to be applied after the damage is done. It is a ridiculous situation, and one that causes immense damage to the pace of progress by diverting researchers away from producing methods of prevention.

CNIO researchers treat heart attacks with new gene therapy based on telomerase enzyme

The enzyme telomerase repairs cell damage produced by ageing, and has been used successfully in therapies to lengthen the life of mice. Now it has been observed that it could also be used to cure illnesses related to the ageing process. Researchers at the Spanish National Cancer Research Centre (CNIO) have for the first time treated myocardial infarction with telomerase by designing a very innovative strategy: a gene therapy that reactivates the telomerase gene only in the heart of adult mice, thus increasing survival rates in those animals by 17% following a heart attack.

"We have discovered that following a myocardial infarction, hearts that express telomerase show less heart dilatation, better ventricular function and smaller scars from the heart attack; these cardiac events are associated with an increased survival of 17% compared to control animals." Furthermore, everything points to cardiomyocytes - the cells responsible for heart beating - being regenerated in those hearts with telomerase, a long searched-for goal in post-heart-attack therapy. The regeneration of heart muscle would counter the formation of scars as a consequence of the heart attack, a tough tissue that hinders cardiac function and increases the likelihood of heart failure.

Telomerase expression confers cardioprotection in the adult mouse heart after acute myocardial infarction

Coronary heart disease is one of the main causes of death in the developed world, and treatment success remains modest, with high mortality rates within 1 year after myocardial infarction (MI). Thus, new therapeutic targets and effective treatments are necessary. Short telomeres are risk factors for age-associated diseases, including heart disease. Here we address the potential of telomerase (​Tert) activation in prevention of heart failure after MI in adult mice. We use adeno-associated viruses for cardiac-specific ​Tert expression. We find that upon MI, hearts expressing ​Tert show attenuated cardiac dilation, improved ventricular function and smaller infarct scars concomitant with increased mouse survival by 17% compared with controls. Our work suggests telomerase activation could be a therapeutic strategy to prevent heart failure after MI.

Some autoimmune diseases can be successfully treated by suppressing or destroying the existing immune system and then transplanting new stem cell populations responsible for generating immune cells. This can result in an effective resetting of the immune system, or at least removal of those parts of it that have become misconfigured to attack the patient's own tissues. It is, however, a pretty drastic process and certainly not one to be undertaken lightly: the sort of chemotherapy required is not a walk in the part for the patient. For autoimmune conditions where even partially effective alternative treatments exist, as is the case for rheumatoid arthritis, for example, researchers have all but abandoned work on the destroy-and-rebuild approach despite some early promising results. Nonetheless, it has been shown to produce results in terms of halting the progression of multiple sclerosis (MS), one of the more serious forms of autoimmunity in which the myelin sheathing of nerves is attacked:

Multiple sclerosis (MS) is a degenerative disease and most patients who receive disease-modifying therapies experience recurrence of the disease process. Three years after a small number of patients with MS were treated with high-dose immunosuppressive therapy (HDIT) and then transplanted with their own hematopoietic stem cells, most of the patients sustained remission of active relapsing-remitting MS (RRMS) and had improvements in neurological function.

Study results indicate that of the 24 patients who received HDIT/HCT, the overall rate of event-free survival was 78.4 percent at three years, which was defined as survival without death or disease from a loss of neurologic function, clinical relapse or new lesions observed on imaging. Progression-free survival and clinical relapse-free survival were 90.9 percent and 86.3 percent, respectively, at three years. The authors note that adverse events were consistent with the expected toxic effect of HDIT/HCT and that no acute treatment-related neurologic adverse events were seen. Improvements in neurologic disability, quality-of-life and functional scores also were noted.

"In the present study, HDIT/HCT induced remission of MS disease activity up to three years in most participants. It may therefore represent a potential therapeutic option for patients with MS in whom conventional immunotherapy fails, as well as for other severe immune-mediated diseases of the central nervous system. Most early toxic effects were hematologic and gastrointestinal and were expected and reversible. Longer follow-up is needed to determine the durability of the response."

Link: http://www.eurekalert.org/pub_releases/2014-12/tjnj-ror122614.php

Studies of many aged brains shows that the progression of various types of dementia correlates with a history of many small, unnoticed strokes. These leave behind small infarcts, areas of tissue death in the brain caused by a local blockage of small blood vessels. The brains of people suffering neurodegeneration tend to have more of these infarcts. Is this causative, however? Some of the past evidence is fairly compelling with regard to causation, but this remains an open question: since aging is a global phenomenon many of its aspects should be expected to correlate with one another regardless of any direct linkage.

Here is another recent paper demonstrating the correlation, in which the researchers show off the capabilities of an evolution of magnetic resonance imaging (MRI) technology that is more capable of picking out these small areas of structural damage than has been the case in the past:

Until recently cortical microinfarcts (CMIs) were considered as the invisible lesions in clinical-radiological correlation studies that rely on conventional structural magnetic resonance imaging. The present study investigates the presence of CMIs on 7.0-T magnetic resonance imaging (MRI) in post-mortem brains with different neurodegenerative and cerebrovascular diseases. One hundred-seventy five post-mortem brains, composed of 37 with pure Alzheimer's disease (AD), 12 with AD associated to cerebral amyloid angiopathy (AD-CAA), 38 with frontotemporal lobar degeneration, 12 with amyotrophic lateral sclerosis, 16 with Lewy body disease (LBD), 21 with progressive supranuclear palsy, 18 with vascular dementia (VaD) and 21 controls were examined. According to their size several types of CMIs were detected on 3 coronal sections of a cerebral hemisphere with 7.0-T MRI and compared to the mean CMI load observed on histological examination of one standard separate coronal section of a cerebral hemisphere at the level of the mamillary body.

Overall CMIs were significantly prevalent in those brains with neurodegenerative and cerebrovascular diseases associated to CAA compared to those without CAA. VaD, AD-CAA and LBD brains had significantly more CMIs compared to the controls. While all types of CMIs were increased in VaD and AD-CAA brains, a predominance of the smallest ones was observed in the LBD brains. The present study shows that 7.0-T MRI allows the detection of several types of MICs and their contribution to the cognitive decline in different neurodegenerative and cerebrovascular diseases.

Link: http://dx.doi.org/10.1016/j.jns.2014.07.061

For much of this year the Bristlecone, the Methuselah Foundation's blog, has published a series of interviews with researchers of note in the field of tissue engineering. They have been quite education, often covering some of the important infrastructural aspects of the research and development process that gain little attention elsewhere. The Foundation has a strong interest in advancing this arm of medicine, and does so through strategic early stage investments, such as in bioprinter startup Organovo, as well as through initiatives such as the New Organ research prize series. This month the Bristlecone published a lengthy three part interview with David Williams of the Tissue Engineering and Regenerative Medicine International Society (TERMIS). Some interesting opinions can be found therein, and you should certainly read the whole thing as there is much more there than is quoted below:

Biomaterials and Clinical Translation

I published a short paper recently called "The Biomaterials Conundrum in Tissue Engineering," and to put it simply, I think we've mostly gotten it wrong. I'm not being too critical, because it was probably inevitable, but the early attempts at tissue engineering involved material scaffolds, and that's where biomaterials come in. The scaffold is the form in which you're going to develop an engineered organ, and the originators felt that they needed to get FDA approval for them. Therefore, they needed to use an FDA approved material, and although this was understandable, I think it was misguided.

The sole criteria for FDA approval for biomaterials used in implantable devices was that the material did no harm. It had to be known to be safe. You're never going to get a scaffold or template material to function properly if all it does is play safe. You need the material to actually stimulate cells through mechanical forces or growth factor delivery, and standard synthetic polymers were never going to do this reliably and routinely. Because of this, I think we need totally different types of materials that try to replicate or represent the micro-environment of the cell. I've been shouting this from the rooftops for a long time now. It can't be an engineered fabricated structure that looks nothing like the cell micro-environment, or we'll never be able to make the cell regenerate the tissues that we want.

We do have a number of pretty good hydrogels that do this, especially biologically-based hydrogels. That's why decellularized extracellular matrix (ECM) is getting so popular. I don't think we're there yet by any means, but there are some interesting approaches around. But the key is that we have to have a different mindset regarding how we develop our biomaterials, and the regulators have to have a different mindset regarding how they regulate them. We can't use the standard tests for safety that the FDA is saying that we still have to use, and that's a big issue at the moment. For the most part, the regulators still want to play it too safe.

Core Principles and Challenges

Bear in mind that what we're trying to do is to take a group of cells and persuade them to do something they don't want to do. That is, to express new extracellular matrix that can then be organized into the structure and function of an organ. I think many of the different scientific principles are in place. We've made big progress already, and to me, the key issue is in putting everything together such that we can develop the structures that function as organs do. We know how to do the little bits, but we still have to explore the complex functioning of the whole.

[Vascularization] is still one of the most important issues. There has been a fair bit of progress made in vascularization, especially in using some small molecules and certain growth factors to encourage newer vascularization. So there are encouraging signs in this area, but it does remain one of the bigger challenges. Take muscle tissue engineering, for example. It's already possible to regenerate small amounts of muscle, but the integration of that into a functional muscle regenerative project is much, much harder. We need to address the integration issues more than anything, and we need to start doing it for the areas where our current therapies are weakest. We had to start somewhere, and so skin, cartilage, and bone were good starting points. In most all of these areas, we've now had some degree of clinical success in alternative treatment modalities. Where we don't have good therapies at the moment is in areas like degenerative disease, especially neurodegeneration and musculo-skeletal regeneration, and I'd like to see more effort being addressed in those areas.

The International Front

It's pretty clear that the United States, and a few countries in Europe, and one or two elsewhere, are at the forefront of developments in these medical technologies in regenerative medicine. But they can't do everything. We have to recognize that there are very good academic, clinical, and commercial entities all around the world. And I think it is appropriate that we interact with them in order to get the best of everything.

Also, when you look at issues of commercialization and clinical translation, we know that here in the U.S., there are - sometimes understandably - many limitations and barriers to how far and how fast we can go. And there are opportunities in other parts of the world where there are different formats and different styles. Part of my rationale is to try to get the best of all possible commercial, clinical, and academic opportunities in different parts of the world.

Below find referenced an interesting view of age-related changes in brain function and memory. As is true throughout the aging body and brain, the higher level changes produced in these intricate systems are far more complex than the few forms of cellular and tissue damage thought to cause aging. Simple damage and a complex system inevitably leads to complex outcomes, but that doesn't necessarily mean it is as hard to fix the damage as it is to understand the system. Consider rust in an ornate, many-legged, load-bearing iron structure as an analogy. Rust is easily dealt with, but it would be hard to try to model or predict exactly the ways in which the structure will weaken and fail over time.

The relatively random spiking times of individual neurons provide a source of noise in the brain. We show how this noise interacting with altered depth in the basins of attraction of networks involved in short-term memory, attention, and episodic memory provide an approach to understanding some of the cognitive changes in normal aging. The effects of the neurobiological changes in aging that are considered include reduced synaptic modification and maintenance during learning produced in part through reduced acetylcholine in normal aging, reduced dopamine which reduces NMDA-receptor mediated effects, reduced noradrenaline which increases cAMP and thus shunts excitatory synaptic inputs, and the effects of a reduction in acetylcholine in increasing spike frequency adaptation.

Using integrate-and-fire simulations of an attractor network implementing memory recall and short-term memory, it is shown that all these changes associated with aging reduce the firing rates of the excitatory neurons, which in turn reduce the depth of the basins of attraction, resulting in a much decreased probability in maintaining in short-term memory what has been recalled from the attractor network. This stochastic dynamics approach opens up new ways to understand and potentially treat the effects of normal aging on memory and cognitive functions.

Link: http://dx.doi.org/10.1016/j.nlm.2014.12.003

This is a look at a specific form of mitochondrial dysfunction in aging heart tissue, with a focus on the sarcoplasmic reticulum structure inside cells responsible for, among other things, storing and pumping calcium ions. Calcium has many roles; calcium ions (Ca2+) are important in signaling for muscle contractions for example. Here it seems that the problem lies in the interaction between two cellular organelles, and is more subtle than just damage to one or other:

Mitochondrial alterations are critically involved in increased vulnerability to disease during aging. We investigated the contribution of mitochondria-sarcoplasmic reticulum (SR) communication in cardiomyocyte functional alterations during aging. Heart function [was] preserved in hearts from old mice (20 months) with respect to young mice (5 - 6 months). Mitochondrial membrane potential and resting O2 consumption were similar in mitochondria from young and old hearts. However, maximal ADP-stimulated O2 consumption was specifically reduced in interfibrillar mitochondria from aged hearts.

Second generation proteomics disclosed an increased mitochondrial protein oxidation in advanced age. Because energy production and oxidative status are regulated by mitochondrial Ca2+, we investigated the effect of age on mitochondrial Ca2+ uptake. Although no age-dependent differences were found in Ca2+ uptake kinetics in isolated mitochondria, mitochondrial Ca2+ uptake secondary to SR Ca2+ release was significantly reduced in cardiomyocytes from old hearts, and this effect was associated with decreased NAD(P)H regeneration and increased mitochondrial reactive oxygen species (ROS) upon increased contractile activity.

[We] identified the defective communication between mitochondrial voltage-dependent anion channel and SR ryanodine receptor (RyR) in cardiomyocytes from aged hearts associated with altered Ca2+ handling. Age-dependent alterations in SR Ca2+ transfer to mitochondria and in Ca2+ handling could be reproduced in cardiomyoctes from young hearts after interorganelle disruption with colchicine, at concentrations that had no effect in aged cardiomyocytes or isolated mitochondria. Thus, defective SR-mitochondria communication underlies inefficient interorganelle Ca2+ exchange that contributes to energy demand/supply mismatch and oxidative stress in the aged heart.

Link: http://dx.doi.org/10.1038/cddis.2014.526

Establishing a research prize is a form of investment in progress only available in the philanthropic world. At the very high level it is easy to say that philanthropists pay people to work on specific tasks. This is simple enough for smaller amounts: transfer a few thousand dollars to a research group and you have bought a very small slice of the time and equipment needed to achieve any particular goal. When we start talking about much larger amounts of money, millions or tens of millions, then there are important secondary effects that occur when making such investments. In these amounts money has gravity, money makes people talk, and money changes behavior and expectations in a far larger demographic than just the recipients. This is well known, and thus investment activities, philanthropic and otherwise, become structured to best take advantage of this halo of effects. Most of the experience in doing this comes from the for-profit world: it doesn't take too long spent following the venture capital industry to see that investment is a lot more complicated than choosing a target and writing a check, and this is exactly because there are many secondary effects of a large investment that can be structured and harvested if investors go about it in the right way.

I theorize that the reason why research prizes remain comparatively rare is that firstly they are an investment strategy restricted to philanthropy, and thus people with the money to burn have little direct experience, and secondly the whole point of the exercise is not in fact paying people to do things directly, but rather creating a situation in which near all of the benefit is realized through the secondary effects generated by the highly publicized existence of a large sum of money. A research prize works by being a sort of extended publicity drive and networking event conducted over a span of years, a beacon to draw attention to teams laboring in obscurity, attract new teams, and raise their odds of obtaining funding. Connections are made and newly invigorated initiatives run beneath the light of a large sum of prize money, but at the end of the day that money becomes more or less irrelevant. It wasn't the important thing, it was merely the ignition point for a much greater blaze of investment and publicity. By the time a team wins, they are typically in a position to raise far more funding than the prize amount provides.

The ideal end result is that a field of science and technology is rejuvenated, taken from obscurity and thrust into the public eye, made attractive to investors, and numerous groups are given the attention and funding they need to carry on independently. This is how it worked for the Ansari X Prize for suborbital flight, and more quietly, for the Mprize for longevity science: in both cases the entire field changed as a result of the existence of the prize and the efforts of the prize organization to draw attention, change minds, and build new networks. But the award of money wasn't the transformative act, and in fact that award didn't really occur at all for the Mprize, but rather change was created through the sum of all of the surrounding effects.

So consider this: people who arrive at the state of being wealthy and wanting to change the world through philanthropy, often after decades of for-profit investment participation, don't have much in the way of comparable experience to guide them in the establishment and operation of research prizes. Thus creation of a research prize falls low in the list of strategies under consideration by high net worth philanthropists. Few people do it, and so there are few examples from which others can learn. It is the standard vicious circle of development, in which steady, grinding bootstrapping is the only way to create change.

Why care? Because research prizes work well. They work exceedingly well. Depending on how you care to plug numbers into equations, a well-run prize of $10 million will generate $150 to $500 million in investment in an industry, and that is just the easily measured result. Just as important is the following change and growth enabled by that initial burst of attention and funding. The Ansari X Prize spawned a number of other prizes in various industries, but I think it remains the case that medicine and biotechnology is poorly served in this respect. Outside of the efforts of the X Prize Foundation, the New Organ prizes, and other independent efforts such as the Palo Alto Longevity Prize, there is little going on. Given the proven utility of prizes there should be many more of them, and yet there are not.

In this context it is interesting to see the X Prize Foundation promoting the prize approach to a scientific audience, one of the demographics that should be more hospitable to prizes and participation in these efforts than is in fact the case.

Incentivizing Breakthroughs

Some inventors and innovators find themselves in a difficult spot, having advanced products beyond basic research - so that they do not usually qualify for government funding - but not near enough to commercialization to appeal to venture capitalists. To avoid this mid-stage "Valley of Death," life-science and technology innovators are spending more of their time searching for new funding sources. The Internet, with its reach and speed powered by social networking, provides a platform for crowdfunding, an area that is expected to grow over the next 10 years. Contributions from angel investors - typically well-connected, wealthy individuals who invest their own money - and incubator sources have doubled since 2007 in the U.S. and increased more than fivefold in Europe. However, these sources have high aversion to risk. There is another way to fill the funding void left by shrinking government budgets and tightening investor belts: incentivized competitions, which can catalyze innovations and accelerate their real-world impact.

At XPRIZE, formed in 1995, we create and foster high-profile competitions that motivate individuals, companies, and organizations across disciplines to develop innovative ideas and technologies to solve humanity's "Grand Challenges." Two of our prize competitions are specifically focused on medical technology. The XPRIZE model is different from that of governments, venture capitalists, or private investors. Our goal is to identify a health-care problem, define what needs to be addressed, and incentivize the development of a solution. There is often a commercial outcome, allowing the developers to get a return on their investment and provide a benefit to the general public. We are trying to focus on areas that are practical and that serve an existing market or will ultimately create a market that does not yet exist. In so doing, we provide an economic incentive for companies to redirect existing technologies towards new and relevant commercial opportunities. At the same time, we help innovators garner attention from investors and attract capital, support, and team members by creating consumer awareness and providing the general public with an early glimpse of performance. We are also able to connect teams with potential funding and sponsorship opportunities through various networking activities. And the evaluation of the products themselves allows for the assessment of competing technologies in a way that would be unlikely to happen until a product actually went to market.

In short, XPRIZE and other incentivized competitions are objective, unaffiliated, third-party catalysts for innovation, creating a channel for science and technology development in between early-stage work funded by the government and late-stage worked picked up by investors. By focusing on major needs in health that have not been met and incentivizing solutions with real commercial potential for delivery in the next three to five years, we can accelerate the pace of health-care improvements.

Mitochondria, the power plants of the cell, have their own small genomes left over from their ancient origins as symbiotic bacteria. This mitochondrial DNA (mtDNA) becomes damaged in ways that evade cellular quality control mechanisms as a consequence of the normal operation of metabolism. Over the course of a human life span this leads to a small population of cells overtaken by dysfunctional mitochondria, emitting a flood of damaging reactive molecules into surrounding tissues. This contribution to degenerative aging could be removed entirely if we had the means to regularly replace and remove these damaged mitochondrial genomes, or alternatively to deliver an ongoing supply of mitochondrial proteins - as DNA damage is only significant because it removes or alters the blueprints required to generate specific proteins. It is the proteins that are needed for correct mitochondrial function to continue. Given a major research and development initiative working prototypes of these repair technologies are actually only a few years away, but despite a number of teams working on these approaches at a slow pace, until much more funding is devoted to this cause that few years away will continue to be the case.

Here is a recent open access review of the mechanisms by which mitochondrial DNA damage is thought to promote the development of atherosclerosis, such as - but not limited to - formation of oxidized low-density lipoprotein (LDL) molecules that aggravate cells in blood vessel walls into an ultimately harmful reaction. They draw in immune cells that try to consume and break down the LDL, but these cells can be overwhelmed to turn into foam cells or die to create a clot of debris that can grow to become a plaque. That in turn can cause a catastrophic blockage of blood flow, and death:

Atherosclerosis, by far the greatest killer in modern society, is a complex disease which can be described as an excessive fibrofatty, proliferative, inflammatory response to damage to the artery wall involving several cell types. Clinical manifestations of atherosclerosis, i.e. mainly coronary artery disease and stroke, are the leading causes of death in all economically developed countries, accounting for up to 65% of total mortality. Many factors appear to contribute to the development of atherosclerosis, [however] the precise mechanisms of atherogenesis are still unclear, even if it is well known that the deposition of intracellular lipids, mainly free and esterified cholesterol, as well as subsequent foam cell formation are the most typical features of early atherosclerotic lesion development. Modified low-density lipoprotein (LDL) is generally thought to be the source of accumulating lipids. Intracellular lipid deposition may act as a trigger mechanism for the development of advanced atherosclerotic lesions.

The mechanisms of mitochondrial genome damage in the development of chronic age-related diseases such as atherosclerosis are not well understood. There is very little data yet showing a causal relationship between mtDNA damage and atherosclerosis, although mitochondrial oxidative stress has been shown to correlate with the progression of human atherosclerosis. Mutations of the mitochondrial genome may play a pathogenic role in the formation of atherosclerotic lesions in arteries. The mitochondrial electron transport chain constantly produces superoxide radical anions, which, in the case of mitochondrial dysfunction, cause the escape of electrons that readily form hydroxyl radicals and hydrogen peroxide from superoxide. These extremely reactive oxygen species (ROS) are risk factors for atherosclerosis associated with lipid and protein oxidation in the vascular wall. ROS formation may trigger a cascade of events such as modification of LDL, inflammation, cellular apoptosis and endothelial injury.

Link: http://dx.doi.org/10.1159/000368923

Some of the important processes in aging are known to be initially protective at lower levels and later harmful. Senescent cell accumulation is a good example, as it acts to suppress cancer incidence by permanently removing the most at risk cells from the cell cycle. Yet as senescent cells gather in numbers over the years their actions significantly degrade tissue and organ function.

In the paper quoted below researchers propose that the formation of advanced glycation end-products (AGEs) has a similar protective effect when it comes to cancer, and provide some other benefits besides. Yet their presence is definitely harmful in a number of ways when significant amounts of long-lived AGEs are present, causing chronic inflammation and degrading the mechanical properties of tissues such as skin and blood vessel walls by forming cross-links between structural proteins.

Fortunately in both of these cases periodic removal - of senescent cells or AGE cross-links - on a timescale of once every decade or so would allow us to have our cake and eat it. It would prevent pathological levels of these changes from emerging, as we know humans are quite capable of living for three decades without suffering serious consequences from aging, while still permitting lower and possibly protective levels to arise.

Non-enzymatic formation of advanced glycation endproducts (AGEs) is associated with degenerative diseases. Chronic accumulation of AGEs with age in tissues especially in the extracellular matrix is well known and at least in part responsible for e.g., collagen crosslinking, tissue stiffening and thus induction of high blood pressure or diastolic heart failure. Binding of soluble AGEs to the receptor for AGEs, RAGE, induces an inflammatory response whereas the soluble form of RAGE (sRAGE) can inhibit inflammatory tissue injury like arteriosclerosis in mouse models.

However, there are a number of indications that AGEs have protective effects as well. AGEs may inhibit lung tumor growth, glyoxal induced AGE modification of human heart muscle can reduce an ischemia reperfusion injury and AGEs from nutrition can reduce ROS induced cell damage. In summary, this indicates that protein glycation behaves like a double-edged sword. It induces tissue aging and degenerative diseases on the one hand, on the other hand, may also have protective effects, indicating a hormetic response.

Link: http://dx.doi.org/10.1016/j.exger.2014.12.013

As noted in a prior post, a great deal of theorizing on aging takes place in the research community. We should expect this as the natural outcome of the study of a very complex and still only partially understood system, which is to say the operation of biology and how that changes over time in any given individual, how it differs between species, and why near universal processes such as aging or the calorie restriction response exist. It is a vast field of study into which scientists have made some inroads: the mountains of data and toil of thousands of researchers today is but the foothills of what is to come in the decades ahead. Coming to a full accounting of our biochemistry is the Great Work for this century, but fortunately we could choose to strike out directly for rejuvenation treatments without needing that complete understanding of aging at a detailed level. As outlined by the SENS research proposals, the scientific community does in fact have a well defined and defensible list of the fundamental forms of damage that cause aging, and can envisage in some detail the therapies needed to repair them - and thus reverse the course of aging. All that needs to happen is for more funding and attention to be directed to that path, away from the natural scientific inclination to dismiss applications of their work and focus instead on completing the grand catalog of metabolism and aging, the aforementioned Great Work.

There is some debate in the aging research community over whether cellular and molecular damage is in fact the root cause of aging, essentially a complex form of wear and tear by stages in a self-repairing system of many interacting parts, or whether damage accumulates with age because of the operation of an evolved genetic program. The former is very much the majority position, and baked into the repair approach to rejuvenation, but the latter is a large enough minority to be generating all sorts of internal schisms and hybrid theories in and of itself. This ties back into ongoing investigations into why aging evolved at all, which has become an especially interesting question over time given the growing list of species wherein individuals do not seem to deteriorate with age as we do, even though they fail at the end, such as naked mole-rats, and a very few species whose members might not age to death at all, such as hydras.

This very readable paper from the Russian research community, where programmed aging theories are much more popular than is the case in the English speaking world, meanders through a range of topics with no particular central thesis: what is known of naked mole-rats and their peculiarly age- and cancer-resistant biology; reconciling differences between scientific factions favoring programmed aging versus aging as damage accumulation; thoughts on how aging may accelerate evolutionary change and thus be beneficial for species survival; oxidative mechanisms in aging; and more. It is all interesting, and much of it still relevant insofar as it considers data on biological mechanisms rather than their causes, a useful insight into the thinking of the programmed aging side of the research community. A few snippets are quoted below:

Review: New Data on Programmed Aging - Slow Phenoptosis

The concept of aging as a special biological program provides an alternative to the hypothesis of random errors. According to this concept, aging is a particular case of the phenomenon of programmed death of an organism, phenoptosis. Aging is assumed to accelerate evolution since over the years the organism weakened by aging is subjected to increasing pressure of natural selection. For example, a fox is hardly a factor of natural selection for young hares, which run much faster than the predator. As noted by Aesop, a hare will always run away from the fox because for the hare it is a matter of life and death, and for the fox - of a dinner. However, age-related sarcopenia reduces the hare's running speed, so the fox gets a chance to win the race. As sarcopenia is one of the early signs of aging in mammals, developing well before senile infertility, foxes could accelerate the evolution of hares by eliminating the slowest and least clever individuals.

The biological literature contains many examples of phenoptosis enhancing the organism's ability to evolve (their "evolvability"). Along with aging, they include different mechanisms providing, on one hand, increase in offspring diversity (which is beneficial for the search for new properties) and, on the other hand, the conservatism of inheriting of already acquired useful traits. These mechanisms, while being undoubtedly useful for evolution, are often counterproductive for the individual, as in the case of aging.

The great physicist Leo Szilard believed the reduction of tissue and organ cellularity to be the main cause of aging. According to Szilard, the problem of aging is not so much connected to the fact that each of our cells works worse, but that the number of these cells dramatically decreases with time. Senile sarcopenia, i.e. the reduction of the number of cells (myofibrils) in skeletal muscles, is a typical example of this phenomenon. Age-related weakening of the quality control could save many cells that otherwise would have been destroyed and thus would have exacerbated the reduction of cellularity. Accumulation of cells with random errors in DNA and proteins in the tissues of aging organisms would be a side effect of such a strategy. Gradual weakening of quality control, resulting in the accumulation of errors, is indeed observed in the course of aging; it serves as the main argument for the supporters of aging as the result of random damage. However, we should not forget that reduction of cellularity is likely to have been originally programmed in the genome as the final stage of ontogenesis. Thus, we come to the situation when aging, having begun as the result of the relevant program, is gradually turning into the process of accumulation of random (stochastic) damage to biopolymers, which remain unnoticed by the weakened systems of quality control of these polymers.

It is clearly the case that a few species have evolved death programs of one sort or another, such as a sudden collapse of tissue maintenance or organ function. Salmon are probably the most familiar example, but they are not the only species to decline and die very rapidly following reproductive efforts. The debate between research factions is not over whether these programs exist at all in the natural world, but whether they are usual, and more specifically whether aging in humans and other higher mammals is guided by programs or not. This is relevant to research strategies because efforts to produce rejuvenation should be targeted at primary causes, not secondary and later manifestations of aging.

A herd of bacteria-like mitochondria exist in every cell in the body, constantly dividing, fusing, and swapping component parts among one another, as well as being destroyed when damaged by cellular quality control mechanisms. Mitochondria are responsible for a range of tasks vital to the cell, but the best known involves the creation of ATP chemical energy stores used to power cell operations. Each mitochondrion has at least one copy of the small set of mitochondrial DNA, separate from the DNA in the cell nucleus. As long term readers know damage to this mitochondrial DNA is implicated as one of the primary causes of degenerative aging, leading to a Rube Goldberg chain of consequences that in the end produces a small population of very dysfunctional cells that export damaging reactive molecules to harm tissues both near and far in the body.

Mitochondrial DNA doesn't just become more damaged with age, the number of distinct mitochondrial genomes in a cell - called the copy number - falls dramatically in all cells in many tissues. This has no straightforward or well-understood relationship with mitochondrial damage: it isn't just the dysfunctional cells that have lower copy numbers, and higher copy numbers may be a response to damaged DNA. Falling copy number doesn't linearly correlate with number of mitochondria or the mitochondrial output in term of necessary energy stores for cellular processes, but it does seem to have a significant impact. As an example, researchers here suggest that reduced mitochondrial copy number and its effects on function are a proximate cause for lost insulin production in type 2 diabetes:

Type 2 diabetes is characterised by an age-related decline in insulin secretion. We previously identified a 50% age-related decline in mitochondrial DNA (mtDNA) copy number in isolated human islets. The purpose of this study was to mimic this degree of mtDNA depletion in MIN6 cells to determine whether there is a direct impact on insulin secretion. Transcriptional silencing of mitochondrial transcription factor A, TFAM, decreased mtDNA levels by 40% in MIN6 cells. This level of mtDNA depletion significantly decreased mtDNA gene transcription and translation, resulting in reduced mitochondrial respiratory capacity and ATP production. Glucose-stimulated insulin secretion was impaired following partial mtDNA depletion, but was normalised following treatment with glibenclamide.

This confirms that the deficit in the insulin secretory pathway precedes K+ channel closure, indicating that the impact of mtDNA depletion is at the level of mitochondrial respiration. In conclusion, partial mtDNA depletion to a degree comparable to that seen in aged human islets impaired mitochondrial function and directly decreased insulin secretion. Using our model of partial mtDNA depletion following targeted gene silencing of TFAM, we have managed to mimic the degree of mtDNA depletion observed in aged human islets, and have shown how this correlates with impaired insulin secretion. We therefore predict that the age-related mtDNA depletion in human islets is not simply a biomarker of the aging process, but will contribute to the age-related risk of type 2 diabetes.

Link: http://dx.doi.org/10.1371/journal.pone.0115433

Various tools are presently under development as means to measure age from tissue samples, such as by looking at DNA methylation patterns. A marker for biological age is very much needed in order to speed up development of treatments for aging, as it is presently very expensive and time-consuming to evaluate any sort of putative longevity-enhancing therapy. This is true even in rodents, where it can cost millions of dollars and take three to five years to run a single life span study - and the costs only grow for longer-lived mammals. If much of that could be replaced by a short test carried out immediately before and after treatment then research could proceed much more rapidly. Here is one example of work that might lead to such a marker for age:

Metabolomic and glycomics analysis of blood samples have successfully been used to identify key molecular mechanisms underlying human health and aging. Additional molecular signatures of health and aging can be found using high-throughput proteomics. However, due to the high cost, this has been relatively understudied. Recently, three studies on aging using high-throughput proteomics identified proteins whose plasma levels and cerebrospinal fluid (CSF) levels substantially change with increasing age. However, these studies either did not apply a correction for multiple testing or did not validate their findings in independent cohorts. Proteomics profiling in the CSF study was obtained using SOMAscan, a Slow Off-rate Modified Aptamer (SOMAmer)-based capture array. SOMAscan involves the use of SOMAmers (single-stranded DNA aptamers) to assay proteins in multiplex using DNA microarrays. As such, SOMAscan quantifies the level of the subproteome of proteins targeted by SOMAmers. A total of 1,129 of these SOMAmers are currently available.

The SOMAscan approach has previously been used by us and others to study plasma proteins related to Alzheimer and related phenotypes. In this study, we use the SOMAscan approach to assess the extent to which proteins are correlated with chronological age in a cohort of female twins with independent replication. We further investigate gene expression levels for those proteins that correlate with age using RNAseq data from whole blood in twins. Finally, we examine the association of specific proteins with factors relating to biologic aging such as birthweight and cardiovascular risk.

Eleven proteins were associated with chronological age and were replicated at protein level in an independent population. These were further investigated at gene expression level in 384 females from the TwinsUK cohort. The two most strongly associated proteins were chordin-like protein 1 and pleiotrophin. Chordin-like protein 1 was also significantly correlated with birthweight and with the individual Framingham 10-years cardiovascular risk scores in TwinsUK. Pleiotrophin is a secreted growth factor with a plethora of functions in multiple tissues and known to be a marker for cardiovascular risk and osteoporosis. Our study highlights the importance of proteomics to identify some molecular mechanisms involved in human health and aging.

Link: http://biomedgerontology.oxfordjournals.org/content/early/2014/08/13/gerona.glu121.long

There are many theories of aging, and we should expect more of them arise in the years ahead. On the one hand there is a growing interest in the science of aging as a place where careers can be made and on the other hand there is a great gulf of missing knowledge when it comes to a full and detailed catalog of exactly how aging actually progresses at the very detailed level of cells and cellular mechanisms. That is very much the type of environment that will lead to more theorizing. The research community has a very defensible list of fundamental differences between old and young tissues, changes that result directly from the ordinary operation of metabolism. There is, however, endless debate over which of these forms of damage are important, how they interact, and how they cause other changes and dysfunction. There is even a higher level debate over whether accumulated damage is in fact the cause of aging, or whether damages instead results from the operation of an epigenetic program that is itself the root cause of aging.

Mountains of data are being gathered on an ongoing basis to feed into this mill. As a process that is actually fairly typical for modern fields wherein the researchers study very complex systems but are collectively nowhere near attaining a full understanding of those systems. We live in an age in which obtaining and managing data in massive volumes is now feasible, and the all too human researchers are often playing catch up in the analysis. So there is a lot of back and forth, many conflicting study results, and everyone of note has their own pet hypotheses when it comes to poorly understood areas of the field. Aging research is far from the only area of scientific study that looks this way at present, and this is how science is done at the cutting edge.

As an aside, the primary and most important conceptual innovation contained in the Strategies for Engineered Negligible Senescence (SENS) is to note that since there exists a defensible list of fundamental differences between old and young tissues, we can skip the full understanding that will likely require decades further to arrive and use that list to work directly on repair biotechnologies now. The majority of the as yet unknown details of how and why simply don't matter all that much from a practical engineering perspective of producing rejuvenation treatments. In this, SENS is firmly in the aging as damage accumulation camp.

Over at the Russian end of the research community there tends to be more support for programmed aging theories. In their most common manifestation these theories suggest that aging is driven by epigenetic changes, and evolutionary processes select for aging to exist in this form. This might be because specific mechanisms are beneficial in youth and are thus selected for despite the fact that they run awry after reproductive life span is ended, a concept known as antagonist pleiotropy. It may be because aging allows for more successful adaptation of the species in the face of environmental change. There are many other evolutionary theories of aging, and there is some overlap between those used to explain programmed aging versus those used to explain aging as an accumulation of damage. The evolutionary explanations for aging are "why" and the mechanisms by which we age are "how", and those two questions can be considered separately from one another.

Just as there is a lot of debate among researchers who see aging as damage accumulation, there is similarly a lot of debate among researchers who theorize on programmed aging. This is an interesting if fairly dense paper from Russian researchers. If I'm reading it correctly, they are suggesting that aging is caused by a drift of set points in the biological mechanisms collectively responsible for maintaining homeostasis, keeping everything roughly the same and in place throughout an organism. That seems to me a layer of explanation on top of the more general idea that epigenetic changes happen in aging and they are the fundamental cause of damage rather than being responses to damage, though the researchers here declare their theory a third way, neither programmed nor damage-based:

Aging Is a Simple Deprivation Syndrome Driven by a Quasi-programmed Preventable and Reversible Drift of Control System Set Points Due to Inappropriate Organism - Environment Interaction

There are two well-known but opposing concepts of the reason for aging. The first supposes that senescence is programmed similarly to the genetic program of development from a zygote up to a mature organism. Genetically determined senile wasting is thought to be associated with the necessity to renovate the population to ensure its adaptation and survival. According to the concept of the stochastic aging (due to accumulation of occasional error and damage), there is no built-in program of aging. There is only a program of development up to the state of maturity, and then the organism should be able to maintain itself limitlessly. However, although the efficiency of repair systems is assumed to be rather high, it is less than 100%. Just this has to result in aging because of accumulation of various errors.

We have continued and developed another approach that considers both programmed and stochastic concepts to be incorrect. Aging is a simple deprivation syndrome driven by preventable and even reversible drifts of control systems set points because of an inappropriate "organism-environment" interaction.

Reading the whole thing, which isn't long enough to fully outline the thinking here, it seems pretty easy to pick holes in this. But the core idea of a set point drift is an interesting one in the context of present debates over the details of aging. That said it is probably not very relevant to the type of research strategy that I support. Fix the damage first, move as rapidly as possible towards saving lives, and then figure out how young turns to old in as much detail as you like - you'll have the time for it.

The immune system is known to play an important role in regeneration, but the details are still being uncovered. Nonetheless at some point in the near future manipulation of immune cells may prove to be a viable alternative path in regenerative medicine, a different way to achieve faster healing or spur tissue regrowth where it does not normally occur.

Cells from the immune system called macrophages - those in charge of devouring invading pathogens, for example - are also responsible for activating skin stem cells and induce hair growth. The researchers did not investigate the relationship between macrophages and hair for fun. This work emerged more than four years ago from an observation [made] while working on another research project. The mice [at] that time received anti-inflammatory drugs, a treatment that also reactivated hair growth. Convinced that the explanation could reside in the existence of close communication between stem cells and immune cells [the researchers] began to experiment with the different types of cells involved in the body's defense system.

After years of investigation, they discovered that when stem cells are dormant, a fraction of macrophages die, due to a process known as apoptosis. This stimulated the secretion of factors from dying and living macrophages, which in turn activated stem cells, and that is when hairs began to grow again. Macrophages secrete a number of factors including a class of proteins called Wnt. Researchers demonstrated the participation of macrophage-derived Wnts by artificially reproducing the natural process by treating macrophages with a Wnt inhibitor drug encapsulated in liposomes. As expected, when they used this drug, the activation of hair growth was delayed.

From a more fundamental perspective, this research is an effort to understand how modifying the environment that surrounds adult skin stem cells can regulate their regenerative capabilities. "One of the current challenges in the stem cell field is to regulate the activation of endogenous stem cell pools in adult tissues to promote regeneration without the need of transplantation."

Link: http://www.eurekalert.org/pub_releases/2014-12/cndi-cra121914.php

A great deal of effort over the past fifteen years has gone into efforts to fully understand how calorie restriction works to improve health and extend life. The research community would like to have sufficient knowledge to produce drugs that mimic this effect. At this point what researchers have is still a sketch, however: near everything in the operation of metabolism changes in response to reduced calorie intake, which has made it very challenging to figure out cause and effect. Meanwhile, new aspects of calorie restriction biochemistry are discovered on a regular basis these days, with no signs of an end in sight. Researchers here find that one of the benefits provided by calorie restriction is not, as thought, due to increased cellular antioxidant responses, but instead involves hydrogen sulfide (H2S) in some yet to be identified way:

Dietary restriction is a type of intervention that can include reduced overall food intake, decreased consumption of particular macronutrients such as protein, or intermittent bouts of fasting. It is known to have beneficial health effects, including protection from tissue injury and improved metabolism. It has also been shown to extend the lifespan of multiple model organisms, ranging from yeast to primates. The molecular explanations for these effects are not completely understood, but were thought to require protective antioxidant responses activated by the mild oxidative stress caused by dietary restriction itself.

[Researchers] demonstrated that one week of dietary restriction increased antioxidant responses and protected mice from liver ischemia reperfusion injury, but surprisingly, this protective effect was intact even in animals that could not mount such an antioxidant response. Instead, the researchers found that the protection required increased production of H2S, which occurred upon reduction of dietary intake of the two sulfur-containing amino acids, methionine and cysteine. When the diet was supplemented with these two amino acids, increased H2S production and dietary restriction benefits were both lost. The investigators also found that genes involved in H2S production were also required for longevity benefits of dietary restriction in other organisms, including yeast, worms, and flies.

Mammalian cells [produce] low levels of H2S, but this is the first time that this molecule has been linked directly to the health benefits of dietary restriction. "This finding suggests that H2S is one of the key molecules responsible for the benefits of dietary restriction in mammals and lower organisms as well. While more experiments are required to understand how H2S exerts its beneficial effects, it does give us a new perspective on which molecular players to target therapeutically in our efforts to combat human disease and aging."

Link: http://www.hsph.harvard.edu/news/press-releases/molecular-mechanism-behind-health-benefits-of-dietary-restriction-identified/

Two more or less opposing ways to think about the evolution of aging are as follows (a) aging is actively selected for because it provides some benefit to species survival, such as increased adaptability to environmental change, or (b) aging occurs in a post-reproductive part of life that is not under selection pressure, and is thus a side-effect of mechanisms that are selected for because they provide benefits during the earlier period of reproductive life span, but which systematically fail over time. To a certain extent the former viewpoint is associated with the minority position that aging is a genetic program of deterioration while the latter viewpoint is associated with the majority position that aging is caused by an accumulation of cellular and molecular damage.

That sweeping generalization obscures a lot of important subtlety, however. The evolution of aging is a fairly dynamic field of theory, and probably won't settle down until the progression of aging from young to old in individuals is cataloged and understood to a far greater level of detail than is presently the case. That will probably post-date the first rejuvenation treatments, however, as that full understanding isn't necessary in order to construct treatments that repair age-related damage. Or at least it is not necessary provided that aging is caused by damage, as I think to be the case, rather than being a very complicated program of genetic changes that cause damage. If aging is a genetic program, then we are in for a very long and expensive road to any meaningful extension of healthy life.

I ran across an open access paper today that presents a novel view of the evolution of aging, one with a focus on our microbial fellow travelers. It is clear that gut bacteria have a modest degree of influence on aging, but is this large enough for microbial populations to be significant in the evolution of aging? This paper takes more of a programmed aging position in arguing that microbial species that help to wear down and kill the host in later life - that promote faster aging through mechanisms such as chronic inflammation, in other words - are selected for because of this outcome, and not just due to an ability to provide benefits in early life.

Does any of this theorizing matter in a practical sense? Yes in the long term: evolution has proven to be a powerful tool in many fields of medicine. Yes for researchers working on understanding the detailed progression of aging. No if we are focused on repair of the cellular and molecular damage that causes aging, as this repair approach enables us to sidestep a full understanding of how aging progresses. The research community has a robust list of the differences between old and young tissues, so we should be working now to fix them all regardless of how they come about or what exactly their role might be or why they evolved in the first place. Still, this is an interesting enough paper and point of view for me to point it out, and you can probably see why the title caught my eye:

Host Demise as a Beneficial Function of Indigenous Microbiota in Human Hosts

The age structure of human populations is exceptional among animal species. Unlike with most species, human juvenility is extremely extended, and death is not coincident with the end of the reproductive period. We examine the age structure of early humans with models that reveal an extraordinary balance of human fertility and mortality. We hypothesize that the age structure of early humans was maintained by mechanisms incorporating the programmed death of senescent individuals, including by means of interactions with their indigenous microorganisms.

First, before and during reproductive life, there was selection for microbes that preserve host function through regulation of energy homeostasis, promotion of fecundity, and defense against competing high-grade pathogens. Second, we hypothesize that after reproductive life, there was selection for organisms that contribute to host demise. While deleterious to the individual, the presence of such interplay may be salutary for the overall host population in terms of resource utilization, resistance to periodic diminutions in the food supply, and epidemics due to high-grade pathogens.

We provide deterministic mathematical models based on age-structured populations that illustrate the dynamics of such relationships and explore the relevant parameter values within which population viability is maintained. We argue that the age structure of early humans was robust in its balance of the juvenile, reproductive-age, and senescent classes. We hypothesize that the human microbiome evolved mechanisms specific to the mortality of senescent individuals among early humans because their mortality contributed to the stability of the general population. The hypothesis that we present provides new bases for modern medical problems, such as inflammation-induced neoplasia and degenerative diseases of the elderly. We postulate that these mechanisms evolved because they contributed to the stability of early human populations, but their legacy is now a burden on human longevity in the changed modern world.

Cellular senescence is a process that serves to reduce cancer risk by removing damaged cells from the cell cycle and irreversibly suppressing their ability to proliferate. Unfortunately it is also one of the root causes of degenerative aging, as when present in large numbers these cells cause significant damage to surrounding tissue structure and function. They don't go away either: by the time old age rolls around, a sizable fraction of skin cells are senescent, for example. Ideally these cells would be destroyed by the immune system, but that only happens for a fraction of them, and in any case the immune system itself progressively fails in all of its tasks due to the damage of aging.

As the tools of biotechnology rapidly become better and cheaper, researchers are discovering new complexities in every area of cellular metabolism, and senescence is no exception. Cells are exceedingly complicated machines. All of the consensus opinions on how senescence works might be thought of as high level generalities, but there are a lot of exceptions and new information. Senescence isn't as absolutely irreversible as thought; it plays a beneficial role in wound healing; it might steer embryonic development; there are a range of novel ways in which cells can enter a senescent state; and so forth.

Fortunately it is possible to short-cut all of this complexity and skip directly to destroying senescent cells. We know they are bad for us in volume regardless of how exactly they are coming into being, and thus the research community should aim at selective removal of these cells, producing a therapy for periodic application that is perhaps based on some of the work on targeting cell types taking place in the cancer research establishment. Say once a decade, since we know that humans can certainly live for at least three decades without significant impact from cellular senescence. Sadly the direct approach is poorly funded in comparison to ongoing investigations of senescence in detail, but this is par for the course in everything that might actually have some meaningful impact on aging. This must change. Meanwhile here is another research paper uncovering yet more of the complexity of cellular senescence:

Many cells within our bodies, including fibroblasts, hepatocytes, lymphocytes, stem cells and germ cells, are in the state of quiescence, defined as a reversible cell cycle arrest with temporary absence of proliferation. Quiescence is not a passive default state, but instead is actively maintained by specific molecular mechanisms. Some of these cells maintain a quiescent state for long periods of time, even years, and quiescent cells are defined to retain the ability to return into the cell cycle. In vivo, quiescence is considered to limit the uncontrolled proliferation of cells, especially stem cells, whose proliferation has to be controlled properly in order to maintain tissue function.

In order to be reversible, quiescence must grant the return into the cell cycle. Consequently, quiescent cells repress transition into terminal differentiation in which cell cycle arrest is irreversible. However, when transition into irreversible cell cycle arrest is suppressed, reversible non-dividing quiescent cells are less protected against cancer development and are subject to tumor development. While short-term quiescent cells were described to be protected against transition into senescence, long-term quiescent cells may protect themselves against malignant transformation by implementing a senescence-associated cell cycle arrest over longer periods of time. Indeed, most of a human foetal skin fibroblast cell population while being long-term quiescent, were observed to transit into senescence. It remains to be shown to what extent these findings, observed for cultured cells, also hold for cells in tissue.

Telomere shortening as a basic concept for aging assumes that each successive cell division acts as a mitotic counting mechanism inducing replicative senescence. According to this concept, induction of quiescence for a defined amount of time would be predicted to prolong the lifespan of fibroblasts in comparison to constantly proliferating cells. In contrast to this prediction, after long-term quiescence primary human foreskin fibroblasts (HFF) were observed to transit into senescence despite of negligible telomere shortening, questioning that cell division and telomeric attrition is necessarily required for senescence. Here we detect that during long-term quiescence also other human fibroblasts enter senescence. Thus, other effects than telomere shortening, like oxidative stress induced DNA damage, may be responsible for this transition. This is supported by the fact that mouse fibroblasts senesce in culture although mice have very long telomeres.

Link: http://dx.doi.org/10.1371/journal.pone.0115597

This is a review of published research in the biodemography of aging produced by one particular group over the past few years. A lot of their work sits within the framework of reliability theory, which is a fairly high-level but useful model of damage and failure in complex systems. When applied to demographic data on aging reliability theory can produce some interesting predictions, notably that we are all born with an initial load of damage - we don't start from a blank slate. This feeds into observations such as those below on statistical differences in longevity correlating with parental age:

Biodemography is a promising scientific approach based on using demographic data and methods for getting insights into biological mechanisms of observed processes. Recently, new important developments have happened in biodemographic studies of aging and longevity that call into question conventional aging theories and open up novel research directions. Recent studies found that the exponential increase of the mortality risk with age (the famous Gompertz law) continues even at extreme old ages in humans, rats, and mice, thus challenging traditional views about old-age mortality deceleration, mortality leveling-off, and late-life mortality plateaus. This new finding represents a challenge to many aging theories, including the evolutionary theory that explains senescence by a declining force of natural selection with age. Innovative ideas are needed to explain why exactly the same exponential pattern of mortality growth is observed not only at reproductive ages, but also at very-old postreproductive ages (up to 106 years), long after the force of natural selection becomes negligible (when there is no room for its further decline).

Another important recent development is the discovery of long-term 'memory' for early-life experiences in longevity determination. Siblings born to young mothers have significantly higher chances to live up to 100 years, and this new finding, confirmed by two independent research groups, calls for its explanation. As recent studies found, even the place and season of birth matter for human longevity. Beneficial longevity effects of young maternal age are observed only when children of the same parents are compared, while the maternal age effect often could not be detected in across-families studies, presumably being masked by between-family variation. It was also found that male gender of centenarian has a significant positive effect on the survival of adult male biological relatives (brothers and fathers) but not of female relatives. Finally, large gender differences are found in longevity determinants for males and females, suggesting a higher importance of occupation history for male centenarians as well as a higher importance of home environment history for female centenarians.

Link: http://dx.doi.org/10.1159/000369011

Progerin is a malformed variant of lamin A, a protein vital in the nuclear lamina. These are structures that provide mechanical support for the cell, but are also involved in a variety of fundamental and important processes in the cell cycle. The genetic disorder Hutchinson-Gilford progeria syndrome, HGPS or progeria for short, is caused by a rare spontaneous mutation that leads to progerin being created in place of lamin A. Cells are malformed and dysfunctional as a result, and patients rarely live past their early teens. Progeria has the appearance of accelerated aging, characterized by poor tissue maintenance and the development of normally age-related diseases such as atherosclerosis, but at root it is a specific dysfunction in cellular metabolism that is thought to play little to no role in aging.

As an aside there are all sorts of ways to break important aspects of cellular biology to produce results that look at least somewhat like accelerating aging at the high level. The class of DNA repair deficiencies fall into this category, but pretty much anything that causes a significant reduction in stem cell activity will do it. At root aging is damage, but it is a particular balance of various forms of damage. It can be argued either way as to whether we should in fact refer to any of these conditions as accelerating aging, given that they involve forms of cellular damage that do not occur to a significant degree in normal aging.

Over the years since the identification of the cause of progeria there has been some investigation into the degree to which progerin exists and causes harm in old people subject to normal aging. Is it in fact the case that the consensus on this as an insignificant effect is correct? That malformed lamin A is present in small amounts in old tissues seems fairly settled, but this is probably to be expected given the rise in random DNA mutations with age. Are these small amounts sufficient to make it a significant cause of degeneration in comparison to all of the other issues that occur in cellular biochemistry with age? These researchers suggest that at least some stem cell populations are accumulating enough progerin over a human life span to make an impact on their function and thus on their ability to maintain tissues. That in turn would indicate that some mechanism other than random mutation is involved. By the sound of it this group should move on to a proof of concept in an animal model at this point, so as to link the observations made in cell cultures to a meaningful effect on health or stem cell activity - or rule it out, as the case may be:

Progerin expression disrupts critical adult stem cell functions involved in tissue repair

The vascular system is under constant mechanical and inflammatory stress. Fluid pressure and sheer stress combined with inflammatory cytokines lead to damage of the arterial compartment primarily, resulting in injury and death of endothelial, vascular smooth muscle cells and pericytes in the arterial and arteriole walls. In order to repair injured arteries and maintain vascular integrity, damaged or dying cells need to be replaced in a rapid and efficient manner. This is achieved by progenitor or stem cells sensing the damage, migrating to the injured area, differentiating into the needed cell phenotype, and modulating the inflammatory milieu at the injury site. Furthermore, sufficient numbers of these cells are needed in order to maintain a vascular reparative capacity throughout adult life. Thus, these stem/progenitor cells need to self-renew and proliferate in order to maintain a suitable pool of cells available for repair.

The arterial compartment is extremely sensitive to progerin expression, demonstrated by the robust atherosclerosis and vascular diseases exhibited by HGPS patients. Progerin is also expressed in atherosclerotic vascular tissues collected from aged, non-HGPS individuals. Both cases indicate a mechanistic role for progerin expression in interfering with general vascular tissue homeostasis. Efficient vascular repair that is unimpaired by disease or aging requires an adult stem cell population that can maintain their immature status (self-renewal), proliferate, detect damaged tissue and migrate toward it, and contribute to tissue repair by decreasing inflammation and differentiating into necessary cell lineages. We have shown that Marrow Isolated Adult Multilineage Inducible (MIAMI) cells, an immature subpopulation of mesenchymal stem cells, can perform all these described functions and participate in the repair of the arterial compartment both in vivo and in vitro. Interrupting any of these key stem cell functions could decrease vascular repair, increase persistent vascular damage, and result in atherosclerosis and eventual vascular accidents.

The results presented here demonstrate that progerin protein interferes with basic, critical stem cell functions that play an essential role during vascular repair. Endogenous progerin expression observed in MIAMI cells collected from a non-HGPS older donor suggest that MIAMI cells can accumulate progerin in vivo, and therefore are likely subject to the effects of progerin expression. One remarkable observation is that progerin mRNA in MIAMI cells from an aged (65-year old) donor appears to be expressed at similar levels when compared to transduced GFP-progerin MIAMI cells. Because it is likely that cells from aged individuals express progerin at lower levels than cells from HGPS patients, we consider our transduced GFP-Progerin MIAMI cells provide a suitable model to assess the effects of progerin expression in the context of physiological aging in a defined stem/progenitor cell population, with implications to age-related disorders during organismal aging.

Here is an open access review of what is known of changes in the endocrine system that occur with aging. This is many steps removed from the low-level cellular and molecular damage that causes degenerative aging. It is a good example of a body-wide set of linkages between organs and signals and processes in which every change or failure in one component part will cause corresponding reactions in all of the other components.

A sizable field of medicine continues to focus on these changes, trying to find ways to shift levels of hormone signals to be closer to measures taken in youth. In past decades this has produced some legitimate treatments for a variety of age-related conditions that are better than nothing, but unfortunately also a fraudulent network of false "anti-aging" claims and purported therapies that cloud the waters and make any online discussion of this topic difficult. Where legitimate, as an approach it is acting at the wrong level, chasing after secondary and later effects in a very complex system rather than addressing the root causes of changing hormone levels. Consequently it has been challenging to produce more than marginal benefits, which is much as you'd expect if you're trying to tinker a broken system into better performance without actually fixing the breakage. Still, here as elsewhere, there is enormous inertia and resistance to the new concepts of addressing root causes rather than messing with metabolism in this way, and researchers continue to work on ever more sophisticated ways of trying to make the broken machinery perform:

Despite the contribution of sustained improvements in health and social wellbeing to linear gains in life expectancy within the developed world, much of older age is impaired by detrimental changes in body composition and function. Complex alterations in hormonal networks which maintain homeostasis and regulate reproduction, metabolism, nutrition and growth may underlie this poor adaptation to later life. The secretion of hormones decreases within most axes, the impact of which is augmented by a reduction in the sensitivity of tissues to their action, and normal circadian rhythms are lost. Endocrine axes manifest these changes with clinically identifiable losses of function such as those seen in the ageing of the reproductive system (menopause and andropause), the growth axis (somatopause) and axes involving the adrenal gland (adrenopause).

The clinical sequelae of these changes are variable but include reductions in bone, skin and skeletal muscle mass and strength, derangement of insulin signalling, increases in adipose tissue and effects on immune function. Consequently, a number of studies have been carried out to assess the benefits of hormonal supplementation in the elderly, but the efficacy of these interventions remains relatively unclear. Both the menopause and subclinical thyroid disease demonstrate the difficulty in reversing endocrine changes in later life, with minimal impact from thyroxine therapy in subclinical hypothyroidism and multiple reports of harm resulting from hormone replacement therapy in peri- and post-menopausal women.

Given these findings, strategies to locally regulate hormone bioavailability by altering pre-receptor metabolism may offer greater therapeutic potential in the fight against age-related disease. This review aims to provide an overview of the ageing endocrine system and its potential impact on health and disease in the elderly. It will postulate that strategies to coordinate pre-receptor hormone metabolism and a greater understanding of putative hormonal longevity pathways may offer key new drug targets in the fight against ageing, and will argue against applying the conventional endocrine maxim of 'block and replace' to hormonal changes seen during ageing.

Link: http://www.karger.com/Article/FullText/367692

Long-term memory is thought to exist as structures within synapses, which is why the destruction of synapses in the earlier stages of neurodegenerative conditions such as Alzheimer's disease causes memory loss. If memory doesn't exist in the synapses, however, then there is more of a possibility of restoration through effective treatments for the condition. At this point models of long-term memory that put the data somewhere other than the synaptic connections between neurons has an uphill road to travel: past years have seen the accumulation of good evidence for synaptic memory storage, such as experiments in which memory in rats is erased and restored. Nonetheless, this is interesting work:

The new study provides evidence contradicting the idea that long-term memory is stored at synapses. "Long-term memory is not stored at the synapse. That's a radical idea, but that's where the evidence leads. The nervous system appears to be able to regenerate lost synaptic connections. If you can restore the synaptic connections, the memory will come back. It won't be easy, but I believe it's possible."

"If you train an animal on a task, inhibit its ability to produce proteins immediately after training, and then test it 24 hours later, the animal doesn't remember the training. However, if you train an animal, wait 24 hours, and then inject a protein synthesis inhibitor in its brain, the animal shows perfectly good memory 24 hours later. In other words, once memories are formed, if you temporarily disrupt protein synthesis, it doesn't affect long-term memory."

The scientists added serotonin to a Petri dish containing a sensory neuron and motor neuron, waited 24 hours, and then added another brief pulse of serotonin - which served to remind the neurons of the original training - and immediately afterward add the protein synthesis inhibitor. This time, they found that synaptic growth and memory were erased. When they re-counted the synapses, they found that the number had reset to the number before the training. This suggests that the "reminder" pulse of serotonin triggered a new round of memory consolidation, and that inhibiting protein synthesis during this "reconsolidation" erased the memory in the neurons.

If the prevailing wisdom were true - that memories are stored in the synapses - the researchers should have found that the lost synapses were the same ones that had grown in response to the serotonin. But that's not what happened: Instead, they found that some of the new synapses were still present and some were gone, and that some of the original ones were gone, too. There was no obvious pattern to which synapses stayed and which disappeared, which implied that memory is not stored in synapses.

Link: http://www.eurekalert.org/pub_releases/2014-12/uoc--lmm121914.php

The cryonics industry provides the only alternative to the grave for people who will age to death prior to the advent of rejuvenation treatments. Sadly, even after four decades of service this remains a small industry and only a tiny fraction of those who die choose to take advantage of what is offered: low temperature preservation sufficient to maintain the fine structure of the brain until such time as the means for revival are created. Everyone else is gone to dust and oblivion, beyond any hope of returning. A number of people have put in a lot of time and effort to describing how the revival of cryopreserved individuals might be achieved under various scenarios, but the bottom line is that it would require some form of mature molecular nanotechnology industry and all its applications, such as swarms of accurately controlled nanorobots, coupled with the sort of precise control over cellular biochemistry, growing from the present cell research community, that we might envisage being the state of the art five decades from now. None of that is impossible or implausible, it is just far away. But if you are stored in liquid nitrogen you have all the time in the world to wait. Many patients have waited for decades already.

The essence of a good cryopreservation is speed. Reaching storage temperature after perfusion with cryoprotectant chemicals that prevent ice crystal formation must happen as soon as possible following clinical death so as to prevent as much loss of structure and cell death as possible. That preservation must happen after natural death is an artifact of the modern legal battle over euthanasia and other aspects of self-determination in end of life decisions: it is illegal to end your own life in most regions and illegal for anyone to help you in near all. Since people can't choose their time, the whole process becomes much more expensive and uncertain. Standby teams and equipment must be on call, for example, and there are any number of accidental circumstances that can delay cryopreservation simply because the time and place cannot be chosen. Further, what if you suffer a condition that destroys your brain along the way? The courts have not been sympathetic to that situation in the past.

Given this legally-ordained environment, I can't emphasize enough just how important it is to be organized and prepared. You can't just sign up as a member with one of the providers like Alcor or the Cryonics Institute and sit back. You must have a plan in place for accidents and unexpectedly fast declines, and you must have a standing plan for the end of your life before it becomes apparent that things are heading that way. When it does happen you'll have other things on your mind, after all.

The Alcor staff posts cryopreservation notices on an ongoing basis that are quite informative from the point of view of learning what not to do, as well as providing a catalog of slings and arrows that can interrupt even the best laid plans. Just the four reports below illustrate that this is often no walk in the park, and the human body fails in unexpected ways and at unexpected times. Alcor and other cryonics organizations try to go above and beyond even when members and their supporters leave little room to create a good outcome in the present legal environment. Beyond that, these notices also put a human face to many of these patients, those generous enough to allow their preservation to be public. These are people just like you and I who are looking ahead to a brighter future, but, like so many of those presently alive and in the later stages of life, have no hope of living to see the rejuvenation treatments that lie just around the corner, relatively speaking. So near and yet so far.

Camelia Petrozzini Becomes Alcor's 130th Patient

Camelia Petrozzini, Alcor member A-2745, was pronounced legally dead on December 1, 2014 in Chicago, Illinois. Petrozzini, a whole body member, became Alcor's 130th patient on December 2, 2014. A-2745, a member who was on Alcor's Watch List due to stage 4 lung cancer, was planning on relocating to Scottsdale to enter into hospice when her remaining time was short. Despite an expectation that she had a few months remaining, she was taken into the hospital in serious condition in late November. Alcor was not notified of her admission until the family called to say her physician expected she had 8-12 hours remaining. Alcor contacted Suspended Animation and requested an immediate deployment to Chicago. While the response team was on the way, Alcor was able to convince the hospital to heparinize the patient, provide chest compressions and immediately begin to cool in the morgue, if she passed before the team arrived.

The patient passed 12 ½ hours later, roughly 60 minutes before Suspended Animation arrived at the hospital. Numerous issues delayed the transfer of the patient out of the hospital but a broken elevator proved to be too much to make the last commercial flight out for the day. To avoid a straight freeze, an air ambulance was secured and the patient arrived at 4 am into Scottsdale, around 21 hours after pronouncement. A neuro procedure commenced and was followed by a quick clean up and reset as another standby had commenced locally.

A-2454 Becomes Alcor's 129th Patient

Confidential Alcor member A-2454 was pronounced legally dead on September 16, 2014 at 7:36 am (Arizona time) in Pittsburgh, PA. A-2454, a whole body member, became Alcor's 129th patient the same day. On the evening of the first day of Alcor's annual Board Summit, we received an emergency Telemed notification that an 87-year-old member had suffered a respiratory arrest following a choking incident and was at a hospital in a suburb of Pittsburg, PA. The individual had been placed on a ventilator, during which a 36-hour therapeutic hypothermia protocol was induced, in an attempt to diminish the damage to the brain and heart caused by the period of prolonged hypoxia.

The deployment committee discussed the likelihood of the individual surviving this event, and based upon the preliminary information provided by the medical providers it was considered quite high. The reporting family member, who previously had his mother cryopreserved with Alcor, considered the situation more grave and was determined to have a standby initiated. He offered to pay for the costs associated with the standby if it did not result in a suspension.

Based upon this request, Alcor decided to send Aaron and his team to the hospital. After the 36-hour protocol ended, it was determined that the individual had zero brain function remaining and the family decided to terminate life support. Within 10 minutes of withdrawing the ventilator, the patient's heart arrested and the team began stabilization and cool down immediately. An air ambulance was used and paid for by the family with hopes that the reduced travel time might mitigate the damage and increase the perfusability of the brain. Unfortunately, extensive cerebral edema had already occurred and was visible upon establishing the burr holes resulting in the perfusion attempt being stopped shortly thereafter.

Hal Finney Becomes Alcor's 128th Patient

Hal Finney, Alcor member A-1436 who chose the whole-body option, was pronounced legally deceased on August 28, 2014 at 8:50 am at the age of 58, in Scottsdale, Arizona. That same day, Hal became Alcor's 128th patient. Hal, who has had cryopreservation arrangements with the Alcor Foundation for over 20 years, was diagnosed with ALS five years ago and placed on Alcor's Watch List and then monitored over the years as his disease process continued to advance. He made it clear that once he lost the ability to communicate, he did not want his vital functions supported any further but should be allowed to cease functioning and promptly be cryopreserved. "It was actually extremely reassuring as the reality of the diagnosis sunk in," Hal wrote in 2009. "I was surprised, because I've always considered cryonics a long shot. But it turns out that in this kind of situation, it helps tremendously to have reasons for hope, and cryonics provides another avenue for a possibly favorable outcome."

Hal's long-stated wishes were to come to Scottsdale once he lost the ability to communicate with family and friends. When that time arrived, he was flown to Scottsdale by air ambulance with his wife, Fran, at his side. Hal and Fran Finney arrived in Scottsdale, Arizona on Tuesday August 26 where Hal was checked into ICU of a hospital near Alcor where the Alcor response team was set-up and waiting. After the family had a chance to say their goodbyes, Hal's ventilator was disconnected and he was allowed to breathe naturally, all while medical providers ensured that he had no conscious awareness of the process. Defying doctors' expectations, he didn't draw his final breath until 38 hours later, shortly before 9:00 am on Thursday August 28. Immediately after pronouncement of legal death, Alcor's standby team went into action, restoring circulation, ventilation, administering an array of medications, and initiating external cooling. Cryoprotective perfusion - to eliminate ice formation - has been completed and Hal is now undergoing cool down to -196C for long term storage where he be cared for until the day when repair and revival may be possible.

Robert Revitz becomes Alcor's 127th Patient

Alcor member, Robert Revitz (A-1963) moved to Scottsdale specifically to be close to Alcor after he started his membership in 2002. He attended monthly Board of Director meetings and local meet-ups when he was able. Struggling from congestive heart failure in addition to bone cancer, he was occasionally admitted into local hospitals for respiratory relief. Alcor's Medical Response Director, Aaron Drake, closely monitored Robert's health for several months.

In 2014, he fell at home where he fractured his hip and never fully recovered following hip replacement surgery. His primary care physician referred him to hospice-at-home in August as his health declined to the point where he could no longer care for himself. Hospice nurses who were caring for him provided frequent updates and eventually called to say that he had taken a turn for the worse. Preferring to conduct a standby in a controlled environment rather than an individual's home, Robert was transferred by ambulance into the same hospital that Alcor typically uses and a standby began. On August 15th, 2014, less than 24 hours after being admitted Robert, a neuro member, was pronounced and became Alcor's 127th patient.

Not all muscles in the body age equally, it seems, and those surrounding the eye are spared many of the degenerative changes that occur elsewhere. Investigating why this is the case may help to inform other lines of research that aim to revert the characteristic age-related decline in stem cell activity, and thereby restore function to increasingly frail tissues. At present groups working on reversal of stem cell aging are largely focused on the stem cell populations associated with muscles, such as satellite cells, as this is where many of the early relevant discoveries occurred, the tissues are easily accessible, and these cell types are fairly well understood and comparatively easy to work with.

Specific muscles are spared in many degenerative myopathies. Most notably, the extraocular muscles (EOMs) do not show clinical signs of late stage myopathies including the accumulation of fibrosis and fat. It has been proposed that an altered stem cell niche underlies the resistance of EOMs in these pathologies, however, to date, no reports have provided a detailed characterization of the EOM stem cell niche.

PW1/Peg3 is expressed in progenitor cells in all adult tissues including satellite cells and a subset of interstitial non-satellite cell progenitors in muscle. These PW1-positive interstitial cells (PICs) include a fibroadipogenic progenitor population (FAP) that give rise to fat and fibrosis in late stage myopathies. PICs/FAPs are mobilized following injury and FAPs exert a promyogenic role upon myoblasts in vitro but require the presence of a minimal population of satellite cells in vivo. We and others recently described that FAPs express promyogenic factors while satellite cells express antimyogenic factors suggesting that PICs/FAPs act as support niche cells in skeletal muscle through paracrine interactions.

We analyzed the EOM stem cell niche in young adult and aged wild-type mice and found that the balance between PICs and satellite cells within the EOM stem cell niche is maintained throughout life. Moreover, in the adult mdx mouse model for Duchenne muscular dystrophy (DMD), the EOM stem cell niche is unperturbed compared to normal mice, in contrast to Tibialis Anterior (TA) muscle, which displays signs of ongoing degeneration/regeneration. Regenerating mdx TA shows increased levels of both PICs and satellite cells, comparable to normal unaffected EOMs. We propose that the increase in PICs that we observe in normal EOMs contributes to preserving the integrity of the myofibers and satellite cells. Our data suggest that molecular cues regulating muscle regeneration are intrinsic properties of EOMs.

Link: http://dx.doi.org/10.3389/fnagi.2014.00328

Life spans in short-lived animals can be made to vary far more in response to circumstances than the life spans of longer-lived animals. In the case of calorie restriction there is an evolutionary explanation in that if periods of famine are longer in relation to length of life there is a selection pressure for the response to scarcity to induce greater longevity in individuals. There will probably be similar explanations for the many other ways in which a given approach can extend life in mice or flies or worms far more than it can in longer-lived mammals.

One of the discoveries made in studies of fly longevity is that neural sensing plays a strong role in guiding life span variations. Flies in fact have all sorts of interesting peculiarities in their linkage between metabolism and aging, such as the great importance of intestinal function to longevity, and the sensory influences discussed below, but it remains to be seen how many of these are of any real relevance to mammals.

The goal of Dr. Pletcher's lab is to identify and investigate genetic mechanisms that are important in aging and age-related diseases in humans by focusing on equivalent, conserved processes in the fruit fly model, Drosophila melanogaster. He views aging as a "physiological behavior" and is seeking to understand the neural mechanisms of its coordination and execution. In a recent seminar at the Buck Institute, Dr. Pletcher discussed how substances like water and sugar can initiate changes in aging processes by specifically affecting sensory neurons. His lab found that in flies, bitter tastes have negative effects on lifespan while sweet tastes had positive effects. Interestingly, the ability to taste water had the most significant impact: flies that couldn't taste water lived up to 40% longer. One possible explanation for these results is that flies that can't taste water might compensate for this perceived water shortage by converting large amounts of their own body fat into water.

"We are interested in learning how social interactions and sensory perception affect lifespan and healthspan. We are currently collaborating with a few mouse labs to answer these questions. Some of the studies we are conducting involve putting mice on a restricted diet while housing them near other mice that get to eat food. We then ask whether deprivation in this type of environment affects glucose intolerance or other physiological characteristics in the dietary restricted mice. Ultimately, we want to understand how environmental perception affects lifespan. We want to determine what's happened in cells that cause lifespan changes at the molecular level. However, we are also interested in determining whether there's a specific region of brain where lifespan is consistently manipulated when you stimulate those neurons - in another word, a longevity regulatory center."

Link: http://sage.buckinstitute.org/interview-with-dr-scott-pletcher-neuronal-control-of-aging-in-flies/

Every few years a new hot thing emerges in the field of drug candidates to slow aging. It was sirtuins for a while and then rapamycin and there will be others in due course. This happens because it is very possible to raise funding, start a company, and make a lot of money from this sort of thing even if - as is always the case to date - nothing of significance ever comes of it in terms of treatments that can actually extend life. As I've said in the past, this all seems like a really great cover story for the real scientific goal of amassing detailed data on the operation of cellular metabolism. The stated goals of slowing aging serve to draw in investment that would otherwise be hard to find at the needed levels: metabolism is ferociously complex, and trying to map it is chewing up billions of dollars. This is work that should be done, and the faster the better, but I think it disingenuous to talk of any real possibility that significant human life extension can result from it in the next few decades.

For real progress in treating aging an entirely different direction in scientific strategy is needed. Not mining the natural world for drug candidates that might slow down aging in poorly understood ways by altering poorly understood metabolic mechanisms, but rather deliberately aimed efforts to repair the known and comparatively well understood forms of damage that cause aging. We can bypass the need for a full and detailed understanding of how this damage interacts with every part of our metabolism to cause aging by taking the well validated and time-proven list of fundamental differences between old tissue and young tissue - a list of forms of cellular and molecular damage - and then repairing those differences. There is even a detailed set of research plans leading to treatments that can achieve this goal, which is a very large departure from the world of slowing aging through metabolic manipulation, where there is no plan to speak of and nowhere near enough knowledge to create one.

This is not even to mention the fact that slowing down damage accumulation can never be as good as repairing damage in terms of benefits delivered, and slowing further damage can do very little for old people who are already very damaged. The old need repair, and repair as a strategy is simply better overall in any case. It continues to amaze me that the clearly far worse, far more expensive, far less understood approach to treating aging is the one that dominates in this small research community.

In any case, every time a new overhyped drug candidate to slow aging emerges people get excited about it. Short memories, if you ask me. But the next time that someone you know in the community becomes fired up about early stage development of an age-slowing drug candidate that extends life in animal studies you can offer some needed perspective by saying "but so does ibuprofen." And what does ibuprofen do for life span in humans? Nothing meaningful enough to show up in five decades of trials, studies, and worldwide usage.

Ibuprofen Use Leads to Extended Lifespan in Several Species, Study Shows

"We first used baker's yeast, which is an established aging model, and noticed that the yeast treated with ibuprofen lived longer. Then we tried the same process with worms and flies and saw the same extended lifespan. Plus, these organisms not only lived longer, but also appeared healthy." The treatment, given at doses comparable to the recommended human dose, added about 15 percent more to the species lives. In humans, that would be equivalent to another dozen or so years of healthy living.

The three-year project showed that ibuprofen interferes with the ability of yeast cells to pick up tryptophan, an amino acid found in every cell of every organism. Tryptophan is essential for humans, who get it from protein sources in the diet. "We are not sure why this works, but it's worth exploring further. This study was a proof of principle to show that common, relatively safe drugs in humans can extend the lifespan of very diverse organisms. Therefore, it should be possible to find others like ibuprofen with even better ability to extend lifespan, with the aim of adding healthy years of life in people."

Enhanced Longevity by Ibuprofen, Conserved in Multiple Species, Occurs in Yeast through Inhibition of Tryptophan Import

Aging is the greatest risk factor for many diseases, which together account for the majority of global deaths and healthcare costs. Here we show that the common drug ibuprofen increases the lifespan of yeast, worms and flies, indicative of conserved longevity effects. In budding yeast, an excellent model of cellular longevity mechanisms, ibuprofen's pro-longevity action is independent of its known anti-inflammatory role. We show that the critical function of ibuprofen in longevity is to inhibit the uptake of aromatic amino acids, by destabilizing the high-affinity tryptophan permease. We further show that ibuprofen alters cell cycle progression. Mirroring the effects of ibuprofen, we found that most yeast long-lived mutants were also similarly affected in cell cycle progression. These findings identify a safe drug that extends the lifespan of divergent organisms and reveal fundamental cellular properties associated with longevity.

The goal of taking decades and billions to add just a few years to adult life expectancy doesn't fill me with glee. If that much time and money are to be expended, and I am to become old waiting, I want far better expected outcomes for success: decades of healthy life and rejuvenation, not pills to very slightly slow down the remaining decline. Fund research into repair biotechnologies after the SENS model, not the same old drug development programs that gave us a better knowledge of sirtuins and little else.

Cells can enter a senescent state in response to damage, ceasing to divide. This reduces the risk of cancer under most circumstances, but is also a part of the wound healing process. This isn't all good, however. Senescent cells secrete factors that harm surrounding tissue function over the long term, and the growing numbers of these cells with age is one of the causes of age-related disease and dysfunction. Researchers here look more deeply into how various mechanisms in a cell conspire to cause senescence. They are aiming to produce a more unified view of the varied entry points to this cell state. You should scroll down in the open access paper to the diagram near the end - this is a collection of mechanisms that really benefits from a visual explanation:

Genome integrity is preserved by the DNA damage response (DDR) that, in the presence of DNA damage, arrests the cell cycle progression while coordinating DNA repair events. If damage is not resolved, cells can enter into an irreversible state of proliferative arrest called cellular senescence. In the past years, a strong link between telomere-initiated cellular senescence and organismal ageing has emerged, [where aging is] associated with accumulation of markers of cellular senescence and DDR persistence at telomeres.

Since the vast majority of the cells in mammals are non-proliferating, how do they age?Telomere-initiated cellular senescence seems to be a plausible mechanism to explain the ageing-associated functional decline of proliferating tissues in vivo. However, it is reasonable to assume that some other mechanisms may be in place in non-proliferating cells in which no telomeric attrition due to the end replication problem is expected to occur, either because these cells are quiescent or differentiated. Surprisingly however, we and others have shown that telomeres might have a central role in senescence establishment independently from their shortening.

In these reports, random DNA damage [leads] to DDR activation that preferentially persists at telomeres over time. Cells with persistent DDR activation show a senescent phenotype that cannot be prevented by exogenous expression of telomerase, further excluding a contribution of telomere shortening. The mechanism proposed to explain this phenomenon is the suppression of effective DNA repair at telomeres by TRF2, a telomeric DNA binding protein. Consistent with this model, DDR activation at telomeres is more frequent in mouse and baboon tissues from aged animals, when compared with their young counterparts. This observation also suggests that having long telomeres may have an important drawback, since more telomeric DNA can offer a wider target for random DNA damage that cannot be repaired. Indeed, in different mammalian species, telomere length and lifespan are inversely correlated.

Link: http://dx.doi.org/10.1016/j.gde.2014.06.009

Life expectancy at birth is a statistical measure, internally consistent and useful for comparisons across time. Insofar as it has a real meaning it is the average expected life span of a person born now if medical technology going forward exactly repeated past availability and cost over the life spans of people presently at the end of life. Obviously that won't happen, but nonetheless this is still a useful way to keep track of progress. Since it is a measure from birth it is greatly influenced by childhood mortality and mortality due to infectious disease, and indeed much of the gains in life expectancy over the past two centuries have been due to reductions in causes of death while young. That is no longer the case now in most parts of the world, however, and ongoing gains have more to do with reduction of mortality in later years.

This study confirms other work that shows the ballpark growth in life expectancy at birth is something like one year with every four calendar years. Adult life expectancy is also climbing, but more slowly - perhaps one year each decade. This present pace will change as the research community starts to deliberately target aging for treatment, which has not previously been the case. Past gains in life expectancy at age 30 or 60 due to improvements in medicine have been somewhat incidental, side-effects rather than deliberately obtained results.

Global life expectancy for both sexes increased from 65.3 years in 1990, to 71.5 years in 2013, while the number of deaths [per year] increased from 47.5 million to 54.9 million over the same interval. Global progress masked variation by age and sex: for children, average absolute differences between countries decreased but relative differences increased. For women aged 25-39 years and older than 75 years and for men aged 20-49 years and 65 years and older, both absolute and relative differences increased. Decomposition of global and regional life expectancy showed the prominent role of reductions in age-standardised death rates for cardiovascular diseases and cancers in high-income regions, and reductions in child deaths from diarrhoea, lower respiratory infections, and neonatal causes in low-income regions.

For most countries, the general pattern of reductions in age-sex specific mortality has been associated with a progressive shift towards a larger share of the remaining deaths caused by non-communicable disease and injuries. For most communicable causes of death both numbers of deaths and age-standardised death rates fell whereas for most non-communicable causes, demographic shifts have increased numbers of deaths but decreased age-standardised death rates. Global deaths from injury increased by 10.7%, from 4.3 million deaths in 1990 to 4.8 million in 2013; but age-standardised rates declined over the same period by 21%. For some causes of more than 100,000 deaths per year in 2013, age-standardised death rates increased between 1990 and 2013, including HIV/AIDS, pancreatic cancer, atrial fibrillation and flutter, drug use disorders, diabetes, chronic kidney disease, and sickle-cell anaemias.

Link: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)61682-2/abstract

Many types of metabolic waste and byproduct molecules are generated by the normal operation of cellular metabolism. You can't run an engine without exhaust or a factory without waste generation. The majority of these unwanted outputs are swept away to be broken down and recycled by a panoply of varied housekeeping mechanisms, but unfortunately this is not not the case for all of them. Some hardy forms of waste linger, accumulating throughout life, and this problem becomes worse in later years as all of the systems in our biology lose their effectiveness due to damage. The damage of aging in living beings is an accelerating downward spiral because it also degrades the very mechanisms that are in place to repair it on an ongoing basis.

Cross-links in the complex structures of the extracellular matrix are a consequence of some classes of metabolic waste, such as advanced glycation end-products (AGEs). The properties of any given tissue are determined by the nanoscale structure and arrangement of proteins in the extracellular matrix, but cross-links degrade that structure by chaining these proteins together. A growing level of cross-linking can reduce elasticity in softer tissues such as skin or blood vessel walls, for example, and that loss of elasticity has serious consequences for health. Similar loss of structural properties can occur for tissues where strength or ability to bear load are the important factors. There are a lot of different types of AGE, many of which are short-lived because a healthy biochemistry is quite capable of removing them. Some are long-lived and resilient, however, such as glucosepane that accounts for the overwhelming majority of AGEs in old human skin.

Despite breaking down AGEs being an obvious potential target for therapies, and this research meshing well with the strengths of the pharmaceutical industry, it is actually the case that very little work takes place on ways to safely remove persistent AGEs from tissues. It can be argued that this is in part due to a high profile failure in AGE-breaker drug development not so many years ago, but also because there are few tools and laboratories capable of working with glucosepane in any meaningful way. It is an odd oversight, one of those scientific blank spots that perpetuates itself because every group than might choose to work on this area looks at the absence of basic tools and then moves on to something easier and more likely to return a profit. The SENS Research Foundation is at present funding a research program to fix this situation by building the tools needed to work with glucosepane.

Here I'll point out an open access review on the topic of cross-links in the collagen structure of the extracellular matrix, with a focus on tendons in particular:

The role of collagen crosslinks in ageing and diabetes - the good, the bad, and the ugly

The non-enzymatic reaction of proteins with glucose (glycation) is a topic of rapidly growing importance in human health and medicine. There is increasing evidence that this reaction plays a central role in ageing and disease of connective tissues. Of particular interest are changes in type-I collagens, long-lived proteins that form the mechanical backbone of connective tissues in nearly every human organ. Despite considerable correlative evidence relating extracellular matrix (ECM) glycation to disease, little is known of how ECM modification by glucose impacts matrix mechanics and damage, cell-matrix interactions, and matrix turnover during aging. More daunting is to understand how these factors interact to cumulatively affect local repair of matrix damage, progression of tissue disease, or systemic health and longevity.

Various approaches have been taken to prevent formation of AGEs (for an excellent review see "Characteristics, formation, and pathophysiology of glucosepane: a major protein cross-link"). For instance, a reduced alimentary glucose uptake has been shown to be beneficial, as have approaches seeking to breakdown or block intermediate molecular interactions. Further efforts have shown potential benefit in "protecting" amino acid residues by agents that competitively bind aldehydes. Complementing these preventative approaches, some therapeutic approaches have sought to break existing AGE crosslinks.

Contrary to the mentioned preventative approaches, crosslink breaking can reverse AGE crosslinking and its deleterious effects on tissue mechanics and matrix remodeling. Since AGE crosslinks in tendon are only secondary complications of diabetes, most anti-AGE work has been done in other tissues (such as skin and arteries). However, their potential effectiveness was first demonstrated using rat tail tendon. In any case, as far as we are aware there is no study testing the ability of crosslink breaking therapies to ameliorate the predisposition of tendon to mechanical damage, or promote "healthy" tissue remodeling at a repair site.

Researchers here find an association between the amount of mitochondrial DNA (mtDNA) in tissues and the risk of frailty and mortality. The less mitochondrial DNA you have, the worse off you are likely to be, or so it seems. It is an interesting result, though at this point we can only speculate about how this relates to the role of mitochondrial DNA damage in aging. The many processes involved in mitochondrial dynamics are collectively exceedingly complex and the amount of mitochondrial DNA in cells has no direct relationship to its quality, yet both can impact health.

[Researchers] analyzed the amount of mtDNA in blood samples collected for two large, human studies that began in the late 1980s and tracked individuals' health outcomes for 10 to 20 years. After calculating how much mtDNA each sample contained relative to the amount of nuclear DNA, the team looked at measures of frailty and health status gathered on the studies' participants over time. On average subjects who met the criteria for frailty had 9 percent less mtDNA than nonfrail participants. And, when grouped by amount of mtDNA, white participants in the bottom one-fifth of the study population were 31 percent more likely to be frail than participants in the top one-fifth. "It makes intuitive sense that decreased mtDNA is associated with bad health outcomes. As we age, our energy reserves decrease, and we become more susceptible to all kinds of health problems and disease."

The researchers also analyzed the age at which participants died. In one of the studies, high levels of mtDNA corresponded to a median of 2.1 extra years of life compared to those with the lowest levels of mtDNA. Using data from both studies, the team found that those with mtDNA levels in the bottom one-fifth of the population were 47 percent more likely to die of any cause during the study period than were those in the top one-fifth. They also found that women had an average of 21 percent more mtDNA than men. This could play a small role in why women live two to four years longer than men on average. The research team would like to take repeated blood samples from individuals over several years to learn if and by how much mtDNA levels decrease over time. What the investigators saw in the current study is that, averaged over the population, an increase of 10 years in age corresponded to 2.5 percent less mtDNA.

Link: http://www.eurekalert.org/pub_releases/2014-12/jhm-aom121614.php

The latest Google Ventures annual report has a third of new investments going to the life sciences and health in the past year. This is of interest principally in the context of Calico Labs and its focus on finding ways to treat aging. This interview provides a little more insight into motivations and goals - such as a strong focus on genetics as a path ahead, something that I think, unfortunately, is going to greatly limit the practical outcomes of these initiatives in terms of years of healthy life added.

Genetics and metabolic studies will broadly improve medicine and drive the creation of new and better tools in biotechnology, as does all new knowledge. Yet we all age in the same way and due to the same underlying processes: genetics are not a big factor in the grand scheme of things, and really only play a larger role in the end stages of aging, the faltering and failure of a very damaged biological system. Alteration of genetic programs and the operation of our metabolism to slow aging is not easy and not the best way forward: the optimistic best near future outcome of drugs that can modestly slow aging is of next to no use to people already old. The best way forward for treating aging is to work on SENS-like strategies of repair of the known forms of cellular and molecular damage that cause aging so as to build actual, working rejuvenation treatments that stop people from being old at all. This is a completely different strategic approach to medicine to that taken by the community focused on the overlap of genetics and aging, but one that has yet to gain the support it merits:

Calico was my idea. I'm super proud of it. It came from a thesis I had that no one was studying aging at the genetic level. What is aging, versus the diseases we associate with aging. Say you have cancer, you have this broad thing we call cancer, we're going to irradiate you, and pump this poisonous material into you and hope more of the bad stuff dies than the good. That is going to seem so medieval when we can fix it on a genetic level, and foundation medicine are the first steps to diagnosing it on a genetic level. Not just, you have breast cancer, but what exactly is going on in the that tumor. That is step one. You can see the path ahead to personalize medicine for people.

New ideas are scary. If you said to most people in 1900, would you like to live to be 100, they would have said no thank you, it seems to so unimaginably bad. Now people expect to live to be 70 or 80, and if you asked if they wanted to live to 100 most would probably say yes. Now ask them if they want to live to 200 and most would say, I don't know about that. But the reality is if you were going to die tomorrow and someone offered you another 10 years, most people would take those 10 years. And the beauty of it is you can always opt out. If you don't that extra time, you can always opt out of the system, but I don't have an interest in opting out of the system, nor do I want the people that I love opting out. It's not about scary immortality. What if your grandmother didn't have to die of congestive heart failure or some debilitating stroke where she can't move half her body? Wouldn't that be a good thing? I find that generally when I can talk to people about it and take some of the scary unknown away it becomes less intimidating.

Link: http://www.theverge.com/2014/12/16/7402411/google-ventures-2014-bill-maris-life-science

The protein α-synuclein is involved in Parkinson's disease in much the same way that β-amyloid is involved in Alzheimer's disease. These particular misfolded proteins accumulate with age to form deposits in everyone's brain tissues, but this is seen to occur to a much greater extent in those suffering from the related neurodegenerative condition. There is a lot of research to suggest that this accumulation of amyloid or synuclein is driving disease pathology and death of brain cells, but equally there is a lot of research to suggest that this is far from a complete picture of all that is going wrong in the failing biochemistry of the aged brain. You'll see a lot more debate on the role of amyloid in Alzheimer's disease because work on α-synuclein has not been a going concern for as many years, while many people are becoming impatient with the lack of meaningful treatments resulting from amyloid-focused research programs. That may or may not result from issues with the theories or the focus on amyloid: just as AIDS researchers had to build the next generation of biotechnologies and knowledge to work with viruses, Alzheimer's researchers have had to build much of the modern basis for understanding and working with the cellular metabolism of the brain along the way. These all remain works in progress.

Regardless, we are entering an age in which it is becoming feasible to substitute action to change the state of a diseased brain in place of painstaking investigations of the unaltered disease process. If it is possible to selectively remove β-amyloid or α-synuclein without greatly altering other biochemistry, for example, then observing the results should go a long way towards settling questions over the role of protein aggregates in age-related neurodegenerative disease. Positive outcomes can then also provide the springboard for developing a therapy based on removal of these misfolded proteins.

Immunotherapy, the use of components of the immune system to achieve therapeutic goals, is one of the most promising of today's new biotechnologies. The immune system has evolved many capabilities that researchers would like to take advantage of in medicine, such as selective destruction of cells and removal of some types of metabolic waste products. Immune cells can in principle be steered towards specific targets, and in recent years some success has been obtained in making this happen for misfolded proteins such as β-amyloid or α-synuclein. Below you'll find a long overview of some present efforts in this direction provided by the folk at the SENS Research Foundation, who have great interest in spurring progress in this field of research. Immunotherapies can in theory do more than just help in treating late stage disease, but might also be tuned to eliminate a range of contributing causes of degenerate aging, such as accumulations of amyloid and senescent cells. Get rid of these and the other unwanted aspects of aged tissue and the process of aging can be slowed, halted, and even turned back given effective enough treatments: it is all just a matter of damage repair.

Bold Leaps Forward for α-Synuclein Immunotherapy

Lewy bodies (LB) and other intracellular α-synuclein (AS) aggregates accumulate in the aging nervous system, and a high burden of such aggregates are hallmark neuropathological signs of Parkinson's disease (PD), Lewy body dementia (LBD), multiple systems atrophy (MSA), and other synucleinopathies. Loss of dopaminergic (DA) neurons in the substantia nigra (SN) to aging processes and toxicity are chiefly responsible for the most overt motor symptoms of PD, and it is on the basis of these symptoms that PD is clinically diagnosed. But prior to the onset of motor symptoms, AS pathology is already present in the peripheral nervous system of aging and especially future PD subjects. It is becoming increasingly clear that LB along with other neuronal protein aggregates are key drivers of "normal" cognitive aging.

In a previous post, we surveyed an exciting new development in rejuvenation biotechnology: the sudden emergence and rapid progress toward the clinic of vaccine- and antibody (Ab)-based immunotherapy to remove α-synuclein aggregates from the aging brain. Therapies applying this paradigm to clear β-amyloid protein (Aβ) plaques and soluble aggregates from patients with Alzheimer's disease (AD) is an extremely active field of research, with multiple active and passive Aβ vaccines currently in human clinical trials.

In the earlier posting, we also surveyed research in applying this same paradigm to α-synuclein (AS) aggregates. Since that post, there have been exciting developments in the progress of the two most advanced of these immunotherapies: PD01A, the AS-targeting active vaccine from Austrian biotechnology startup AFFiRiS AG, developed using its patented "AFFITOME" neo-antigen discovery platform of molecular mimicry; and PRX002, a humanized monoclonal Ab (mAb) under development from Prothena Corp PLC, the successor of aggregate-clearing immunotherapy pioneer Élan Pharmaceuticals. In the ensuing months, the two companies have published detailed, promising animal studies of their immunotherapies, including preclinical efficacy studies in animal models of human synucleinopathies. And both immunotherapies are now advancing through early-stage human clinical trials.

The entry of these two AS-targeting rejuvenation biotechnologies into human clinical testing would seem to mark an inflection point. As recently as two years ago, there was little evidence of any academic or biotech industry interest in pursuing clearance of AS as a therapeutic approach to PD, LBD, or other synucleinopathies of aging: after a promising 2005 report, there had been virtual silence. Today, two AS aggregate-clearing immunotherapies have advanced into human testing, with one using an active vaccine approach and the other a passive mAb infusion strategy. Either or both may prove effective. One might speculate that each of these damage-repair therapeutics may exhibit differential targeting of particular AS species or brain regions, as different clinical synucleinopathies exhibit distinct regional localizations and conformations of AS pathology.

You should read the whole thing, as there are some interesting points made in the concluding sections regarding the ongoing siloing of knowledge in many scientific programs relevant to future human rejuvenation treatments. Medical research is enormously broad as well as deep nowadays, and no one researcher can see more than a sketch of what is going on elsewhere. So it is the tendency of researchers in one field to fail to see the opportunity to combine their narrow focus on treatment with those of other distantly removed research groups. Thus otherwise promising lines of research are dropped because the resulting therapies should be best applied in conjunction with, say, stem cell treatments, or removal of other metabolic wastes, or some other biotechnology.

Collections of twins are the closest that researchers can get in humans to an ideal study situation in which a large number of genetically identical individuals follow the same life courses. Comparison studies with as many factors as possible made the same are a good way to tease out relevant details from an exceedingly complex system that is still poorly understood as a whole. That system here is the sum total of human cell and tissue biology, and its changing operation over the course of a life span: the map of metabolism is at present really only a sketch of the outlines, and contains many large blank areas when it comes to the precise details. An example of the use of twin studies is to identify twin pairs where one has a medical condition and the other does not (a set of "disease-discordant" twins), a situation that should make it much easier to identify important differences and thus more quickly identify the most relevant biochemical mechanisms involved in the development and progression of that medical condition.

Monozygotic (MZ) twins share nearly all of their genetic variants and many similar environments before and after birth. However, they can also show phenotypic discordance for a wide range of traits. Differences at the epigenetic level may account for such discordances. It is well established that epigenetic states can contribute to phenotypic variation, including disease. Epigenetic states are dynamic and potentially reversible marks involved in gene regulation, which can be influenced by genetics, environment, and stochastic events. Here, we review advances in epigenetic studies of discordant MZ twins, focusing on disease.

The study of epigenetics and disease using discordant MZ twins offers the opportunity to control for many potential confounders encountered in general population studies, such as differences in genetic background, early-life environmental exposure, age, gender, and cohort effects. Recently, analysis of disease-discordant MZ twins has been successfully used to study epigenetic mechanisms in aging, cancer, autoimmune disease, psychiatric, neurological, and multiple other traits. Epigenetic aberrations have been found in a range of phenotypes, and challenges have been identified, including sampling time, tissue specificity, validation, and replication. The results have relevance for personalized medicine approaches, including the identification of prognostic, diagnostic, and therapeutic targets. The findings also help to identify epigenetic markers of environmental risk and molecular mechanisms involved in disease and disease progression, which have implications both for understanding disease and for future medical research.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4254430/

Adoptive T cell therapies are one of the most promising methodologies for immunotherapy at the present time. This small trial is for pediatric cancer, and one might argue that you'd expect better results from immunotherapy in children, however. The aged immune system is much less effective at all of its jobs. As is the case for stem cell therapies and their issues in treating the old, we can hope that the challenge of immune aging will simply be an incentive for the research community to develop means to overcome it so that cancer immunotherapies can work at peak effectiveness. After all, cancer in children is rare in comparison to cancer in the old. The economic incentives thus steer developers to put considerable effort into enabling cancer treatments to work well for the old, given a promising line of research to work on.

11 of the 13 patients treated thus far in a clinical trial using genetically reprogrammed T cells to treat relapsed acute lymphoblastic leukemia have achieved complete remission, confirmed by highly sensitive tests designed to detect minute amounts of cancer cells. The trial includes patients with acute lymphoblastic leukemia who have relapsed after a bone marrow transplant and typically have only a 10% to 20% chance of survival with standard treatment. Using immunotherapy, which reprograms the body's T cells to hunt down and destroy cancer cells, researchers have seen an 85% complete remission rate. "In this population of patients, a treatment with a 20% response rate would be considered a success. Having 11 out of 13 patients achieve a complete remission is incredible, but we will keep working until we have 100% in remission."

In the first phase of the trial, [researchers] treated 13 patients with relapsed acute lymphoblastic leukemia using cancer immunotherapy. This phase was designed to demonstrate the safety and efficacy of cancer immunotherapy as a treatment for leukemia and to determine the optimal dose of engineered T cells to administer to patients. Of the 13 patients treated, 12 responded to the treatment and 11 achieved complete remission. One of these patients has since relapsed; the remaining ten are in ongoing remission. The second phase of the trial, which is expected to begin in 2015, will allow even more patients to be treated with what researchers determine is the optimal dose of reengineered T cells. "Our goal is to eventually offer immunotherapy to patients when they are first diagnosed with cancer so they don't have to endure transplants or prolonged chemotherapy and radiation."

Link: http://www.seattlechildrens.org/Press-Releases/2014/Seattle-Children-s-Reprogrammed-T-Cell-Immunotherapy-Clinical-Trial--Boasts-85--Complete-Remission-Rate-in-Children-with-Relapsed-Leukemia/

The SENS Research Foundation funds and coordinates rejuvenation research, various ongoing programs that aim to build the foundations of real, working treatments to reverse the causes of aging. Aging is a matter of accumulating cellular and molecular damage, all of which can in principle be repaired, and where in most cases there is a very clear, planned path ahead to the creation of the necessary biotechnologies for repair. The Foundation staff identify the areas most in need of help in the modern research community: stem cell research needs very little assistance, for example, while work on removal of cross-links in tissues would still be going nowhere and have next to no funding if not for the efforts of the SENS Research Foundation and its allies. The work of the Foundation is very important, as it directly speeds progress towards an end to the pain, suffering, and disease caused by aging.

This year a group of us assembled a $100,000 matching fund, and on October 1st challenged the community to donate a further $50,000, with all donations going to expand the SENS Research Foundation's scientific programs. The generous matching fund founders were Christophe and Dominique Cornuejols, Dennis Towne, Håkon Karlsen, Jason Hope, Methuselah Foundation, Michael Achey, Michael Cooper, and Fight Aging! Over the past three months, more than 500 people have donated in support of SENS rejuvenation research, and I'm pleased to note that the challenge has been met. As a result of your efforts our grand total of $150,000 will be added to the Foundation research budget in the coming year.

This is no small thing: early stage biotechnology research is not as expensive as you might think. This much money can cover the contributions of several talented young researchers to a year-long program of cutting-edge investigation into one particular cause of aging and the therapies that may help to treat it. Your efforts collectively make a real difference - and not just because you are helping to fund progress in research. Successful fundraisers held in public demonstrate that practical efforts to bring an end to degenerative aging do have a strong base of support, and that in turn attracts others to support this cause. Success in grassroots fundraising is also a very necessary part of bringing high net worth philanthropists and traditional funding sources to support these research programs. People capable of making very large donations for research never lead from the front, but rather always join in at a later stage. They are cautious and very conservative in what they support. They rely on people like us to light their way and illuminate the worthy causes by the fact that we are gathering to speak out and materially support these goals.

So celebration is called for: we set out to raise money for to expand the most important medical research in world, and we did just just that. If you missed out, it is never too late to donate, however. Another matching grant is now in place for the last few weeks of the year, provided by yet another generous supporter. Here is the latest from the SENS Research Foundation:

Fight Aging $50,000 Challenge Grant Completed

SENS Research Foundation is pleased to announce that you, our generous supporters, have helped us to achieve our $50,000 Fight Aging Challenge Grant Goal. Every dollar you gave us was tripled by the group of generous donors at Fight Aging! We are so very grateful to everyone who contributed on SRF's behalf. We thank you all. Our #GivingTuesday challenge, in which SRF's own Aubrey de Grey offered to match the first $5,000 given was also met on December 2nd. In fact, that $5,000 was quadrupled - making $20,000! Thanks to Aubrey and everyone who helped make our first #GivingTuesday a success.

New $10,000 Challenge Begins Today!

Everyone at SRF is thrilled at the success of these recent fundraising endeavors, but as a nonprofit we depend on continuing support. We are excited to note that a new challenge grant has been received from Ronny Hatteland, AutoStore - Software Developer. For every dollar we receive from now until the end of the year (December 15 - 31st), the first $10,000 will be matched by Ronny's generous gift. Ronny says, "The work of the SENS Research Foundation gives us all a chance to secure ourselves a healthy future and an extended lifetime to continue to embrace all that life has to offer us. I am very pleased to support SENS Research Foundation and I encourage all of you to join me."

You can donate to the SENS Research Foundation at their website, and since it is a 501(c)3 charitable organization all donations are tax deductible.

Periodontitis produces chronic inflammation that is associated with a raised risk of cardiovascular disease and worse cognitive decline in aging. At some point in the near future researchers will be able to control or eliminate the mouth bacteria that cause periodontitis, but for the moment we're all stuck with diligent maintenance as a primary strategy. Here is another good reason to keep up with that work:

The accumulation of amyloid-β (Aβ) plaques is a central feature of Alzheimer's disease (AD). First reported in animal models, it remains uncertain if peripheral inflammatory and/or infectious conditions in humans can promote Aβ brain accumulation.

Periodontal disease, a common chronic infection, has been previously reported to be associated with AD. Thirty-eight cognitively normal, healthy, and community-residing elderly (mean age, 61 and 68% female) were examined. Linear regression models (adjusted for age, apolipoprotein E, and smoking) were used to test the hypothesis that periodontal disease assessed by clinical attachment loss was associated with brain Aβ load using 11C-Pittsburgh compound B (PIB) positron emission tomography imaging.

After adjusting for confounders, clinical attachment loss (≥3 mm), representing a history of periodontal inflammatory/infectious burden, was associated with increased PIB uptake in Aβ vulnerable brain regions. We show for the first time in humans an association between periodontal disease and brain Aβ load. These data are consistent with the previous animal studies showing that peripheral inflammation/infections are sufficient to produce brain Aβ accumulations.

Link: http://dx.doi.org/10.1016/j.neurobiolaging.2014.10.038

Much insight into the mechanisms of aging and metabolism in mammals has been obtained from studies of yeast, which might seem a little odd at first glance. Nonetheless many aspects of aging and variations in response to circumstances such as calorie restriction are fairly universal and certainly very ancient from an evolutionary perspective. They are shared across a broad range of species, and thus it can be cost-effective to run rapid studies in very short-lived species that are very unlike us. There are nonetheless important differences between these species and limits to what can be learned, however, and the research community is probably approaching these limits.

This is a very readable open access paper on the subject of whether or not yeast studies in aging are past their time, but note that the full paper is in PDF format only:

The success of experimental biology was possible due to the use of model organisms. It is believed that the mechanisms of aging have a universal character and they are conserved in a wide range of organisms. Yeast are a very popular model organism. The use of the budding yeast Saccharomyces cerevisiae as a model organism of gerontology was based on two essential assumptions. The first of them is that the existence of the reproduction limit of each single cell is a consequence of the aging process. In other words, it was assumed that unavoidable death of each individual cell is not a side effect of the chosen strategy of reproduction (budding), as was postulated, but of the aging process. The second assumption was that as the number of daughters produced by a single cell is rather independent of the conditions of growth and on the time that reproduction takes, therefore the age and longevity of yeast can be expressed as a number of the daughter cells produced, instead of units of time. In that case the conclusions drawn from the studies based on such unusual units cannot be directly applicable for other organisms. The comparison can be made only if the units used are at least proportional.

The definition of aging encompasses two different, although probably causally connected phenomena. The term senescence describes various adverse effects which decrease efficiency of vital processes and lead to visible structural changes of the organism. Unavoidable death of individuals seems to be a direct consequence of aging. From evolutionary point of view, aging is treated in two ways, as a programmable or not programmable process. Programmable theories treat aging as a process of adaptation, which is a specific mechanism leading to the altruistic death of an individual for the benefit of the population, and thus preventing a too high density of a population (Medawar Theory). However non-programmable theories, among which the most popular is the disposable soma theory, treat aging as a kind of trade-off between investment in reproduction and maintenance of the somatic cells. In this sense, priority lies in reproduction while aging is just a stochastic accumulation of damage that leads to impairment of functions and consequently to death. This opinion, which is probably right, has been recently challenged because a number of arguments were collected suggesting a quasi-programmable character of the proximal causes of death. The hyperfunction hypothesis, can be considered a part of the theory of antagonistic pleiotropy. Both seem to explain at least some aspects of the aging process.

Study of the aging process requires to designate certain universal criteria that would allow for their analysis regardless of the type of the model organism used. One such criterion which also corresponds to the definition of this process is to increase the mortality rate as a function of time and a decrease in fertility. However, these criteria even though adequate for many organisms, have raised some doubts as to their versatility, especially if we take into consideration the phenomenon of 'negligible senescence'. This term was introduced in relation to the specific group of organisms for which the mostly used criteria for aging cannot be used. This group includes among others turtles, rockfish or mole-rats. In these species a typical decrease in fertility or increased mortality with age is not observed. Also, no changes indicating a 'progressive loss of function' with age were observed there. Thus, the question arises about the universality of the aging process in the living world and universality of the mechanisms of aging.

Link: http://www.ncbi.nlm.nih.gov/pubmed/25493441

AMD, age-related macular degeneration, results in progressive retinal damage and consequent blindness in the central portion of the visual field. Like many age-related conditions at root it is caused by damage and failures in tissues that happen to everyone, but in some people this rises more rapidly to levels sufficient to cause noticeable pathology. Lifestyle choices with a negative impact on circulation and chronic inflammation, such as lack of exercise, obesity, and smoking, all raise the risk of suffering this form of degenerative blindness. But if everyone lived long enough, we'd all get it eventually: absent treatments for aging, missing out on any specific age-related disease at the present time is really just a matter of being nailed by something else first.

Of course we'd like to do better than rolling the dice and taking bets on what kills us first. We want the means to repair the slowly accumulating forms of cellular and molecular damage that cause aging - to miss out on all of the consequences of aging and continue living in good health and youthful vigor. This will be a new strategy in medicine, one that at present has only recently gained acceptance in the mainstream research community. Working to treat aging itself is a departure for the scientific community, which up until now in has focused on trying to patch over the consequences of aging, the many varied age-related diseases such as AMD, one by one. This end stage of aging is a complex forest of dysfunction and failing, flailing biological systems struggling to cope, and progress in any sort of meaningful treatment has been correspondingly expensive and the benefits marginal.

Aging has simple roots, however, just a few forms of cellular dysfunction and hardy waste products that result from the normal operation of our metabolism. Like rust in an intricate metal structure, the end result of simple damage accumulating in a system as complicated as human biology is by necessity very complex. Damage spirals out in chains of cause and effect, as systems that rely upon one another progressively fail in their function. There is a little of genetics and a lot of lifestyle choice in the risks of any particular age-related condition versus another, but mostly it is dumb luck: small random events in your biology snowball into large differences over time. Why focus on trying to manipulate and manage the complicated end results when you could focus on removing the simpler causes? It is well past time for this change in medical strategy.

AMD is a poster child for some attempts to repair the causes of aging because there is a fairly direct link between retinal cell death and one form of hardy, lingering metabolic waste product generated in the normal course of being alive:

Age-related macular degeneration is the leading cause of blindness in people over the age of 65. It is caused or exacerbated by the accumulation of A2E (a toxic byproduct of vitamin A metabolism) in the cells in the retina of the eye. A2E is resistant to breakdown in the lysosome, and therefore accumulates in the lysosomes of retinal pigment epithelial cells throughout life, until the cells become disabled and vision begins to fade. Enzymes that could break down A2E would thus lead to a regenerative cure for age-related macular degeneration.

Direct links are good because it makes for a more straightforward test case and proof of principle. The evidence to date strongly suggests that repair, in this case breaking down waste products, will cause benefits. So there is less likelihood of research efforts becoming bogged down in questions of interpretation or tracing cause and effect through several or more layers of poorly understood biological mechanisms. This is important when there is as little funding for rejuvenation research like this as is presently the case: work must be efficient and lead as directly as possible to solid proof for the repair approach as a research strategy.

Here is an interesting review of what is known of the mechanisms of AMD as well as the present mainstream approaches to treatment - a list that does not at this time include the approach of breaking down metabolic waste products like A2E known to contribute to the condition. It is a small illustration of the larger point that aiming at repair of root causes is a whole new paradigm for the research community, and one that is only just starting to gain greater acceptance. It is still the case that the overwhelming majority of research on age-related disease that you see today is not informed by that viewpoint on strategy and goals:

Present and Possible Therapies for Age-Related Macular Degeneration

AMD is an umbrella term that encompasses two pathologically overlapping, yet distinct, processes: geographic atrophy (GA) (dry) AMD and neovascular (wet) AMD. Clinically, the presentation of AMD differs depending upon the development of neovascular or GA AMD. Unfortunately, both GA and neovascular AMD orchestrate a progressive and unremitting sequential loss of central vision within the affected eye(s) cumulating to blindness.

Our current understanding behind the pathogenesis of AMD stipulates that there is no predominant aetiological factor dictating the development of AMD. Rather, there is a multifactorial element to AMD, whereby interactions between several facets intertwine and coordinate a cascade of sequential steps that provide the appropriate environment for AMD to flourish. However, implicated for both forms of AMD are the involvement and degeneration of four principle ocular regions: the outer retina, the retinal pigment epithelium (RPE), Bruch's membrane (BM), and the choriocapillaris. Although the intricate processes explaining their degeneration still remain elusive, four mechanisms have been postulated as being imperative to the formation of AMD: lipofuscinogenesis, drusogenesis, inflammation, and choroidal neovascularisation; the former three aspects are critical to formation of both types of AMD, whereas the last represents the final stage in the development of neovascular AMD.

Lipofuscinogenesis

Over the course of senescence, there is progressive dysfunction of the RPE, thereby inducing a state of metabolic insufficiency which results in the formation and accumulation of lipofuscin. Deemed highly potent, due to the major component of lipofuscin being N-retinylidene-N-retinyl ethanolamine (A2E), the A2E produced has the ability to interfere with the functional aspects of the RPE, thus triggering apoptosis of the RPE with subsequent development of GA. Furthermore, the accumulation of A2E within the RPE has been shown to increase the risk of choroidal neovascularisation and so neovascular AMD.

Drusogenesis and Inflammation

Defined as "discrete lesions consisting of lipids and proteins", these amorphous deposits accumulate within the region situated between the RPE and the BM. Their clinical significance differs as relatively few quantities of small, hard drusen have been identified in over 95% of the elderly population and are regarded as a benign occurrence. Nevertheless, presence of large, hard and/or large, soft drusen has been recognised as increasing the risk of AMD. One component of this affiliation orientates around the physical displacement, and resulting death, of clusters of photoreceptors within the RPE overlying the drusen, thus leading to GA AMD.

Another dimension to the relationship between drusogenesis and AMD occurs through the indirect influence of drusen on the immune system. Indeed, identification of several components of the immune system within drusen has raised the possibility that drusen mediated inflammation may lead to notable degeneration and disruption.

Choroidal Angiogenesis

There is a delicate balance within endothelial cells residing in the retinal vasculature between factors that promote and inhibit angiogenesis. However, in neovascular AMD, there is a pathological shift in favour of factors promoting angiogenesis. It is postulated that the inflammation and recruitment of several components of the immune system trigger the release of proangiogenic mediators such as VEGF, thereby forming a milieu that favours angiogenesis. Regardless of the exact mechanism, progression to neovascularisation leads to the formation and extension of permeable, weak, and leaky vessels from the vascular choriocapillaris to the avascular choroid which, in turn, induces local oedema but, more profoundly, acute central vision loss resulting from haemorrhage with successive development of a fibrous scar.

The next generation of cancer treatments are all about targeting, finding ways to distinguish and destroy only cancer cells, to as to produce therapies that are much more effective, even against late stage metastatic cancer, and have few side effects. The present staples of chemotherapy and radiation therapy are arduous and only partially effective precisely because they are not very selective. It is easy to destroy cells, but hard to destroy only particular cells. One of the more promising lines of research and development for targeted cell destruction is immunotherapy: making use of the existing capabilities of immune cells and directing them to attack cancer cells:

When immunologist Michel Sadelain launched his first trial of genetically engineered, cancer-fighting T cells in 2007, he struggled to find patients willing to participate. Studies in mice suggested that the approach - isolating and engineering some of a patient's T cells to recognize cancer and then injecting them back - could work. But Sadelain did not blame colleagues for refusing to refer patients. "It does sound like science fiction," he says. "I've been thinking about this for 25 years, and I still say to myself, 'What a crazy idea'."

Since then, early results from Sadelain's and other groups have shown that his 'crazy idea' can wipe out all signs of leukaemia in some patients for whom conventional treatment has failed. And today, his group at the Memorial Sloan Kettering Cancer Center in New York City struggles to accommodate the many people who ask to be included in trials of the therapy, known as adoptive T-cell transfer.

[This is] the promise of engineered T cells - commonly called CAR (chimaeric antigen receptor) T cells - for treating leukaemias and lymphomas. The field has been marred by concerns over safety, the difficulties of manufacturing personalized T-cell therapies on a large scale, and how regulators will view the unusual and complicated treatment. But those fears have been quelled for some former sceptics by data showing years of survival in patients who once had just months to live. "The numbers are pretty stunning. Companies have clearly decided that it's worth the pitfalls of how much this therapy is going to cost to develop."

Link: http://www.nature.com/news/immune-cells-boost-cancer-survival-from-months-to-years-1.16519

Senescent cells stop dividing and secrete various factors that, among other things, damage surrounding tissue structure and encourage senesence in nearby cells. It would be best if they were removed, and they often are, either through programmed cell death or destroyed by the immune system. Some always remain however, and remain for the long term: their accumulation is one of the causes of degenerative aging. Senescence has some positive roles, however: when it occurs in response to a damaged tissue environment that leads to a greater risk of cells becoming cancerous then senescence can help reduce those odds by removing the cells most at risk from active duty. In addition senescence appears to be a necessary part of shaping tissue during embryonic growth.

Current investigations of senescence have turned up another beneficial role: some of the molecules secreted by senescent cells are a part of the processes of wound healing. Fortunately this is no obstacle to the future production of therapies to periodically clear senescent cells from the body, and thus remove this contribution to the aging process. Just don't use the treatments when you happen to be injured.

[Researchers] identified a single factor secreted by senescent cells that cause them to promote wound healing. It's a crucial discovery for researchers who are working on developing treatments to clear the body of senescent cells as a way to stem the development of age-related disease. "We are now able to identify what senescent cells express that makes them beneficial. This means we will be able to simply provide that factor while we eliminate senescent cells to prevent a deleterious side effect before it even occurs."

[Researchers] used two different mouse models: in the first, senescent cells can be visualized and eliminated in living animals; in the second, mutations in two key genes block the senescence program. Following a skin wound, senescence occurs early on in cells that produce collagen and line blood vessels. The senescent cells accelerated wound closure through the secretion of PDGF-AA, a growth factor contained within blood platelets, making it the "good guy" in this portrayal of senescence. "We were able to apply recombinant PDGF-AA topically to mice that had senescent-free wounds. It rescued delayed wound closure and allowed the mice to heal normally."

The researchers also found that senescent cells were present only for a short time during tissue repair, in contrast to the persistent presence of senescent cells in aged or chronically damaged tissues. Moreover, they say the fact that PDGF-AA was activated very early upon senescence induction in cell culture suggests the time-dependent regulation of secretory factors might, in part, explain the beneficial vs. deleterious effects of senescent cells. The possibility of eliminating senescent cells holds great promise and is one of the most exciting avenues currently being explored in efforts to extend healthspan. This study shows that we can likely harness the positive aspects of senescence to ensure that future treatments truly do no harm."

Link: http://sciencedaily.com/releases/2014/12/141211124526.htm

Research into treatments for the direct consequences of obesity may be, like much of aging research at the moment, the cover story set up by metabolic researchers in order to raise funds from a system that demands some connection, however tenuous, to the end goal of building treatments. In fact the principal goal of these scientific groups is to catalog and completely understand the massive complexity of cellular metabolism. Making use of that knowledge for any purpose other than to speed up other areas of the cataloging process is a distant second concern. A lot of modern medical research makes much more sense if viewed through this lens, though I can't vouch for the accuracy of its cynicism. It is generally true that knowledge is the primary goal of science, while it is more typically the engineering disciplines whose members work on building new applications of that knowledge. The line between scientist and engineer - between researcher and clinician - was always blurry and indistinct, however, and remains so today.

We live in a world in which wealth has been generated to such an extent that our natural urges, evolved for scarcity, now guide us to harm ourselves. Food, transport, and comfort are so cheap in wealthier regions of the world that simply failing to care and plan for diet and health will turn a thin individual into a considerably overweight individual in a matter of a handful of years. In some parts of Asia the transition from rural subsistence poverty to a society of such wealth happened in a single lifetime, bringing the demographics of disease and longevity into line with the US and Western Europe in that short span of years. Thus there are a lot of overweight individuals nowadays: we are a lot wealthier today even than fifty years ago in measures that matter, such as cost of calories and transportation. As a result a lot more money flows into medical services related to the health consequences of being overweight, and - follow the money - a large amount of funding exists for work on medical means to address these conditions. This is largely centered around work on treating type 2 diabetes, but it is also true that there is a greater level of funding for numerous other conditions much more commonly suffered by those who are overweight.

There is far less funding for the strategy of simple self control and just eating less, but that's what you get in an age of comfort. People want to be told they are fine, there is nothing they did wrong, and that the research community is working on zero-effort, write-a-check methods for making everything right in the world. People don't want to be told to adjust their expectations and diet while simultaneously exercising their willpower, even if that approach can reverse being overweight and reverse type 2 diabetes to boot. A lot of wishful thinking sloshes around in this ecosystem.

The inevitable consequence of giving a lot of researchers a lot of money to do something about obesity, even if they are principally focused on building the Grand Map of Metabolism, is that someone, somewhere, might actually come up with a treatment that works. I can assure you that there is a lot more funding out there for work on obesity and type 2 diabetes, conditions that the vast majority of patients choose to suffer - and worse, choose on a daily basis to continue to suffer - than for meaningful research into treating aging. Does success make it all worthwhile in comparison to other things those resources might have purchased in the research community? That is a question without an answer.

The best hypothetical treatment for obesity is probably one that does absolutely nothing other than make the patient eat less. That seems to be the case in the research noted below, so one has to wonder to what degree the rest of the panoply of effects they describe are relevant to the end result:

Another success on the path to cure adult-onset diabetes, obesity

A new treatment for adult-onset diabetes and obesity developed by researchers has essentially cured lab animals of obesity, diabetes and associated lipid abnormalities through improved glucose sensitivity, reduced appetite and enhanced calorie burning. In preclinical trials, the new peptide - a molecular integration of three gastrointestinal hormones - lowered blood sugar levels and reduced body fat beyond all existing drugs.

These preclinical results advance the clinical work the team announced last year that a peptide combining the properties of two endocrine hormones, GLP-1 and GIP, was an effective treatment for adult-onset diabetes. This new molecule includes a third hormone activity, glucagon. "A number of metabolic control centers are influenced simultaneously, namely in the pancreas, liver, fat depots and brain. The benefits of the previously reported individual co-agonists have been integrated to a single molecule of triple action that provides unprecedented efficacy to lower body weight and control metabolism."

The triple hormone specifically and equally targets three receptors of GLP-1, GIP and glucagon. GLP-1 and GIP predominantly contribute to enhancing insulin action and reducing blood glucose. GLP-1 also curbs appetite, while glucagon primarily increases the long-term rate at which calories are burned and improves liver function.

A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents

We report the discovery of a new monomeric peptide that reduces body weight and diabetic complications in rodent models of obesity by acting as an agonist at three key metabolically-related peptide hormone receptors: glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon receptors. Such balanced unimolecular triple agonism proved superior to any existing dual coagonists and best-in-class monoagonists to reduce body weight, enhance glycemic control and reverse hepatic steatosis in relevant rodent models. We demonstrate that these individual constituent activities harmonize to govern the overall metabolic efficacy, which predominantly results from synergistic glucagon action to increase energy expenditure, GLP-1 action to reduce caloric intake and improve glucose control, and GIP action to potentiate the incretin effect and buffer against the diabetogenic effect of inherent glucagon activity.

Research in mice suggests that using cell therapies to remove scarring on the cornea that clouds vision might actually be a comparatively simple process:

Treating the potentially blinding haze of a scar on the cornea might be as straightforward as growing stem cells from a tiny biopsy of the patient's undamaged eye and then placing them on the injury site, according to mouse model experiments conducted by researchers. "The cornea is a living window to the world, and damage to it lead to cloudiness or haziness that makes it hard or impossible to see. The body usually responds to corneal injuries by making scar tissue. We found that delivery of stem cells initiates regeneration of healthy corneal tissue rather than scar leaving a clear, smooth surface."

[Researchers] had previously developed a technique to obtain ocular stem cells from tiny biopsies at the surface of the eye and a region between the cornea and sclera known as the limbus. Removal of tissue from this region heals rapidly with little discomfort and no disruption of vision. After collecting biopsies from banked human donor eyes, the team expanded the numbers of cells in a culture plate. They conducted several tests to verify that they these cells were, in fact, corneal stem cells.

The team then tested the human stem cells in a mouse model of corneal injury. They used a gel of fibrin, a protein found in blood clots that is commonly used as a surgical adhesive, to glue the cells to the injury site. They found the scarred corneas of mice healed and became clear again within four weeks of treatment, while those of untreated mice remained clouded. "Even at the microscopic level, we couldn't tell the difference between the tissues that were treated with stem cells and undamaged cornea. We were also excited to see that the stem cells appeared to induce healing beyond the immediate vicinity of where they were placed. That suggests the cells are producing factors that promote regeneration, not just replacing lost tissue."

Link: http://www.upmc.com/media/NewsReleases/2014/Pages/som-study-shows-stems-cells-clear-cloudy-cornea.aspx

Researchers have successfully used a scaffold approach to regrow the menicus in a joint:

Researchers have devised a way to replace the knee's protective lining, called the meniscus, using a personalized 3D-printed implant, or scaffold, infused with human growth factors that prompt the body to regenerate the lining on its own. The therapy, successfully tested in sheep, could provide the first effective and long-lasting repair of damaged menisci, which occur in millions of Americans each year and can lead to debilitating arthritis. "At present, there's little that orthopedists can do to regenerate a torn knee meniscus. Some small tears can be sewn back in place, but larger tears have to be surgically removed. While removal helps reduce pain and swelling, it leaves the knee without the natural shock absorber between the femur and tibia, which greatly increases the risk of arthritis."

[The] approach starts with MRI scans of the intact meniscus in the undamaged knee. The scans are converted into a 3D image. Data from the image are then used to drive a 3D printer, which produces a scaffold in the exact shape of the meniscus [made] of polycaprolactone, a biodegradable polymer that is also used to make surgical sutures. The scaffold is infused [with] connective growth factor (CTGF) and transforming growth factor β3 (TGFβ3). [The] sequential delivery of these two proteins attracts existing stem cells from the body and induces them to form meniscal tissue. This is accomplished by encapsulating the proteins in two types of slow-dissolving polymeric microspheres, first releasing CTGF (to stimulate production of the outer meniscus) and then TGFβ3 (to stimulate production of the inner meniscus). Finally, the protein-infused scaffold is inserted into the knee. In sheep, the meniscus regenerates in about four to six weeks. Eventually, the scaffold dissolves and is eliminated by the body.

Link: http://newsroom.cumc.columbia.edu/blog/2014/12/10/3d-printed-meniscus/

Cells are complex machines that have many carefully regulated states. One of those states is senescence, in which the cell permanently exits the cell cycle, stops dividing, and begins to secrete a variety of molecules that, among other things, degrade surrounding extracellular matrix structures and encourage nearby cells to also become senescent or change their behavior in other ways. This senescent state seems to be a tool that originally evolved to help manage embryonic growth: senescent cells are found in embryos in places that suggest they are managing shape or tissue transitions during development.

Evolution promiscuously reuses everything that emerges in biology, and at some point cellular senescence became a reaction to damage likely to cause cancer. Toxins, stress, and the various forms of cellular and molecular damage of aging can provoke cells into more readily becoming senescent, either directly or through changes in the signaling environment in tissues. Cancers result from damage to nuclear DNA, producing cells capable of unfettered replication. Senescence is a form of defense that removes potentially cancerous cells from consideration, or at least to some degree. Cancers and cellular senescence are two aspects of our biology in the midst of a long-running evolutionary struggle: the story of the lengthening of human life span in comparison to other primates is one of a moving balance between death by cancer and death by failing tissue function. Many of the most important mechanisms in aging, cellular senescence included, can be viewed in that context. However, too much cellular senescence actually promotes some forms and aspects of cancer precisely because of the various molecules secreted by these cells. There is a tipping point between cancer suppression and cancer promotion determined by the changes in the cellular environment caused by the presence of senescent cells. It is a complex situation.

Senescent cells sometimes destroy themselves through programmed cell death mechanisms that serve to remove damaged cells from circulation before they cause issues, and are sometimes destroyed by the immune system. Those that linger stick around for the long term, however, accumulating in ever increasing numbers. To make things worse, as the immune system declines with aging it does an increasingly poor job of removing these cells, so even as the pace of creation accelerates due to age-damaged tissues, the policing mechanisms are in decline. A sizable percentage of adult skin cells are senescent by the time old age rolls around, for example.

In an ideal world, the perfect situation for adult cellular senescence would be if all these cells in fact destroyed themselves fairly promptly, say within a few days. That is a long way removed from the present situation, but it is something that near future medicine could achieve. The cancer research community is developing all sorts of ways to precisely target cells based on their particular biochemical differences, usually and most easily based on differences in surface chemistry, the molecules presented on the exterior of the cell membrane. Many cancers are distinctive enough to target in this way, and so an industry of research and development has for years been working on the use of altered viruses, designer nanoparticles, and the like, that can find and bind to particular combinations of cell surface chemistry, and once there deliver some form of traditional cancer therapy in the tiny dosage needed to destroy a single cell. Manufacturing tens of millions of such devices for each dose of a therapy promises a very effective next generation of treatments that nonetheless have few side-effects - a world removed from the present standards of chemotherapy and radiation therapy.

Turning these prototype cancer therapies into senescent cell clearance treatments is a very plausible path forward. The roadblock in the way is the need for a good, reliable marker to determine which cells are senescent and which are not. Some of the most interesting work on senescent cell clearance has focused on p16 as a marker for cellular senescence, but this is not as discerning as would be liked despite the successes achieved to date in mice. A couple of other lines of research have looked promising in recent years, such as using lysosomal hydrolases or TRF2 as markers. We are still waiting on a research group to pull this all together, but meaningful removal of senescent cells remains probably the closest item in the rejuvenation toolkit to actual realization.

Here is recent news in which the research team seem fairly confident they have a good marker for senesence in the form of a combination of proteins. They have tried a couple of different cell lines by the sound of it, but I'd want to see more diverse tissues tested; there is no necessary reason to expect cellular senescence to generate usefully similar surface chemistry in all of the most common cell types in the body, though it would be pleasant if that did turn out to be the case. That said, despite the lack of funding for senescent cell clearance with the explicit goal of treating aging it seems there is still some progress, as illustrated by the fact that these cancer researchers are aware enough of efforts in that direction to talk about it at all:

Study offers future hope for tackling signs of aging

"What we have found is a series of novel markers - a way to detect senescent cells. What is more, we have shown that they can be used to predict increased survival in certain types of cancer. Until now, good protocols to help spot these cells have been sadly lacking. Our research has described new markers located on the surface of the old cells. This makes these markers particularly useful to quickly identify these cells in laboratory and human samples using a range of techniques."

As a first clinical application of these markers, the researchers observed that they were present in high numbers in samples from different types of cancer and that this correlated with a better prognosis of the disease. This was particularly evident in breast cancer. "These markers could be useful tools not only to study senescent cells in the lab but also they could be developed into diagnostics to help predict survival in cancer patients. Moreover, they could also be used in the future to define strategies to selectively eliminate the old cells from the tissues and thus reduce their effects on promoting ageing in healthy subjects."

Characterization of novel markers of senescence and their prognostic potential in cancer

Cellular senescence is a terminal differentiation state that has been proposed to have a role in both tumour suppression and ageing. This view is supported by the fact that accumulation of senescent cells can be observed in response to oncogenic stress as well as a result of normal organismal ageing. Thus, identifying senescent cells in in vivo and in vitro has an important diagnostic and therapeutic potential.

The molecular pathways involved in triggering and/or maintaining the senescent phenotype are not fully understood. As a consequence, the markers currently utilized to detect senescent cells are limited and lack specificity. In order to address this issue, we screened for plasma membrane-associated proteins that are preferentially expressed in senescent cells. We identified 107 proteins that could be potential markers of senescence and validated 10 of them (DEP1, NTAL, EBP50, STX4, VAMP3, ARMX3, B2MG, LANCL1, VPS26A and PLD3). We demonstrated that a combination of these proteins can be used to specifically recognize senescent cells in culture and in tissue samples and we developed a straightforward fluorescence-activated cell sorting-based detection approach using two of them (DEP1 and B2MG).

Of note, we found that expression of several of these markers correlated with increased survival in different tumours, especially in breast cancer. Thus, our results could facilitate the study of senescence, define potential new effectors and modulators of this cellular mechanism and provide potential diagnostic and prognostic tools to be used clinically.

Chronic inflammation is important in neurodegenerative conditions such as Alzheimer's disease, but how much of that is due to age-related dysfunction of the immune system versus the presence of pathogens? Inflammation is a necessary part of the immune response when it is working correctly, after all. Some thoughts on that matter in this open access paper:

Alzheimer's disease (AD) is a complex disease resulting in neurodegeneration and cognitive impairment. Investigations on environmental factors implicated in AD are scarce and the etiology of the disease remains up to now obscure. The disease's pathogenesis may be multi-factorial and different etiological factors may converge during aging and induce an activation of brain microglia and macrophages. This microglia priming will result in chronic neuro-inflammation under chronic antigen activation. Infective agents may prime and drive hyper-activation of microglia and be partially responsible of the induction of brain inflammation and decline of cognitive performances.

Age-associated immune dysfunctions induced by chronic subclinical infections appear to substantially contribute to the appearance of neuro-inflammation in the elderly. Individual predisposition to less efficient immune responses is another relevant factor contributing to impaired regulation of inflammatory responses and accelerated cognitive decline. Life-long virus infection may play a pivotal role in activating peripheral and central inflammatory responses and in turn contribute to increased cognitive impairment in preclinical and clinical AD.

Link: http://dx.doi.org/10.1186/s12979-014-0022-8

Cancer is thought to be a disease of aging because we accumulate randomly distributed damage to nuclear DNA as we age. The older you are the more of this damage you have. Sooner or later the right combination of mutations occur in a cell that slips past the monitoring of the immune system and other defensive systems, which themselves decline with age due to other forms of damage, and it runs amok to grow a cancer. It remains an open question as to whether this nuclear DNA damage in aging is significant in any other way besides cancer over the present length of a human life span, though it is the default assumption in the research community that this is the case.

There is no good evidence, however, to show that DNA damage and only DNA damage is the cause of other meaningful changes in cellular metabolism characteristic of aging. You can of course correlate damage with progress in aging, and show that calorie restriction - to pick one example - slows the accumulation of nuclear DNA damage along with other measures of aging, but aging is a global phenomenon: these correlations don't even come close to implying direct causation. Finding a more definitive connection is an experiment that lies somewhere in the near future, enabled by more capable biotechnologies and a novel study setup devised by clever researchers.

In any case, this recent research is one narrow example of a way in which random nuclear DNA damage causes cancer - or rather more cancer in this case:

For a small percentage of cancer patients, treatment aimed at curing the disease leads to a form of leukemia with a poor prognosis. Conventional thinking goes that chemotherapy and radiation therapy induce a barrage of damaging genetic mutations that kill cancer cells yet inadvertently spur the development of acute myeloid leukemia (AML), a blood cancer. But a new [study] challenges the view that cancer treatment in itself is a direct cause of what is known as therapy-related AML. Rather, the research suggests, mutations in a well-known cancer gene, P53, can accumulate in blood stem cells as a person ages, years before a cancer diagnosis. If and when cancer develops, these mutated cells are more resistant to treatment and multiply at an accelerated pace after exposure to chemotherapy or radiation therapy, which then can lead to AML, the study indicates.

The researchers initially sequenced the genomes of 22 cases of therapy-related AML, finding that those patients had similar numbers and types of genetic mutations in their leukemia cells as other patients who developed AML without exposure to chemotherapy or radiation therapy, an indication that cancer treatment does not cause widespread DNA damage. "This is contrary to what physicians and scientists have long accepted as fact. It led us to consider a novel hypothesis: P53 mutations accumulate randomly as part of the aging process and are present in blood stem cells long before a patient is diagnosed with therapy-related AML."

Researchers have known that patients with therapy-related AML are more likely than other AML patients to have a high rate of P53 mutations in their blood cells. The gene is a tumor suppressor and normally works to keep cell division in check and maintain the structure of chromosomes inside cells. But when both copies of the gene are disabled by mutations, cancer can develop. Surprisingly, when the researchers analyzed blood samples from 19 healthy people ages 68-89 with no history of cancer or chemotherapy, they found that nearly 50 percent had mutations in one copy of P53, an indicator that many people acquire mutations in this gene as they age.

Link: http://www.newswise.com/articles/genetic-errors-linked-to-aging-underlie-leukemia-that-develops-after-cancer-treatment

Common genetic variants contribute to individual differences in longevity when considered statistically across thousands of individuals and decades of their lives. But even statistically common genetic variations are not particularly important until later life. For all but a few unlucky individuals with rare genetic conditions, the difference between comparative health and comparative frailty at the end of middle age is a matter of lifestyle choices and environment, not genes. After that, however, genetics becomes increasingly important as an influence. It is important to realize that, again, this is only when considered statistically. For every centenarian with a given genetic variation there are scores of other individuals with that very same variant who died at much younger ages. Odds of survival that are improved from 1% to, say, 1.5% remain terrible odds.

The dominant theme emerging from research into the genetics of longevity within our species is that individual variants have very small effects. Further, most statistical associations between specific genetic differences and human longevity are not replicated when studies are repeated with different populations. This tends to be true even for different study populations in the same region - see a recent investigation of associations between FOXO3A and longevity for a good example of this outcome. So in addition to being small, effects are very complicated and highly variable between even very similar genetic lineages. At present there are really only two good associations discovered to date, variants of APOE and FOXO3A, and even these are hard to extract from the data at times.

The situation is somewhat better when it comes studies of age-related conditions and genetics. There are a wide range of robust associations for various conditions in which certain genetic variants seem to imply a lower resistance to specific disease processes that occur in everyone. Investigating the biochemistry of a disease tends to turn up candidate genetic variants in the process of obtaining a better understanding of what exactly is going wrong. You might look at what is known of genetic associations with Parkinson's disease for a good example of how this tends to work out in practice.

To further complicate things, most work in biology and medicine doesn't start with humans, and this is especially true of longevity science. People, mice, flies, worms, and even yeast are all part of the same evolutionary tree and share a surprising number of genes and mechanisms relating to the intersection of metabolism and longevity - which is where you'll most likely find the engines driving natural variations between individuals, as well as the fine details of the ongoing progressive global systems failure that is aging. This common evolutionary heritage is why researchers can obtain insights into human aging and metabolic processes from yeast and flies, and if that can be done it is certainly a whole lot cheaper than trying the same wait and see studies in people.

This doesn't mean that any of this is straightforward, however. People are not mice, and considerably progress in finding longevity-associated genes and single gene mutations that reliably extend life in rodents has not yet led to any similar advances in a coherent mapping of the human genetics of longevity. This short note on the topic is from the lead at one of the groups involved in sequencing the bowhead whale genome in search of explanations for its lengthy life span, thought to be in excess of two centuries:

Why genes extending lifespan in model organisms have not been consistently associated with human longevity and what it means to translation research

A recent paper reports the largest genome-wide association study of human longevity to date. While impressive, there is a remarkable lack of association of genes known to considerably extend lifespan in rodents with human longevity, both in this latest study and in genetic association studies in general. Here, I discuss several possible explanations, such as intrinsic limitations in longevity association studies and the complex genetic architecture of longevity.

Yet one hypothesis is that the lack of correlation between longevity-associated genes in model organisms and genes associated with human longevity is, at least partly, due to intrinsic limitations and biases in animal studies. In particular, most studies in model organisms are conducted in strains of limited genetic diversity which are then not applicable to human populations. This has important implications and, together with other recent results demonstrating strain-specific longevity effects in rodents due to caloric restriction, it questions our capacity to translate the exciting findings from the genetics of aging to human therapies.

Of the 51 gene manipulations extending lifespan in mice, how many would still extend lifespan in genetically heterogeneous mice and by how much? How many would be detrimental? When considering potential applications of the genetics of aging one should keep in mind that these have not been replicated in humans and that even in model organisms these are derived from a very small selection of clones that do not represent the whole species.

For me this is one more item to add to the great mountain of evidence telling us that manipulation of genetics and the operation of metabolism so as to slow aging simply isn't the right path forward. It is too hard, too slow, an attempt to alter an enormously complex and poorly understood system in non-trivial ways, and has too poor an outcome even if successful in comparison to other strategies. Slowing aging can't help the old, and it would be a real shame if all of the effort and investment of the next few decades leads only to therapies that do little for the young and nothing for those of us who helped to bring them about.

To move rapidly towards treatments for aging we should look at cataloging the differences between young tissues and old tissues, determine which of those differences are fundamental and primary, not caused by any of the others, and build the means to revert those differences. The state of knowledge about aging is far further advanced towards that goal than towards a goal of safe metabolic re-engineering.

Comparative biology is a matter of studying differences between species that might provide insight into how particular cellular mechanisms of interest actually work - or might be altered so as to work better. The world has many species that regenerate more proficiently than we do, or live very much longer than would be expected for their size, or show other desirable characteristics as a result of their own particular evolved biology. How is this achieved at the level of cells and molecular mechanisms, and is it possible to recreate some of these changes in humans? These are questions that comparative biologists seek to answer, using the biology of other species as a shortcut to obtain environments that would otherwise be challenging or impossible at present to set up in the lab.

The authors of the paper quoted below argue that failing to take advantage of the panoply of varied evolved biochemistries in the natural world is holding back medical research. I'd suggest that disparities in regulation have a lot more to do with the differences they point out in progress in computing versus medicine. Regardless, there is certainly utility in the use of comparative biology to obtain new knowledge:

The pace at which science continues to advance is astonishing. From cosmology, microprocessors, structural engineering, and DNA sequencing our lives are continually affected by science-based technology. However, progress in treating human ailments, especially age-related conditions such as cancer and Alzheimer's disease, moves at a relative snail's pace. Given that the amount of investment is not disproportionately low, one has to question why our hopes for the development of efficacious drugs for such grievous illnesses have been frustratingly unrealized. Here we discuss one aspect of drug development - rodent models - and propose an alternative approach to discovery research rooted in evolutionary experimentation. Our goal is to accelerate the conversation around how we can move towards more translative preclinical work.

For more than a century, most biomedical research has relied primarily on mice and rats to study the basic biology, progression, and prevention of disease, with the overarching premise that "below the skin" all organisms are molecularly and biochemically alike. Indeed, several seminal discoveries and human therapies have been made using the premise of rodent models. However, advances in certain areas, especially age-related diseases, have been slow. In fact, one can argue that the numerous reported 'cures' for rodent obesity, cancer, and Alzheimer's disease have ultimately burdened the collective resources of the community to the point that a re-evaluation of the preclinical paradigm must be undertaken.

There is a growing call for additional discovery tools in biomedical research that provide more translative predictability for diseases that generally afflict humans in later life. Animal models that are considered long-lived on the basis of their body size are essential to fill the gap assessing the immutable role of time in aging and the manifestation of age-related diseases. Use of extremely long-lived models such as the naked mole-rat, or species that have adapted to extreme environments also enables one to evaluate whether nature has already evolved the appropriate mechanisms to overcome the environmental threats that contribute to sporadic and late onset diseases. An alternative approach towards target discovery employs natural, extreme biology where evolutionary experimentation has overcome many biological challenges. For instance, obesity is a natural and necessary state to survive months of fasting in hibernating animals. To this end we studied grizzly bears (Ursus arctos horribilis) before, during, and after hibernation to determine the effects of natural obesity on insulin sensitivity and cardiac function.

Link: http://www.impactaging.com/papers/v6/n11/full/100704.html

Paul Allen is funding a new large-scale life science project to follow up on the Brain Atlas. This time the goal is to fill in the unknown reaches of cellular metabolism:

Billionaire Paul Allen has a new target for scientific philanthropy: Unraveling the inner workings of human cells. The Microsoft co-founder announced a $100 million, five-year grant to establish the Allen Institute for Cell Science in Seattle. The grant is one of Allen's largest, on par with the $100 million he committed earlier this year to fight Ebola in West Africa, and a $100 million grant in 2003 to establish the Seattle-based Allen Institute for Brain Science. He has since plowed an additional $300 million into the brain institute.

The goal is to better understand the teeming world inside cells, where thousands of organelles and millions of molecules interact in a dynamic ballet that researchers are just beginning to fathom. Diagrams in biology textbooks make it seem like cell structure and function have already been nailed down. Scientists have, indeed, learned a lot about different cell types, the role of organelles like the nucleus, and specific pathways, like the chain of events that causes muscle cells to contract. But there's a big gap when it comes to understanding the way cells function as a whole. "We really don't have a good idea of how normal cells work, and what goes wrong in disease. People spend careers trying to understand little parts of the cell, but nobody has stitched it together - because it's too complicated for any individual to study."

The institute will take on the challenge by combining new technologies, like microscopes that can visualize living cells in three dimensions, with enough computational firepower to make sense of the flood of data that will result. [Researchers] hope to develop computer models that mimic living cells. If they succeed, those models could also shed light on what goes haywire in cancer and other diseases and help develop cures. "Our output will be a kind of visual, dynamic atlas that shows where all of these things are in the cell and how they change over time."

Link: http://seattletimes.com/html/localnews/2025193609_allencellxml.html

As I'm sure you're all aware, back in October Fight Aging! launched a matching fundraiser in support of the work of the SENS Research Foundation. Together Christophe and Dominique Cornuejols, Dennis Towne, Håkon Karlsen, Jason Hope, Methuselah Foundation, Michael Achey, Michael Cooper, and Fight Aging! established a $100,000 matching fund and challenged the community to donate another $50,000 by the end of the year, with all of this going to expand ongoing rejuvenation research programs. The SENS Research Foundation coordinates scientific efforts essential for the near future production of therapies capable of repairing the cellular and molecular damage that causes aging. The Foundation staff also advocate in and beyond the research community, organize noted conferences such as this year's Rejuvenation Biotechnology 2014, and help to build the next generation of enthusiastic scientists, people who see treatments for aging as the hot new thing in cutting edge biotechnology.

The Foundation takes a very careful, strategic view on research, and focuses funding on fields needed for tomorrow's rejuvenation toolkit but which are at present stalled, ignored, or poorly funded - such as work on mitochondrial DNA repair and removal of various forms of harmful metabolic waste, such as those that clog up and damage lysosomes with age. Early stage research in most areas of biotechnology is becoming quite cheap these days, and a lot can be done with a few hundred thousand dollars, a few smart young scientists, and an established academic laboratory with space to spare. Certainly it is possible to unjam fields that are stuck because no-one wants to invest the time to build the basic tools needed for any meaningful work to take place, as is the case for breaking down glucosepane cross-links in human tissues, or where present relevant research is largely intended for use with comparatively rare genetic diseases, and thus is funded below the levels needed to ensure reliable progress, as is the case for some of the work relevant to working around the contribution of mitochondrial DNA damage to aging.

Which is all to say that grassroots efforts at the level of our Fight Aging! SENS fundraiser are meaningful and important. We light the way and attract later, wealthier donors, and further do actually help to ensure that good research is accomplished with our funds. I'm pleased to say that the community has shown considerable generosity and support, especially in the last week since Giving Tuesday and an offer by Aubrey de Grey to further match donations that day. At present with three weeks to go more than 500 people have pitched in and we are just a little over three thousand dollars short of our goal of $50,000. Thank you to all who have helped!

So if you have friends who are on the fence, or even friends who have never heard of the SENS Research Foundation and efforts in the scientific community to bring an end to pain, suffering, and disease in aging, then now is a good time to reach out.

In the field of tissue engineering at present the work on simpler tissues and smaller tissue sections is the closest to widespread commercial realization. Most of the leading lines of research and development involve the use of decellularization, in which donor tissue, which can be from a different species, is stripped of its cells leaving behind the intricate structure of the extracellular matrix. That acts as a scaffold to guide repopulation with cells grown from a patient sample, producing functional tissue ready for transplantation. Here is a short interview with a tissue engineer working on the generation of bone sections:

At the moment, the only way to get bone for grafts is to cut it out of a human. If you need a piece of bone for, say, your ankle, they'll cut it out of your hip. There are several million of these bone-grafting procedures done every year worldwide. The idea is to grow bone from a patient's own cells so they won't need that second surgery and so the implanted bone won't be immunologically rejected. First, we'll take a CT scan to get the 3D structure of a patient's bone and use a high-precision machine to carve a decellularised bovine bone into the required shape. Then we'll take fat tissue from a patient and extract stem cells from it. We combine the stem cells with the piece of carved bone and put it into a bioreactor. That's where the magic happens - after three weeks in the bioreactor we have a piece of bone ready for implantation.

We're working in pigs at the moment but will use the same principle for humans. Pigs are a good fit for the bone we're working on. We wanted a strong proof of concept so chose the most difficult bone in the head - the temporomandibular joint for the jaw. Pigs are great because they've got a very similar sized head to humans and use the bone in a similar way, in a kind of circular chewing motion. The science is getting really close. We're about to start a second, larger study in pigs and are doing work in preparation for human clinical trials with the FDA. We are also planning small-scale implantations in humans in the next year and a half. So pretty soon hopefully!

Link: http://www.theguardian.com/technology/2014/dec/07/bones-grown-lab-biotech-grafts

The Golgi apparatus is a large structure in the cell that sets up transport of proteins to cell components by packaging and labeling the proteins to ensure they are sent to specific destinations. It is also involved in numerous other processes, such as the synthesis of some important proteins used by cell components, and far from all of these roles are fully cataloged and understood. It is known that rising levels of amyloid beta (Aβ) in and between brain cells characteristic of Alzheimer's disease harms the Golgi apparatus, and here researchers dig deep enough into this process to find a way to block that damage to see what happens:

Alzheimer's disease (AD) progresses inside the brain in a rising storm of cellular chaos as deposits of the toxic protein, amyloid-beta (Aβ), overwhelm neurons. An apparent side effect of accumulating Aβ in neurons is the fragmentation of the Golgi apparatus, the part of the cell involved in packaging and sorting protein cargo including the precursor of Aβ. But is the destruction the Golgi a kind of collateral damage from the Aβ storm or is the loss of Golgi function itself part of the driving force behind Alzheimer's?

The unsurprising part of the answer was that rising levels of Aβ do lead directly to Golgi fragmentation by activating a cell cycle kinase, cdk5. The surprising part of the answer was that Golgi function can be rescued by blocking cdk5 or shielding its downstream target protein in the Golgi, GRASP65. The even more surprising answer was that rescuing the Golgi reduced Aβ accumulation significantly, apparently by re-opening a normal protein degradation pathway for the amyloid precursor protein (APP).

The researchers now say that Golgi fragmentation is in itself a major - and until now an unrecognized - mechanism through which Aβ extends its toxic effects. They believe that as Aβ accumulation rises, damage to the Golgi increases, which in turn accelerates APP trafficking, which in turn increases Aβ production. This is a classic "deleterious feedback circuit". By blocking cdk5 or its downstream target, that circuit can be broken or greatly slowed.

Link: http://www.newswise.com/articles/rescuing-the-golgi-puts-brakes-on-alzheimer-s-progress

It has been some years since sarcopenia was coined as a name for the characteristic loss of muscle mass and strength that occurs with aging, one of many attempts - some successful - to carve off an aspect of aging and obtain regulatory approval to work on treating it. It remains the case that making an official disease of sarcopenia is an ongoing process of lobbying with no end in sight, however. Without that blessing of the state there is no legal path to the translation of promising research into commercial clinical treatments, and thus far less incentive for the major funding sources to invest in any of the research needed to even get to the point at which commercial development is plausible.

In countries like the US only treatments for one of a list of defined diseases are considered for approval by the FDA, very much a case of all that is not permitted is forbidden. Even if sound and proven treatments exist and are widely used elsewhere in the world, people can be ruined financially and potentially go to jail for a long time for offering those treatments in the US. This was the case for first generation stem cell therapies for quite a number of years, for example. One of the large problems for the near future of longevity science as a whole is that aging itself is not considered a medical condition by the FDA and similar regulatory bodies. For so long as that is the case all meaningful early clinical development must occur in other regions of the world, and more importantly there will continue to be far less funding for research than might otherwise be the case.

Back to sarcopenia, however. There is indeed loss of muscle mass in aging, and this is a major cause of the frailty of later life. There is much more to the underlying processes than just a simple loss of mass, however. It is much more complex than that, as this review notes. The quoted portions are from the introduction and summary, and in between there is a more detailed overview of some of the mechanisms mentioned - it makes for interesting reading within the context that the practice of calorie restriction slows the progression of sarcopenia.

It is not just muscle mass: a review of muscle quality, composition and metabolism during ageing as determinants of muscle function and mobility in later life

Worldwide estimates predict 2 billion people will be aged over 65 years by 2050. A major current challenge is maintaining mobility and quality of life into old age. Impaired mobility is often a precursor of functional decline, disability and loss of independence. Sarcopenia which represents the age-related decline in muscle mass is a well-established factor associated with mobility limitations in older adults. However, there is now evidence that not only changes in muscle mass but other factors underpinning muscle quality including composition, metabolism, aerobic capacity, insulin resistance, fat infiltration, fibrosis and neural activation may also play a role in the decline in muscle function and impaired mobility associated with ageing. Importantly, changes in muscle quality may precede loss of muscle mass and therefore provide new opportunities for the assessment of muscle quality particularly in middle-aged adults who could benefit from interventions to improve muscle function.

Several longitudinal studies suggest that muscle mass alone cannot fully explain the loss of muscle strength and physical function in older adults. Estimates of the rate of change in muscle strength with age derived from a cross-sectional cohort have also been suggested to underestimate actual yearly changes in muscle strength. In the Health, Ageing, and Body Composition (Health ABC) study, the decline in muscle strength during ageing was reported to be two- to five fold greater than the loss of muscle mass in older adults aged 70-79 years over a 3-year follow-up period. Furthermore, there was wide inter-individual variability in changes in muscle cross-sectional area and muscle strength in older adults, such that muscle mass and muscle strength were well-preserved in some individuals but not others.

It will be important in future to better understand the main factors which underpin changes in muscle quality with age, which may well precede changes in muscle mass or be of greater functional significance in ageing muscles, with declining size. In addition, a universal consensus definition of muscle quality is necessary. Muscle quality is typically used to describe muscle strength or power per unit of muscle mass, therefore does not encompass muscle aerobic capacity which is closely associated with mobility and important for activities of daily living. Currently, there is a large gap in our knowledge on the primary determinants of muscle quality in middle-aged adults. The development of muscle quality assessment tools that encompass muscle quality and which are sensitive to small changes within muscle that precede a decline in muscle function would enable individuals to take preventative steps to maintain healthy muscle.

When considering the impact on life expectancy and long-term health the data tells us that obesity and smoking are in the same ballpark. Here is a recent research publication that puts some numbers to the very real costs of being overweight. The results are similar to those produced in past studies:

Researchers used data from the National Health and Nutrition Examination Survey (from years 2003 to 2010) to develop a model that estimates the annual risk of diabetes and cardiovascular disease in adults with different body weights. This data from almost 4,000 individuals was also used to analyze the contribution of excess body weight to years of life lost and healthy years of life lost.

Their findings estimated that individuals who were very obese could lose up to 8 years of life, obese individuals could lose up to 6 years, and those who were overweight could lose up to three years. In addition, healthy life-years lost were two to four times higher for overweight and obese individuals compared to those who had a healthy weight, defined as 18.5-25 body mass index (BMI). When one considers that these individuals may also develop diabetes or cardiovascular disease earlier in life, this excess weight can rob them of nearly two decades of healthy life. The age at which the excess weight accumulated was an important factor and the worst outcomes were in those who gained their weight at earlier ages. "The pattern is clear - the more an individual weighs and the younger their age, the greater the effect on their health. In terms of life-expectancy, we feel being overweight is as bad as cigarette smoking."

Link: http://muhc.ca/newsroom/news/obesity-may-shorten-life-expectancy-8-years

This article talks generally about the current directions in aging research and recent developments while managing to entirely avoid mention of SENS-style rejuvenation research. Reading this you'd think that the only possible approach to aging involves altering our metabolism to work in a different way so as to slow down aging, and that periodic repair of damage without altering metabolism to reverse aging doesn't even exist as an idea.

The focus is on Calico Labs and Human Longevity, Inc., but a range of other topics are covered. With one or two exceptions this is essentially a list of technologies and approaches that I don't expect to produce either meaningful treatments to extend life or ways to reverse the consequences of aging in the old. It is new paint on the existing investigation of the fine details of exactly how young tissue becomes old tissue. Obtaining that knowledge is the scientific impulse, and should indeed be accomplished, but the applications of it in the near term won't result in ways to meaningfully move the needle on human longevity. Look at the much-hyped sirtuin research over the past fifteen years for a preview of the next decade of research into the genetics and metabolic changes of longevity: the generation of a mountain of data that probably helps to inform some areas of medical development, but no life extending treatments, and no reasonable expectation of producing anything except a very expensive way to slightly slow down the aging process even in the best possible success case.

The quest to end aging, rife with bizarre and doomed therapies, is perhaps as old as humanity itself. And even though researchers today have more sophisticated tools for studying aging, the hunt for drugs to prevent human decay has still seen many false leads. Now, the field hopes to improve its track record with the entrance of two new players, Calico, which launched in September 2013, and Human Longevity, which entered the stage six months later. South San Francisco-based Calico, founded by Google with an initial commitment of at least $250 million, boasts an all-star slate of biotechnology industry leaders. Human Longevity was founded by genome pioneer Craig Venter and hopes to use a big data approach to combat age-related disease.

The involvement of high-profile names from outside the aging field - and the deep pockets of a funder like Google - have inspired optimism among longevity researchers. "For Google to say, 'This is something I'm putting a lot of money into,' is a boost for the field. There's a tremendous amount of excitement. "We've made inroads over the past 20 years or so. But I think there's a long way to go."

Calico appears to be taking the approach that worked for Barron and Levinson at Genentech, the pioneering biotechnology company that has become among the more successful drug companies in the world by making targeted medicines - largely engineered proteins - that disrupt disease pathways in diseases such as cancer. The hallmark of Genentech's approach has been to dissect the pathways involved in disease and then target them with biotechnology drugs.

Such an approach is representative of one way to cure aging: targeting the diseases that become more prevalent as people grow older. This follows the argument that treating such diseases is itself treating aging. The opposing view is to see aging as an inherently pathological program that, if switched off or reprogrammed, could be halted. But because regulators don't consider the progression of life itself a disease, the semantic debate is moot to drug companies: they can only get drugs approved by targeting diseases that become more common with age, such as cancer, diabetes and neurodegenerative disorders.

"The way Calico has said they are approaching this is the right way, which is to understand some fundamental aspects of the aging process and see how intervening in them affects that process." But so far that approach has been difficult to translate successfully into interventions that delay aging or prevent age-related disease. But the legion of companies that have failed to commercialize these discoveries is large, and some in the field now think that further progress can be made only by studying human aging.

Link: http://www.nature.com/nm/journal/v20/n12/full/nm1214-1362.html

I rarely write obituaries, because once you start where do you stop? Perhaps a hundred and fifty thousand lives are lost every day, most due to aging and its consequences, and it isn't just the few people you happened to exchange emails with who are worthy of notice. Yet monuments are at root a selfish undertaking on behalf of the living, and we can easily bury ourselves in mourning and symbolism. Ultimately one has to ask: is this an initiative about death or is this an initiative about life? The world has too many thinly disguised death cults. Cruelly, even after yet another individual in one's personal circle of vision succumbs to the frailty of age all of our lives go on as before. We're still here with the same old to-do list in front of us - or at least we will be until we are not. But that is rather the point: we want to eliminate this part of the human condition, build the medical technologies to repair the breakages that cause aging and thus prevent all of its attendant suffering and death.

I've long admired the oldest people in this community. They participate with no hope at all of benefiting personally from the technologies they support: that is true altruism. It will be, I'd think, twenty years under even the best of circumstances before comparatively crude first generation rejuvenation treatments as envisaged in the SENS proposals become available. If you are in later life it is vanishingly unlikely that you will survive for long enough to benefit meaningfully from present research. Yet that research must happen. Someone must be first to benefit, and someone must be last to miss out.

So we get to this news from the Gerontology Research Group (GRG), providing notice of the death of their founder and organizer in chief Stephen Coles, a researcher and advocate for longevity science. This had been expected, I think, given the details of his ongoing public battle with cancer. He took full advantage of having a rough timeline at the end to ensure a good cryopreservation:

Dr. Stephen Coles passed away in Scottsdale on December 3 of complications of pancreatic cancer and was cryopreserved. He was 73. Scottsdale is where Alcor is, and Steve had traveled there last week to be close to the cryonics foundation.

He tracked the oldest people in the world for over 20 years, and published the most recent five years of his research in the journal PLoS ONE. Dr. Coles performed autopsies on 12 "supercentenarians," people who are 110 years old or older, more than any other pathologist, and determined TTR Amyloidosis as a predominant cause of death.

There is an obituary in the LA Times. For as long as I've been involved in advocacy, Coles has networked with fellow researchers and gathered data on late age survival. With his connections as a hub the GRG mailing list became a cosmopolitan watering hole at which gerontologists, other researchers, and advocates with many varied views on aging and medicine debated points and rubbed shoulders. In recent years Coles' own work helped to shape the SENS Research Foundation strategy of funding potential treatments for TTR amyloidosis, a condition in which misfolded transthyretin builds up in solid masses to clog blood vessels and organs. This condition may be a true final limiting factor on human life span, killing those who survive everything else. Or at least it will be until therapies exist, and the development of those therapies is presently underway - though, as always in matters related to aging, with too little funding for truly rapid progress.

Cryonics is the sensible choice for anyone finding themselves in Coles' position. It is the only presently available shot at making death a hiatus rather than oblivion, and it is one slice of the grand self-destructive tragedy of the modern human condition that next to nobody chooses this path. Preservation of the fine structure of the brain means preservation of the mind, and given continued storage a patient can wait for as long as needed for future molecular nanotechnologies capable of restoring a cryopreserved individual. That isn't impossible, just very hard. But instead all those lives, all those individuals, are lost.

To change this state of affairs many more respected people at the hub of their own networks of influence must make a very public choice to be cryopreserved. This is really no different than the sort of effective advocacy needed to change the present public disinterest in living longer lives through rejuvenation therapies. If we want to see a world without frailty and disease in aging then more people have to speak out and act accordingly: we don't lack the ability to get to this goal, but rather lack the widespread will to do the job. Each of us can only be the one person in this parade, of course, but congratulations and thanks should pass to Coles for choosing to be that one on both fronts.

And that must stand in place for the numerous obituaries and mentions I could have written in recent years. As the community grows there are ever more older members and so more people vanishing over time from the mailing lists and blogs. But what can you do? Fifty years ago you could do nothing but wish. Today, however, you can make a material difference: support the research, support the organizations, help to speed our progress towards the day on which people stop suffering and dying of old age.

When looking at most of the past extension of human life since the 1700s the major causes were better sanitation and control of infectious disease, with the largest effects on life expectancy at birth arising from lowered childhood mortality, even though there was also a steady increase in adult life expectancy. When looking back at the late 20th and early 21st century period from a safe distance of a century or so, the similar high level summary of the drivers of life extension will probably focus on greatly increased control over cardiovascular disease and the resulting steep decline in late life mortality due to this cause. There are many other improvements in medicine that have occurred in the past fifty years, but this is the one that stands out if you look at the data.

This period of medical strategy and development is coming to an end, however, and the summary of the next age in medicine with regard to its effects on human longevity will be that this was the time in which researchers started to directly address the processes of aging and, separately, brought cancer largely under medical control. Progress in the future of life expectancy at this point in time is overwhelmingly a matter of success in intervening in the aging process, building biotechnologies to repair the cellular and molecular damage that causes aging and thus prevent or turn back age-related frailty and disease.

If aging is purely a matter of damage we should expect all improvements in long term health to also extend life to some degree. If there is less damage then the machinery lasts longer - it really is that simple a concept, even though the machinery of our biology is very complex. Studies of changing life expectancy such as the one quoted below continue to find that aging appears to be plastic, and that present trends in reduced old age mortality are continuing in those regions with better access to medical technology. The only limits on life are imposed by a present inability to fix the problems that kill us, and that can be changed by funding the right research:

In high-income countries, life expectancy at age 60 years has increased in recent decades. Falling tobacco use (for men only) and cardiovascular disease mortality (for both men and women) are the main factors contributing to this rise. In high-income countries, avoidable male mortality has fallen since 1980 because of decreases in avoidable cardiovascular deaths. For men in Latin America, the Caribbean, Europe, and central Asia, and for women in all regions, avoidable mortality has changed little or increased since 1980. As yet, no evidence exists that the rate of improvement in older age mortality (60 years and older) is slowing down or that older age deaths are being compressed into a narrow age band as they approach a hypothesised upper limit to longevity.

Link: http://dx.doi.org/10.1016/S0140-6736(14)60569-9

FOXO3A is one of the very few genes where single nucleotide polymorphism variants are fairly reliably shown to correlate with statistical variations in human aging across populations. Generally genetic correlations with aging do not replicate between study groups, which implies that the effects of genetic variations on aging are individually very small and overall highly varied and complicated. As these researchers show, even in the case of FOXO3A variants it is hard to establish associations reliably:

In this study, we investigated the association of variation in the second consistently confirmed longevity-associated gene, FOXO3A, with aging-related phenotypes in the oldest-old. The Discovery sample was 1200 participants randomly drawn from 1651 eligible members of the Danish 1905 Birth Cohort Study. For replication of the findings observed in the Discovery sample, we used data on 1279 individuals from two additional population-based surveys of oldest-old Danes: the Danish 1910 and 1915 Birth Cohort Studies. We explored four phenotypes known to predict their survival, that is, cognitive function, self-reported health, hand grip strength, and activity of daily living (ADL). Moreover, we included data on five self-reported diseases: diabetes, cancer, cardiovascular disease, osteoporosis, and bone fracture, as these are either investigated in genetic association studies and/or are supported by foxo animal models.

We found FOXO3A variation to show nominal significant association with two of the investigated phenotypes; ADL and bone fracture. This does, however, not exclude relevance of FOXO3A variation for the remaining seven phenotypes or for the physiological processes behind these phenotypes; it is possible that more statistical power is needed to detect such associations, especially if these are of small effect size. Furthermore, as the foxo3a protein has a wide array of downstream targets, which themselves affect a wide range of cellular and physiological processes, it may simply be difficult to pinpoint the candidate phenotypes, which FOXO3A potentially affects. The association between FOXO3A variation and bone fracture was not accompanied by a concurrent association with osteoporosis. However, these two phenotypes cannot be expected to be completely interchangeable, as osteoporosis is often underdiagnosed and undertreated.

We could not formally replicate the associations of FOXO3A variation with ADL and bone fracture in another sample of Danish oldest-olds. There are a number of possible reasons for this. First of all, it may indicate that these were merely chance findings or that the Replication sample could be underpowered with respect to small effect sizes. However, another explanation could be that the individuals of the Replication sample were slightly older (94.7-100.9 years) than the individuals of the Discovery sample (92.2-93.8 years). This could potentially be of importance if the associations are not constant with age.

Link: http://onlinelibrary.wiley.com/doi/10.1111/acel.12295/full

The Methuselah Foundation, the organization behind the New Organ initiative, places a strong emphasis on tissue engineering as one of the important pillars of the future of improved health and longevity. The Foundation invested in bioprinting company Organovo back when they were an early stage startup and maintains a strong relationship with that organization and its allies today.

The important thing to realize about much of the still young tissue engineering industry, bioprinting included, is that therapies involving constructed tissues are not yet a major concern for commercial development - although there is a lot of research taking place with that in mind. By necessity the initial products that provide revenue for the next phase of development must make use of small amounts of tissue, as the challenges in constructing scaffolds and blood vessel networks for larger structures are still a significant hurdle. At this point that largely means selling production line model tissues to research focused institutions in the pharmaceutical industry, where scientists can use them to conduct better and more consistent studies. There is a world of difference between cells in a flat petri dish and cells organized into a functional tissue. Many lines of research flounder on that difference, and given widely available model tissues these unfortunate projects might have been redirected or adjusted much more rapidly.

Here is an example of the sort of tissue product that is emerging from the industry at the moment, clearly aimed at research institutions as customers. This line of business is a logical stepping stone on the way to the eventual goal of building real, functional organs from scratch as needed. Each advance along the way has to be made profitable in order to support the next stage:

Organovo Announces Commercial Release of the exVive3D Human Liver Tissue

Organovo's exVive3D Liver Models are bioprinted, living 3D human liver tissues consisting of primary human hepatocytes, stellate, and endothelial cell types, which are found in native human liver. The exVive3D Liver Models are created using Organovo's proprietary 3D bioprinting technology that builds functional living tissues containing precise and reproducible architecture. The tissues are functional and stable for at least 42 days, which enables assessment of drug effects over study durations that well beyond those offered by industry-standard 2D liver cell culture systems.

Organovo has previously shown that exVive3D Liver Models produce important liver proteins including albumin, fibrinogen and transferrin, synthesize cholesterol, and possess inducible cytochrome P450 enzymatic activities. The exVive 3D Liver has successfully differentiated between structurally related compounds with known toxic and non-toxic profiles in human beings, and the model has also been employed successfully in the detection of metabolites at extended time points in vitro. Importantly, the configuration of the bioprinted liver tissues enables both biochemical and histologic data to be collected so that a customer can investigate compound responses at multiple levels.

Separately, the Methuselah Foundation is presently working with Organovo and a number of research institutions to put the latest in tissue printers into the hands of more researchers. This is another way to help speed things up in the laboratory: more tools for more workers.

Organovo Collaborates with Yale team to develop 3-D Organ Tissues for Surgical Transplantation Research

"We are excited to begin this collaboration with Organovo and are honored to be part of Methuselah's University 3D Bioprinter Program, which gives our key researchers access to cutting-edge 3D bioprinting technology," said Dr. John Geibel, Vice Chairman, Director of Surgical Research, and Professor of Surgery and Cellular and Molecular Physiology at Yale University. "This collaboration is a great way to bring the best minds of both worlds to solve a major research and medical goal - using bioprinting to produce transplantable tissues."

Under Methuselah's University 3D Bioprinter Program, Methuselah is donating at least $500,000 in direct funding to be divided among several institutions for Organovo bioprinter research projects. This funding will cover budgeted bioprinter costs, as well as other aspects of project execution. "Developing organs for surgical implantation will take meaningful efforts and focused partnerships. This collaboration with Yale, which combines their expertise and technology with our own, is one important step in progressing towards implantable, therapeutic tissues," said Keith Murphy, chairman and CEO of Organovo. "We are grateful to the Methuselah Foundation for their generous gift that gives those working towards significant breakthroughs in organ bioprinting an opportunity to use the NovoGen bioprinter and enable greater access to Organovo's powerful platform."

Ordinary somatic cells can be reprogrammed into induced pluripotent stem cells (iPSCs) capable of generating any cell type in the body, provided that a methodology is established to reliably guide the cells down that path of differentiation. This reprogramming is sufficiently straightforward that near any lab can carry it out, which has led to rapid progress in this part of the field in recent years: a lot of effort has focused on developing the means to create specific cell types from pluripotent cells. Why so much interest in the research community? Because a key part of the infrastructure needed for the coming decades of cell therapies, regenerative medicine, and tissue engineering is a low-cost, reliable source of any cell type desired, rapidly created to order from an easily obtained patient tissue sample such as skin or blood.

Induced pluripotency is currently the leading contender technology for wholesale production of patient-matched cells by virtue of ease of use, but it is not without its complexities. Here, for example, researchers show that the reprogramming of human cells isn't producing as much of a clean slate as might be expected based on work in mice:

[Researchers] have discovered that human stem cells made from adult donor cells "remember" where they came from and that's what they prefer to become again. This means the type of cell obtained from an individual patient to make pluripotent stem cells, determines what can be best done with them. For example, to repair the lung of a patient with lung disease, it is best to start off with a lung cell to make the therapeutic stem cells to treat the disease, or a breast cell for the regeneration of tissue for breast cancer patients. By contrast, the iPSCs of mice, which are widely used in stem cell research, have no memory. "So, if you only studied the mouse alone, you'd never uncover this opportunity."

"We've shown that human induced pluripotent stem cells have a memory that is engraved at the molecular/genetic level of the cell type used to make them, which increases their ability to differentiate to the parent tissue type after being put in various stem cell states. So, not all human iPSCs are made equal. Moving forward, this means that iPSC generation from a specific tissue requiring regeneration is a better approach for future cellular therapies. Besides being faster and more cost-efficient in the development of stem cell therapy treatments, this provides a new opportunity for use of iPSCs in disease modeling and personalized drug discovery that was not appreciated before."

Link: http://www.eurekalert.org/pub_releases/2014-12/mu-nai120114.php

Fibrosis is a type of scarring in which excessive connective tissue is created in response to damage. It plays an important role in the pathology of a range of age-related conditions, but does this process have its origins in a sufficiently narrow set of mechanisms that it could be selectively suppressed or disabled entirely in the near future?

[Researchers] have identified what they believe to be the cells responsible for fibrosis, the buildup of scar tissue. Fibrotic diseases, such as chronic kidney disease and failure, lung disease, heart failure and cirrhosis of the liver, are estimated to be responsible for up to 45 percent of deaths in the developed world. "Previous research indicated that myofibroblasts are the cells responsible for fibrosis. But there was controversy around the origin of this cell. Identifying the origin could lead to targeted therapies for these very common diseases."

With the knowledge that fibrosis appears to radiate from blood vessels, [researchers] examined the hedgehog signaling pathway, which normally regulates organ development but whose roles in the adult are less clear. They noticed that in adult mice, a hedgehog pathway gene called Gli1 was specifically expressed in a rare group of cells located around blood vessels in all solid organs. This pattern suggested that the cells might play a role in fibrosis. To test this hypothesis the researchers tagged this protein in tissue with varying forms of fibrosis, and found that these cells proliferated by almost 20-fold under chronic injury and turned into myofibroblasts. "We believe that this cell population is responsible for about 60 percent of all organ myofibroblasts. Most organs develop fibrosis as we age. Specifically, in the kidney we lose one percent of kidney function as a result of fibrosis for each year that we age."

Using a genetic strategy in mice, the researchers were able to ablate these Gli1 cells, while leaving other cells unharmed. In mice with kidney and cardiac fibrosis, the ablation of these cells resulted in reduction in fibrosis and rescued heart function. "We've found that these Gli1 progenitor cells differentiate into myofibroblasts, and in fibrotic disease, when they are ablated, we can rescue organs and organ function." Researchers note that the genetic strategy employed in the preclinical model is not feasible in humans. For this reason, future research involves the exploration of drugs that could specifically target and shut off these fibrosis-causing stem cells with the hope that either an existing drug or a new drug could translate to a potential therapy for humans.

Link: http://brighamandwomens.org/about_bwh/publicaffairs/news/pressreleases/PressRelease.aspx?PageID=1944

Giving Tuesday falls on December 2nd this year, today in fact, and I have to say that this is a far more admirable manufactured publicity event than the preceding Black Friday and Cyber Monday. In this case the motivation is to encourage more people to do good by helping charitable causes to meet their year end fundraising goals: a little mainstream social pressure to make the world a better place to add to that already present in many communities. We could all do more, of course, but the person without a charitable urge is, I think, no more than a person who hasn't yet found the way in which he or she wishes to change the world. When you do find a goal that speaks to you then generosity comes easily: there are always many fellow travelers to discover, and some of those people will be further ahead in the game, having organized to the point of setting up non-profit initiatives to advance the cause. If you want to get anything done in earnest there must be collaboration, networking, research, and sundry other projects, and to be effective in the long term all of that must be funded in some way, shape, or form. Hence the drive for donations.

There are many causes in the world for which the limiting factor on speed of progress is not money. Those are the truly hard jobs. For everything else, helping things along can become very simple: write a check, click the PayPal button, make a donation. Provided you've done the legwork to ensure you are donating to a sound charity performing proven good work, then congratulations - you are helping to make the world a better place. Funding the efforts needed to get the job done is a vital part of the bigger picture for any cause.

The charitable cause I favor above all others is the medical research needed to bring about the end of frailty, disease, and death as a result of aging. Aging is by far the greatest cause of human suffering in every part of the world, even those with other terrible problems. In a more reasonable world we wouldn't find ourselves in the position of having to persuade anyone that, yes, researching the means to treat and reverse aging is the most important goal in the world at present, the goal that will help the most people at the least cost. We are in that position, however, and progress in this research is absolutely limited by funding and little else. There are hundreds of researchers in the present life science community who, if given grants, would gleefully drop their present research in favor of working on ways to repair the cellular and molecular damage that causes aging. It is ever a challenge to bring funding into this community however: aging research is a small and comparatively unattended branch of medical science, and longevity science is a tiny field of that tiny branch. The public at large have not yet woken up to realize that the possibility of turning back the painful consequences of old age is, given sufficient funding, just a few decades away.

So it is Giving Tuesday, and you are sitting there with a few dollars in your pocket, and there is a PayPal button on the SENS Research Foundation donation page. Make a donation and it will be matched at $2 for every $1 you donate by the Fight Aging! matching fund founders, and also by a further $1 for today only by Aubrey de Grey personally. If you're here reading this, then there is perhaps a certain level of interest on your part in helping to assure a personal future that involves less disability, less pain, and less age-related disease. The only way that will happen is if the best and most promising research programs - such as those funded by the SENS Research Foundation - achieve more traction in the years to come. The way that starts is with more public interest and more grassroots donations: so it is up to you.

We know you share our conviction that a world without age-related disease is possible - and our commitment to making that world a reality.

So we would like to encourage everyone who is able to make a donation to SENS Research Foundation on #GivingTuesday and post, tweet, blog and let others know about how your are celebrating #GivingTuesday.

Today only the first $5,000 of your donations will be quadrupled thanks to our ongoing Fight Aging! Challenge Grant and the generosity of Aubrey de Grey, who will match every donation made today up to $5,000.

Join us and be a part of a global celebration of a new tradition of generosity.

Inflammation is an important component of Alzheimer's disease pathology. Therefore some researchers focus on possible ways to damp down this inflammation by developing more sophisticated ways to control the activities of varied types of neuroglia, the immune cells of the brain:

Activated microglia are associated with the progression of Alzheimer's disease (AD), as well as many other neurodegenerative diseases of aging. Microglia are therefore key targets for therapeutic intervention. β-amyloid (Aβ) deposits activate the complement system, which, in turn, stimulates microglia to release neurotoxic materials. Research has focused primarily on anti-inflammatory agents to temper this toxic effect. More recently there has been a focus on converting microglia from this M1 state to an M2 state in which the toxic effects are reduced and their phagocytic activity toward Aβ enhanced.

Studies in transgenic mice have suggested a number of possible anti-inflammatory approaches but they may not always be a good model. An example is vaccination with antibodies to Aβ, which is effective in mouse models, but has repeatedly failed in clinical trials. Biomarker studies indicate that AD commences many years prior to clinical onset. A hopeful approach to a disease-modifying treatment of AD is to administer agents that inhibit the inflammatory stimulation of microglia or successfully convert them to an M2 state. However, any such treatment must be started early in the disease.

Link: http://dx.doi.org/10.1517/14728222.2014.988707

Failing kidney function is a serious issue for many older people, and at this time comparatively little can be done about it:

Chronic kidney disease (CKD) affects at least one in four Americans who are older than 60 and can significantly shorten lifespan. Yet the few available drugs for CKD can only modestly delay the disease's progress towards kidney failure. [Researchers] focused on a central feature of CKD: the "fibrosis" process. This is a pathological response to chronic kidney stress that includes an abnormal buildup of fibrous collagen, a loss of capillaries a die-off of important kidney cells called tubular epithelial cells, and other changes that progressively reduce a kidney's ability to filter the blood properly.

The researchers compared the patterns of gene activity in fibrotic and normal human kidney tissue samples. They found abnormal patterns in gene networks linked to inflammation and sharp drops in activity in gene networks that support energy metabolism in the fibrotic samples. The fact that inflammation is a factor in CKD was already well known, so [researchers]] aimed their investigation at two types of energy metabolism - glucose oxidation and fatty acid oxidation - that seemed markedly reduced in the fibrotic samples. "What we found is that the tubular epithelial cells preferentially use fatty acid oxidation as their energy source in normal conditions. Even when fatty acid metabolism drops in the context of CKD, these cells don't switch to burning glucose for energy."

In human tubular epithelial cells, artificially reducing fatty acid metabolism quickly brought about fibrosis-like signs, including the buildup of fat molecules (unspent fuel) and the deaths of many affected cells. That fat buildup in kidney cells had been hypothesized to be a significant cause of cell death in CKD fibrosis, [but] the fat accumulation on its own had minimal impact. The more important factor in fibrosis was the loss of energy in the cells as fatty acid metabolism dropped. Researchers also found evidence that the shutdown of fatty acid metabolism in tubular epithelial cells is caused in large part by the growth factor TGFβ. This factor is known to promote fibrosis and has been linked to high blood glucose levels, high blood pressure, and inflammation - all triggers of CKD. "We hope to develop new compounds [that] boost enzymes more specifically related to fatty acid metabolism. In that way we might be able to greatly slow the progress of CKD."

Link: http://www.uphs.upenn.edu/news/News_Releases/2014/12/Susztak/

Telomeres are the caps of repeating DNA sequences at the ends of chromosomes. A little of that length is lost with each cell division, and telomeres thus form a part of the limiting mechanism that prevents most cells in the body from simply proliferating forever. That is fairly important: when the limiting processes fail, we call the result cancer. There are mechanisms to lengthen telomeres, however, such as the activity of the enzyme telomerase for example. Stem cells must maintain themselves capable of replication so as to ensure a continual supply of new daughter cells with long telomeres to maintain tissue health, and telomerase allows that to happen. Telomeres and telomerase do various other things too, such as influence patterns of gene expression, as nothing in a cell ever acts in just one process. That would be far too easy.

Average telomere length is most commonly measured in the leukocytes, or white blood cells, from a blood sample. This can be correlated to age and health, though there are subtleties here and some ongoing discussion on the best way to construct these measures, as well as whether or not some of these measurement mothods are in fact useful at all. The shifts in average telomere length over time may be a reflection of the pace at which stem cells are active to introduce new long-telomere daughter cells into circulation, which in turn has some relation to aging because stem cell populations tend to decline in response to the rising levels of cellular damage that cause degenerative aging. This stem cell decline is most likely an evolved balance between cancer risk and tissue failure that arose to lengthen human life span in comparison to that of other primates, a consequence of our greater intelligence and culture that allowed older individuals to contribute meaningfully to the survival of their grandchildren and thus selected for greater longevity. This is all a simplified sketch of what remains a debated and more complex picture, however. The point to take away is that telomere length looks a lot more like a marker of aging than a cause.

That all said, telomere length as measured by today's young medical startup companies is not really a particularly good measure of aging or ill health, especially taken in isolation for one individual at a single point in time. It is a very blunt tool at this point, nowhere near as accurate as, say, the DNA methylation patterns that can indicate chronological age to within a few years. It is also open for debate as to what shorter average telomere lengths for white blood cells really actually indicate in any given situation, given how dynamic they are in response to transient illness - something that may have more to do with immune system state than anything else. So it is wise, I think, to pay attention to studies of this nature that point out further issues with the use of telomere length measures in any single tissue:

Comparison of the Relative Telomere Length Measured in Leukocytes and Eleven Different Human Tissues (PDF)

The relative length of telomeres measured in peripheral blood leukocytes is a commonly used system marker for biological aging and can also be used as a biomarker of cardiovascular aging. However, to what extent the telomere length in peripheral leukocytes reflects telomere length in different organ tissues is still unclear. Therefore, we have measured relative telomere length (rTL) in twelve different human tissues (peripheral blood leukocytes, liver, kidney, heart, spleen, brain, skin, triceps, tongue mucosa, intercostal skeletal muscle, subcutaneous fat, and abdominal fat) from twelve cadavers (age range of 29 week of gestation to 88 years old).

The highest rTL variability was observed in peripheral leukocytes, and the lowest variability was found in brain. We found a significant linear correlation between leukocyte rTL and both intercostal muscle and liver rTL only. High rTL variability was observed between different organs from one individual. Furthermore, we have shown that even slight DNA degradation leads to false rTL shortening. Despite the relatively low number of individuals analyzed and the large age span of the donors, we suggest that there is a very low correlation between the rTL within most tissues and the rTL in blood leukocytes. Thus, the use of leukocytes as a source of DNA for rTL analysis for the estimation of individual "tissue age" is questionable.

Since telomerase activity and cell turnover rates vary widely throughout the different tissue types of the body, it shouldn't be surprising at all to find that average telomere length in different tissues may or may not be meaningfully correlated with either age of the tissue or between different tissues of the same age. But as the authors point out, this isn't a large sample, and they are criticizing an already fairly weak correlative tool. As is often the case more data wouldn't hurt.

This is a revolutionary era in biology and biotechnology, one of the many consequences of it also being a revolutionary era in computation. Sustained and rapid progress is under way in hundreds of important fields of medicine in laboratories around the world, and this state of affairs is the reason why we have the opportunity to reach for the construction of rejuvenation treatments and the defeat of degenerative aging:

In the last two decades we have witnessed a paradigm shift in our understanding of cells so radical that it has rewritten the rules of biology. The study of cellular reprogramming has gone from little more than a hypothesis, to applied bioengineering, with the creation of a variety of important cell types. By way of metaphor, we can compare the discovery of reprogramming with the archeological discovery of the Rosetta stone. This stone slab made possible the initial decipherment of Egyptian hieroglyphics because it allowed us to see this language in a way that was previously impossible. We propose that cellular reprogramming will have an equally profound impact on understanding and curing human disease, because it allows us to perceive and study molecular biological processes such as differentiation, epigenetics, and chromatin in ways that were likewise previously impossible.

Stem cells could be called "cellular Rosetta stones" because they allow also us to perceive the connections between development, disease, cancer, aging, and regeneration in novel ways. Here we present a comprehensive historical review of stem cells and cellular reprogramming, and illustrate the developing synergy between many previously unconnected fields. We show how stem cells can be used to create in vitro models of human disease and provide examples of how reprogramming is being used to study and treat such diverse diseases as cancer, aging, and accelerated aging syndromes, infectious diseases such as AIDS, and epigenetic diseases such as polycystic ovary syndrome. While the technology of reprogramming is being developed and refined there have also been significant ongoing developments in other complementary technologies such as gene editing, progenitor cell production, and tissue engineering. These technologies are the foundations of what is becoming a fully-functional field of regenerative medicine and are converging to a point that will allow us to treat almost any disease.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4228919/

A great piece on the cryonics industry, with a focus on Alcor. Cryonics providers offer indefinite low-temperature storage for those who will die prior to the advent of effective rejuvenation therapies. This is the only shot at a longer life in the future available to those people, a demographic that may turn out to include all of us if things go poorly in medical research and advocacy over the next few decades. A cryopreserved individual has all the time in the world to wait for future restoration technologies to arise, as provided that the fine structure of the brain is maintained in the preservation process then the mind continues to exist, on hold:

In terms of the revival end of things, it's a long way off. [Alcor] isn't doing a whole lot of research there because it's too much of a cap on what we can do. There is a startup company that I can't really talk about that that's doing that, trying to grow tissues, grow organs. The whole field of regenerative medicine is really relevant to what we're doing. We benefit from a lot of other fields of research, like nanomedicine and the people trying to cryopreserve organs. They've actually managed to cryopreserve a rabbit kidney, keep it there for several months and then rewarm it, implant it in the rabbit and have it function. You can do it with all kinds of single tissues - it's very common now to cryopreserve corneas, sperm, eggs - there are dozens of tissue types that can be cryopreserved and then rewarmed. Going from a single tissue to a whole organ is much more difficult.

What we would imagine is that the brain would actually be repaired cell by cell, which is why we want to minimize the damage we do because there are a lot of neurons to be fixed. We do know that under good conditions we are preserving brains very well - we can look at vitrified brain tissue from animals under an electron microscope and it looks great. You can see the membranes are all intact, the neurons are all connected, it looks perfectly preserved.

Everything we know about personality tells us that it's stored in physical changes in the brain. Apart from very short term memory where the last few minutes is all electrical activity, anything longer than that is stored in changes in the neurotransmitter connections in the brain. That's what we're preserving under good circumstances. We're not just being speculative and taking a leap of faith. We've started a program of doing CT scans of our neuro patients. We can get really good readings of people's brains and see how we're doing.

It looks worse if we can't perfuse the brain [with cryoprotectants] and get ice crystal damage, but it doesn't mean it's destroyed. It's going to look bad to us, but in our view, we look at it like, the functional ability of the brain's been destroyed, but function is not really crucial. What really matters is that you're storing enough of the structure that some future technology can look at it and say "this membrane's been damaged really badly, but we know how to put it back together."

Link: http://motherboard.vice.com/read/the-art-of-not-dying-or-being-frozen-until-you-can-come-back