Fight Aging!

Freedom absolutely implies the freedom to die: if you don't own your own life, then what do you own? If you wish to assign yourself a duty to die, because you feel a burden, or for whatever reasons you have, then go right on ahead. The people you're doing it for won't be anywhere near as moved as you'd like to think, but euthanasia of all sorts should have far more respect as a personal choice than is presently the case. One of the most offensive interventions enforced by most modern states is to make it next to impossible for a person to safely and painlessly end his life in the manner and time of his own choosing.

But that is choice. A duty to die in the other sense of duty, that of an obligation imposed upon you by an often nebulous collection of other people, folk who are not in fact signed up to die right now themselves, is a whole other outrage. It is a particularly banal form of evil that oozes through the broadening debate on medical costs and rationing. This debate will only grow while dysfunctional centralized medical systems persist: you can either have a near-as-possible free market in which people are responsible for their costs and providers have to compete ruthlessly for customers, or you can have terrible service, shortages, and waste. Pick one. No-one has to worry about the availability or fit of shoes in the US, but the current medical system bears more semblance to the provision of shoes in the old USSR than it does to the modern US shoe marketplace - and the consequences of that command and control structure are plain to see.

The growth in biotechnology and the concurrent need for radical new advances in medicine for a growing number of comparatively wealth elderly should be an unparalleled opportunity for researchers, businesses, and consumers alike, the incentive for a great leap forward in the same manner as the recent decades-long burn of accelerating computing power. Instead, via the dark alchemy of heavy government regulation, this opportunity has been transformed into waste and the standard issue tragedy of the commons that attends any trough of public funds, its battles argued in the language of entitlement.

So as the pigs root around the trough, their incentives are not to develop better means and technologies, not to expand the set of paying customers by better serving those customers, but rather to find ways to cut costs, to deliver less, to push some of the other pigs away from the feed. Perverse incentives lead to perverse outcomes, and hence we are back to the duty to die, and that rhetoric is usually explicitly linked with costs of entitlement, as in the "fair innings" argument that has been taking place in the UK for some years.

Against a Duty To Die

In a 2008 interview, Baroness Mary Warnock, a leading moral philosopher, said that people suffering from dementia had a duty to commit suicide: "If you're demented, you're wasting people's lives - your family's lives - and you're wasting the resources of the National Health Services". Warnock also claimed that there was "nothing wrong" with helping people to die for the sake of their loved ones or society. Well known for her support of euthanasia, Warnock expressed in the interview the hope that people will soon be "licensed to put others down" if they are unable to look after themselves.

While such claims are controversial, they are persistent and seem to crop up from time to time in public debates and scholarly literature. In the United States, former Colorado Governor Richard Lamm expressed a similar view almost 30 years ago. Referring to the elderly as "leaves falling off a tree and forming humus for the other plants to grow up," he told a meeting of the Colorado Health Lawyers Association, "you've got a duty to die and get out of the way" and "let the other society, our kids, build a reasonable life".

Social scientists have noted that the elderly often worry about being a burden on others, especially family members. In the period leading up to their deaths, elderly people who subsequently committed suicide reported that their lives had been lived and that they were now a burden on others. Little is known about the experiences of elderly people who live and die alone, but in one qualitative study of this population, participants characterized a good death as being able to die without becoming a burden to others. There is a small but growing body of evidence suggesting that worry about creating a burden on others is common among people of all ages who are near the end of life.

As is the case for most ethics viewpoints this quoted piece above takes the state of medical science as it is, and only asks how bad behavior might change for the better within this environment (while largely ignoring the regulatory causes of the economic incentives that lead to this behavior). This is woeful but widespread. In an age of change such as ours we should always ask first and foremost how technology might be developed to alleviate suffering, because the answer is usually that meaningful results can be obtained comparatively rapidly, in a handful of years given broad support.

The behavioral change that I'd like to see is for more people to wake up and support greater funding and development in the life sciences, as this is the key to eliminating the greatest causes of pain, suffering, and death. Along the way that would also steamroller the apparently thorny ethics issues that accompany that pain, suffering, and death, but that is hardly the point of the exercise. If you don't like the color of the wall, don't analyze it or work around it, but instead go out and buy some paint. The world is what we make of it.

But that point aside, it is hard to use technology to solve the consequences of regulation that slows progress and even diminishes the incentives to create progress in science - unless it is technology that helps you travel far enough away that regulatory bodies can't keep up. I think that medical tourism will the way in which most of the newest possibilities in medicine arrive over the next few decade. Not every region has yet become as hostile to progress in medicine as the UK or the US, and many of these regions also lack the steady stream of semi-officially propagated nonsense that there is a duty to die if you are old and in ill health.

Heat shock proteins are involved in the hormetic response to mild levels of molecular damage, such as that induced by heat, in which cells increase their housekeeping and maintenance activities. If the damage is mild then the end result is a net gain: cells remain on alert and tissues are kept more free of damage and functional than would otherwise be the case. This ultimately translates into greater healthy longevity, and this effect can be observed by measuring levels of heat shock proteins in similar species with different life spans:

The longevity of an organism is directly related to its ability to effectively cope with cellular stress. Heat shock response (HSR) protects the cells against accumulation of damaged proteins after exposure to elevated temperatures and also in aging cells. To understand the role of Hsp70 in regulating life span of Daphnia, we examined the expression of Hsp70 in two ecotypes that exhibit strikingly different life spans.

Daphnia pulicaria, the long lived ecotype, showed a robust Hsp70 induction as compared to the shorter lived Daphnia pulex. Interestingly, the short-lived D. pulex isolates showed no induction of Hsp70 at the mid point in their life span. In contrast to this, the long-lived D. pulicaria continued to induce Hsp70 expression at an equivalent age.

We further show that the Hsp70 expression was induced at transcriptional level in response to heat shock. The transcription factor responsible for Hsp70 induction, heat shock factor-1 (HSF-1), although present in aged organisms did not exhibit DNA-binding capability. Thus, the decline of Hsp70 induction in old organisms could be attributed to a decline in HSF-1's DNA-binding activity. These results for the first time, present a molecular analysis of the relationship between HSR and life span in Daphnia.

Link: http://dx.doi.org/10.1016/j.mad.2014.04.001

One can take the perspective a human is more like a city than an individual, where the noteworthy populace is of diverse origins. The cells of the body are just one demographic, and there are also the microbial population of the gut and the mitochondria to consider. All are joined into a symbiotic relationship, but one that is not completely free from acts of mutual antagonism among its membership.

Longevity is a complex trait whose genetics has been extensively studied since many years. Understanding the genetic makeup that predisposes to longevity is an urgent challenge owing to the explosion of the elder population in western as well as in emerging countries.

Usually the studies on the genetics of human longevity are restricted to the analysis of nuclear genome (nDNA). However, another essential genome, that is, the mitochondrial genome (mtDNA), is part of the genetic machinery of each cell. Despite its limited length, the mtDNA encodes for few genes that constitute a quantitatively relevant group because of the high copy number of mtDNA in each cell.

These two genomes do not work in the void and life/survival, as well as ageing and longevity, depends on their complex interaction with environment/lifestyle. To this scenario we have to add another level of genetic complexity represented by the microbiota, that is, the whole set of bacteria that live in different anatomical districts of our body with their whole set of genes (microbiome). Indeed, the most comprehensive view is to consider human being as a "metaorganism" resulting from the close relationship with symbiont microbial ecosystems. A particular attention has been recently devoted to the gut microbiome (GM). The GM probably represents the most adaptable genetic counterpart of the human metaorganisms, being extremely plastic in response to age-related physiological changes in diet and modification in lifestyle.

Thus, the result of the ageing process is defined by the sum of a number of factors both biological and nonbiological (environmental and stochastic). Therefore while the ageing research based on the study of animal models starts assuming the existence of major genes that determine longevity, in humans this assumption represents an oversimplification. The study of human model imposes a more holistic view of the genetics to grasp the complex dynamics of the interaction between the environment, stochasticity, and the three genetics of the host (nDNA, mtDNA, and GM).

Link: http://dx.doi.org/10.1155/2014/560340

Most people are completely unaware of the great discontinuity in medical science that lies just ahead. They look back, and project forward based on what they see in the past - and no matter that we are in an era of sweeping, rapid change and progress. The average fellow in the street is laboring under the delusion that his future life will look much like that of his parents. But nothing could be further from the truth.

For centuries advances in medicine have provided a gradual increase in adult life expectancy, so slow that there really isn't a large enough gap to remark upon between the life spans of parent and child. The pace today is about a year gained every decade, and this despite very impressive recent advances in preventing and patching over the late stage consequences of cardiovascular aging. When the patching becomes more effective for one facet of aging, at the moment that just means that more people have the chance to be killed by something else, just a little further down the line. Aging is a global phenomenon in the body, and everything declines and fails at roughly the same time, give or take. If not heart failure, then dementia. If neither of those, then cancer. Or stroke, or atherosclerosis, or eventually poorly studied forms of amyloidosis that clog the heart and blood vessels.

If the approach to medicine continues to be a process of picking late stage dysfunction and failure, one item at a time, and producing marginally better ways of patching it up, then sure, this trend in increased longevity will continue very slowly, a year every decade. None of these gains in healthy life span are deliberate; they are all unintentional side-effects. Why should we expect a side-effect to be anything other than small? The only reason it is steady and continuing is that aging is damage, and medicine cannot be anything other than a process of repairing damage.

The coming discontinuity in medicine is this: researchers are going to start actually trying to treat aging directly as the medical condition it is. They will pin it down, produce ways to slow it or, far better, repair its root causes. They will at some point stop fumbling around with poor initial directions and marginally useful dead ends, such as calorie restriction mimetics, and start to produce effective therapies, such as implementations of SENS-like regenerative medicine. The business of "life extension" and "anti-aging" will be clawed back from the frauds and the cranks and the supplement sellers and the cosmetics companies and handed over to legitimate medical developers who produce procedures that actually do what it says on the label: reverse the course of degenerative aging.

The point here is that there is a world of difference between not trying at all to treat aging, the underlying cause of all age-related disease, and putting the weight of the medical research community behind deliberate attempts to treat aging. The present slow trend in life expectancy is the outcome of not trying. The future trend, based on thousands of researchers working hard to defeat aging and its causes, is going to look very different indeed.

These are exciting times to be in medical research. Yet the public at large is oblivious, and perhaps even disinterested. The view of aging in our culture is in no way similar to the view of cancer: that urge to do something about it is missing. Without widespread support funding at the large scale rarely emerges, however. At this time, then, it is very important for researchers to stand up on their soapboxes, a thing that scientists are notoriously reluctant to do, and make the case for the coming era of treatments for aging and all age-related disease. This is an example of the the sort of thing I mean, from a fellow who has been quite vocal on this topic in recent years:

The Coming Age of Unprecedented healthy Life Extension and Why You Should Be Cheering It On!

Have you given serious thought to what it would be like to live to age 120 plus? Recent polls in the US and Canada revealed that a large majority of people were decidedly not in favour of using biomedical interventions to be able to live past 120. No surprise you say? After all, why would anyone want to extend the part of our lives that we would rather avoid? Why prolong an old age that brings loss of independence, painful debilitating illnesses, mental decline - not to mention huge medical bills! Over eighty percent of our lifetime medical expenses occur in the last few years of life.

But wait! What if you could be in better physical and mental health in 20 years, than you are now? Would that change your view towards what is called by futurists and aging researchers "radical life extension"?

Imagine yourself in your late 80's happily playing tennis, in your 90's hiking around Machu Picchu, getting a second masters degree in literature and then in your 100's writing a best-selling novel (something you never thought of doing until you were 97!). What if this could all be done while helping the planet develop into a more sustainable, healthy place to live?

Sound too futuristically phantasmagoric? Maybe not! Consider that retirement planning is about the future - your future. And given the acceleration of change in our world, consider that your future will be dramatically different than your past. Perhaps the most important feature about your future is that radical healthy life extension is coming. Just how soon it arrives is up to us, our openness to it, our actions supporting it: we are all invited to embark on a grand new exploration into a never-before-seen-world of radical healthy life extension enabled by technology. But for it to manifest fully is a choice, our choice.

Calorie restriction increases life span and greatly improves health in almost all species tested to date. The relative degree of life extension is much greater in short-lived species, however. Human calorie restriction is not expected to improve life expectancy by more than 5-10% at most. Still, human studies have demonstrated that the practice of calorie restriction produces health benefits such as resistance to age-related disease to a degree that cannot be obtained through any other available technique or technology at the present time - though regular exercise comes close.

Researchers have shown that at least some of the response to calorie restriction stems from sensing levels of amino acids in the diet. In mammals similar results can be obtained by restricting dietary methionine without reducing calories, for example. It is still the early days when it comes to dissecting the calorie restriction response into its component parts, however, the better to understand and replicate it with drugs. Here is an example of this sort of research, in which scientists are working with flies to link calorie restriction and dietary amino acid level alterations to various known longevity-related aspects of metabolism:

Dietary restriction (DR) is an intervention whereby a considerable reduction of food intake, just short of malnutrition, extends lifespan. This has been demonstrated to be effective in a wide range of evolutionarily diverse organisms, from yeast to invertebrates and mammals, and is considered one of the most robust environmental interventions to extend lifespan in laboratory organisms. Moreover, the longevity promoting effects of DR are accompanied by a range of health benefits. DR rodents had a delayed onset or a lesser severity of age-related diseases such as cancer, autoimmune diseases and motor dysfunction and improved memory. In C. elegans, DR was shown to reduce proteotoxicity. DR rhesus monkeys were found to have improved triglyceride, cholesterol and fasting glucose profiles, and a reduced incidence of diabetes, cancer, cardiovascular disease and brain atrophy.

Reduced signalling through the insulin/IGF-like (IIS) and Target of Rapamycin (TOR) signalling pathways also extend lifespan. In Drosophila melanogaster the lifespan benefits of DR can be reproduced by modulating only the essential amino acids in yeast based food. Here, we show that pharmacological downregulation of TOR signalling, but not reduced IIS, modulates the lifespan response to DR by amino acid alteration. Of the physiological responses flies exhibit upon DR, only increased body fat and decreased heat stress resistance phenotypes correlated with longevity via reduced TOR signalling. These data indicate that lowered dietary amino acids promote longevity via TOR, not by enhanced resistance to molecular damage, but through modified physiological conditions that favour fat accumulation.

Some long-lived TOR and IIS pathway mutants [in other species] have increased fat levels. Given that not all fat mutants are long-lived, it is likely that if fat levels are causally involved in extending life, the quality of fat accumulated is important. It would be interesting in future work to determine how lipid profiles change under different dietary conditions, to identify the specific types of lipids that are altered, and whether experimental manipulation can enhance lifespan.

Link: http://www.impactaging.com/papers/v6/n5/full/100665.html

These researchers take an interesting approach to boosting the activity of stem cells so as to effect regeneration, demonstrating their approach in teeth. By the look of it this is effectively a means of induced hormesis, taking advantage of a very general cellular response to mild stress, but in a more controlled way than has been possible in the past:

The team used a low-power laser to trigger human dental stem cells to form dentin, the hard tissue that is similar to bone and makes up the bulk of teeth. What's more, they outlined the precise molecular mechanism involved, and demonstrated its prowess using multiple laboratory and animal models. It turns out that a ubiquitous regulatory cell protein called transforming growth factor beta-1 (TGF-β1) played a pivotal role in triggering the dental stem cells to grow into dentin. TGF-β1 exists in latent form until activated by any number of molecules.

Here is the chemical domino effect the team confirmed: In a dose-dependent manner, the laser first induced reactive oxygen species (ROS), which are chemically active molecules containing oxygen that play an important role in cellular function. The ROS activated the latent TGF-β1 complex which, in turn, differentiated the stem cells into dentin. Nailing down the mechanism was key because it places on firm scientific footing the decades-old pile of anecdotes about low-level light therapy (LLLT), also known as Photobiomodulation (PBM).

Since the dawn of medical laser use in the late 1960s, doctors have been accumulating anecdotal evidence that low-level light therapy can stimulate all kind of biological processes including rejuvenating skin and stimulating hair growth, among others. The clinical effects of low-power lasers have been subtle and largely inconsistent. The new work marks the first time that scientists have gotten to the nub of how low-level laser treatments work on a molecular level, and lays the foundation for controlled treatment protocols.

Link: http://wyss.harvard.edu/viewpressrelease/155/researchers-use-light-to-coax-stem-cells-to-repair-teeth

At the highest level one can measure the health and pace of progress in a field by counting conferences. Conferences are not where advances happen, but they are an inevitable byproduct of progress and growth in research. When more researchers are focused on a field and their output of significant new scientific results flows faster, then more conferences will tend to take place.

The field of aging research is, sad to say, still a small adjunct office to the great edifice of medical science. The pursuit of enhanced longevity through treating aging as a medical condition is just one small corner desk in that office. We'll see this sorry state of affairs change in our lifetimes, judging by the way things are going, but that process of growth can never proceed fast enough for my liking. Thus there are still all too few conferences devoted to the science of aging and longevity in comparison to those taking place for any truly large section of the medical research community. Nonetheless, they do exist. Last month, for example, the third International Conference on Genetics of Aging and Longevity was held in Sochi, Russia. As for the earlier conferences in the series it was well attended by noted names in aging research. Maria Konovalenko of the Science for Life Extension Foundation attended and offers this report from the event:

Third International "Genetics of Aging and Longevity" Conference Featured Research on Multiple Ways to Combat Aging

More than 200 participants from North America, Europe and Asia met in post-Olympic Sochi for five days this April, as world-famous anti-aging researchers exchanged ideas at the third International Conference on Genetics of Aging and Longevity. They discussed progress and remaining obstacles, in their efforts to deepen our understanding of this complex phenomenon and develop strategies for interventions.

The central themes of the conference included (1) identification of molecular targets for lifespan-extending drugs, (2) understanding the protective genotypes of centenarians and exceptionally long-lived animal species, (3) the complex roles and interactions of genetic determinants, epigenetic regulation, metabolism, gut microbiota, lifestyle and environment in shaping the aging process, (4) developing technologies for artificial growth, cryopreservation and transplantation of organs, and (5) new technologies, including gene-editing nanoparticles and artificial chromosomes, as prospective anti-aging tools.

Some of the few dozen presentations are worth noting, though much of this might be old news for readers here:

Judith Campisi (Buck Institute for Research on Aging) presented a new transgenic mouse model to visualize and eliminate senescent cells in mice based on their elevated expression of the p16INK4a gene.

Shay Soker (Wake Forest School of Medicine) presented recent advances in growing of organs in bioreactors. Simple organs like cornea, blood vessels and bladder are relatively easy to grow, whereas growing of complex organs like liver, kidney and pancreas requires scaffolds. Bioscaffolds can be isolated for the purpose of study by decellularisation of naturally grown organs.

Gregory Fahy (21st Century Medicine, Inc.) presented achievements and difficulties in vitrification of organs. Sophisticated cryoprotective cocktails, and protocols for tissue perfusion at high pressure prior to freezing, and rapid warming methods were developed. Nevertheless, the main problem that remains is different optimal cooling rate for different cell types and organ zones.

Much of modern medicine does not address root causes. If there is one clear item that has to change in order for the research community to effectively address degenerative aging, it is this. It is perhaps understandable as to how we find ourselves in this position: most research into specific diseases starts at the end point, with the full-blown late-stage manifestation of the condition, and works backwards from there. The role of the research has long been to understand what is going on at the level of cells and proteins in the late stages of disease, and then trace back the chain of relationships and interactions to earlier stages. Thus progress leads into the middle stages of cause and effect, and most potential treatments built using modern tools of biotechnology tend to be ways to interfere in proximate causes, not root causes. The people who catalog root causes and work on ways to repair them, aiming to prevent large numbers of medical conditions with a small number of treatments, are still a small minority in medical research, unfortunately.

This is a good example of the sort of thing I'm talking about here: it doesn't address the reasons why blood flow becomes disturbed, but seeks to decouple that from a raised risk of atherosclerosis. This will be beneficial if it works, but it does nothing to address the real issues or the other problems that said issues causes.

In atherosclerosis, plaques preferentially develop in arterial regions of disturbed blood flow (d-flow), which alters endothelial gene expression and function. Here, we determined that d-flow regulates genome-wide DNA methylation patterns in a DNA methyltransferase-dependent (DNMT-dependent) manner.

Induction of d-flow by partial carotid ligation surgery in a murine model induced DNMT1 in arterial endothelium. In cultured endothelial cells, DNMT1 was enhanced by oscillatory shear stress (OS), and reduction of DNMT with either the inhibitor 5-aza-2′-deoxycytidine (5Aza) or siRNA markedly reduced OS-induced endothelial inflammation. Moreover, administration of 5Aza reduced lesion formation in 2 mouse models of atherosclerosis.

We determined that d-flow in the carotid artery resulted in hypermethylation within the promoters of 11 mechanosensitive genes and that 5Aza treatment restored normal methylation patterns. Of the identified genes, HoxA5 and Klf3 encode transcription factors that contain cAMP response elements, suggesting that the methylation status of these loci could serve as a mechanosensitive master switch in gene expression. Together, our results demonstrate that d-flow controls epigenomic DNA methylation patterns in a DNMT-dependent manner, which in turn alters endothelial gene expression and induces atherosclerosis.

Link: http://dx.doi.org/10.1172/JCI74792

Xenotransplantation, the transplantation of tissue from animals to humans, is a potential stepping stone technology to bridge the gap between today and a future in which all tissues can be grown to order from a patient's own cells. Xenotransplantation is not yet a completely practical possibility, as it has greater issues of immune rejection than transplantation between humans, but several lines of research are bringing it closer. One of these is decellularization, stripping cells to leave the scaffold of the extracellular matrix that is then repopulated with the recipient's own cells. Another is to genetically alter the donor animal to remove proteins that will trigger rejection:

[Researchers have] been investigating ways to allow the human body to accept organ and tissue transplants from animals. [The] team developed a strain of inbred miniature swine with organs that are close in size to those of adult humans. Since pig organs implanted into primates are rapidly rejected due to the presence of the Gal (alpha-1,3-galactose) molecule, [they] used the strain [to] generate miniature swine in which both copies of the gene encoding GalT (galactosyltransferase), the enzyme responsible for placing the Gal molecule on the cell surface, were knocked out.

When insufficient undamaged skin is available for grafting, tissue from deceased donors is used as a temporary covering. But deceased-donor skin grafts are in short supply and expensive - disadvantages also applying to artificial skin grafts - must be carefully tested for pathogens and are eventually rejected by a patient's immune system. Once a deceased-donor graft has been rejected, a patient's immune system will reject any subsequent deceased-donor grafts almost immediately.

When [the researchers] used skin from these Gal-free pigs to provide grafts covering burn-like injuries on the backs of baboons - injuries made while the animals were under anesthesia - the grafts adhered and developed a vascular system within 4 days of implantation. Signs of rejection began to appear on day 10, and rejection was complete by day 12 - a time frame similar to what is seen with deceased-donor grafts and identical to that observed when the team used skin grafts from other baboons.

As with the use of second deceased-donor grafts to treat burned patients, a second pig-to-baboon graft was rapidly rejected. But if a pig-to-baboon graft was followed by a graft using baboon skin, the second graft adhered to the wound and remained in place for around 12 days before rejection. The researchers also showed that acceptance of a second graft was similar no matter whether a pig xenograft or a baboon skin graft was used first.

Clearly there is a way to go yet, but even just a better source of useful temporary grafts for burn victims is an improvement on the current situation, and the researchers are talking about organizing clinical trials based on this work.

Link: http://www.eurekalert.org/pub_releases/2014-05/mgh-sgf052714.php

Many and varied are the harmful medical conditions that emerge with increasing age. The consensus position in the research community is that tracing back the biochemical chains of cause and effect to root causes, something that is not yet possible for many common medical conditions, will show that all age-related conditions and their complexities are the consequences of a comparatively small number of types of cellular and molecular damage. That damage accumulates with age to cause secondary effects, which in turn cause further issues, and by the time the process of dysfunction rises to the level of being called a disease it has become a huge mess of broken mechanisms, confusion, and dead ends. With that as the starting point for research into treating age-related disease it is no wonder that all too many conditions are not yet fully understood in terms of a clear chain of consequences from top to bottom.

Hypertension, you might think, is such a simple medical condition that it couldn't possibly be stuck in this situation. It is quite simply high blood pressure, something that places all sorts of physical, mechanical stress on important parts of the circulatory system. Pretty much every fatal thing that can go wrong with your heart and blood vessels is aggravated by hypertension. Yet the root causes and middle region of the chain of cause and effect for the rising incidence of hypertension with age are not nailed down at this point: it is all very much up for debate.

Here researchers take a different strategy to the normal approach of painstakingly tracing relationships between proteins in cells, starting at the end point of full blown disease and working backwards one step at a time. They are instead using computer modeling to try to constrain the bounds of the possible, to narrow down the region of study for those who will come afterwards to piece together mechanisms and interactions. Their argument, in short, is that you don't need anything more than the process of arterial stiffening that occurs with aging to explain the observed effects of hypertension:

Arterial Stiffening Provides Sufficient Explanation for Primary Hypertension

Hypertension is highly age-related and affects more than 1 billion people worldwide. It is a major source of morbidity and mortality as it makes us more prone to experience heart failure, stroke, and kidney disease. Despite intense research efforts over several decades, there is still no consensus on what are the primary causes of this disorder.

Here we present a computational physiology model which shows that the increase in arterial stiffness that follows with age is sufficient to account for an overwhelming amount of experimental and clinical data on hypertension. We demonstrate quantitatively that the stiffening causes the baroreceptors, the blood-pressure sensors located in the arterial wall, to misinform the highly complex machinery responsible for blood pressure regulation. This misinformation occurs because the baroreceptors are strain sensitive, not pressure sensitive, and with stiffening the aortic wall strain ceases to be a good proxy for aortic blood pressure.

Contrary to wide-held conceptions, the blood pressure regulation may thus become compromised without any other detrimental physiological change of the regulatory machinery. Our results therefore suggest that arterial stiffness represents a major therapeutic target by which an otherwise intact physiological machinery may be exploited for blood pressure regulation.

Aha, you might say, but assuming this research pans out it just swaps one unknown chain of cause and effect for another that is only one item shorter. Instead of working to figure out what is going on in hypertension, scientists are instead figuring out what is going on in arterial stiffening. As it happens this is actually a good swap, as much more is known of the causes of blood vessel stiffening with age.

For example, the formation of advanced glycation end product (AGE) cross-links shackles layered proteins in tissues and is one well-researched direct cause of age-related stiffness in blood vessel walls and loss of elasticity in skin. In humans just one type of cross-linking compound called glucosepane accounts for almost all such cross-links in the most studied tissues. Getting rid of glucosepane and removing its contribution to degenerative aging requires only a single successful drug development program to produce a safe means of breaking down the compound. Unfortunately this has yet to see much interest from pharmaceutical companies, despite the great size of the market for an effective AGE-breaker drug.

If you spend much time watching the research and development community, you'll see many areas like this, in which obvious near term goals of great potential benefit are little pursued. Progress, sad to say, isn't always ruthless and rational, and gaping holes of this nature can last for decades. Thus in the field of glucosepane research the only initiatives of note at the present time are set in motion by philanthropic funding, such as the programs coordinated by the SENS Research Foundation.

An editorial from the Longevity and Healthspan journal:

Mitochondria are indispensable for aerobic life. Depending on the tissue and species, they normally occupy 2-20% of the volume of a cell, and it can be up to 50%. They have their own DNA and undergo constant motion, fusion and fission. They provide the cell with ATP formed during the oxidation of carbohydrate, proteins and fats and are involved in a range of metabolic pathways. They help regulate cellular calcium levels, trigger apoptosis, and can generate reactive oxygen species that are used in cellular signalling and can cause oxidative damage.

The role of mitochondria in aging and disease remains contentious more than 40 years after the mitochondrial free radical theory of aging was first proposed. The hallmark of a useful hypothesis is that it stimulates further work and drives progress in its field. The free radical theory of aging has certainly done that since Harman proposed it in its general form in 1956 and in a more mitochondrially-oriented form in 1972. This theory proposes that the primary cause of aging is mitochondrial production of free radicals and the mitochondrial damage that ensues. The evidence that has been gathered over the years has led to adjustments and refinements in the formulation of the hypothesis as different authors have attempted to articulate it more precisely and to square it with experimental observations; as a result there have been numerous updates and overviews. Many of these have been very influential. However, the perspective has become increasingly critical as the predicted beneficial effects of many antioxidant treatments and genetic manipulations have failed to materialise.

Where does that leave us today? On the one hand, many of the manipulations that should decrease aging and increase longevity according to the classical versions of the mitochondrial free radical theory of aging have failed to do so, implying that the theory is wrong, or at best deeply flawed. On the other hand, some of these manipulations have been very successful, implying that that the theory refracts some underlying reality and still has significant value as a guide to thought and experiment.

Link: http://dx.doi.org/10.1186/2046-2395-3-7

For some years a number of researchers, such as Robert Freitas, have modeled and proposed designs for nanomechanical robots capable of interacting with and repairing cells or replacing some of the tasks of cells so as to conduct those tasks far more efficiently. This is early groundwork in a field that has yet to exist beyond concepts and models: the actual construction of such things still lies in the future. On this topic Frank Boehm, the author of a comparatively recent book on medical nanorobot design, pointed me in the direction of an interesting piece on the design of medical nanorobots to remove lipofuscin from cells, which is quoted below.

Lipofuscin is made up of metabolic wastes that cells cannot break down, and it clogs up the cellular recycling system, leading to a deterioration of cellular function as damage builds up. Where it happens in long-lived cells this process contributes to a range of age-related conditions. Liposfuscin removal will be a going concern in the years ahead if the SENS Research Foundation does well with its research programs and in persuading other organizations to join in, but the near future of this project won't involve nanorobotics. It will be a matter of adapting bacterial enzymes that are both safe to introduce to the body and highly effective at breaking down the various compounds that make up lipofuscin. Still, we should look farther ahead as well, as mechanical medical nanomachinery will almost certainly be plausible to manufacture and control effectively twenty to thirty years from now.

It is conceivable that the future development of nanomedical robotics [might] enable the capacity for the therapeutic removal of lipofuscin from individual cells in massively parallel fashion. Conceptual dedicated autonomous nanodevices (~200 nm in diameter - where one nanometer is a billionth of a meter) might penetrate the cell membranes of neurons and other cells and undertake the removal of lipofuscin through various means.

Advanced autonomous nanodevices might precisely locate lipofuscin granules by exploiting its strong fluorescence signatures [to] match with onboard reference spectral profiles. The prospective armamentarium at the disposal of these autonomous diamondoid "defuscin" class nanodevices [might] allow for the complete eradication of lipofuscin aggregates utilizing a feedthrough digestive strategy. These entities may be propelled by arrays of oscillating piezoelectric "fins" or via integrated magnetic nanoparticles, which might be activated and controlled externally. The conical inlet port of the nanodevice would be lined with molecules that possess high affinities for A2E [a primary lipofuscin constituent] and other lipofuscin elements.

Once a lipofuscin granule has been captured it would proceed to be drawn into the core, where it would be digested by potent encapsulated enzymes or nanomechanically minced into a liquid state and subsequently purged from the outlet port. This functionality would be similar to Freitas's microbivore artificial mechanical phagocytes, which operate under a "digest and discharge" protocol"

Link: http://www.nanobotmodels.com/node/73

Most people don't really care as to how many years of life they have left. It isn't an interesting topic for them, and is thought about rarely if at all. If pushed for preferences, the average follow reverts to not wanting to rock the boat, to go with the observed defaults: to live as long as his grandparents, or just a little bit more than his peers, enough to make the point without being crass. But this is not really an expression of preference, it is simply going with the flow, the knee-jerk desire for conformity and hierarchy. Of course most people are in relatively good health and a demise by aging is still decades away, which might as well be never given the human psychology of time preference. Life is busy and it is easy to push future concerns to one side in favor of the day to distractions, needs, and pleasures.

You can conduct a survey of such views yourself. If you are reading this post, the odds are good that you have a very different view on the future of your life than do your friends and family. If you talk to healthy people you'll find that most are surprisingly indifferent to the length of time they have left before aging greatly harms and then kills them. It only becomes a pressing concern when that time remaining drops into territory that instinctively makes a person uncomfortable: a month or a year, perhaps.

One of the aspects of ancient Stoic philosophy is that length of life and even present health is of little concern when it comes to happiness. Will triumphs over circumstance, as present state of mind is under the control of anyone who strives for that goal. To quote Epictetus, the stoic can be "sick and yet happy, in peril and yet happy, dying and yet happy, in exile and happy, in disgrace and happy." In times when life was far more perilous and fraught with sickness and discomfort than is the case now, these sorts of considerations were not academic exercises.

Is a Longer Life a Happier Life? Stoicism and Happiness

My faltering commitment to stoicism was brought to the forefront of my mind quite recently when I read an article by Eyjolfur Emilsson entitled "On the length of a good life". The article outlines and advocates the stoic (and Epicurean) view that "a life, once happy, does not become any happier by lasting longer". That is to say: we don't need long or indefinite lives in order to be truly happy and content.

There is far more to stoicism than this small slice relating to happiness and length of life. It certainly isn't the "philosophy of what I'd do anyway," but this small slice does more or less reflect the default view of the public at large. Most people strive for happiness in the moment and ignore their future longevity, which one might argue is some mix of (a) following the example set by the norms of past behavior, (b) a response to lack of certainty and control over the future value of money and other forms of wealth, and (c) that all-too-short human time preference again.

But so what if we have a world of people who hold stoic views with respect to longevity and years of health remaining, but without any real intent of doing so. Why does this matter? It matters because defeating aging and age-related disease is a grand goal in medicine. Even if the prototype technologies might be pushed to the point of demonstration in mice for a billion dollars and ten to twenty years of work, well within the purchasing power of a large multinational research company or collaboration of billionaire philanthropists, vast resources and many hands will be needed to translate that into a full, mature, worldwide clinical industry. At this sort of scale at least a sizable minority of the population must support the goal in question for it to have a hope of moving from possibility to reality. There are many grand engineering projects and industries that might already exist in a different world but which in ours have too little public support to move forward rapidly: irrigating the Sahara, a low-cost orbital lift industry, commercial small-scale nuclear reactors, and so forth.

The near future of human longevity is not just a matter of research and building the tools needed to repair the damage of aging, but it is also, vitally, a process of convincing enough people that this is even worth doing. Anyone who has spent time looking at exactly what it means to be old, at the drawn out pain and suffering inherent in the age-related failure of all organs and bodily systems, might be forgiven for thinking that we live in a madhouse. But nonetheless, most people simply don't care about research, medicinal science, progress in clinical applications of medicine, or the future of their health, or how long they will live. These things are not important to them, and won't be until such time as they are in the clinical system asking how their pain and lost function can be assuaged - which is far too late.

The practice of calorie restriction reduces the risk of suffering cancer, just as it reduces risk of suffering all other common age-related conditions. However if you do become unlucky and develop cancer, calorie restriction tends to improve the outcome, shifting the odds in your favor: there is a range of research to demonstrate that calorie restriction augments the effectiveness of cancer treatments, for example.

According to a study [the] triple negative subtype of breast cancer - one of the most aggressive forms - is less likely to spread, or metastasize, to new sites in the body when mice were fed a restricted diet. [When] mouse models of triple negative cancer were fed 30 percent less than what they ate when given free access to food, the cancer cells decreased their production of microRNAs 17 and 20 (miR 17/20). Researchers have found that this group of miRs is often increased in triple negative cancers that metastasize. This decrease in turn increased the production of proteins involved in maintaining the extracellular matrix. "Calorie restriction promotes epigenetic changes in the breast tissue that keep the extracellular matrix strong. A strong matrix creates a sort of cage around the tumor, making it more difficult for cancer cells to escape and spread to new sites in the body."

In theory, a drug that decreased miR 17 could have the same effect on the extracellular matrix as calorie restriction. However, targeting a single molecular pathway, such as the miR17 is unlikely to be as effective as calorie restriction. Triple negative breast cancers tend to be quite different genetically from patient to patient. If calorie restriction is as effective in women as it is in animal models, then it would likely change the expression patterns of a large set of genes, hitting multiple targets at once without toxicity. Breast cancer patients are often treated with hormonal therapy to block tumor growth, and steroids to counteract the side effects of chemotherapy. However, both treatments can cause a patient to have altered metabolism which can lead to weight gain. In fact, women gain an average of 10 pounds in their first year of treatment. Recent studies have shown that too much weight makes standard treatments for breast cancer less effective, and those who gain weight during treatment have worse cancer outcomes. "That's why it's important to look at metabolism when treating women with cancer."

In order to test that this hypothesis is true in humans, [the researchers are] currently enrolling patients in the CaReFOR (Calorie Restriction for Oncology Research) trial. As the first trial like it in the country, women undergoing radiation therapy for breast cancer receive nutritional counseling and are guided through their weight loss plan as they undergo their treatment for breast cancer.

Link: http://www.eurekalert.org/pub_releases/2014-05/tju-fcw052114.php

Vice here interviews Aubrey de Grey of the SENS Research Foundation, an organization that coordinates and funds work on the necessary foundations for rejuvenation treatments, near future therapies that will repair the known cellular and molecular damage that causes aging:

Aubrey de Grey has been called many things. "Transhumanist" is one of them, but one he dislikes. "Immortalist" is the tag used to describe him and his colleague Bill Andrews in a documentary shown at South by Southwest this March, though de Grey rolls his eyes when someone drops the word "immortality."

The British gerontologist considers himself a "simple medical researcher," but his research is about fiddling with cells to stop ageing in human beings, and potentially postponing death indefinitely. If it's not immortality (in de Grey's world, you could still be dispatched by an infectious disease or a shotgun), it's quite a close beast.

He believes that tackling the individual illnesses that haunt old people's lives is a fundamentally flawed strategy; the right course of action is to act at the cellular level to prevent ageing from setting off those illnesses in the first place. His Silicon Valley-based foundation-cum-laboratory, the SENS Research Foundation, is completely devoted to this feat.

In the past, de Grey's views were often met with skepticism or hostility, when not openly guffawed at. That has not completely changed, but the idea that ageing should actually be regarded as a disease, and that it might even be treated as such, is increasingly gaining ground. Recently, that's been given a boost by research into tackling ageing on a genetic level. He initiated me in the science and doctrine of which he's the standard-bearer, most of which can be summarized in one question: If we could really wipe old age and death off the planet, why shouldn't we?

Link: http://motherboard.vice.com/read/meet-aubrey-de-grey-the-researcher-who-wants-to-cure-old-age

Methionine is an essential amino acid. Our metabolism cannot produce it, but is nonetheless an important raw material for the manufacture of proteins, and thus must be obtained in the diet. If you don't obtain enough of it, you die. Fortunately just about any sensible diet, and even most deficient diets, contain far more than you actually need to get by. Very few foodstuffs are lacking in methionine.

If you are the sort who likes undertaking strict and novel diets for the inherent challenge involved, rather than the outcome, then you should give up whatever you are doing right now and give a low methionine diet a try. You will be faced with challenging research to identify appropriate levels of methionine for a human low methionine diet, poor and contradictory nutritional data on the methionine content of various foodstuffs, and a comprehensive avoidance list that includes most of the standard staples and fallback alternatives used in the recipes of any given culinary tradition. I feel quite sorry for those who are forced into such a diet through suffering one of a few rare medical conditions such as homocystinuria, as the challenges inherent in organizing your own low methionine diet almost rise to the level of making the expensive tailored medical diets produced by a variety of big name companies look cost-effective.

Why undertake a low methionine diet if not forced to do so by pressing medical circumstances? For the same reasons one would undertake calorie restriction or intermittent fasting, both of which are far easier propositions: just like these two options, methionine restriction has been shown to extend life and improve health in a range of laboratory species. The evidence for calorie restriction to bring health benefits to human practitioners is compelling, and further bolstered by a mountain of animal studies results accumulated over decades. In the case of methionine restriction there is, so far as I know, only very sparse data for humans, but a good enough set of data from rodent studies to make it interesting. Methionine restriction is likely an important underlying mechanism for the operation of calorie restriction, which makes sense as a lesser intake of food generally means a lesser intake of methionine. Thus anyone advocating that you give methionine restriction a try for health reasons would argue on the basis of studies in mammals that strongly suggest it is a cause of calorie restriction benefits, and then point to the supporting data mountain for calorie restriction.

Caveat emptor, of course. I'm one who has in the past debated whether it is wise to try alternate day fasting given that there is much more data for straight calorie restriction, so you can probably imagine my views on methionine restriction. Being a conservative late adopter in all things has a lot going for it.

In a like fashion the research community is generally very conservative and and slow-moving in most matters. It takes a while, sometimes decades, for research to percolate through the system. Methionine restriction is beginning to be considered more widely among those who work with calorie restriction or fasting, however. So we have the small symposium noted below, for example, as a sign that folk are talking on this topic. Where there is presently discussion and modest scientific meetings there will later be conferences and commercial ventures - and possibly better and more reliable information on whether and how to practice methionine restriction were one inclined to do so:

The First International Mini-Symposium on Methionine Restriction and Lifespan

It has been 20 years since the Orentreich Foundation for the Advancement of Science, under the leadership Dr. Norman Orentreich, first reported that low methionine (Met) ingestion by rats extends lifespan. Since then, several studies have replicated the effects of dietary methionine restricted (MR) in delaying age-related diseases.

We report the abstracts from the First International Mini-Symposium on Methionine Restriction and Lifespan held in Tarrytown, NY, September 2013. The goals were (1) to gather researchers with an interest in MR and lifespan, (2) to exchange knowledge, (3) to generate ideas for future investigations, and (4) to strengthen relationships within this community. The presentations highlighted the importance of research on cysteine, growth hormone (GH), and ATF4 in the paradigm of aging. In addition, the effects of dietary restriction or MR in the kidneys, liver, bones, and the adipose tissue were discussed.

The symposium also emphasized the value of other species, e.g., the naked mole rat, Brandt's bat, and Drosophila, in aging research. Overall, the symposium consolidated scientists with similar research interests and provided opportunities to conduct future collaborative studies.

Among the presentations discussed is one of the only studies on methionine restriction in humans I've seen, preliminary and brief as it was. It is worth noting in passing that in comparison to the mild reduction in methionine here, rodent life span studies on methionine restriction tend to cut down methionine levels in the diet by a much larger proportion.

Previous findings in rodent models that dietary MR increases maximum lifespan and reduces the development of aging-related impairments suggest that MR may have important implications as a preventive or therapeutic strategy in humans. However, to date, there have been few studies aimed at translating these pre-clinical findings to the clinic.

To this end, we conducted a short-term controlled cross-over feeding study of MR in healthy adults. This study consisted of two isocaloric diet groups (control and 86% MR). Our objectives were to determine the feasibility of feeding an MR diet and to assess the effects of MR on relevant blood biomarkers. The study was conducted with 12 healthy adults and consisted of two 3-week experimental feeding periods with a 2-week washout. The MR diet was well-tolerated by all subjects with no negative side-effects reported.

Decreases in plasma levels of Met (22%) and cysteine (15%) were observed in the MR group after 3 weeks. MR significantly decreased plasma total cholesterol (15%), LDL (23%), and uric acid (25%), but had no effects on leptin, adiponectin, IGF-1, or glutathione.

Altogether, these findings demonstrate the feasibility of a MR diet in humans and indicate that MR has significant short-term effects on blood lipids similar to those observed in laboratory animal models. In addition, the lack of effects on blood adipokines and glutathione are consistent with more recent laboratory findings that indicate that restrictions in both Met and Cys may be required for the full range of beneficial effects on adipokines and longevity.

This popular science piece argues that the future of bioartificial organ development will be a process of top down and bottom up tissue engineering attempts eventually meeting somewhere in the middle, and there providing the ability to generate complex replacement organs to order:

Although a body, no less than a car, may eventually need replacement parts, surgeons cannot simply place an order at the Organ Zone. One alternative to waiting for a donor organ is to handcraft one. Doing so is as inconvenient at it sounds. First, you need a scaffold. This, too, can come from a donor, a cadaver even, provided all the cells are removed, leaving only extracellular matrix consisting of collagen or cartilage. To date, this approach has been used to accomplish relatively simple repairs in human patients. For example, scaffolds fashioned from cadaver materials and plastics have been seeded with stem cells to create new windpipes.

While optimism does seem to be in order, this approach to tissue engineering, with its arduous and time-consuming shaping of scaffolds and pipetting of stem cells, has something of a preindustrial, handicraft feel to it. Moreover, it seems inherently resistant to the sort of top-down optimization you might see in an industrial setting. Mass production would seem to be out of the question. But what about mass customization? Mass customization refers to a kind of bottom-up process that relies on computer-aided design (CAD) tools and rapid prototyping platforms such as 3D printers. Since it was learned that more than 90% of bioprinted cells manage to survive the rigors of bottom-up processing, researchers interested in generating 3D replacement organs have been pressing the "print" button. If they succeed, they will create an industry that has the distinction of skipping the mass production phase of industrial development.

That may seem too large a chasm to cross. The other side may be reached, however, partly thanks to insights gleaned from top-down systems. For example, it is already well understood that printing an organ won't be as simple as dropping cells and supporting materials in the right place and calling it a finished product. An organ grows and develops over time amidst a storm of signals and signal responses, and these depend on environmental cues and cellular sensitivities and propensities for self-organization. Exactly how all these interactions can be orchestrated is unclear, but researchers, undaunted, are pressing forward.

Link: http://www.genengnews.com/insight-and-intelligence/top-down-bottom-up-approaches-converge-on-bioficial-organs/77900140/

Much of the work on the aging of stem cells in recent years has focused on muscle stem cells, and has shown that to a large degree the progressive decline in function with age is not due to a loss of stem cells, but rather because these cells become less active and stop doing their jobs. This is probably an evolved reaction to rising levels of cellular damage that serves to reduce the risk of cancer, but which comes at the cost of increasing frailty as tissue maintenance falters.

Researchers are making inroads into understanding the signal mechanisms involved in this process of stem cell decline. Work is already underway on the development of potential treatments based on at least temporarily overriding these signals in the old. Here is another example of relevant research in this field, which uncovers an aspect of aging in stem cells that is inherent to the cells themselves rather than being a property of the surrounding tissue and its protein signals:

The elderly often suffer from progressive muscle weakness and regenerative failure. We demonstrate that muscle regeneration is impaired with aging owing in part to a cell-autonomous functional decline in skeletal muscle stem cells (MuSCs). Two-thirds of MuSCs from aged mice are intrinsically defective relative to MuSCs from young mice, with reduced capacity to repair myofibers and repopulate the stem cell reservoir in vivo following transplantation. This deficiency is correlated with a higher incidence of cells that express senescence markers and is due to elevated activity of the p38α and p38β mitogen-activated kinase pathway.

We show that these limitations cannot be overcome by transplantation into the microenvironment of young recipient muscles. In contrast, subjecting the MuSC population from aged mice to transient inhibition of p38α and p38β in conjunction with culture on soft hydrogel substrates rapidly expands the residual functional MuSC population from aged mice, rejuvenating its potential for regeneration and serial transplantation as well as strengthening of damaged muscles of aged mice. These findings reveal a synergy between biophysical and biochemical cues that provides a paradigm for a localized autologous muscle stem cell therapy for the elderly.

Link: http://dx.doi.org/10.1038/nm.3464

All sorts of disparate functions in higher animals have evolved to influence one another. In part this is because evolution produces promiscuous reuse of component parts, so any one given gene or the protein it encodes may have numerous functions and impact numerous different biological systems. Coupled with the fact that there are an awful lot of proteins making up our cellular machinery, this means that any attempt to alter the operation of metabolism so as to reliably and safely slow aging and extend healthy life is a challenging prospect. Researchers have spent a few billion of dollars and more than a decade simply trying to recreate the known and well-researched enhancements to health and longevity produced by calorie restriction. There is no available therapy to show for this work as of yet, and it is clear that there remains a fair way to go to reach even a good, comprehensive, and defensible model of how this one single type of metabolic alteration works. It is a ferociously complex business.

Then there are many other normally hidden linkages between, on the one hand, parts of metabolism that have nothing to do with longevity and, on the other hand, parts that do in fact influence both aging and health. These relationships do not tend to come into play in nature in the same dramatic manner as the metabolic shift brought on by calorie restriction - otherwise they wouldn't be hidden. But when you have a laboratory and modern biotechnology, all sorts of sometimes surprising connections can be uncovered. Take this connection between a component of pain sensing and insulin metabolism, for example:

No Pain, Big Gain

Mice lacking the pain receptor TRPV1 live longer than controls and have more youthful metabolisms. While searching for an explanation for the mutant rodents' longevity, the researchers discovered that the animals responded to glucose extraordinarily efficiently even once they reached advanced age. Young mice with healthy metabolisms rapidly clear glucose from their blood streams, while it tends to linger in older mice with metabolic disorders. The mice without TRPV1 were able to produce spikes in insulin and to clear the glucose throughout their lives, whereas the control mice were less able to ramp up insulin production to clear glucose as they aged.

Curious about how TRPV1 influences insulin production, the researchers switched to another model organism: Caenorhabditis elegans. When C. elegans lost the worm equivalents of TRPV1, the mutant worms lived up to 32 percent longer than did controls.

Through experiments in both C. elegans and mice, the researchers found that overactive TRPV1 reduces longevity through setting off a calcium-signaling cascade. In mice, this eventually leads to over-production of the neuropeptide CGRP in sensory neurons that innervate the pancreas. The presence of CGRP in these neurons suppresses insulin secretion. As a final test, the researchers blocked CGRP in elderly wild-type mice. Following sustained treatment, the animals' metabolic functions began to resemble those of younger mice. [Researchers] hypothesized that TRPV1 is overactive in older mice due to chronic inflammation, which is known to activate the pain receptor and is a hallmark of type 2 diabetes.

TRPV1 Pain Receptors Regulate Longevity and Metabolism by Neuropeptide Signaling

The sensation of pain is associated with increased mortality, but it is unknown whether pain perception can directly affect aging. We find that mice lacking TRPV1 pain receptors are long-lived, displaying a youthful metabolic profile at old age. Loss of TRPV1 inactivates a calcium-signaling cascade that ends in the nuclear exclusion of the CREB-regulated transcriptional coactivator CRTC1 within pain sensory neurons originating from the spinal cord. In long-lived TRPV1 knockout mice, CRTC1 nuclear exclusion decreases production of the neuropeptide CGRP from sensory endings innervating the pancreatic islets, subsequently promoting insulin secretion and metabolic health.

In contrast, CGRP homeostasis is disrupted with age in wild-type mice, resulting in metabolic decline. We show that pharmacologic inactivation of CGRP receptors in old wild-type animals can restore metabolic health. These data suggest that ablation of select pain sensory receptors or the inhibition of CGRP are associated with increased metabolic health and control longevity.

Thus chronic pain isn't just a horrible experience resulting from the damage of aging, but rather in and of itself causes further harm and dysregulation of metabolism. No-one said life is fair, and this is all the more reason to work on ways to effectively treat aging and and its consequences.

Much of the focus in Alzheimer's research remains on amyloid beta and the processes by which it accumulates in the brain. This researcher is one of a number of attempts over the years to produce a drug candidate that interferes beneficially in these mechanisms:

A molecular compound [restored] learning, memory and appropriate behavior in a mouse model of Alzheimer's disease. The molecule also reduced inflammation in the part of the brain responsible for learning and memory. [This] is the second mouse study that supports the potential therapeutic value of an antisense compound in treating Alzheimer's disease in humans. "Our current findings suggest that the compound, which is called antisense oligonucleotide (OL-1), is a potential treatment for Alzheimer's disease."

OL-1 blocks the overexpression of a substance called amyloid beta protein precursor, which normalized the amount of amyloid beta protein in the body. Excess amyloid beta protein is believed to be partially responsible for the formation of plaque in the brain of patients who have Alzheimer's disease.

Scientists tested OL-1 in a type of mouse that overexpresses a mutant form of the human amyloid beta precursor gene. Like people who have Alzheimer's disease, [the] mice have age-related impairments in learning and memory, elevated levels of amyloid beta protein that stay in the brain and increased inflammation and oxidative damage to the hippocampus - the part of the brain responsible for learning and memory.

Scientists found that learning and memory improved in the genetically engineered mice that received OL-1 compared to the genetically engineered mice that received random antisense. They also tested the effect of administering the drug through the central nervous system, so it crossed the blood brain barrier to enter the brain directly, and of giving it through a vein in the tail, so it circulated through the bloodstream in the body. They found where the drug was injected had little effect on learning and memory.

Link: http://www.slu.edu/x94193.xml

The axons that link neurons in the nervous system can grow to great length, up to several feet long in human limbs for example. Thus it isn't enough just to be able to replace or repair cells in the nervous system when building regenerative treatments, the axons must also be considered. Here researchers demonstrate a first step towards axon regrowth, which is to get it to happen at all. Creating restoration of function is the next step that must be built on this foundation:

Axons in the central nervous system (the CNS, consisting of brain, eyes and spinal cord) cannot regenerate after an injury in higher animals such as mice and humans. Earlier work had shown that axon growth can be blocked by disabling the proteins B-RAF and C-RAF, part of the RAF-MEK growth-signaling pathway involved in neuronal development. This growth-signaling pathway is inactive in adult animals.

To isolate the effects of B-RAF in the nervous system, [researchers] genetically engineered mice so that B-RAF in neurons could be turned on at will. Activation of B-RAF enabled normal growth of sensory axons in mouse embryos that lacked a crucial nerve growth-signaling pathway and would normally not develop proper sensory innervation.

The researchers then tested whether boosting B-RAF in adult mice could help repair injured sensory axons, which are not part of the CNS. In mice with identical neuronal injuries, those with activated B-RAF showed significant axon regrowth. The regenerating axons even reconnected with the spinal cord, seemingly unchecked by the inhibitory cues that normally inhibit regeneration in the adult spinal cord.

Next, the researchers set their sights on the more elusive goal - regeneration inside the adult CNS. In an encouraging step towards fulfilling that dream, the researchers found that B-RAF activation strongly enhances axon regeneration in injured optic nerve. Moreover, when they combined B-RAF activation with another manipulation, the inactivation of the PTEN gene, the combined axon regeneration was even greater than they had expected from a simple additive effect.

Link: http://www.burke.org/media/news/2014/05/bmri-scientists-identify-pathway-for-regeneration/207

Aubrey de Grey is the co-founder of the SENS Research Foundation and the originator of SENS, the Strategies for Engineered Negligible Senescence. To my eyes SENS is the most important of present initiatives aimed at producing treatments for degenerative aging: de Grey has led the production of a work of synthesis, drawing together important research from widely disparate reaches of the medical research community, produced by researchers often unaware of the relevance of their work to aging or the efforts of scientists in unrelated fields. The sum of this joined research supports (a) the identification of specific forms of cellular and molecular damage as the causes of aging, and (b) sound and detailed research plans for the production of means to repair this damage, and thereby reverse the effects of degenerative aging.

Synthesis is an often overlooked and important activity in the sciences: someone has to survey the diverse strands of progress in a field as complex as medicine, draw the connections that are rarely apparent to researchers at the cutting edge, deeply immersed as they are in advancing their own narrow but deep specialties. It isn't just a matter of joining puzzle pieces, however. Synthesis also means establishing ties between researchers who will benefit from an exchange of knowledge, but would not have become aware of one another without outside intervention. All fields of science go through periods of fragmentation and exploration, accompanied by a rapid expansion in knowledge, but this also tends to create divides of mutual ignorance and lack of communication between specialties. This is only natural: there are only so many hours in the day, and no one person can know everything there is know about what thousands of researchers in hundreds of laboratories are up to. Thus forming the foundations for the next phase of development in medical science requires initiatives that focus on synthesis, networking, and review: building connections and identifying which pieces of the puzzle join together.

Aubrey de Grey is of course only one of the more visible folk involved in the work of the SENS Research Foundation. There are scores of researchers and other people in a broad network involved in creating better odds for the development of rejuvenation therapies in our future, which is not to mention the thousands of donors who have helped to raise millions of dollars to fund the initial stages of research. As in all such initiatives someone has to be the visible spokesperson, to raise awareness and present the goal of defeating aging to a public that is only just starting to think of this as a possibility.

Here are a couple of recent interviews with de Grey; one audio podcast from Radio New Zealand, and a video from the St. Gallen Symposium in Switzerland.

Aubrey de Grey: extending longevity

English author and theoretician in the field of gerontology, and the Chief Science Officer and co-founder of the SENS Research Foundation. Duration:  45′ 58″.

One-on-One: an investigative interview with Aubrey de Grey

Aubrey de Grey (GB), Chief Science Officer & Co-Founder, SENS Research Foundation. Topic Leader: Stephen Sackur (GB) Presenter HARDtalk, BBC Broadcasting House.

This, I think, is a great example of what emerges as a consequence of the distorting effects of regulation on medical research. Because it costs a ridiculous amount of money and time to push anything new past the regulators of the FDA, there is a great focus on generating very marginal new uses of drugs that have already been approved. Thus instead of forging ahead to build radically improved new technologies, things far better than mere drugs, much of the research community does nothing more than tinker with what is already known. This is a terrible thing to be happening at a time when the research community is finally shedding its inhibitions regarding the treatment of aging, and researchers feel able to speak openly about the goal of extending health human life spans. It is a stupendous waste of potential, and the cost is measured in lives lost.

Rapamycin, an antibiotic and immunosuppressant approved for use about 15 years ago, has drawn extensive interest for its apparent ability - at least in laboratory animal tests - to emulate the ability of dietary restriction in helping animals to live both longer and healthier. A big drawback to long-term use of rapamycin [is] the increase in insulin resistance, observed in both humans and laboratory animals. The new research identified why that is happening. It found that both dietary restriction and rapamycin inhibited lipid synthesis, but only dietary restriction increased the oxidation of those lipids in order to produce energy.

Rapamycin, by contrast, allowed a buildup of fatty acids and eventually an increase in insulin resistance, which in humans can lead to diabetes. However, the drug metformin can address that concern, and is already given to some diabetic patients to increase lipid oxidation. In lab tests, the combined use of rapamycin and metformin prevented the unwanted side effect.

"If proven true, then combined use of metformin and rapamycin for treating aging and age-associated diseases in humans may be possible. This could be an important advance if it helps us find a way to gain the apparent benefits of rapamycin without increasing insulin resistance. It could provide a way not only to increase lifespan but to address some age-related diseases and improve general health. We might find a way for people not only to live longer, but to live better and with a higher quality of life."

Link: http://oregonstate.edu/ua/ncs/archives/2014/may/research-explains-action-drug-may-slow-aging-and-related-disease

Syndrome X patients do not develop physically in childhood, and thus appear to not be aging. However this is an extreme malfunction of developmental programs, not an absence of aging. The operation of their metabolism still generates all of the forms of damage that lead to degenerative aging, but these individuals die young and so none of that is given the chance to rise to the level of displaying the recognizable symptoms of aging.

Some people persist in trying to make the link that doesn't exist, however. This popular science article is a decent coverage of what is presently called Syndrome X and present thoughts on theories of aging. The researcher whose work on Syndrome X is mentioned here has adopted a variant view of aging as a genetic program, and seeks to sequence the few known Syndrome X patients in search of the common genetic cause in the hopes that this will inform considerations of normal aging. I, among others, think that this is a futile quest, though it may produce the path to curing Syndrome X in the future, should it turn out to have a simple root cause in genetic mutation.

Richard Walker has been trying to conquer ageing since he was a 26-year-old free-loving hippie. Walker, now 74, believes that the key to ending ageing may lie in a rare disease that doesn't even have a real name, "Syndrome X". He has identified four girls with this condition, marked by what seems to be a permanent state of infancy, a dramatic developmental arrest. He suspects that the disease is caused by a glitch somewhere in the girls' DNA.

Most scientists say that ageing is not caused by any one culprit but by the breakdown of many systems at once. Our sturdy DNA mechanics become less effective with age, meaning that our genetic code sees a gradual increase in mutations. Telomeres, the sequences of DNA that act as protective caps on the ends of our chromosomes, get shorter every year. Epigenetic messages, which help turn genes on and off, get corrupted with time. Heat shock proteins run down, leading to tangled protein clumps that muck up the smooth workings of a cell. Faced with all of this damage, our cells try to adjust by changing the way they metabolise nutrients and store energy. To ward off cancer, they even know how to shut themselves down. But eventually cells stop dividing and stop communicating with each other, triggering the decline we see from the outside.

Scientists trying to slow the ageing process tend to focus on one of these interconnected pathways at a time. Some researchers have shown, for example, that mice on restricted-calorie diets live longer than normal. Other labs have reported that giving mice rapamycin, a drug that targets an important cell-growth pathway, boosts their lifespan. Still other groups are investigating substances that restore telomeres, DNA repair enzymes and heat shock proteins.

During his thought experiments, Walker wondered whether all of these scientists were fixating on the wrong thing. What if all of these various types of cellular damages were the consequences of ageing, but not the root cause of it? He came up with an alternative theory: that ageing is the unavoidable fallout of our development.

Most researchers agree that finding out the genes behind Syndrome X is a worthwhile scientific endeavour, as these genes will no doubt be relevant to our understanding of development. They're far less convinced, though, that the girls' condition has anything to do with ageing. "It's a tenuous interpretation to think that this is going to be relevant to ageing," says David Gems, a geneticist at University College London.

Link: http://www.bbc.com/future/story/20140520-the-girls-who-never-age

Some aspects of aging cannot be repaired through the use of therapies that manipulate or deliver stem cells. Accumulations of metabolic waste that the body cannot break down occur both inside and in between cells, for example. Growing levels of DNA damage, both nuclear and more importantly mitochondrial, also cannot be addressed with stem cell treatments that look much like today's transplant therapies. This still leaves many secondary consequences of aging that can be partially repaired by inducing temporarily enhanced regeneration in an old individual, however. Joint and heart tissue damage are perhaps the most obvious, but there is a much longer list of benefits to be realized even using comparatively crude stem cell transplants.

Eventually the successors to today's treatments will provide more comprehensive fixes to the issues of aging stem cells. At present they are temporary patches that do little to address the root causes of dysfunction - and so the mechanisms of aging will proceed to eat away what has been shored up at an ever faster rate. But treatments in the foreseeable future will provide wholesale replacement of worn cell populations, such as the age-damaged cells of the immune system, or renewal of specific populations of stem cells to restore tissue maintenance to something closer to youthful levels, organ by organ. There will also be a move beyond cell transplants towards efforts to reprogram or signal existing cells in order to alter their behavior. These treatments will provide a more lasting bulwark against aging, though without other forms of repair therapy to achieve such goals as clearing metabolic waste and repairing DNA damage, this too will be broken down all too quickly.

The stem cell research field is admirably focused on repair of age-related conditions. Much of the future revenue of this field depends on producing effective regeneration in the old, as the aged suffer almost all of the conditions that are most obviously treated with stem cell technologies. Thus the research community must find ways to make these treatments work and work well in aged individuals. The dynamics of the situation forces researchers to get to grips with the nature of aging insofar as it impacts stem cell function.

Here a researcher considers the work that must yet be accomplished in order to produce means of reliably manipulating the stem cells present within an individual's brain. The goals here include spurring greater feats of repair and regeneration, or the creation of a larger stream of new brain cells to make up losses due to age and injury.

Endogenous stem cells for enhancing cognition in the diseased brain

Adult neural progenitor cells or neural stem cells (NSCs) persist in the adult human brain [and] some brain regions display an unexpected capacity for newborn neuron migration and survival. Several milestones need to be achieved prior to considering functional repair [in the brain through use of NSCs]. These include, but may not be limited to:

(1) Understanding the mechanisms leading to NSC quiescence and loss with aging. Several mechanisms are involved in the different regulatory steps of NSC self-renewal and loss. We will emphasize some of the mechanisms leading to NSC loss with aging. Once these mechanisms are identified, we should be able to amplify the pool of NSCs and direct their differentiation.

(2) Identifying the molecules responsible for fate determination of NSCs and their daughter cells to generate glia or neurons of different types, including interneurons and long projection neurons.

(3) Determining the inhibitory molecules that make the adult brain resistant to repair. Some repair has been reported in the cortex of rodents, but it is abortive possibly due to an unfriendly environment.

(4) Finally, although we can genetically manipulate NSCs in rodents, it is a different issue in humans. Delivery systems need to be improved. Each of this point is further discussed below.

Despite the hurdles outlined above and the length of time that will be required for achieving brain repair and cognitive enhancement, we cannot fail to pursue our investigations of the four fields outlined above. Overall, the present energetic study of stem cell biology and brain delivery systems will provide a better understanding of brain development, endogenous responses to injuries, and additional therapeutic approaches for brain repair, and hold great promise for broadening the therapeutic options available for maintaining and restoring cognition following brain injury and during neurodegenerative diseases.

That living, being alive and active and enjoying the potential that this brings, is good in and of itself is an axiom for those who work in medicine, including those who work towards the tools needed to extend healthy life and rejuvenate the old. If life is not good and valuable, then why bother? Yet if you look around at what does and does not take place in this world of ours, you might be forgiven for thinking that most people do not in fact place as great a value on life as they might. Here is an article on this theme from the Movement for Indefinite Life Extension.

We have become really good at being indifferent to the most widespread forms of death, in order to spare ourselves from stressing out on futilely trying to do something about it. Now that we have the tools and techniques, and the times have changed, we have to change that way of thinking from indifference back toward letting that horror affect us. Horror benefits us in that it is our cue to be driven to action to make sure that the horror can't happen again.

A few days ago I was thinking about a typical farm hand of Medieval times, walking outside to smell the heavy wet grass and earth of a cold wet spring day. Focus on your heartbeat, feel it pulsing. Theirs pulsed like that. They thought of their hearts stopping and of how it couldn't possibly be lost to the dust of history anytime soon. You think that, too. Their hearts are lost to the dust of history. Yours is next. So many tangled groves in forests have had the wind blowing through them for all of these years, without one person, without one spoken word, in a place near a stream, where there was once a mighty, crackling stone fireplace that warmed multiple generations of families across the 6th through 8th centuries. It was a place that hosted countless memories which later tormented the souls of dying, now long-dead grandfathers.

They don't deserve to be dead. They deserve what they earned: the world that is paying exponentially exciting, satiating, and fullfillingly valuable dividends today. This is an incredibly motivating and driving factor in what pushes me to pursue indefinite life extension. People take on a variety of diverse augmentations over time, becoming unique collections of intriguing insight - dynamic power tools for slicing and dicing the elements. We can't afford for these wealths of rare and powerful abilities and resources to be pillaged and killed off. Sometimes it seems as if life-extensionists like me have to explain to people why it's bad to let people be killed before we can get down to business in a worldwide effort to reach the goals that can get this done.

Link: http://www.rationalargumentator.com/index/blog/2014/05/motivated-time-prospectors/

Cryonics is the low-temperature preservation of your body and brain as soon as possible after death. It is the only option available for people today that offers any sort of a chance at a longer life in the future, as for so long as the structures in the brain that store the data of the mind are preserved then it is possible for future technology to restore an individual to life. That restoration will not be easy and isn't possible today, but we can envisage the sort of nanodevices and repair strategies that would be needed, and a cryopreserved individual has time on his or her side. Despite its potential to save lives, cryonics remains a small and largely non-profit industry consisting of just a few primary providers and a handful of support companies. Few people indeed avail themselves of this option.

Alcor is one of the two long-standing cryonics providers present in the US and the staff there have in the past proven that they will go the extra mile for their members, striving to produce the best outcome possible even when they are presented with impossible circumstances. The last time I made this point, it was to remind people that if you want a good cryopreservation, one that follows on as close to immediately after death as possible, then don't leave things to the last minute and don't make it hard for the organizations involved to deliver.

A-2531, a neurocryopreservation member, was declared legally dead at 10:15am (MST) on Tuesday May 6, 2014 and became Alcor's 124th patient.

Shortly after 9 am local time, Alcor received a call from a member in Alabama claiming to have been shot by an intruder. After immediately calling police and medical services in the area, we stayed on the phone with him as much as he allowed. It soon became apparent that he had not been shot but was intending to shoot himself in the chest and had already taken a large dose of sleeping pills. Clearly deeply distressed emotionally, he called one or two family members to say goodbye, but still wanted Alcor to cryopreserve him. As we soon learned, hearing the police arriving, he cut off our phone call and shot himself before anyone could prevent him.

We immediately contacted an attorney to be ready to file an injunction to try to block the expected autopsy. (This is a powerful reason never to kill yourself, no matter how distressed you are, if you want to be successfully cryopreserved.) With great good fortune, the police and coroner declared the cause of death obvious, took blood samples, and quickly released our member. Two members of Alcor's response team got on a plane the same afternoon, did a field washout, circulated medications, and performed a neuro separation. The patient arrived at Alcor on Wednesday at 2:10 am. After a longer than usual perfusion for a neuro case, perfusion was completed at 7:32am.

Link: http://www.alcor.org/blog/alcors-124th-patient-2531/

I'm not overly worried about cancer, or at least not in comparison to all of the other things likely to cause me pain, suffering, and death a couple of decades from now. I think that present work on targeted cell killing technologies will lead to a suite of treatments that are robust enough, therapies and infrastructure that will reduce the risks and consequences of cancer to an acceptably low level over the period of time in which we will be availing ourselves of the first generation of rejuvenation treatments. Or at least that will be the case if matters proceed well and growth continues on an accelerating path for those fields of aging and longevity science most likely to produce meaningful results.

The big risk here is the same as for any nascent technological revolution: that the world continues to focus on things that don't really matter all that much, a category which includes a lot of the mainstream aging science, sad to say, and thus the rejuvenation research community fails to grow and fails to realize useful treatments in time for my old age in the 2040s. I think that the odds of this failure coming to pass are much higher than the chances of the cancer community failing to deliver over the same time frame. I will be astounded and unhappy in equal measure to find that cancer has not been wrestled into a state akin to that of tuberculosis by 2040: a minor threat, once a dreadful killer, kept caged by advanced medical technology.

Thus I am not overly worried about cancer; it is a concern in life, just like road safety and general health, but not an overwhelming concern. As is the case for stem cell medicine cancer research is enormously well funded. It is not a field that needs any more help and support than it already has in order to make good progress towards bringing cancer under medical control - though of course this is the case because plenty of people don't agree with me, and are willing to step up and do something about it. Researchers are well on the way to realizing the next generation of treatments that will soon enough replace chemotherapy and radiotherapy, consisting of far more effective targeted approaches that employ nanoparticles, immune cells, bacteria, and viruses to destroy cancer cells with minimal side-effects.

Here are a few representative papers and research results from the cancer community, published recently:

Oncolytic viral therapy: targeting cancer stem cells

Cancer stem cells (CSCs) are defined as rare populations of tumor-initiating cancer cells that are capable of both self-renewal and differentiation. Extensive research is currently underway to develop therapeutics that target CSCs for cancer therapy, due to their critical role in tumorigenesis, as well as their resistance to chemotherapy and radiotherapy.

To this end, oncolytic viruses targeting unique CSC markers, signaling pathways, or the pro-tumor CSC niche offer promising potential as CSCs-destroying agents/therapeutics. We provide a summary of existing knowledge on the biology of CSCs, including their markers and their niche thought to comprise the tumor microenvironment, and then we provide a critical analysis of the potential for targeting CSCs with oncolytic viruses, including herpes simplex virus-1, adenovirus, measles virus, reovirus, and vaccinia virus.

Herpes-loaded stem cells used to kill brain tumors

Cancer-killing or oncolytic viruses have been used in numerous phase 1 and 2 clinical trials for brain tumors but with limited success. In preclinical studies, oncolytic herpes simplex viruses seemed especially promising, as they naturally infect dividing brain cells. However, the therapy hasn't translated as well for human patients. The problem previous researchers couldn't overcome was how to keep the herpes viruses at the tumor site long enough to work.

[Researchers] turned to mesenchymal stem cells (MSCs) - a type of stem cell that gives rise to bone marrow tissue - which have been very attractive drug delivery vehicles because they trigger a minimal immune response and can be utilized to carry oncolytic viruses. [Researchers] loaded the herpes virus into human MSCs and injected the cells into glioblastoma tumors developed in mice. Using multiple imaging markers, it was possible to watch the virus as it passed from the stem cells to the first layer of brain tumor cells and subsequently into all of the tumor cells.

Using imaging proteins to watch in real time how the virus combated the cancer, [researchers] noticed that the gel kept the stem cells alive longer, which allowed the virus to replicate and kill any residual cancer cells that were not cut out during the debulking surgery. This translated into a higher survival rate for mice that received the gel-encapsulated stem cells.

New Method Sneaks Drugs into Cancer Cells Before Triggering Release

Biomedical engineering researchers have developed an anti-cancer drug delivery method that essentially smuggles the drug into a cancer cell before triggering its release. The method can be likened to keeping a cancer-killing bomb and its detonator separate until they are inside a cancer cell, where they then combine to destroy the cell.

The technique uses nanoscale lipid-based capsules, or liposomes, to deliver both the drug and the release mechanism into cancer cells. One set of liposomes contains adenosine-5'-triphosphate (ATP), the so-called "energy molecule." A second set of liposomes contains an anti-cancer drug called doxorubicin (Dox) that is embedded in a complex of DNA molecules. When the DNA molecules come into contact with high levels of ATP, they unfold and release the Dox. The surface of the liposomes is integrated with positively charged lipids or peptides, which act as corkscrews to introduce the liposomes into cancer cells.

In a mouse model, the researchers found that the new technique significantly decreased the size of breast cancer tumors compared to treatment that used Dox without the nanoscale liposomes.

Researchers still don't have a complete and clear picture as to how calorie restriction extends life and produces considerable health benefits. At present the research consists of a large bucket of metabolic changes with varying confidence levels in their involvement as longevity-assurance mechanisms. Reduction in visceral fat tissue seems important, as does the chain of events that starts with sensing levels of methionine in the diet, and also upregulation of the cellular housekeeping processes of autophagy.

There is plenty of room yet to raise up previously unexamined changes to a greater level of importance, however, or to argue over which of the presently better known mechanisms provide a greater contribution to the end result. I expect this process of discovery and argument to continue: as this paper indicates, calorie restriction changes an enormous number of discrete elements of metabolism, and most of these elements interact with one another in complex ways within the vast network of change and feedback. There is more than enough work here for another generation of researchers.

Dietary restriction (DR) extends longevity and delays the occurrence and progression of age associated diseases in a range of organisms. The ubiquity of these effects suggests there should be conserved common molecular pathways underlying how animals slow aging in response to DR. Such mechanisms that might be elucidated in model organisms may therefore apply to mammals and even perhaps primates including humans

One approach to discover such underlying mechanisms of longevity assurance is to study age-dependent gene expression in DR relative to normal-diet animals. Perhaps unsurprisingly, a great many genes are seen to differ between these groups and it is likely that only a fraction of these actually participate in the mechanisms that directly confer longevity assurance.

The breadth of overall transcript changes in response to diet is illustrated by meta-analysis of publicly available transcriptional studies. [Researchers] compiled 40 DR gene expression cases in mouse and identified 12,214 differentially expressed genes. Fewer analyses of chronic differences between DR and normal food have been conducted with Drosophila. [Researchers] examined the chronic effect of DR with samples taken at six and eight different age points in the control and DR cohorts respectively over the course of their lifespan. This design identified 2,079 genes whose transcript abundance associated with adult diet.

Besides rapidly adjusting transcript profiles to acute changes in diet, diet switches rapidly alter age-specific mortality. When switched from protein to non-protein diets, the age-specific mortality of formally protein-fed adults quickly adopts the mortality rate and trajectory of a continuously non-protein-fed cohort. Remarkably, when flies are shifted from a rich diet to just a relatively restricted diet, within days the cohort adopts the same trajectory of low age-specific of adults continuously maintained on restricted diet (and vice versa for cohorts switched from restricted to rich diets). These observations suggest that the molecular, cellular and physiological changes caused by DR to extend lifespan must occur within a short time frame after adults experience an alternative diet.

Link: http://www.impactaging.com/papers/v6/n5/full/100662.html

The protein GDF-11 has recently been shown to influence the decline in muscle stem cell function with aging and other aspects of aging in mice. Alterations in circulating levels of GDF-11 can restore stem cell activity in aged individuals, in at least some tissues, though there is the strong possibility that overriding this age-related reaction to rising levels of cellular damage may lead to cancer.

GDF-11 is related to myostatin, a protein shown to guide muscle growth. Loss of myostatin leads to very muscular individuals, and as is the case for for GDF-11 scientists are considering the development of treatments based on manipulating levels of this protein. Here researchers present more context for these overlapping mechanisms based on fly studies:

Using transgenic RNAi screening, we recently discovered several myokines that regulate lifespan and muscle aging in the fruit fly Drosophila melanogaster. Among the myokines regulating the lifespan of Drosophila, we found Myoglianin, a TGF-beta ligand expressed primarily by skeletal muscle and glia. Drosophila Myoglianin is homologous to human GDF11 and Myostatin (GDF8), two highly related TGF-beta ligands that circulate in the bloodstream in mammals.

We found that Drosophila Myostatin (Myoglianin) extends lifespan and delays systemic aging by acting on muscle, adipocytes, and possibly other tissues. These effects were not due to feeding or changes in muscle mass, suggesting that Drosophila may be a convenient system for testing the direct signaling roles of Myostatin without the indirect confounding effects deriving from the increased muscle mass observed in Myostatin knock-out mice. In fact, these mice have increased insulin sensitivity and decreased adiposity due to higher nutrient utilization in muscle (and consequent reduced nutrient availability for other tissues) deriving from the doubling in muscle mass, which is a prominent feature of Myostatin knock-out mice.

In addition to Myostatin, Myoglianin is homologous to the related factor GDF11. A previous study in mice showed that GDF11 levels decline during aging and that this contributes to developing age-related cardiac hypertrophy. The finding that the GDF11 homolog Myoglianin preserves muscle function during aging in Drosophila suggests that GDF11 may also have anti-aging effects on tissues other than the heart. Indeed very recent studies have shown that GDF11 delays skeletal muscle and brain aging in mice, suggesting that GDF11 is an evolutionarily conserved, general regulator of tissue aging.

Link: http://www.impactaging.com/papers/v6/n5/full/100666.html

It is becoming clear that genetic contributions to natural variations in longevity are highly complex. In humans the effects discovered to date are almost always very small, and are very few indeed have been replicated between study populations. This points to the relationship between genes and longevity within a species consisting of a network of modest effects, all of which interact with one another and environmental influences. Thus any specific genetic variant might have some small positive effect in one study and no effect or some small negative effect in another, and thus might be true even if the two study populations are recruited from exactly the same city, neighborhood, or well-defined ethnicity. What this suggests to me is that it will take a long time to make any headway in deciphering this web of relationships, and the result at the end of the day, after possibly decades of work, will be no great ability to extend life through genetic alteration. Knowledge will be the primary outcome, which is good for science, but not so good for us as individuals desiring to live longer lives.

Will someone one day turn up a simple human genetic alteration that has effects as impressive as some of the single gene longevity mutations in mice or lower animals? It might still happen, but I think that the odds are tiny and fading as more is discovered of the complex morass of human genes and longevity variations. It is a swamp of thousands of small effects. Like calorie restriction, which has sizable results on mouse longevity and nowhere near the same outcome for human longevity, genetic alterations known to produce large gains in short-lived mammals just don't do the same in humans. You might look at growth hormone receptor mutants: in mice they can live 60% longer. In humans, a similar population are merely somewhat resistant to diabetes and cancer, with no great signs of longevity besides that.

Here is news of research into the relationship between calorie restriction and mitochondrial gene variants that reinforces the points I make above. It is all an intricate web of relationships, with every strand individually making only a small contribution to the whole. This is not an easy path to extending life, and should not be the dominant way forward for longevity science despite the fact that the tools for working with genes are now very cheap. That would be like searching beneath the lamp, simply because it is where it the light falls. There is a lot that can be done in medicine with genetics, but I'm dubious that a fast path to rejuvenation treatments is one of them.

Interactions may matter most for longevity

If studying a single gene or a diet that might extend longevity is like searching for a fountain of youth, then a new study calls for looking at something more like the whole watershed. [Biologists] who experimentally throttled three such factors in fruit flies found that lifespan depended more on interactions among the factors than on the factors themselves. "I think the main lesson is that these interaction effects are as significant or important as the [single] effects, such as diet effects alone or genetic effect alone. Traditionally that's what people have focused on: looking for a gene that extends longevity or a diet that extends longevity."

When researchers have looked at single or even pairs of factors in a wide variety of organisms, they've made many valuable findings about the biology of aging. But sometimes scientists have been unable to replicate each other's findings in seemingly similar experiments. Often this is attributed to mysterious "background effects," presumably other genes that were not properly accounted for. The new study chose to put such background effects into the foreground to examine dietary effects on aging in several panels of different nuclear and mitochondrial genetic pairings.

G×G×E for Lifespan in Drosophila: Mitochondrial, Nuclear, and Dietary Interactions that Modify Longevity

It is widely recognized that mitochondrial function plays an important role in longevity and healthy aging. Considerable attention has been focused on the extension of longevity by caloric or dietary restriction and mutations that alter this process, and these interventions commonly are associated with shifts in mitochondrial function. While the genetic bases of these effects are the focus of much interest, relatively little effort has been directed at understanding the role that mitochondrial DNA (mtDNA) polymorphisms play in the diet restriction response.

This work presents a comprehensive effort to quantify the effects of mtDNA variants, nuclear genetic variants and dietary manipulations on longevity in Drosophila, with a focus on testing for the importance of the interactions among these factors. We found that mitochondrial genotypes can have significant effects on longevity and the diet restriction response but these effects are highly dependent on nuclear genetic (G) background and the specific diet environment (E). For example, a mitochondrial haplotype that shortens lifespan in one nuclear background or diet regime shows no such effect when the genetic background or diet regime is changed.

Our experiments indicate that identifying individual mitochondrial, nuclear or dietary effects on longevity is unlikely to provide general results without quantifying the prevalent mitochondrial × nuclear × diet (G×G×E) interactions.

Work progresses on therapies that use reprogrammed stem cells derived from easily obtained patient tissue samples, such as small pieces of skin:

Researchers have shown for the first time in an animal that is more closely related to humans that it is possible to make new bone from stem-cell-like induced pluripotent stem cells (iPSCs) made from an individual animal's own skin cells. The study in monkeys [also] shows that there is some risk that those iPSCs could seed tumors, but that unfortunate outcome appears to be less likely than studies in immune-compromised mice would suggest.

The researchers first used a standard recipe to reprogram skin cells taken from rhesus macaques. They then coaxed those cells to form first pluripotent stem cells and then cells that have the potential to act more specifically as bone progenitors. Those progenitor cells were then seeded onto ceramic scaffolds that are already in use by reconstructive surgeons attempting to fill in or rebuild bone. And, it worked; the monkeys grew new bone.

Importantly, the researchers report that no teratoma structures developed in monkeys that had received the bone "stem cells." In other experiments, undifferentiated iPSCs did form teratomas in a dose-dependent manner. The researchers say that therapies based on this approach could be particularly beneficial for people with large congenital bone defects or other traumatic injuries. Although bone replacement is an unlikely "first in human" use for stem cell therapies given that the condition it treats is not life threatening, the findings in a primate are an essential step on the path toward regenerative clinical medicine.

Link: http://www.eurekalert.org/pub_releases/2014-05/cp-fto050714.php

Myelin is the sheathing of nerves, and loss of myelin contributes to a number of debilitating diseases. This loss is also shown to occur to a lesser degree in aging, so just as for many types of disease it is worth keeping an eye on the progression of treatments such as the one discussed here. This paper is open access, but the full version is in PDF format only at the moment.

Using a viral model of the demyelinating disease multiple sclerosis (MS), we show that intraspinal transplantation of human embryonic stem cell-derived neural precursor cells (hNPCs) results in sustained clinical recovery, although hNPCs were not detectable beyond day 8 posttransplantation. Improved motor skills were associated with a reduction in neuroinflammation, decreased demyelination, and enhanced remyelination.

In summary, we demonstrate that transplantation of hNPCs into a mouse model of viral-induced demyelination results in prolonged clinical recovery up to at least 6 months in spite of the disappearance of transplanted hNPCs after only a week. Our findings extend the existing evidence that long-term engraftment is not important for sustained clinical and histologic recovery. Our evidence points to secreted factors produced by the hNPCs in the local environment as the regulators of T cell fate and remyelination activity by endogenous OPCs. Because they are produced by the hNPCs used in our study and have known effects on T cell development, members of the TGF-b family are strong candidates as triggers initiating clinical recovery.

As an aside, note that this is one of numerous studies in which the benefits derived from cell therapies are shown to have little to do with ongoing activities of the transplanted cells themselves. The cells change the environment and behavior of native cells even when they are only present for a comparatively short time.

Link: http://dx.doi.org/10.1016/j.stemcr.2014.04.005

At some point in the next ten to twenty years the public at large, consisting of people who pay little attention to the ins and outs of progress in medicine, will start to wake up to realize that much longer healthy lives have become a possibility for the near future. The preliminaries to this grand awakening have been underway for a while, gradually, and will continue that way for a while longer. A few people every day in ordinary walks of life notice that, hey, a lot of scientists are talking about greatly extending human life spans these days, and, oh look, large sums of money are floating around to back this aim. There will be a slow dawning of realization, one floating light bulb at a time, as the concept of radical life extension is shifted in another brain from the "science fiction" bucket to the "science fact" bucket.

Some folk will then go back to what they were doing. Others will catch the fever and become advocates. A tiny few will donate funds in support of research or pressure politicians to do the same. Since we live in an age of pervasive communication, we see this process as it occurs. Many people are all to happy to share their realizations on a regular basis, and in this brave new world everyone can be a publisher in their own right.

Here is an example that I stumbled over today; a fellow with a day to day focus in a completely unrelated industry took notice and thought enough of what is going on in aging research to talk about it. He is still skeptical, but not to the point of dismissing the current state and prospects for longevity science out of hand: he can see that this is actionable, important knowledge.

What if de Grey and Kurzweil are half right?

I think these guys - and the whole movement to conquer aging - is fascinating. I am highly skeptical of the claims, however. Optimism is all well and good, and I have no off-hand holes to poke in their (very) well-articulated arguments. But at the same time, biology is fiendishly complex, the expectations beyond fantastical.

Still though, I have to wonder: What if guys like de Grey and Kurzweil are half right, or even just partially right? What if, 30 years from now, it becomes physically impossible to tell a 30-year-old from a 70-year-old by physical appearance alone? It sounds nutty. But it's a lot less nuttier, and a lot closer to the realm of possibility, than living to 1,000 - which, again, some very smart people have taken into their heads as an achievable thing.

People who don't take care of themselves are insane. Ok, not actually "insane." But seriously, given the potential rewards AND the risks, not taking care of your body and mind - not treating both with the utmost respect and care - seems absolutely nuts. At the poker table I see these young kids whose bodies are already turning to mush, and a part of me just wants to grab them by the shirt collar and say "Dudes! What the hell is WRONG with you!!!"

If it is possible - just realistically possible, mind you - that I could still be kicking ass and taking names at 125 years old, then I want to be working as hard as I can to preserve and maintain my equipment here and now. No matter what miracles medical science will achieve in future, working from the strongest, healthiest base possible will always improve the potential results, perhaps by an order of magnitude. Individuals who go into old age with fit, healthy bodies and sound minds, and longstanding habits to maintain both, may find potential for extended performance at truly high quality of life that was never before imaginable.

As the foundations of rejuvenation biotechnology are assembled and institutions like the SENS Research Foundation continue to win allies in the research community and beyond, the number of people experiencing this sort of epiphany will grow. The more the better and the sooner the better, as widespread support for the cause of defeating aging through medical science is necessary for more rapid progress: large scale funding always arrives late to the game, attracted by popular sentiment. The faster we get to that point the greater our chances of living to benefit from the first working rejuvenation treatments.

There are many ways in which you can sabotage your future health, but putting on weight and smoking are the most popular choices. They even have similar harmful effects on life expectancy: a decade or more of life lost. At the level of cells and tissue structures the effects of smoking look a lot like accelerated aging in some ways - which should not be surprising if we consider aging as nothing more than accumulated damage to the biological machinery of the body. This is a theme taken up in the paper quoted here:

Chronic obstructive pulmonary disease (COPD) is a disease that usually presents clinically at an advanced age, after years of smoking cigarettes. It is usually believed that aging and its biological consequences are important mechanisms in the disease pathogenesis. This concept has maintained the focus of studies on COPD in old-age individuals.

Here we analyze the possible role of aging from a different point of view and introduce different concepts that might be considered useful additions to the understanding of the disease. Essentially, we propose and show evidence that COPD is a disease of the young susceptible smoker that progresses over time and manifests in older age because we live longer and not so much because of the effect of aging itself; we examine the concept of cell senescence, the basis of tissue aging, and how stressors like the ones produced by smoking can accelerate cell senescence with all of its untoward consequences in COPD. We thus finally suggest that COPD might accelerate aging rather than be a consequence of it.

In conclusion, we suggest that COPD could be considered a disease of the predisposed young individual that manifests clinically in old age because we live longer, with all of its consequences.

Link: http://www.ncbi.nlm.nih.gov/pubmed/24821602

It is well known that calorie restriction extends life in near all species in which it has been tested. In mammals much of this effect seems to operate through sensing low levels of methionine, an essential amino acid. Here researchers show that in flies in addition to mechanisms that react to the level of food intake there is a also water sensor that separately and distinctly alters metabolism so as to extend healthy life:

Sensory inputs are known to control aging. The underlying circuitry through which these cues are integrated into regulatory physiological outputs, however, remains largely unknown. Here, we use the taste sensory system of the fruit fly Drosophila melanogaster to detail one such circuit. Specifically, we find that water-sensing taste signals alter nutrient homeostasis and regulate a glucagon-like signaling pathway to govern production of internal water production. This metabolic alteration likely serves as a response to water sensory information. This control of metabolic state, in turn, determines the organism's long-term health and lifespan.

We found that loss of the critical water sensor, pickpocket 28 (ppk28), altered metabolic homeostasis to promote internal lipid and water stores and extended healthy lifespan. Additionally, loss of ppk28 increased neuronal glucagon-like adipokinetic hormone (AKH) signaling, and the AKH receptor was necessary for ppk28 mutant effects. Furthermore, activation of AKH-producing cells alone was sufficient to enhance longevity, suggesting that a perceived lack of water availability triggers a metabolic shift that promotes the production of metabolic water and increases lifespan via AKH signaling.

Link: http://dx.doi.org/10.1073/pnas.1315461111

Philanthropist Jason Hope is of late writing a series of posts on SENS, the Strategies for Engineered Negligible Senescence. SENS is both a research program and an initiative for change in medical research: the aim is to produce the applications of biotechnology needed to create actual, real, working rejuvenation treatments. Which is to say forms of medicine that can bring aging under control by repairing the known causes of degeneration, the damage in and between cells that causes age-related disease and ultimately death. A sufficiently good implementation of this suite of repair treatments will prevent the young from becoming old, and restore the old to good health and vigor - but even partial treatments and early prototypes will provide sufficient benefits to merit commercial developments.

This is the vision, and at present the SENS Research Foundation works on making this a reality with a modest yearly budget of a little more than $4 million dollars and a network of allies within the advocacy and life science communities. This involves identifying those areas in which the present efforts are lacking, or the tools are absent, or no-one is making enough of an effort, and stepping in to bridge that gap using some combination of funding and persuasion.

It is sad to say, but - once you look beyond the fields of stem cell and cancer research - gaps are more or less all there is to see. Meaningful progress towards other needed forms of rejuvenation treatment is conspicuous by its absence. In comparison to stem cell research, the initiatives elsewhere in what will one day be a much broader field of regenerative medicine are sparse, a lab here and a lab there dabbling in matters like mitochondrial repair or building AGE-breakers, to pick two examples. This is far from the energetic and well funded research centers needed for a good rate of progress.

Jason Hope put in half a million dollars a few years ago to help get work underway to bridge one of these research gaps, that related to breaking down the cross-links that build up in important tissue structures with age. This form of damage has detrimental results that include a loss of tissue elasticity that contributes to a range of age-related conditions, yet the life science research community is present ill-equipped to work with the most relevant cross-link compounds in any meaningful way. Here Hope discusses some of the ongoing research that he has funded:

Extracellular Matrix Stiffening

The extracellular matrix acts as a sort of scaffolding that provides support and cushioning to the surrounding cells. The extracellular matrix, or ECM, is an interlinking mesh of fibrous proteins and a few other substances that make the matrix both strong and elastic. The extracellular matrix is very resilient and, in a perfect world, changes very little from the time you are born until you die. In this imperfect world inside the human body, however, blood sugar and other substances bathe the proteins and other compounds of the extracellular matrix. This constant exposure causes unhealthy crosslinks to develop between ECM proteins.

This crosslinking limits the flexible, independent movement of the proteins in the extracellular matrix in that area, causing stiffness and a loss of shock absorption. In time, crosslinking in the extracellular matrix causes it to lose its primary function, leading in turn to dysfunction in the cells, tissues and organs it serves.

Breaking these ECM crosslinks reverses the damage and prevents further pathology. Breaking heart and arterial ECM crosslinks, for example, can reverse stiffening in the heart and blood vessels. In 2011, SENS Research Foundation and the Cambridge University Institute of Biotechnology announced the establishment of a new SENS Research Foundation Laboratory at Cambridge. A targeted donation enabled scientists in the Cambridge SENS center and Dr. David Spiegel's Yale lab to investigate various solutions to glucosepane crosslinks.

One of the first challenges to breaking unhealthy ECM crosslinks is to detect their presence. Dr. Spiegel has developed a technique to synthesize glucosepane in a laboratory. Researchers can now use this synthesized glucosepane to develop reagents capable of detecting glucosepane crosslinking. Scientists can then use those reagents as an aide in the development and testing of new glucosepane-breaking drugs.

Progress in this area could also enable the Cambridge group to develop a method to deal with another major obstacle in breaking ECM crosslinks  -  measuring glucosepane cleavage, first in the test tube then in animal and human tissues. Researchers can use this method to determine the effect a candidate drug has on breaking glucosepane crosslinks. In the course of their research, the Cambridge researchers have already concluded that none of the commercially available methods for detecting crosslinks effectively detects glucosepane  -  and they aren't particularly good at detecting other crosslinks, either! In fact, many of the ECM antibodies currently in use do not even bind to crosslinks.

The findings of both Dr. Spiegel's group and the Cambridge group underscore the need for novel crosslink-breaking therapies. The work performed by both groups further our efforts in developing novel anti-crosslink therapies.

Reducing calorie intake for a comparatively short period of time very early in life is here shown to have life-long effects in mice. This provides more insight into the way in which metabolism in shorter-lived mammals has evolved to react to temporary famine conditions, producing more robust health and up to 40% longer life spans for life-long calorie restriction. It is interesting that even a short period of low calorie intake early in life can have the effects noted in this study.

We humans share the same evolutionary heritage of nutrient sensing mechanisms intended to alter our metabolic processes based on calorie intake, and the beneficial effects of calorie restriction on measures of health are quite similar to those in mice, but calorie restriction doesn't extend our life by anywhere near the same proportion. The consensus in the scientific community is that calorie restriction will extend human life by perhaps 5% or a little more. On the other hand, the health benefits are greater than those produced by any presently available medical technology or lifestyle choice.

The action of nutrients on early postnatal growth can influence mammalian aging and longevity. Recent work has demonstrated that limiting nutrient availability in the first three weeks of life (by increasing the number of pups, in the crowded litter (CL) model) leads to extension of mean and maximal lifespan in genetically normal mice. In this study we aimed to characterize the impact of early life nutrient intervention on glucose metabolism and energy homeostasis in CL mice. In our study we used mice from litters supplemented to 12 or 15 pups and compared those to control litters limited to 8 pups.

At weaning and then throughout adult life, CL mice are significantly leaner and consume more oxygen relative to control mice. At 6 months of age, CL mice had low fasting leptin concentrations, and low-dose leptin injections reduced body weight and food intake more in CL female mice than in controls. At 22 months, CL female mice also have smaller adipocytes compared to controls. Glucose and insulin tolerance tests show an increase in insulin sensitivity in 6 month old CL male mice, and females become more insulin sensitive later in life. Furthermore, β-cell mass was significantly reduced in the CL male mice and was associated with reduction in β-cell proliferation rate in these mice. Together, these data show that early life nutrient intervention has a significant lifelong effect on metabolic characteristics which may contribute to the increased lifespan of CL mice.

Link: http://dx.doi.org/10.1152/ajpendo.00031.2014

A number of approaches to Alzheimer's disease don't seek to address the underlying causes of pathology, but rather shore up crucial mechanisms that are harmed. This approach is actually very common throughout modern medicine, and it is something that I think has to change in order to improve the effectiveness of medical research and development. This is an example of the type:

"Several years ago we discovered that NAP, a snippet of a protein essential for brain formation, which later showed efficacy in Phase 2 clinical trials in mild cognitive impairment patients, a precursor to Alzheimer's. Now, we're investigating whether there are other novel NAP-like sequences in other proteins. This is the question that led us to our discovery. NAP operates through the stabilization of microtubules - tubes within the cell which maintain cellular shape. They serve as 'train tracks' for movement of biological material. This is very important to nerve cells, because they have long processes and would otherwise collapse. In Alzheimer's disease, these microtubules break down. The newly discovered protein fragments, just like NAP before them, work to protect microtubules, thereby protecting the cell."

[The researchers] looked at the subunit of the microtubule - the tubulin - and the protein TAU (tubulin-associated unit), important for assembly and maintenance of the microtubule. Abnormal TAU proteins form the tangles that contribute to Alzheimer's; increased tangle accumulation is indicative of cognitive deterioration. [Researchers tested] both the tubulin and the TAU proteins for NAP-like sequences. After confirming NAP-like sequences in both tubulin subunits and in TAU, [they then] tested the fragments in tissue cultures for nerve-cell protecting properties against amyloid peptides, the cause of plaque build up in Alzheimer patients' brains.

"From the tissue culture, we moved to a 10-month-old transgenic mouse model with frontotemporal dementia-like characteristics, which exhibits TAU pathology and cognitive decline. We tested one compound - a tubulin fragment - and saw that it protected against cognitive deficits. When we looked at the 'dementia'-afflicted brain, there was a reduction in the NAP parent protein, but upon treatment with the tubulin fragment, the protein was restored to normal levels."

Link: http://www.aftau.org/newsroom?7d56804a-22df-4c4b-a09d-d1cacd9b1135

One can draw a timeline of stem cell research that has stem cell therapies in the modern sense emerging as an evolution of bone marrow transplantation: as biotechnology became more sophisticated researchers identified the agents producing beneficial effects in these treatments, meaning the stem cells found in bone marrow, and from there got rid of much of the baggage to create a new generation of better and more focused therapies. This sketch is a gross oversimplification of a complex period of development in medical science, but will suffice for this post.

Today, as stem cell therapies are becoming a mainstream commercial concern, entering the phase of growth and improvement that attends the heyday of every technology, researchers are already laying the groundwork for the next evolution in this series of treatments. For just as stem cells are the agents of change identified in bone marrow, so too are various signaling proteins the agents of change that might be identified in stem cells. The bone marrow was dispensed with once biotechnology was up to the task and in the next round of progress so too will be the cells.

While not true (or at least not yet proven) for all stem cell treatments, it has become increasing clear in recent years that many cell transplants produce benefits not because the transplanted cells are themselves doing much in the way of building or shoring up tissue, but rather because they are altering the local signaling environment in ways that instruct native cells to get back to work - or even to perform works of regeneration that they never would have accomplished under normal circumstances. So what prevents researchers from throwing out the cells today and just using the signals? The fact that these signaling changes are still very poorly understood. Inroads are being made, and you might recall recent work on the roles of GDF-11 or FGF-2 in this vein, but they are still just inroads.

Here is an open access example of exploration in the this direction, a task well suited to the modern tools of biotechnology, focused on the measurement and cataloging of protein levels and epigenetic patterns. The cost of these tools has dropped so precipitously this past decade that I imagine matters will progress quite rapidly towards an index of all of the regenerative signals of consequence altered by stem cell transplants.

Mechanisms of action of hESC-secreted proteins that enhance human and mouse myogenesis

Adult stem cells persist in the body as we age, but their regenerative capacity declines over time, leading to an inability of tissues and organs to maintain homeostasis and repair damage with advancing age. Old skeletal muscle loses its regenerative ability due to the failure of satellite cells (muscle stem cells) to divide and generate fusion competent myoblasts and terminally differentiated myofibers in response to muscle injury or attrition.

Previous studies have demonstrated that aging of the stem cell niche is responsible for the decline of tissue regeneration and productive homeostasis not only in skeletal muscle but also in a variety of postnatal tissues, and that old muscle can be rejuvenated to repair almost as well as young through several means. These findings may prove to be important for the development of therapies for age-related tissue degeneration and trauma. However, not all of the factors that influence the niche are known, and the various physiological molecules and balance of signaling crosstalk that modulate healthy regeneration are not well established. In addition, while numerous approaches have been utilized to reverse age-related tissue deterioration in murine models, none are suitable for clinical translation. As one example, skewing the signaling strength of one pathway (either up or down) over a long timespan is likely to be deleterious for cells and tissues, potentially leading to more cellular dysregulation or oncogenic progression. In contrast, modulation of multiple interactive signaling pathways to their "youthful" levels may have beneficial effects on tissue repair and maintenance.

Our initial study demonstrated that embryonic stem cells produce soluble proteins that robustly enhance adult muscle stem cell function even in an aged environment, and that production of such proteins is lost when these cells differentiate. Furthermore, the MAPK pathway was determined to be critical in modulating the activity of these embryonic protein(s). These findings are supported by microarray analysis conducted on cardiomyocytes subjected to hESC-conditioned medium, demonstrating that MAPK pathway signaling was among the main induced signaling cascades. Here we uncover the molecular identity of active hESC-produced proteins and demonstrate that specific FGFs are sufficient to enhance mouse and human myogenesis.

While FGFs had significant effects on cell proliferation of human and mouse myogenic progenitors, antibody neutralization of FGF-2, FGF-6 or FGF-19 did not significantly reduce the pro-myogenic properties of hESC conditioned medium, [suggesting that] many other active growth factors and MAPK ligands are secreted by the hESCs. Ultimately, the precise molecular definition of most of the pro-regenerative proteins from the hESC secretome will allow one to design optimal therapeutic applications with low off-target and side effects.

There is plenty of evidence to show that shorter people tend to live longer. Here is more of the same:

Short height and long life have a direct connection in Japanese men, according to new research based on the Kuakini Honolulu Heart Program (HHP) and the Kuakini Honolulu-Asia Aging Study (HAAS). "We split people into two groups - those who were 5-foot-2 and shorter, and 5-4 and taller. The folks that were 5-2 and shorter lived the longest. The range was seen all the way across from being 5-foot tall to 6-foot tall. The taller you got, the shorter you lived."

The researchers showed that shorter men were more likely to have a protective form of the longevity gene, FOXO3, leading to smaller body size during early development and a longer lifespan. Shorter men were also more likely to have lower blood insulin levels and less cancer. "This study shows, for the first time, that body size is linked to this gene. We knew that in animal models of aging. We did not know that in humans. We have the same or a slightly different version in mice, roundworms, flies, even yeast has a version of this gene, and it's important in longevity across all these species."

[Researchers] noted that there is no specific height or age range that should be targeted as a cut-off in the study, in part because "no matter how tall you are, you can still live a healthy lifestyle" to offset having a typical FOXO3 genotype rather than the longevity-enhancing form of the FOXO3 gene.

Link: http://manoa.hawaii.edu/news/article.php?aId=6515

A part of the genetic contribution to survival to extreme old age may have to do with adaptations allowing for better mitochondrial function despite accumulated damage. Or it could be the case that in extreme old age mitochondria are significantly different in structure to merely old age, and this is a global phenomenon for all who make it that far. Either way, this is interesting research; you might want to skip to figure 6 in the discussion section of the paper for a graphical summary of the authors' hypothesis.

Mitochondria have been considered for long time as important determinants of cell aging because of their role in the production of reactive oxygen species. In this study we investigated the impact of mitochondrial metabolism and biology as determinants of successful aging in primary cultures of fibroblasts isolated from the skin of long living individuals (LLI) (about 100 years old) compared with those from young (about 27 years old) and old (about 75 years old) subjects.

We observed that fibroblasts from LLI displayed significantly lower complex I-driven ATP synthesis and higher production of H2O2 in comparison with old subjects. Despite these changes, bioenergetics of these cells appeared to operate normally. This lack of functional consequences was likely due to a compensatory phenomenon at the level of mitochondria, which displayed a maintained supercomplexes organization and an increased mass. This appears to be due to a decreased mitophagy, induced by hyperfused, elongated mitochondria.

The overall data indicate that longevity is characterized by a preserved bioenergetic function likely attained by a successful mitochondria remodeling that can compensate for functional defects through an increase in mass, i.e. a sort of mitochondrial "hypertrophy".

Link: http://www.impactaging.com/papers/v6/n4/full/100654.html

The SENS Research Foundation is one of the few organizations in the world at present earnestly coordinating work on the biotechnologies needed to create treatments to halt and reverse degenerative aging. It is, like many disruptive, game-changing groups in medical research, almost entirely funded by philanthropic donations, many of which were provided by long-time readers here.

One of the ugly little secrets in life science research is that it is near impossible to obtain funding for anything other than small, incremental advances in which all of the proving work has already been accomplished on someone else's dime. New leaps in medical research are thus dependent on a mix of philanthropy and very creative budgeting. Hence when the medical community has stultified and needs to be kicked and pestered into a new era of improvement, as has been the case for aging research for at least two decades, don't look to the big established organizations to produce that change. They have suffered the fate of all establishments, ossified to the point of being incapable of revolutionary advances, or even actively resisting such change. Almost all such advances thus initially arrive from small groups that grow outside the mainstream flow of funds, making their cases incrementally, until all of a sudden there is a great shift in the tides and everyone does things the new way.

Would that there were more persistent cellular-repair-oriented initiatives like SENS aiming to upend the research community, so as to raise the odds of the great shift in aging research happening in any given year. But I think they will arrive in time. To work on repair of the causes of aging is so obvious a concept in hindsight that I don't think it can go ignored for too much longer, especially given the steadily growing interest it this field in the past few years.

The latest SENS Research Foundation newsletter arrived in my in-box today, bearing a reminder about the Rejuvenation Biotechnology Conference to be held later this year. For me, however, the best part of the newsletter is the section in which quality answers are provided to questions about the science of SENS submitted by Foundation supporters.

Question Of The Month #3: Making SENS Part Of Medicine

Q: I understand that aging specifically isn't an accepted target for therapy for regulatory purposes at present. How, then, will you get non-experimental therapies utilizing regenerative medicine techniques for the specific pathology of aging available to the common consumer?

A: That isn't nearly as big a challenge as is often portrayed. Remember, the damage-repair approach of SENS isn't an all-in-one treatment with the indication "aging," but a divide-and-conquer strategy to develop a suite of rejuvenation biotechnologies that each remove, repair, replace, or render harmless one of many specific form of cellular and molecular damage that accumulate in aging bodies. Thus, no one rejuvenation biotechnology will arrest or reverse the degenerative aging process or prevent all of its diseases and disabilities. Ironically, then, even if regulators were to develop an indication for "aging," individual rejuvenation biotechnologies wouldn't qualify!

By contrast, most forms of aging damage can be quite clearly linked with specific diseases of aging: beta-amyloid protein and malformed tau species for Alzheimer's; lysosomal aggregates in the arterial macrophage/foam cell with atherosclerosis (and through it heart attacks and stroke); cross-linked proteins with hypertension (and through it congestive heart failure, renal disease, and stroke); alpha-synuclein and Parkinson's disease; and so on.

In other cases, rejuvenation biotechnologies could initially be licensed as treatments for certain genetic disorders, even though the cause of the pathology underlying those diseases may not be related to the universal degenerative aging process. This is true, for instance, for most mitochondriopathies (inherited disorders of the mitochondria, many of which are caused by mutations in individual protein-encoding mitochondrial genes). Even though the mutations in these patients are inherited rather than acquired as a result of later metabolic mishaps, the same damage-repair approach (allotopic expression of the protein from the nucleus) can be used to replace the missing or defective protein in the mitochondrial energy-production chain and restore normal cellular function.

So the great majority of rejuvenation biotechnologies - and probably all of them - can be developed as therapies for diseases that are either already accepted as licensable indications, or in a few cases are very likely to be accepted soon (notably, sarcopenia (the loss of muscle mass and quality with aging)). Whether degenerative aging is "a disease" or not, and whether it is recognized as such by regulators, is of no consequence to the practical business of turning rejuvenation biotechnology into therapies against its associated conditions.

It is thought that one of the greatest hurdles to growth in public support of longevity science is the fact that most people assume increased longevity through medicine would mean being old, frail, and in pain for longer. This is very much not the case, however: the goal is always to extend or restore the period of healthy life, and given that aging is an accumulation of damage in and between cells it might not even be possible to engineer a situation in which people are older for longer rather than younger for longer. Either you repair the underlying damage that causes aging by implementing something like the SENS research program, in which case people will be all-round healthier for longer, or you don't. In the latter case you have the present situation in mainstream medicine of an expensive, only marginally beneficial, and ultimately futile process of trying to keep heavily damaged machinery running at all.

The state of present mainstream medicine is what people see and what they assume to be the case in the future, however. It is strange that we live in a time of constant change, and yet the average fellow in the street assumes that the present is a good model for what lies ahead. The relationship between aging and medicine is about to change radically, as the research community for the first time works towards directly treating the causes of aging. But to make good progress here, to raise the necessary funds, the public must be on board and supportive in the same way as they are for stem cell research or cancer research. That has yet to happen, however, and this is why we need advocacy and persuasion.

The media obsesses over the inevitable "secret" that centenarians reveal as the reason for their exceptionally long life. Scientists study centenarians and their families to isolate the causes for longevity - so that we may be able to distribute it to everyone. But centenarians are not the key to unlocking the mysteries of health and longevity - on the contrary, they epitomise our fears of growing old.

In Greek mythology, mortality was the distinguishing feature between gods and men; gods were immortal while men suffered from death (that, and the whims of the gods above them). In the story, Eos, the goddess of the dawn falls in love with a mortal man called Tithonus. Eos cannot bear the thought that Tithonus will die, so she asks Zeus to make him immortal, to which he agrees. The only problem is that she forgot to ask for eternal youth. Tithonus cannot die, but he progressively suffers from all the ill health and frailties of old age.

Centenarians are the living embodiment of Tithonus' curse. Contrary to what the media would like to portray (and some studies), many centenarians suffer ill health and frailty associated with old age, which can also affect research. Most are wheelchair or bed-bound, many suffer from dementia, muscle loss, hearing loss, eyesight loss and lack control of their orifices. When given the choice between healthy life and long life with ill health, most people choose the former. Centenarians are not a mystery of nature; they are old people who happen to suffer the damages of ageing a bit longer than others.

If we are to grow old and remain in good health, we have three options. We can try to improve our metabolism such that it generates less harmful byproducts or we can find a way to clean these up these byproducts. Or, we can deal with the consequences of this accumulation of damage over time. Medicine has mainly focused on the third option, dealing with the consequences of ageing disease such as dementia, cancer and diabetes. But though we may have added few years to our lives, we certainly haven't added life to our years.

Link: http://theconversation.com/the-curse-of-centenarians-epitomise-our-fears-about-growing-old-24002

When considering survival in early old age lifestyle is more important than genetics, but genetic lineage becomes increasingly important for survival in extreme old age. This is reflected in the increased frequency of the few known genetic variants associated with longevity in older populations: those without the variants have a higher mortality rate, and so the relative proportion of those with the variants rises over time.

Researchers here demonstrate that this effect has been gently diminishing in recent decades, and thus cohorts of the oldest people born more recently include more individuals without longevity-associated genetic variants. This would be the expected outcome in an environment of consistently improving medical technology. Past improvements in medicine have only indirectly impacted the processes that drive aging, however, or provide only limited benefits to people suffering from age-related conditions because the treatments don't address the underlying causes of aging. They are essentially patches on a fast-growing hole, which is better than nothing, but not a solution.

Gene variants found to associate with human longevity in one population rarely replicate in other populations. The lack of consistent findings may partly be explained by genetic heterogeneity among long-lived individuals due to cohort differences in survival probability. In most high-income countries the probability of reaching e.g. 100 years increases by 50-100% per decade, i.e. there is far less selection in more recent cohorts. Here we investigate the cohort specificity of variants in the APOE and FOXO3A genes by comparing the frequencies of the APOE ε4 allele and the minor alleles of two variants in FOXO3A at age 95+ and 100+ in 2712 individuals from the genetically homogeneous Danish birth cohorts 1895-96, 1905, 1910-11, and 1915.

Generally, we find a decrease in the allele frequencies of the investigated APOE and FOXO3A variants in individuals from more recent birth cohorts. Assuming a recessive model, this negative trend is significant in 95+ year old individuals homozygous for the APOE ε4 allele or for the FOXO3A rs7762395 minor allele. For the APOE ε4 allele, the significance is further strengthened when restricting to women. Supportive, but non-significant, trends are found for two of the three tested variants in individuals older than 100 years.

Altogether, this indicates that cohort differences in selection pressure on survival to the highest ages are reflected in the prevalence of longevity gene variants. Although the effect seems to be moderate, our findings could have an impact on genetic studies of human longevity.

Link: http://dx.doi.org/10.1016/j.exger.2014.04.018

There comes a point in the study of antioxidant supplementation as a means to extend healthy life, after decades of work and thousands of scientific studies in which all the more rigorous results and meta-analyses indicate no effect or negative effects, at which one has to conclude than this is not merely an ambiguous or poorly understood outcome, but rather the case that in fact antioxidant supplementation has no effect or negative effects. Those studies in which some benefit is shown can be written off as the effects of inadvertent calorie restriction, an issue that is very prevalent in studies run prior to about ten years ago and still quite common now. Alternately, they used model organisms and other experimental situations in which the metabolic biochemistry was of little relevance to a healthy human.

Antioxidant therapies can be helpful in treating some medical conditions, and researchers are discovering that mitochondrially targeted antioxidants - still something that you can't obtain from a store - have some effect on health and longevity in addition to being a potential treatment for some degenerative eye conditions. But if you are taking commonplace antioxidant supplements in the hope of some benefit, then the overwhelming weight of evidence suggests that you are hoping in vain.

Hope springs eternal, of course, and the voice of the scientific community is soft in this matter when compared to the marketing efforts of companies selling antioxidants. The level of funding that flows into science from that direction also has its distorting effects. There are certainly scientists who talk about the present balance of evidence as ambiguous, and will cheerfully do so in a paper that lists scores of studies that show no great or relevant benefit.

From my point of view it seems as though focusing on the study of commonplace antioxidant supplements and health in this day and age is an avoidance of those fields of research that might actually meaningfully extend healthy human life spans. Antioxidants aren't going to achieve that goal, not even the impressive new mitochondrially targeted compounds. The way to the future is rather to be found via technologies such as gene therapy, the creation of engineered bacterial enzymes to clear out metabolic waste, immune therapies, stem cell treatments and other regenerative medicine, and a panoply of further modern approaches to repairing the damage of aging.

The following paper is largely a litany of antioxidant studies in which no relevant benefits were observed, and yet the researchers mark the field as ambiguous and finish with a comment that more work is needed to build a better way of delivering antioxidant supplements - quite missing their own conclusion, it seems. Hope springs eternal, but it is way past time to move on to better and more promising science in this modern age of biotechnology and progress.

Effect of Antioxidants Supplementation on Aging and Longevity

Organic compounds and structures composed of them are thermodynamically unstable in an oxygen-containing atmosphere. Molecular oxygen, in its triplet basal state, is rather unreactive due to the spin restriction. However, formation of oxygen free radicals and other reactive oxygen species (ROS) opens the gate for potentially deleterious oxidative reactions of oxygen. Seen from that perspective, the "Free Radical Theory of Aging" (FRTA), now more commonly termed the oxidative damage theory of ageing, seems to address a key facet of intrinsic biological instability of living systems. The basic idea of the FRTA is that free radicals and other ROS, formed unavoidably in the course of metabolism and arising due to the action of various exogenous factors, damage biomolecules, and accumulation of this damage are the cause of age-related diseases and aging.

If FRTA is true, antioxidants should slow down aging and prolong lifespan. This apparently obvious conclusion has stimulated enormous number of studies aimed at finding a relationship between levels of endogenous antioxidants and lifespan of various organisms on the effects of addition of exogenous antioxidants on the course of aging and lifespan of model organisms. Pubmed provides more than 13300 hits for conjunction of terms "antioxidant" and "aging or ageing." However, in spite of the plethora of studies, the answer to the question if exogenous antioxidants can prolong life is far from being clear.

Generally, the effects of antioxidant supplementation in model organisms are disappointing. Many studies showed no effect or even negative effects on the lifespan. Only in some cases considerable prolongation of lifespan was obtained and in organisms which are evolutionarily quite distant from mammals. In some cases, mean but not maximal lifespan was affected, which may be caused by reduction of mortality due to diseases rather than interference with the aging process itself. An apparently obvious conclusion from the plethora of studies could be that antioxidants cannot be expected to prolong significantly the lifespan, especially of mammals, which does not support the FRTA.

In summary, while beneficial effects of antioxidant supplements seem undoubtful in cases of antioxidant deficiencies, additional studies are warranted in order to design adapted prescriptions in antioxidant vitamins and minerals for healthy persons.

A web of correlations exist between wealth, education, intelligence, and natural variations in human longevity. It is thus interesting to see that one of the genes associated with longevity and aging also has an effect on cognition - though not the effect that was initially expected:

Scientists have known for more than a decade that people and animals tend to live longer if they have high levels of Klotho in their bodies. And that led [researchers] to wonder whether a hormone that protects the body against aging might also protect the brain. So the team set out to see whether Klotho offered a way to "prevent the cognitive decline that comes with aging."

To find out, they studied more than 700 people between the ages of 52 and 85. About 1 in 5 of these people had a form of the Klotho gene that causes their bodies to produce high levels of the Klotho hormone. The team expected to find that people with high levels of the hormone experienced less cognitive decline than people with lower levels. "In fact what we found was not consistent with our hypothesis. We were completely surprised."

What they found was that the people with lots of Klotho experienced just as much cognitive decline as other people. Their brains weren't protected against aging at all. But their brains were different nonetheless. "Those that carried the genetic variant that increased their Klotho levels showed better cognitive performance across the lifespan." At any given age, people with lots of Klotho scored higher on tests of learning and memory, language and attention.

To learn more, the team began studying mice that had been genetically engineered to produce high levels of the mouse version of Klotho. "Elevating klotho made the mice smarter across all the cognitive tests that we put them through." A look at the brains of these mice suggested a reason. There was evidence that in areas involved in learning and memory, Klotho was causing a change that strengthened the connections between brain cells.

Link: http://www.npr.org/blogs/health/2014/05/08/310787094/anti-aging-hormone-could-make-you-smarter

Researchers uncover a novel alteration of cellular metabolism that extends life in yeast and worms, and has similar effects in human cells as it does in nematode cells:

Epigenetics comprises multiple regulatory layers, including chromatin packaging - the orderly wrapping of DNA around histone proteins in the cell nucleus. By altering this DNA packaging, cells can control when and how genes are expressed. "Aging is, in part, the accumulation of cellular stress. If you can better respond to these stresses, this ameliorates the damage it can cause."

[Researchers] looked for chromatin-associated genes that could influence longevity by searching for genes that already were implicated in epigenetic regulation that might extend lifespan when deleted in the yeast, Saccharomyces cerevisiae. One such gene improved lifespan by about 25 percent. [The] team asked whether the gene ISW2 is part of previously identified longevity pathways, especially those associated with caloric restriction, a well-known strategy for extending lifespan. But pathways involving a form of chromatin modification (histone acetylation) came up empty, as did an alternate pathway involving growth control, suggesting ISW2 functions through a never-before-seen mechanism.

The team then looked for answers in the function of the ISW2 protein, and found that its absence alters the expression of genes involved in protecting cells from such stresses as DNA damage. Deletion of ISW2 increases the expression and activity of genes in DNA-damage repair pathways - an effect also seen during calorie restriction. The gene ISW2, it turns out, is involved in chromatin remodeling - it controls the spacing and distribution of the histone "spools" around which DNA wraps. Normally, ISW2 dampens stress-response pathways, possibly because overactivation of these pathways is deleterious early in life. Deletion or inactivation of the ISW2 gene activates those pathways, priming the cells to more effectively handle stress-associated genetic scars as cells age.

This effect is not limited to yeast. When [the team] reduced the levels of a related gene in the nematode worm, Caenorhabditis elegans, they observed a 15 percent improvement in longevity, which is similar in magnitude to the lifespan extension observed in other worm longevity pathways. Similarly, knocking down expression of a human homolog in cultured human cells boosted the expression of stress-response genes that, again, like yeast, occur in DNA-damage repair pathways.

Link: http://www.eurekalert.org/pub_releases/2014-05/uops-pys050614.php

Nematode worms are one of the most studied types of organism, and many genetic alterations known to extend healthy life span by slowing aging were first demonstrated in the nematode species C. elegans. Numerous important low-level cellular processes and components are very similar in all animals, so studying the aging of worms is in fact a very cost-effective way to obtain insight into mammal biochemistry. Nematodes are very short-lived and comparatively cheap to maintain, and so much of the exploratory work in the aging research community takes place in these and other lower animals.

Over the course of recent decades it has become clear that mitochondria, the power plants of the cell, play an important role in degenerative aging. They emit damaging reactive oxygen species (ROS) in the course of turning food into chemical energy stores for the cell, and by a complicated process this starting point leads to the creation of a small population of dysfunctional cells that export toxic, broken proteins into their surroundings. This is one of the causes of aging.

Many of the ways of extending life in laboratory animals change the degree to which mitochondria generate reactive oxygen species, such as by disabling some portions of the intricate assembly of proteins inside each mitochondrion known as the electron transport chain. Interestingly in nematode worms there are examples of genetic and other changes that either lower or raise ROS output but in both cases induce life extension. The high level theory here is that less in the way of ROS emission means less damage to clean up, but modestly greater ROS production can boost the performance of cellular maintenance processes and thus more than offset the additional damage. The situation is probably more complex than this, however. The path between two points in a biological system is rarely a straight line.

Here researchers are tracing the mechanisms that connect increased ROS levels to greater life span in nematode worms, and joining more of the dots along the way:

What doesn't kill you may make you live longer

Programmed cell death, or apoptosis, is a process by which damaged cells commit suicide in a variety of situations: to avoid becoming cancerous, to avoid inducing auto-immune disease, or to kill off viruses that have invaded the cell. The main molecular mechanism by which this happens is well conserved in all animals, but was first discovered in C. elegans.

[Researchers] found that this same mechanism, when stimulated in the right way by free radicals, actually reinforces the cell's defenses and increases its lifespan. The findings have important implications. "Showing the actual molecular mechanisms by which free radicals can have a pro-longevity effect provides strong new evidence of their beneficial effects as signaling molecules. It also means that apoptosis signaling can be used to stimulate mechanisms that slow down aging. Since the mechanism of apoptosis has been extensively studied in people, because of its medical importance in immunity and in cancer, a lot of pharmacological tools already exist to manipulate apoptotic signaling. But that doesn't mean it will be easy."

The Intrinsic Apoptosis Pathway Mediates the Pro-Longevity Response to Mitochondrial ROS in C. elegans

The increased longevity of the C. elegans electron transport chain mutants isp-1 and nuo-6 is mediated by mitochondrial ROS (mtROS) signaling. Here we show that the mtROS signal is relayed by the conserved, mitochondria-associated, intrinsic apoptosis signaling pathway (CED-9/Bcl2, CED-4/Apaf1, and CED-3/Casp9) triggered by CED-13, an alternative BH3-only protein.

Activation of the pathway by an elevation of mtROS does not affect apoptosis but protects from the consequences of mitochondrial dysfunction by triggering a unique pattern of gene expression that modulates stress sensitivity and promotes survival. In vertebrates, mtROS induce apoptosis through the intrinsic pathway to protect from severely damaged cells.

Our observations in nematodes demonstrate that sensing of mtROS by the apoptotic pathway can, independently of apoptosis, elicit protective mechanisms that keep the organism alive under stressful conditions. This results in extended longevity when mtROS generation is inappropriately elevated. These findings clarify the relationships between mitochondria, ROS, apoptosis, and aging.

The search continues for efficiently measured patterns of DNA methylation that correlate tightly to either chronological or biological age, with the latter being somewhat more useful than the former, as it could be used to rapidly evaluate the effectiveness of potential future rejuvenation treatments. Speed in evaluation is a driver of rapid progress, as it allows for more rapid exploration and avoidance of dead ends. Thus it is well worth keeping an eye on progress towards useful biomarkers of aging.

We perform a comprehensive analysis of methylation profiles to narrow down 102 age-related CpG sites in blood. We demonstrate that most of these age-associated methylation changes are reversed in induced pluripotent stem cells (iPSCs). Methylation levels at three age-related CpGs - located in the genes ITGA2B, ASPA and PDE4C - were subsequently analyzed by bisulfite pyrosequencing of 151 blood samples.

This epigenetic aging signature facilitates age predictions with a mean absolute deviation from chronological age of less than 5 years. This precision is higher than age predictions based on telomere length. Variation of age predictions correlates moderately with clinical and lifestyle parameters supporting the notion that age-associated methylation changes are associated more with biological age than with chronological age. Furthermore, patients with acquired aplastic anemia or dyskeratosis congenita - two diseases associated with progressive bone marrow failure and severe telomere attrition - are predicted to be prematurely aged.

Our epigenetic aging signature provides a simple biomarker to estimate the state of aging in blood. Age-associated DNA methylation changes are counteracted in iPSCs. On the other hand, over-estimation of chronological age in bone marrow failure syndromes is indicative for exhaustion of the hematopoietic cell pool. Thus, epigenetic changes upon aging seem to reflect biological aging of blood.

Link: http://dx.doi.org/10.1186/gb-2014-15-2-r24

Mutation of INDY, I'm Not Dead Yet, was one of the first longevity enhancing genetic alterations to be discovered in flies. Here researchers link this healthy life extension to preservation of intestinal stem cell function, work that has been helped along by the discovery in recent years of the great importance of the intestinal stem cell population and intestinal function in fly aging. One of the genes altered in that research to enhance stem cell function has now been linked to INDY:

The Drosophila Indy (I'm Not Dead Yet) gene encodes a plasma membrane transporter of Krebs cycle intermediates, with robust expression in tissues associated with metabolism. Reduced INDY alters metabolism and extends longevity in a manner similar to caloric restriction (CR); however, little is known about the tissue specific physiological effects of INDY reduction. Here we focused on the effects of INDY reduction in the Drosophila midgut due to the importance of intestinal tissue homeostasis in healthy aging and longevity.

The expression of Indy mRNA in the midgut changes in response to aging and nutrition. Genetic reduction of Indy expression increases midgut expression of the mitochondrial regulator spargel/dPGC-1, which is accompanied by increased mitochondrial biogenesis and reduced reactive oxygen species (ROS). These physiological changes in the Indy mutant midgut preserve intestinal stem cell (ISC) homeostasis and are associated with healthy aging. Genetic studies confirm that dPGC-1 mediates the regulatory effects of INDY, as illustrated by lack of longevity extension and ISC homeostasis in flies with mutations in both Indy and dPGC1. Our data suggest INDY may be a physiological regulator that modulates intermediary metabolism in response to changes in nutrient availability and organismal needs by modulating dPGC-1.

Link: http://www.impactaging.com/papers/v6/n4/full/100658.html

Methuselah Foundation and SENS Research Foundation are presently partnering to issue a quarterly update on rejuvenation biotechnology research to members of the 300, each of whom has committed to donating $25,000 over 25 years to help fund the development of effective treatments for degenerative aging. The last time I checked, there were in fact very nearly 300 members of the 300 - just a few places are left. It is a great initiative that helped launch the Methuselah Foundation more than ten years ago and raised the first significant funds for the Mprize for longevity science and early SENS research. You might read Michael Rae's 2004 essay "Why I Joined the Three Hundred" for more on that topic.

I am a member of the 300 myself, and consider it money well spent. The Methuselah Foundation has engineered a great deal of beneficial change in the aging research and related medical development communities over the years, all of it funded by philanthropic donations. It is no coincidence that prior to the Foundation's existence the research community and funding institutions were a mix of hostile and dismissive towards research aimed at extending healthy life spans, whereas today the prevailing culture is much more accepting of that goal. A lot of work behind the scenes aided in accomplishing that transformation.

The first edition of the present quarterly rejuvenation biotechnology newsletter was sent out back in January, so consider this a reminder if you didn't get around to reading it. Here is a link to the latest:

Rejuvenation Biotechnology Update, Volume 1 / Issue 2, April 2014

The Methuselah Foundation is thrilled to partner with SENS Research Foundation in order to bring out the most recent advancements in tissue engineering, regeneration, and rejuvenation research for members of The 300.

Because it doesn't take a scientist to understand the vital importance of investing in healthy life extension, these newsletters attempt to frame three significant studies from the past 3-6 months as accessibly and approachably as possible, describing how each one fits into the broader landscape of longevity research.

Long term human reconstitution and immune aging in NOD-Rag (-)- chain (-) mice.

This study shows that this strain of immune-deficient mice is able to receive a transplant of human immune stem cells, and to live longer-term with a "humanized" immune system where part of the immune cells in the mouse are derived from humans. One interesting aspect of this study is that it suggests that parts of the immune system might be able to be rejuvenated in a persistent way using human progenitor/stem cells. This is exciting because of the observation that the virus, cytomegalovirus or "CMV," appears to contribute to human immune senescence by reducing the proportion of naive T cells in aging. Moreover, thymic involution, the reduction in size and function of the thymus, has been observed in human aging. This is also assumed to contribute to reduced immune function in human aging.

The animal model in this paper could also be very useful as a tool for studying the effects of aging on the human immune system, while still using mice as the subjects, which are easier to use in research because of their small size, well known genetics, fast reproduction, and because they are mammals.

A novel in vitro three-dimensional bioprinted liver tissue system for drug development

In this study, the researchers used a proprietary 3D bio-printing technology to create liver constructs that simulate a human liver environment. They started by using hepatocytes (liver cells), and then added other cell types found or near in the liver. These cells began to integrate and interact with one another to create a kind of "simulated liver." They then tested this "liver simulation system" by testing for activity of a critically-important liver enzyme family involved in drug metabolism and detoxification of substances foreign to the body. They also tested whether these integrated cell systems would die quickly or live and function for a prolonged period of time, and they observed healthy, persistent functioning.

The drug development and approval process is immensely burdensome, time-consuming, and expensive. A very large proportion of this cost is due to the rigorous human testing that must be done to ensure the drug's safety. We're excited to see the advancement of biologically-relevant drug-testing systems by which drug companies can rigorously test small molecules without harm to living humans. These kind of "human simulations" can be valuable because they may dramatically reduce the cost of testing and ultimately deliver successful, safe drugs to people who need them, both more cheaply and more quickly.

Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging

The subject of this study involved a compound intimately involved in the biochemistry of creating energy in our bodies. This particular compound is called "nicotinamide adenine dinucleotide", or "NAD+". NAD+ is well-known for its involvement in many biological processes involved in energy transfer, including those in the mitochondria. NAD+ has been observed to decline during advancing age, as is mitochondrial function. Knowing NAD+ is so closely involved in mitochondrial function suggests that if one were to replenish NAD+ in old age, one might also restore mitochondrial function. This might have quite a number of benefits, because doing so could enhance energy production in the body's cells, thereby possibly enhancing muscular function, brain function, and exercise output, among other things. For example, calorie restriction, which has been observed to "slow" various aspects of aging in many different organisms, appears to preserve both NAD+ concentrations and mitochondrial function during aging.

SENS Research Foundation (SRF) has a research program dubbed "MitoSENS" that addresses a different reason for age-related mitochondrial dysfunction. The present study focuses on a reversible decline in energy production capacity across most cells in the aging body due to altered metabolism, and reports that raising NAD+ in old mice improved mitochondrial function to that of young mice. SRF is more concerned about a tiny minority of cells in the body that harbor irreversible deletions in mitochondrial DNA, which push the cells into an abnormal metabolic state that ultimately causes them to poison far-flung cells all across the body. There is no reason to think that [a NAD+ boosting] treatment would have any positive effect on the underlying mitochondrial DNA deletions. If it did not, these may still need to be properly addressed to achieve persistent and complete human rejuvenation.

Amyloid levels in the brain are very dynamic, capable of changing rapidly. That amyloid builds up with age to contribute to the development of neurodegenerative conditions such as Alzheimer's disease points to a slow breakdown in the balance of generation and clearance. The choroid plexus is a filtration system for cerebrospinal fluid, and hence a place to look for failures, such as a progressive loss of the protein machinery needed to extract amyloid from the brain:

Accumulation of amyloid-beta peptides (Aβ) results in amyloid burden in normal aging brain. Clearance of this peptide from the brain occurs via active transport at the interfaces separating the central nervous system (CNS) from the peripheral circulation. The present study was to investigate the change of Aβ transporters expression at the choroid plexus (CP) in normal aging.

Morphological modifications of CP were observed by transmission electron microscope. Real-time RT-PCR was used to measure mRNA expressions of Aβ42 and its transporters, which include low density lipoprotein receptor-related protein-1 and 2 (LRP-1 and -2), P-glycoprotein (P-gp) and the receptor for advanced glycation end-products (RAGE), at the CP epithelium in rats at ages of 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33 and 36 months. At the same time, the mRNA expressions of oxidative stress-related proteins were also measured.

The results showed that a striking deterioration of the CP epithelial cells and increased Aβ42 mRNA expression were observed in aged rats, and there was a decrease in the transcription of the Aβ efflux transporters, LRP-1 and P-gp, no change in RAGE mRNA expression and an increase in LRP-2, the CP epithelium Aβ influx transporter. These results suggest the efficacy of the CP in clearing of Aβ deceases in normal aging, which results in the increase of brain Aβ accumulation. And excess Aβ interferes with oxidative phosphorylation, leads to oxidative stress and morphological structural changes. This in turn induces further pathological cascades of toxicity, inflammation and neurodegeneration process.

Link: http://www.ncbi.nlm.nih.gov/pubmed/24777406

Much of the cancer research community is focused on a search for specific proteins that will produce beneficial effects if levels are augmented or restricted. Here is an example of the sort of work presently taking place:

A research team [reports] that inhibiting a single protein completely shuts down growth of pancreatic cancer, a highly lethal disease with no effective therapy. Their [study] demonstrates in animal models and in human cancer cells that while suppressing Yes-associated protein (Yes) did not prevent pancreatic cancer from first developing, it stopped any further growth. "We believe this is the true Achilles heel of pancreatic cancer, because knocking out Yes crushes this really aggressive cancer. This appears to be the critical switch that promotes cancer growth and progression."

The study was conducted in mouse models of pancreatic ductal adenocarcinoma (PDAC), which accounts for all but five percent of human pancreatic cancers. These mice have a mutation in the KRAS gene, as well as a mutation in their p53 gene. "More than 95 percent of pancreatic cancer patients have a KRAS mutation and about 75 percent have a mutation in p53, so these mice provide a natural model of the human disease."

Because it has been very difficult to devise drugs that target either KRAS or p53, in this study the researchers looked for other potential druggable targets involved in uncontrolled growth of pancreatic cancer. They found that Yes was over-expressed in both mouse models and human samples of PDAC, and they discovered that the KRAS mutation found in most pancreatic cancer activates Yes.

Because Yes is over-expressed in other cancers, such as lung, liver and stomach tumors, researchers are already working on small molecule drugs that will inhibit activity of the protein and its partnering molecules. "KRAS and p53 are two of the most mutated genes in human cancers, so our hope is that a drug that inhibits Yes will work in pancreatic cancer patients - who have both mutations - and in other cancers with one or both mutations."

Link: http://www.eurekalert.org/pub_releases/2014-05/gumc-ho042914.php

The practice of calorie restriction involves reducing dietary calorie intake while still obtaining optimal levels of necessary micronutrients. In near all species tested to date this greatly enhances health and slows all measures of aging. In mice, for example, maximum life spans of up to 40% greater than normal are exhibited in calorie restriction studies. In longer-lived species the degree of life extension obtained is smaller, but the health benefits still large. There is no medical technology at present that can provide anywhere near same degree of improvement in long and short term measures of health to humans, based on the evidence to date. Nonetheless, lifelong calorie restriction in humans is not expected to provide more than a 7% gain in life span.

The mechanisms of action by which calorie restriction works are much debated despite having been under intense investigation for more than a decade: inroads have been made and evidence gathered, but there is still plenty to argue over when it comes to which of the known mechanisms are more important. There is a strong case to be made for low levels of visceral fat tissue to be important in long-term health, however: if you simply surgically remove visceral fat from mice they live significantly longer. Another well studied mechanism is the metabolic reaction to low levels of methionine, an essential amino acid that is not manufactured in the body but must be obtained from diet. Methionine restriction that does not reduce calorie intake but in which diet is structured to include only minimal safe levels of methionine produces similar results to calorie restriction in rodents.

Autophagy is also known to be a mechanism of importance in calorie restriction and methionine restriction, both of which spur increased levels of autophagy. In fact there is some evidence to suggest that calorie restriction depends on autophagy to work its benefits. But what is autophagy? It is the name given to housekeeping processes that minimize the presence of damaged cellular components by recycling them. Many of the methods of extending life and slowing aging in laboratory animals discovered over the past twenty years have also been shown to involve increased levels of autophagy. If we consider that aging is just a matter of damage accumulation, then this makes sense.

In the paper quoted below researchers join another dot in this mass of evidence by showing that methionine restriction, like calorie restriction, requires autophagy to produce benefits - which goes some way to reinforcing its claim as one of the primary mechanisms involved in calorie restriction. This work was carried out in yeast, which is normally a good reason to wait until someone reproduces it in mammals before commenting, but in the case of calorie restriction there has been a very good correspondence between its behavior in yeast, flies, nematode worms, and mammals. As in one, so in all the others.

Lifespan Extension by Methionine Restriction Requires Autophagy-Dependent Vacuolar Acidification

Health- or lifespan-prolonging regimes would be beneficial at both the individual and the social level. Nevertheless, up to date only very few experimental settings have been proven to promote longevity in mammals. Among them is the reduction of food intake (caloric restriction) or the pharmacological administration of caloric restriction mimetics like rapamycin. The latter one, however, is accompanied by not yet fully estimated and undesirable side effects. In contrast, the limitation of one specific amino acid, namely methionine, which has also been demonstrated to elongate the lifespan of mammals, has the advantage of being a well applicable regime. Therefore, understanding the underlying mechanism of the anti-aging effects of methionine restriction is of crucial importance.

With the help of the model organism yeast, we show that limitation in methionine drastically enhances autophagy, a cellular process of self-digestion that is also switched on during caloric restriction. Moreover, we demonstrate that this occurs in causal conjunction with an efficient pH decrease in the organelle responsible for the digestive capacity of the cell (the vacuole). Finally, we prove that [this] autophagy-dependent vacuolar acidification is necessary for methionine restriction-mediated lifespan extension.

The ability to engineer blood vessel networks is one of the most important hurdles standing between the present state of the art in tissue engineering and the creation of large, functional tissue masses. Tissue of any meaningful size requires an intricate web of tiny blood vessels to support it, and that network must be tied into existing blood vessels in the body. The need for blood vessels is one of the reasons why decellularization of donor organs is a useful strategy at the present time: the extracellular matrix stripped of donor cells supplies the needed blood vessel structures, complete with chemical cues to guide new cells into the right places to reform the vessels.

In the case of organ engineering, one major obstacle keeping researchers from crafting functioning organs is the inability to ensure adequate blood supply to the nascent organ. Even if an entire organ can be constructed using all the appropriate cell types, its survival in the body depends on its access to oxygen and nutrients. Thin layers of tissue such as cartilage can get by with the simple diffusion of these life-giving compounds across tissue boundaries and do not require the construction of blood vessels to survive once implanted in a body. But more complex engineered tissues and organs require functional blood vessels to deliver oxygen and nutrients and to remove waste products.

But engineering functional blood vessel networks is not an easy task. Researchers must understand the mechanisms that drive the formation of blood vessels in order to guarantee consistent results and optimal survival of engineered tissues and organs. How do endothelial cells self-organize into functional networks? Do the cells require external cues to form stable vessels? How do they interact with neighboring cells to ensure expedient microvessel formation?

In 2008 [researchers] found that combining mesenchymal stem cells (MSCs) from human bone marrow with human endothelial cells prompted the formation of robust vascular networks. In some ways, this was a bit surprising, because the added stem cells were not really functioning in a typical stem-cell capacity. They were not differentiating into endothelial cells, nor were they being converted into the cell types that MSCs normally give rise to, such as bone, cartilage, or fat. Instead, they were somehow acting as "builders" to help organize the "building blocks" - the endothelial cells - into a functional network.

Recent work suggests that the interaction between [MSCs] and endothelial cells may also apply to blood-vessel cells derived from human induced pluripotent stem cells (iPSCs). [Human] iPSCs can generate both endothelial cells and pericytes, and that combining such iPSC-derived cells creates robust vessels. Because iPSCs can be derived from individual patients and tailored to their specific needs while minimizing the risk of immune rejection, this approach may help equip made-to-order iPSC-derived organs with the iPSC-derived blood vessels they need to survive.

Link: http://www.the-scientist.com/?articles.view/articleNo/39796/title/Building-Flesh-and-Blood/

The laboratory rat lineage used in this study, spontaneously hypertensive rats, was bred decades ago to exhibit high blood pressure, and predates modern genetic engineering methods. So I think there are fair odds that the beneficial results shown in this paper will hold up in normal rats or other models of hypertension.

Hypertension is a highly prevalent disease associated with cardiovascular morbidity and mortality. Recent studies suggest that patients with hypertension also have a deficiency of certain cardiac peptides. Previously we demonstrated that a single intravenous injection of the myocardium-tropic adeno-associated virus (AAV) 9-based vector encoding for proBNP prevented the development of hypertensive heart disease (HHD) in spontaneously hypertensive rats (SHRs). The current study was designed to determine the duration of cardiac transduction after a single AAV9 injection and to determine whether cardiac BNP overexpression can delay the progression of previously established HHD, and improve survival in aged SHRs with overt HHD.

To evaluate the duration of cardiac transduction induced by the AAV9 vector, we used four week old SHRs. Effective long-term selective cardiac transduction was determined by luciferase expression. A single intravenous administration of a luciferase-expressing AAV9 vector resulted in efficient cardiac gene delivery for up to 18-months. In aged SHRs (9-months of age), echocardiographic studies demonstrated progression of HHD in untreated controls, while AAV9-BNP vector treatment arrested the deterioration of cardiac function at six months post-injection (15-months of age).

Aged SHRs with established overt HHD were further monitored to investigate survival. A single intravenous injection of the AAV9-vector encoding rat proBNP was associated with significantly prolonged survival in the treated SHRs (613 ± 38 days, up to 669 days) compared to the untreated rats (480 ± 69 days, up to 545 days). These findings support the beneficial effects of chronic supplementation of BNP in a frequent and highly morbid condition such as HHD.

Link: http://www.impactaging.com/papers/v6/n4/full/100655.html

SENS, the Strategies for Engineered Negligible Senescence is a disruptive research and advocacy program that aims to build the foundations of rejuvenation treatments over the next few decades. It is the logical extension of the discovery over the past century of which forms of cellular and molecular damage characterize old tissues, and thus can be defensibly theorized to be the cause of aging. The key realization at the core of SENS is that researchers can work towards effective treatments for aging by repairing this damage even when they don't fully understand all the complex, intricate nuances of the progression from undamaged to damaged. To draw an analogy, you don't need a full molecular-scale model of rust progression to be able to effectively maintain metal structures: paint, oil, and regular inspection suffices. The knowledge necessary is much less encompassing and the costs much lower than those required to develop that full molecular-scale model.

So it is with aging, except vastly more complicated as a matter of research and development than dealing with rust on metal. We should expect it to cost a fantastic amount of money and time to develop a full understanding of aging, and the achievement of that goal lies a long way in the future. Meanwhile, repairing the damage we know about is a very viable large research program, something that could be brought to fruition at a cost of a billion dollars and ten to twenty years if all went much as expected.

SENS initiatives have nowhere near a billion dollars in funding at the present time. They are mostly coordinated by the fairly young SENS Research Foundation, with an annual budget that has grown to a little more than $4M, and include conferences that have been held every other year for more than a decade now. These events are attended by a range of noteworthy scientists from numerous fields of medical research, and the materials presented are always interesting.

The sixth conference was held at the end of last year, and as is usually the case it takes some months for videos of the presentations to be processed and uploaded to the SENS Research Foundation YouTube channel. I noted more presentations this year focused on the logistics of actually getting treatments to market, and it might be taken as an encouraging sign that more people think that it is worth spending time on planning at this stage. Two videos of interest are linked below, but there are a good fifty or so presentations to look through, so take some time and browse.

Legal problems of registering substances and therapies to cure aging

A number of compounds are known to have some anti-aging effects, reducing the rate of aging or extending the lifespan in animals and probably in humans. At the same time, these drugs are not widely marketed to the general public as cures against aging, which probably causes unnecessary losses of healthy life years for many people.

Health experts blame the international legal framework, which only allows registering drugs against certain diseases. This refers to Food and Drug Administration in the United States, and other national agencies which all follow the World Health Organization's guidelines for drug registration. As a result, some geroprotective substances are registered as either drugs against certain diseases (for example, diabetes) or food supplements.

One of the reasons named for this situation is that aging is not in the official list of diseases in the International Classification of Diseases. At the same time, there is a number of conditions which are not considered as diseases, like pregnancy, but there are medicines which are prescribed for these conditions.

Another problem is that most anti-aging drugs and therapies are supposed to have preventive rather than treating effects for a broad spectrum of diseases, and it would take long and expensive clinical trials to justify their beneficial effects. Registering geroprotective substances as medicines for more than one disease seems to be a workable solution. However, geroprotective effects can be more pronounced for some conditions, and much smaller for others, which would make it difficult for them to compete with drugs targeting specific diseases.

Another option is to promote the inclusion of aging into the official disease classifications which would require coordinated advocacy efforts at the global level. Alternatively, conditional registration of new drugs and therapies to cure and prevent aging should be developed and promoted. In any case, a system for testing drugs and therapies to cure aging effectiveness should be established.

In sum, the most promising strategies to ensure registration of new drugs and therapies to cure aging are: advocacy for acknowledging age related conditions like sarcopenia as treatable diseases; international lobbying to acknowledge aging as a treatable and partly preventable condition; promoting legal framework for conditional registration for the drugs and therapies to cure aging.

Accelerating translational research processes from bench to clinic

The productivity of medical innovation has been in decline, and this threatens the commitment of both public and private funders. However, there are both disruptive technologies and disruptive ideas that promise a turnaround. CASMI is exploring both, and developing testable models for change - including new open innovation-based discovery models, adaptive licensing of medicines, the use of real world data in development, and the personalisation of therapy on both genomic and behavioural grounds. With the support of SENS, CASMI is also investigating the translational issues facing cell therapy, so that the highly promising science delivers patient benefit as speedily and affordably as possible.

Ordinary somatic cells can be reprogrammed into a state similar to that of embryonic stem cells, and the results are known as induced pluripotent stem cells (iPSCs). These can in theory be used to generate any type of cell, once a specific recipe of signals and environment is established for that cell type. One goal is to generate sources of patient-matched cells to order so as to facilitate regenerative therapies, but at this stage it is just as important to be able to generate cells for research - to build useful models of specific age-related and genetic conditions and thus rigorously investigate the underlying biochemistry.

It has been established that some properties exhibited by cells in old tissue are removed or lessened by the process of generating IPSCs. This is most interesting and probably a bonus when it comes to use in therapies, but quite inconvenient if your interest lies in building models of age-related or genetic conditions, as some of the basis for the condition is stripped out by the process of generating the cells that you want to use. Here is a discussion on this topic, in which researchers involved in studying Hutchinson-Gilford progeria syndrome (HGPS) seek ways to "re-age" the cells they are work with:

Age is the most important risk factor in many late-onset disorders such as Parkinson's disease (PD) as illustrated by the fact that PD patients do not develop symptoms until later in life. Therefore, it is imperative to consider age as well as genetic mutations when attempting to model these diseases in vitro.

Previously, it was unclear whether a donor cell from an old individual would maintain its age-associated properties following conversion into other cell fates ex vivo. However, recent studies have presented evidence that markers of cellular age, including mitochondrial fitness and telomere length, are reset to a young-like state when old donor fibroblasts are reprogrammed to iPSCs.

Indeed, our own study defines a broad set of age-associated markers, and we demonstrate the rejuvenation of old donor fibroblasts based on those markers. The corresponding iPSCs derived from old donors no longer exhibit features that distinguish old from young primary cells including abnormal nuclear morphologies, accumulated DNA damage, increased reactive oxygen specifies (ROS), reduced levels of a set of nuclear organization proteins, and loss of heterochromatin markers. We could not be sure, however, whether pluripotency simply suppresses "age" by downregulating age-related proteins such as progerin. Indeed HGPS iPSCs also show a loss of the age-associated markers at the pluripotency stage.

Therefore, iPSCs were differentiated into a fibroblast-like cell in order to match the phenotype of the donor fibroblasts used for reprogramming. We were able to show that similar to the pluripotency stage, iPSC-derived fibroblasts from old donors appear "young", suggesting that the cell's intrinsic molecular clock is reset following the reprogramming step. In contrast, HGPS iPSC-derived fibroblasts quickly upregulate progerin (the disease-causing protein) during differentiation, resulting in the re-induction of age-associated phenotypes. Based on these findings we hypothesized then that the difficulties of modeling late-onset disease in differentiated iPSCs could be caused by the fact that they are too "young" and that the implementation of defined genetic cues such as progerin overexpression may be sufficient to reintroduce age-associated markers.

Link: http://www.impactaging.com/papers/v6/n4/full/100653.html

As you might know, in recent years researchers have joined the circulatory systems of old and young mice and seen that this causes stem cells in the old mice to return to work in greater numbers, somewhat reversing a number of measures of aging. Stem cell function declines with age in response to damage, and this reduces the risk of cancer due to damaged cells running awry. Thus there is a strong possibility that forcing old tissues to behave as though young by changing the signaling environment - such as by using young blood - will result in a greatly raised risk of cancer. This risk remains to be quantified.

Researchers are beginning to isolate specific signaling changes that lead to stem cell decline in aging, and the protein GDF11 is a promising start - though no doubt far from the only important signal. Boosting levels of GDF11 in old mice has already been shown to improve heart function. Here researchers find other benefits:

Injections of a protein known as GDF11, which is found in humans as well as mice, improved the exercise capability of mice equivalent in age to that of about a 70-year-old human, and also improved the function of the olfactory region of the brains of the older mice - they could detect smell as younger mice do. Studies examined the effect of GDF11 in two ways. First, by using what is called a parabiotic system, in which two mice are surgically joined and the blood of the younger mouse circulates through the older mouse. And second, by injecting the older mice with GDF11, which in an earlier [study] was shown to be sufficient to reverse characteristics of aging in the heart.

GDF11 is naturally found in much higher concentrations in young mice than in older mice, and raising its levels in the older mice has improved the function of every organ system thus far studied. "From the previous work it could have seemed that GDF11 was heart specific, but this shows that it is active in multiple organs and cell types. Prior studies of skeletal muscle and the parabiotic effect really focused on regenerative biology. Muscle was damaged and assayed on how well it could recover."

"The additional piece is that while prior studies of young blood factors have shown that we achieve restoration of muscle stem cell function and they repair the muscle better, in this study, we also saw repair of DNA damage associated with aging, and we got it in association with recovery of function, and we saw improvements in unmanipulated muscle. Based on other studies, we think that the accumulation of DNA damage in muscle stem cells might reflect an inability of the cells to properly differentiate to make mature muscle cells, which is needed for adequate muscle repair."

"We think an effect of GDF11 is the improved vascularity and blood flow, which is associated with increased neurogenesis. However, the increased blood flow should have more widespread effects on brain function. We do think that, at least in principle, there will be a way to reverse some of the cognitive decline that takes place during aging, perhaps even with a single protein. It could be that a molecule like GDF11, or GDF11 itself, could reverse the damage of aging."

It is worth noting that these results are all over the news at the moment, which I imagine has nothing to do with the merits of the science and everything to do with the fact that a company has been formed and is presently raising venture funding to commercialize this treatment. There is a sort of alchemy underway behind the scenes where influence and money is turned into press attention so as to obtain a better valuation.

Link: http://hsci.harvard.edu/news/functioning-aged-brains-and-muscles-mice-made-younger

The US popular press turns out a few articles each year on the topic of longevity science, and most are intrinsically flawed. The problem here is that your average journalist will structure such a piece as a partial survey of all aspects of a topic that are either easily noticed - or easily interviewed - and which seem applicable to the general theme. All of these items are given equal weight, however, so there is no real distinction made between serious research into therapies to treat aging, frivolous pronouncements by health gurus, the "anti-aging" supplement industry, efforts to produce calorie restriction mimetics, research into the genetics of aging, practicing calorie restriction and exercise, and so forth. All of these absolutely night-and-day different things are treated as though they are of equal import and consequence, all just the same sort of widget clustered together in the same box.

Even positions and disputes between researchers and people outside the scientific community are flattened into equality in such an article. Thus outright nonsense is ranked equally in importance with serious research, and research that might greatly extend life is placed at the same level as research that cannot possibly achieve that goal. Simple good health practices that can add a few years to life are treated as being just as valuable and important as work on ways to create actual, working rejuvenation treatments that could extend healthy life by centuries. This is the poisonous rubric of journalistic balance at work. Somewhere along the way sense is dispensed with and meaning thrown out.

It is like reading a tourist guide to your home town written by someone who has never set foot there. It is a mere echo of reality, a fiction using real names and in which all of the useful data is omitted and obscured. Of course every subject is covered just as poorly by the media, not just the one I happen to know something about. It is simply hard to discern when you are unfamiliar with the topic at hand - and this is something to bear in mind while reading the news.

The even-handed pretense that everything has the same level of significance begins with the subtitle in this article and goes on from there. This practice is one of the many things that we seek to change through advocacy: to raise the level of awareness to the point at which the press will begin to include some hierarchy of usefulness in their coverage of longevity science. So here I'll just quote a SENS-related portion of this article, and note that the rest exhibits the issues mentioned above:

So You Want to Live Forever: Immortality through advanced technology and primitive diet

Aubrey de Grey believes that the current approach of geriatric medicine to the systemic breakdowns that aging entails is "pitiful." "Cardiovascular disease is the number-one killer in the West today, and we know that it's caused by fatty deposits in the major arteries. So we try stents or manipulating cholesterol levels with Lipitor. But we know now that the problem isn't so much cholesterol as oxidized cholesterol [small, dense, chemically-modified particles that the aging human body isn't able to deal with via its own natural enzymes]. Oxidized cholesterol isn't properly processed, that is, carried away by the enzymes, so it poisons the arteries."

He maintains that his SENS-sponsored research, some of it conducted on the foundation's premises and some in university laboratories, has pointed to a better way to clear that "bad" cholesterol out of clogged arteries: "We've been able to identify genes and enzymes in bacteria that we should be able to inject into our own human cells to bring about this cleansing process," de Grey explained. "In 2006-2007 we succeeded in identifying some of them, and we've been able to have that research published. We put extra enzymes that kill bad cells into a human cell culture, and they worked. They're the kind of [bacteria] that we need to fix problems in the human body. Then we can work on arteriosclerosis in mice, and then we'll have clinical trials in humans.

"The problem right now is that people think of aging as a universal phenomenon, but diseases such as heart disease are thought of as separate phenomena. But they're universal! Ninety-nine percent of the money spent on age-related research is spent on attempts to cure those diseases. But you can't cure people of side effects; you have to be able to cure aging itself. So what we want to see is preventative medicine, periodically cleaning up certain areas. Let's take Alzheimer's. We know that there are three factors: senile plaques in the brain, tangles in neurons, and cell death. We solved the plaque problem 15 years ago. You can clean up the plaques​ - ​but no cognitive goals for patients are being met. That's because we don't know the role that plaques play or their cause. Aging is this multifaceted. What we need to do is clean up lots of things at the same time. Initially, this could be a cleanup every 10 years. Then later, we might develop injections or oral medications. Right now, though, we have a 50-50 chance of getting it all into place in about 25 years."

Indeed, de Grey is confident that if we can figure out how to repair just seven bodily systems prone to breakdown​ - ​ranging from chromosomal mutations over time to protein junk accumulated from the cell disintegration that accompanies aging​ - there is no reason for any of us to die. The only obstacle he sees to our living, say, at least 5,000 years (unless we're unlucky enough to be hit by a car or whatever will substitute for a car in 7000 a.d.) is the money that SENS and its affiliated scientists committed to the hope of realizing eternal or near-eternal life need to develop those complex repair systems that they envision. "If we had ten times the money we have now, we could work at three times the speed," de Grey told me.

There are numerous examples of studies that use mice genetically engineered to suffer forms of shortened life span with the appearance of accelerated aging. One has to be very cautious in reading anything into this sort of work, however: it is rarely of any great relevance to normal aging, as it creates and then attempts to ameliorate an entirely artificial situation. The appearance of accelerated aging is not in fact accelerated aging, but is rather often caused by mechanisms that are of little importance in normal aging. Even when the mechanisms are relevant, the overall metabolic circumstances can render it impossible to determine whether or not a partial treatment will be of any use in normal aging. The gold standard for relevance when evaluating new methods is the extension of life in unmodified mice, but unfortunately this is expensive and slow.

The publicity materials quoted below are a good example of research in animals exhibiting shortened life spans. Here scientists are investigating a protein involved in the induction of cellular senescence. As is often the case, however, from the structure of the work it is impossible to tell whether or not their drug candidate will be of any use as a treatment to lower levels of cellular senescence in normal aging and thus produce benefits such as extended health and life span. Those tests will still have occur:

When cells or tissue age - called senescence - they lose the ability to regenerate and secrete certain proteins, like a distinctive fingerprint. One of those proteins, PAI-1 (plasminogen activator inhibitor) has been [a focus of] research, originally as it relates to cardiovascular disease. "We made the intellectual leap between a marker of senescence and physiological aging. We asked is this marker for cell aging one of the drivers or mechanisms of rapid physiological aging?"

For the study, [researchers] used mice bred to be deficient in a gene (Klotho) that suppresses aging. These mice exhibit accelerated aging in the form of arteriosclerosis, neurodegeneration, osteoporosis and emphysema and have much shorter life spans than regular mice. [These] rapidly aging mice produce increased levels of PAI-1 in their blood and tissue.

Then scientists fed the rapidly aging mice TM5441 - the experimental drug - in their food every day. The result was a decrease in PAI-1 activity, which quadrupled the mice's life span and kept their organs healthy and functioning. "This is a completely different target and different drug than anything else being investigated for potential effects in prolonging life. It makes sense that this might be one component of a cocktail of drugs or supplements that a person might take in the future to extend their healthy life."

Link: http://www.northwestern.edu/newscenter/stories/2014/04/experimental-drug-prolongs-life-span-in-mice.html

The accelerated aging condition Hutchinson-Gilford Progeria Syndrome (HGPS) is not in fact accelerated aging, but only appears that way. It is caused by dysfunctional lamin A, a protein vital to nuclear structure in cells, and this dysfunction leads to all sorts of cellular issues and damage. Malformed lamin A does show up in normal aging in very small amounts, but it is unclear whether or not this is significant in comparison to other causes of aging, and whether it is a primary or secondary effect. Researchers have also managed to extend life in mice by manipulation of lamins, which is intriguing but may not be relevant to either human aging or progeria as the mechanisms of action are not yet fully understood. Still, all told it seems worth keeping an eye on progress in the development of treatments for progeria:

In cells from people with HGPS, the nucleus is marked out because, unlike a normal cell's round nucleus, HGPS cell nuclei are drastically misshapen. Scientists believe this makes the cells more fragile, contributing to HGPS patients' symptoms. Proteins called Lamin A and Lamin C play a vital role in nuclear architecture, acting as 'scaffolding' for the nucleus. In HGPS, however, mutations in the gene that makes these proteins mean they cannot shape the nucleus correctly.

[Researchers] found that one compound - which they were able to improve, yielding a molecule that they have named Remodelin - effectively improved the damaged nuclei, restoring their shape. Further tests revealed that doing so also improved the health of the cells, making them grow and divide more normally. "Most drugs work by binding to something in the cell, so we went fishing. We attached a chemical 'hook' to Remodelin, incubated it with cell extracts, and examined what was attached to it when we reeled it back in." The target they fished out was NAT10, a protein not previously associated with ageing or HPGS. "From our following work, we now know that Remodelin works by inhibiting NAT10, so we have gone from finding a potential drug to identifying its target and mechanism-of-action."

The next stage of the research, which is already underway, is to see if Remodelin works in animal models of the disease; if it does, the researchers will be able to trial the drug in patients.

Link: http://www.cam.ac.uk/research/news/remodelling-damaged-nuclei-could-lead-to-new-treatments-for-accelerated-ageing-disease

Why does any species live as long as it does? The high-level answer is that present length of life is an evolved consequence of adaptations that allow a species to succeed in occupying its niche, via competitive success for individuals in propagating their genes. You don't see the losers in this process, as they have vanished. There is fierce debate over the nature of the relationship between desirable adaptions that provide evolutionary success and consequent length of life, and the debate is very different for different species and different circumstances. In general, however, researchers who hold that aging is a process caused by accumulated cellular and molecular damage view aging as a sort of shadow cast by natural selection operating on youthful individuals. There is great selection pressure upon young biology, the fight for success in early life, and a species can boast successful adaptations that enhance reproductive success but which nonetheless exist at the expense of individual health and survival in later life.

Some models suggest that this shadow of aging is in and of itself necessary for the long-term survival and success of species, as aging species tend to outcompete ageless species during periods in which the environment changes. Since there have been innumerable such episodes in our evolutionary past, it is perhaps not too surprising that aging species are far more numerous than those few species that might be ageless.

A process that is advantageous in youth but becomes harmful in aging is known as a form of antagonistic pleiotropy: the human immune system is perhaps a good example of a system that has this property. It is structured so as to be effective in youth, but some of the very same aspects that make it so effective at the outset of life - such as the inflammatory immune response and the ability to remember specific threats indefinitely - contribute to immune system failure in later life.

In humans a big question lingers over our comparative longevity. Why did we evolve to live for so much longer than our primate cousins? One proposal is the grandmother hypothesis, which essential points to a combination of culture and intelligence as the root of human longevity. Once a post-reproductive individual can materially contribute to the success of his or her descendants, then a selection effect for greater longevity comes into play, one that doesn't exist in primate species that are not intelligent enough to have this ability.

To pick another species in which the situation is radically different, we could look at salmon. Salmon undergo a very sudden aging process after spawning, and the details of this process are strongly driven by the habits of bears who feed on salmon. Some bear populations prefer to feed on older salmon, and in those rivers salmon age more slowly.

The influence of predation on the evolution of aging is an established body of theory in the evolutionary science community. It is generally accepted that greater predation will tend to favor the evolution of shorter life spans, even if only because it allows for adaptations that ensure early reproductive success but which place a great physiological burden on later life. Mechanisms that instead ensure a longer reproductive life span will not be selected if individuals are largely eaten young.

All species are different, however, and there is always room for argument in this field. Which is why you will see such things as researchers crunching the numbers in support of the dominant viewpoint on predation and longevity:

Predators predict longevity of birds

In birds, variation in life-span extends from parrots such as the Sulphur-crested cockatoo that can become more than 100 years old, to the small Allen's hummingbird with a maximum life-span of only 4 years, a 25 fold difference. How can this variation be explained?

The classical evolutionary theory of ageing, first proposed by the famous evolutionary biologist George C. Williams over 50 years ago, gives an answer. The theory predicts that high mortality rates in adult animals due to predation, exposure to parasites and other randomly occurring events will be associated with shorter maximum life-spans. This is because under high external mortality most individuals will already be dead (eaten or succumbed to disease) before natural selection can act on rare mutations that cause healthier ageing. The theory has since been further developed and tested in a number of experimental and comparative studies. Yet contradictory results have caused scientists to cast doubt on its validity.

[Researchers] have now tested this theory using a comprehensive database on estimates of maximum life-span of 1396 bird species, 1128 from free-living species and 268 from birds kept in captivity. The researchers used a global distribution map of these species, included data on their morphology and reproductive rate, and estimated predation rate.

By means of complex statistical analysis methods they found that in the investigated bird species maximum longevity is negatively related to the number of predator species occurring within the same geographical area. This means that the more predator species are present in the same habitat and the more evenly they are distributed, the lower is the life span of the respective species. This relationship supports the classical theory of ageing, and remains valid when other life history traits known to influence longevity such as body mass and clutch size are included into the statistical model. Indeed, larger species live longer, and those that reproduce fast (lay more eggs) live shorter lives. Remarkably, the observed pattern showing longer life-spans when fewer predators are present emerges no matter how the analysis was done: at the species level, at a finer regional scale (groups of species within a certain area) or even when comparing entire bioregions.

Recently researchers have made inroads in using the embryonic development process of mesenchymal condensation to generate tissue engineered teeth, or at least to show promising signs of progress along that road. Here this same process is turned to building cartilage, a type of tissue that has proven to be very challenging to engineer. Its mechanical properties are crucial to its role in the body, and these properties depend absolutely on the small-scale arrangement of cells and extracellular matrix. Even slight differences result in artificial tissue that is just an arrangement of cartilage cells, not the real thing, and not up to the task of supporting weight in joints.

Here researchers are claiming to have generated cartilage that is sufficiently similar to natural cartilage to be a candidate for use in the clinic:

[Researchers] have successfully grown fully functional human cartilage in vitro from human stem cells derived from fat tissue. "We've been able - for the first time - to generate fully functional human cartilage from mesenchymal stem cells by mimicking in vitro the developmental process of mesenchymal condensation. This could have clinical impact, as this cartilage can be used to repair a cartilage defect, or in combination with bone in a composite graft grown in the lab for more complex tissue reconstruction."

Many groups studied cartilage as an apparently simple tissue: one single cell type, no blood vessels or nerves, a tissue built for bearing loads while protecting bone ends in the joints. While there has been great success in engineering pieces of cartilage using young animal cells, no one has, until now, been able to reproduce these results using adult human stem cells from bone marrow or fat, the most practical stem cell source. [This] team succeeded in growing cartilage with physiologic architecture and strength by radically changing the tissue-engineering approach.

The general approach to cartilage tissue engineering has been to place cells into a hydrogel and culture them in the presence of nutrients and growth factors and sometimes also mechanical loading. But using this technique with adult human stem cells has invariably produced mechanically weak cartilage. [So the researchers] came up with a new approach: inducing the mesenchymal stem cells to undergo a condensation stage as they do in the body before starting to make cartilage.

The lubricative property and compressive strength - the two important functional properties - of the tissue-engineered cartilage approached those of native cartilage. The researchers then used their method to regenerate large pieces of anatomically shaped and mechanically strong cartilage over the bone, and to repair defects in cartilage. The team plans next to test whether the engineered cartilage tissue maintains its structure and long-term function when implanted into a defect.

Link: http://engineering.columbia.edu/columbia-engineers-grow-functional-human-cartilage-lab

Mirroring some of the work taking place in the tissue engineering field with decellularized donor tissue, in which the donor's cells are removed and then the structure left behind repopulated with the recipients cells, researchers here are using extracellular matrix (ECM) material from pig tissue as the basis for scaffolds to spur regrowth in large muscle injuries:

When a large volume of muscle is lost, typically due to trauma, the body cannot sufficiently respond to replace it. Instead, scar tissue can form that significantly impairs strength and function. Pig bladder ECM has been used for many years as the basis for medical products for hernia repair and treatment of skin ulcers. It is the biologic scaffold that remains left behind after cells have been removed. [Previous research] suggested that ECM also could be used to regenerate lost muscle by placing the material in the injury site where it signals the body to recruit stem and other progenitor cells to rebuild healthy tissue.

For the Muscle Tendon Tissue Unit Repair and Reinforcement Reconstructive Surgery Research Study, five men who had at least six months earlier lost at least 25 percent of leg muscle volume and function compared to the uninjured limb underwent a customized regimen of physical therapy for 12 to 26 weeks until their function and strength plateaued for a minimum of two weeks. Then [researchers] surgically implanted a "quilt" of compressed ECM sheets designed to fill into their injury sites. Within 48 hours of the operation, the participants resumed physical therapy for up to 26 additional weeks.

The researchers found that three of the participants, two of whom had thigh injuries and one a calf injury, were stronger by 20 percent or more six months after the surgery. Biopsies and scans all indicated that muscle growth had occurred. Two other participants with calf injuries did not have such dramatic results, but both improved on at least one functional measure and said they felt better.

Link: http://www.eurekalert.org/pub_releases/2014-04/uops-rma043014.php