Fight Aging!

The Society for Venturism has been a part of the cryonics advocacy community since the 1980s, and so is one of the older portions of the modern transhumanist movement. The cryonics industry, which has existed in a rigorous form since the 1970s, focuses on preserving the brain and thus the structure of the mind following death, so as to offer a chance at restoration to life and health by future medical technologies, such as those that might be built on a foundation of molecular nanotechnology and medical nanorobotics. The chance of success is unknown, but very much greater than zero, which are the odds you'll get when opting for the traditional choice of grave, gravestone, and oblivion. Over the decades cryonics providers have moved from simple freezing and its attendant issues of tissue damage to the modern process of vitrification and a practiced procedure of standby and support for terminal patients.

Cryonics is an important part of the longevity science community, for all that it garners far too little attention from the world at large: billions will die before methods of rejuvenating the old and preventing age-related frailty become widespread throughout the world even under the best case scenarios of funding and public support. Cryonics is a way for those who will age to death too soon to have a shot at the future of greatly extended lives and youth.

Still, while the cryonics community has grown and become more professional and research-oriented with time, it has failed to find the footing and support for an earnest transition into the mainstream. The number of people cryopreserved to date is around 250 or so, a miniscule fraction of those who have died over the past four decades and who had the funds to hand to choose cryopreservation. In recent years, the public and press view of cryonics has become less hostile and much more understanding, however. New cryonics organizations have been established or are in the process of establishment outside the US. So there is hope that the process of growth and improvement will continue at a faster pace in the future.

Venturist Society FAQ Cryonics Conference

The convention this year has a lineup of prominent and inspirational speakers in the fields of cryonics, radical life extension and transhumanism, including Aubrey de Grey, Ph.D., Max More, Ph.D. and experts in other areas.

The name of the convention will be the FAQ Cryonics Convention. FAQ, as most people know, stands for Frequently Asked Questions. This convention will be open to people who are already signed up for cryonics, and for prospects for cryonics as we also we expect a good turnout from people who are thinking about joining. [It is] to be held at Don Laughlin's Riverside Resort in Laughlin, Nevada on October 25, 26 & 27, 2013.

Aubrey de Grey, of the SENS Research Foundation, will be giving this presentation:

A biologist's view on why cryonics is feasible: Many non-biologists presume that cryonics must be fantasy because it is not mainstream. This is a reasonable inference for those who do not appreciate how appallingly balkanised biology is, with almost all biologists being expert in only a very narrow area and having no time to study other areas. Since a field's reputation for infeasibility is a reason not to pay attention it, this parlous situation is self-fulfilling. In this talk I will see to rectify it.

Simpler forms of exterior soft tissue are among the first candidates for tissue engineering, and work continues on ways to produce tissue structures such as ears:

Scientists have built an artificial human ear by combining living tissues from cows and sheep and growing them around a flexible wire frame that retains the correct anatomical shape of the organ. It is the latest development in 3D tissue engineering where substitute organs are made in the laboratory in the hope of using them to replace the damaged or missing body parts of patients. The artificial ear is described as a "proof of concept" prototype, and further research and development will be needed before it could be used in clinical transplants on patients.

A key feature of the artificial ear is a cartilage scaffold with an embedded titanium wire which retains the shape of the structure as well as maintaining its flexibility. "The technology is now under development for clinical trials, and thus we have scaled-up and redesigned the prominent features of this scaffold to match the size of an adult human ear and to preserve the aesthetic appearance after implantation."

Collagen connective tissue from a cow was formed into the shape of a human pinna - the fleshy visible part of the ear - and held in place by titanium wire. The porous collagen was then "seeded" with ear cartilage cells taken from a sheep and the cells grew within the porous collagen fibres. The scientists grew the ear on mice and rats lacking an immune system to show that it was possible for it to be connected to a blood supply without tissue rejection. In a human transplant, the ear would have to be either made from a patient's own stem cells or used with anti-rejection drugs. An important feature of the technology is that the ear can be designed to look as natural as possible by pulling the skin taut over the wire and cartilage frame using vacuum suction.

Link: http://www.independent.co.uk/news/science/scientists-grow-an-ear-from-living-tissue-8738618.html

Exercise is known to reduce the risk of suffering Alzheimer's disease, but it also brings reliably greater benefits to Alzheimer's patients than any presently available medical technology. Exercise is in general very beneficial for elderly people, all too few of whom undertake enough exercise these days. The future of medical science will ultimately make lifestyle choices such as a calorie restricted diet and regular moderate exercise irrelevant as determinants of health and longevity, but for now they are the best available option to slow degeneration and improve long-term health.

New research [shows] that exercise may improve cognitive function in those at risk for Alzheimer's by improving the efficiency of brain activity associated with memory. Memory loss leading to Alzheimer's disease is one of the greatest fears among older Americans. While some memory loss is normal and to be expected as we age, a diagnosis of mild cognitive impairment, or MCI, signals more substantial memory loss and a greater risk for Alzheimer's, for which there currently is no cure. The study [is] the first to show that an exercise intervention with older adults with mild cognitive impairment (average age 78) improved not only memory recall, but also brain function, as measured by functional neuroimaging (via fMRI).

Two groups of physically inactive older adults (ranging from 60-88 years old) were put on a 12-week exercise program that focused on regular treadmill walking and was guided by a personal trainer. Both groups - one which included adults with MCI and the other with healthy brain function - improved their cardiovascular fitness by about ten percent at the end of the intervention. More notably, both groups also improved their memory performance and showed enhanced neural efficiency while engaged in memory retrieval tasks.

Tests and imaging were performed both before and after the 12-week exercise intervention. Brain scans taken after the exercise intervention showed a significant decrease in the intensity of brain activation in eleven brain regions while participants correctly identified famous names. The brain regions with improved efficiency corresponded to those involved in the pathology of Alzheimer's disease, including the precuneus region, the temporal lobe, and the parahippocampal gyrus.

Link: http://www.umdrightnow.umd.edu/news/exercise-may-be-best-medicine-alzheimers

With yearly budget of several million dollars, the SENS Research Foundation has grown a long way beyond the founding group of a few advocates and researchers. Life scientists in laboratories around the world, including the Foundation's research center in California, presently work on the foundations of human rejuvenation detailed in the Strategies for Engineered Negligible Senescence (SENS). There are forms of cellular and intracellular damage that harm us and cause degenerative aging, and in every case researchers can clearly describe what needs to be accomplished in order to repair that damage. The only obstacles to rapid progress towards the medical control of aging are (a) funding and (b) obtaining the widespread public support and understanding needed to generate that funding.

Aging is the greatest form of harm to humanity that presently exists: it causes more death and suffering than all forms of disease, violence, and accident combined. The golden future of medicine involves finding ways to reduce the cost of aging, and preferably eliminate it altogether through periodic repair procedures. Curing degenerative aging will save more lives than any other human endeavor to date, and more lives than any other endeavor can possibly save. Research into human rejuvenation is the most important activity presently taking place in the world today by any rational measure.

(And yet it is also probably the least funded in comparison to its importance. Little medical research is well funded of course, in comparison to the benefits it can produce, but that is the way of the world. We spend billions on circuses and war, billions more on trying to cope with the consequences of sickness and aging, but next to nothing on ways to dramatically improve the human condition by eliminating that sickness and aging. Given how small a sliver of economic activity is devoted to improving medicine, it's amazing that progress is as fast as it is).

The SENS Research Foundation is presently running a series of profiles of the researchers and interns who are helping to push forward the boundaries of the possible in medical science. Few people are doing work that is more important than that funded by the Foundation:

The Youngest Thiel Finalist: SRF's Thomas Hunt

Before I joined SRF, I started out as a curious and active member of the Do-It-Yourself (DIY) bio community. As a young teen, I got involved with BioCurious in its earliest days to help build the BioCurious lab. I also participated in other organizations like the Health Extension Salon and Thiel Fellowship Under20 Summits before applying for a 20Under20 Fellowship this past year.

Currently I volunteer at SRF four days a week. I spend my time conducting research to understand a poorly understood pathway that plays a key role in cancer cell immortality called alternative lengthening of telomeres, or ALT. I keep current with new developments in my field by reading scientific papers at the cutting edge of ALT work, and I am currently in charge of studying POT1, a protein that could negatively affect ALT activity. I am also performing experiments on cancer cells to test for ALT activity.

When I'm not at SRF, I've designed my own home schooling curriculum, where I get to choose which subjects I want to study. I take local college classes that I feel will assist me in my research goals, like chemistry and public speaking. I love telling people about the latest discoveries in science, and have spoken at The University of California, Santa Cruz (UCSC) about genetic modification.

Amutha Boominathan: Moving vulnerable mitochondrial genes to the safety of the nucleus

After moving to the Bay Area I was looking for mitochondria research labs that would fit my experience and expertise where I could further my career. I came across the MitoSENS project at SRF's Research Center and was very excited. It seemed like 'the' perfect place, almost like an extension of what I was doing in my postdoc lab. So I sent my CV, cold, to the info address listed, and Daniel forwarded my CV to Oki [Matthew O'Connor, SRF's Principal Investigator]. We had a good talk about the project and I volunteered for a short bit before coming on full-time this year.

We all know that mitochondria are the cell's "powerhouse" for energy. One interesting fact about these organelles is that they have their own DNA in addition to the nuclear DNA that we are all aware of. However, the mitochondrial DNA is prone to mutations due to constant exposure from ROS (reactive oxygen species) generated through the OX-PHOS system. This is because the mitochondrial DNA is not encased in a nuclear envelope nor does it have efficient repair mechanisms to correct mutations as they occur. To mitigate this weakness, our goal here at SRF is to move the mitochondrial genes to the nucleus, where it's safer to express them for function. This would let mitochondria keep producing energy normally, even after mitochondrial mutations have occurred.

Jayanthi Vengalam: Engineering backup mitochondrial genes

Here at SRF, we're working to engineer expressions of "backup" copies of vulnerable mitochondrial genes, located in the safer location of the cell's nucleus. To explore and refine methods to safely accomplish this, we've taken four cell lines from patients suffering from inherited mitochondrial mutations, and made stable lines that express their improved mitochondrial gene constructs. We've begun collecting data which confirms the targeting of gene transcripts and proteins, as well as the functional activity of the mitochondrial energy system.

Our two primary goals this year are to definitively confirm the localization of allotopically-expressed proteins at the inner membrane of mitochondria, and to demonstrate that our allotropic expression systems can functionally rescue cells with each of several missing or severely mutated mitochondrial genes. I spend most of my time engineering different targeting tags on the various proteins we are trying to target to the mitochondrial OxPhos system and testing the engineered genes in the cell lines.

Aging is a sad thing, and it's important to me to contribute to research that helps understand and alleviate suffering. Mitochondrial abnormalities contribute to general problems of aging most people traditionally think of as inevitable, but also affect acute diseases such as diabetes, Parkinson's and Alzheimer's. Our mission is a noble one.

Mission isn't everything, though; you have to like the people your work with, too. I really like that everyone here is not only abstractly passionate about SRF's mission, but also truly committed to uncovering the real scientific truths in what they want to accomplish. Some more traditional workplaces have such a product or hierarchically-oriented management focus that it's hard to get real research done; here, if I have a question or a research problem, it's really natural to just go talk to someone about it honestly face-to-face.

It is fairly well established by this point that calorie restriction boosts the cellular housekeeping processes known as autophagy. Damaged components, broken proteins, and other issues are more readily dealt with, destroyed, and recycled when an individual is on a low calorie rather than high calorie diet. Increased levels of autophagy are known to be associated with many of the methods of slowing aging demonstrated in laboratory animals, which leads some researchers to think that it is one of the more important aspects of the way in which metabolism determines variations in longevity. With that in mind, here is one of a range of studies that confirm the association between calorie restriction and increased autophagy:

Diet has been long recognized as a modulator of kidney health in both humans and experimental models. Calorie restriction (CR) can retard the progression of many age-associated molecular, physiological, and pathological processes which occur in tissues with high oxidative demand, such as kidney, skeletal muscle, heart, and brain. In contrast, feeding mice with a high-calorie diet results in age-related obesity, cardiovascular diseases, and other metabolic disorders, and it shortens lifespan. A high-calorie (HC) diet induces renal injury and promotes aging, and calorie restriction (CR) may ameliorate these responses. However, the effects of long-term HC and CR on renal damage and aging have been not fully determined.

Autophagy is an evolutionarily conserved process in eukaryotic organisms. Cytoplasmic constituents are sequestered in double-membrane structures to form autophagosomes, which fuse with lysosomes to form autolysosomes. The cytoplasmic components are degraded by acid hydrolases, and the degradation products are released into the cytosol and recycled into biological structures or to supply energy during periods of starvation. Autophagy is critical for survival during nutrient deprivation, as it enables recycling of macromolecules to provide new nutrients and energy in yeast and mammals. Another key function of autophagy is to remove damaged organelles such as mitochondria and aberrant macromolecules, to prevent further injury to cells. Therefore, impairment of autophagy will lead to a progressive accumulation of damaged macromolecules and organelles in somatic cells, increased oxidative damage and accelerated aging.

We evaluated the expression of [markers of autophagy] in the kidneys of 24-month-old Fischer 344 rats. We also observed mitochondrial structure and autolysosomes by transmission electron microscopy. Expression of the autophagosome formation marker LC3/Atg8 and markers of mitochondrial autophagy (mitophagy) were markedly decreased in the kidneys of the HC group, and markedly increased in CR kidneys. Transmission electron microscopy demonstrated that HC kidneys showed severe abnormal mitochondrial morphology with fewer autolysosomes, while CR kidneys exhibited normal mitochondrial morphology with numerous autolysosomes. Markers of aging, such as p16 and senescence-associated-galactosidase, were increased significantly in the HC group and decreased significantly in the CR group. The study [suggests] that HC diet inhibits renal autophagy and aggravates renal oxidative damage and aging, while CR enhances renal autophagy and ameliorates oxidative damage and aging in the kidneys.

Link: http://dx.doi.org/10.1371/journal.pone.0069720

You might recall research involving parabiosis, in which researchers joined the circulatory systems of an old and a young mouse to measure the effects of signaling changes in the cellular environment that occur with age - and to see what the results would be if changes in the old environment were reversed. Prior investigations were conducted in cell cultures, exposing old cells to young blood or vice versa, which is how the fact that this resulted in interesting changes was noted in the first place.

Researchers here are walking down the same path with calorie restriction: it seems that changes are observed if you take blood serum from a calorie restricted individual and expose cells to it. This suggests that one component of the mechanisms by which calorie restriction extends life and improves health involves changes to the chemical makeup of the cellular environment, as one might expect:

Calorie restriction (CR) without malnutrition is the most robust intervention to slow aging and extend healthy lifespan in experimental model organisms. Several metabolic and molecular adaptations have been hypothesized to play a role in mediating the anti-aging effects of CR, including enhanced stress resistance, reduced oxidative stress and several neuroendocrine modifications. However, little is known about the independent effect of circulating factors in modulating key molecular pathways.

In this study, we used sera collected from individuals practicing long-term CR and from age- and sex-matched individuals on a typical US diet to culture human primary fibroblasts and assess the effects on gene expression and stress resistance. We show that treatment of cultured cells with CR sera caused increased expression of stress-response genes and enhanced tolerance to oxidants. Cells cultured in serum from CR individuals showed a 30% increase in resistance to H2O2 damage. Consistently, SOD2 and GPX1 mRNA, two key endogenous antioxidant enzymes, were increased by 2 and 2.5 folds respectively in cells cultured with CR sera. These cellular and molecular adaptations mirror some of the key effects of CR in animals, and further suggest that circulating factors contribute to the CR-mediated protection against oxidative stress and stress-response in humans as well.

Link: http://impactaging.com/papers/v5/n8/full/100584.html

The coming generation of medical therapies will be distinguished from those of the past decades by their specificity: they will target only those cells that need to be destroyed, altered, or reprogrammed, rather than being indiscriminately infused into the body to hit all cells. In a world in which researchers cannot target specific cells, the development of therapies is focused on finding things that won't kill the patient. Treatments are deployed because they are just a bit more harmful to, say, cancer cells than they are to all other cells. This is, needless to say, no walk in the park for the patient.

A targeted therapy, on the other hand, will by design have few side effects. The method of destroying or altering targeted cells can be ramped up to optimal levels of effectiveness because it won't bleed over to impact many other cells. Indeed, with the addition of some form of targeting and delivery mechanism such as nanoparticles even the old chemotherapies for cancer can be turned into highly effective, low impact treatments that kill only cancer cells and don't make the patient sick at all.

This is the future, and not just for cancer treatments. So it's worth keeping an eye on research in the field of targeting and delivery, as any new methodology with a broad application has the potential to greatly impact the effectiveness of many types of medical therapy over the next ten to twenty years.

I noticed an example of this sort of thing today, wherein researchers are engaged in the first steps of building a generic cell labeling platform. Instead of incorporating the ability to detect surface markers into a delivery mechanism, it might be possible to standardize delivery systems to identify cells by a small set of constructed labels. Labeling technologies would perform the work of identifying specific cell types by their (very varied, very complex) surface chemistry, and then applying labels to those cells. So a treatment would be a two-step process in which cells are labeled, that result is validated, and then the therapy is applied, targeted to those labels. With these technologies, a standard set of labels becomes an API of sorts, enabling specialization of research and development into labeling and delivery camps, something that always speeds progress and reduces costs where it occurs.

Molecular robots can help researchers build more targeted therapeutics

In the new study, scientists have designed molecular robots that can identify multiple receptors on cell surfaces, thereby effectively labeling more specific subpopulations of cells. The molecular robots, called molecular automata, are composed of a mixture of antibodies and short strands of DNA. These short DNA strands, otherwise called oligonucleotides, can be manufactured by researchers in a laboratory with any user-specified sequence.

The researchers conducted their experiments using white blood cells. All white blood cells have CD45 receptors, but only subsets have other receptors such as CD20, CD3, and CD8. In one experiment, [researchers] created three different molecular robots. Each one had an antibody component of either CD45, CD3 or CD8 and a DNA component. The DNA components of the robots were created to have a high affinity to the DNA components of another robot. DNA can be thought of as a double stranded helix that contains two strands of coded letters, and certain strands have a higher affinity to particular strands than others.

The researchers mixed human blood from healthy donors with their molecular robots. When a molecular robot carrying a CD45 antibody latched on to a CD45 receptor of a cell and a molecular robot carrying a CD3 antibody latched on to a different welcoming receptor of the same cell, the close proximity of the DNA strands from the two robots triggered a cascade reaction, where certain strands were ripped apart and more complementary strands joined together. The result was a unique, single strand of DNA that was displayed only on a cell that had these two receptors.

The addition of a molecular robot carrying a CD8 antibody docking on a cell that expressed CD45, CD3 and CD8 caused this strand to grow. The researchers also showed that the strand could be programmed to fluoresce when exposed to a solution. The robots can essentially label a subpopulation of cells allowing for more targeted therapy. The researchers say the use of increasing numbers of molecular robots will allow researchers to zero in on more and more specific subsets of cell populations.

"The automata trigger the growth of more strongly complementary oligonucleotides. The reactions occur fast. In about 15 minutes, we can label cells." In terms of clinical applications, researchers could either label cells that they want to target or cells they want to avoid. "This is a proof of concept study that it works in human whole blood. The next step is to test it in animals."

If aging is a matter of accumulating damage, then we would expect all successful efforts to improve health to also result in some degree of extended healthy life. Biology is very complex, and so the situation on the ground inside an aging body isn't as simple as the accumulation of damage in a non-self-repairing entity such as a chair or a building, but the fact that human life span and health in old age are both steadily increasing alongside general improvements in medical technology supports the view of aging as damage.

With the exception of the year or two just before death, people are healthier than they used to be. Effectively, the period of time in which we're in poor health is being compressed until just before the end of life. So where we used to see people who are very, very sick for the final six or seven years of their life, that's now far less common. People are living to older ages and we are adding healthy years, not debilitated ones. The study results are based on data collected between 1991 and 2009 from nearly 90,000 individuals who responded to the Medicare Current Beneficiary Survey (MCBS).

"There are two basic scenarios that people have proposed about the end of life. The first argues that what medical science is doing is turning us into light bulbs - that is, we work well until suddenly we die. This is also called the rectangularization of the life curve, and what it says is that we're going to have a fairly high quality of life until the very end. The other idea says life is a series of strokes, and medical care has simply gotten better at saving us. So we can live longer because we've prevented death, but those years are not in very good health, and they are very expensive - we're going to be in wheelchairs, in and out of hospitals and in nursing homes."

While researchers have tried to tackle the question of which model is more accurate, different studies have produced competing results. One reason for the confusion [is] that such efforts are simply looking at the wrong end of someone's life. "Most of our surveys measure health at different ages, and then use a model to estimate how long people have to live. But the right way to do this is to measure health backwards from death, not forwards. We should start when someone dies, then go back a year and measure their health, then go back two years, three years, and so on."

"There seems to be a clear relationship between some conditions that are no longer as debilitating as they once were and areas of improvement in medicine. The most obvious is cardiovascular disease - there are many fewer heart attacks today than there used to be, because people are now taking cholesterol-lowering drugs, and recovery is much better from heart attacks and strokes than it used to be. A person who suffered a stroke used to be totally disabled, but now many will survive and live reasonable lives. People also rebound quite well from heart attacks."

Link: http://www.eurekalert.org/pub_releases/2013-07/hu-lll072513.php

The senescence.info team recently added a new online database to the collection available at the site:

The LongevityMap is based on manually-curated data from over 200 genetic association studies of longevity. Each entry includes a brief description of the study and major findings, as well as the specific population studied and other relevant information. Entries are mapped (if appropriate) to genes, chromosomal regions and SNP ID which can be queried.

Negative results are also included in the LongevityMap to provide visitors with as much information as possible regarding each gene and variant previously studied in context of longevity. As such, the LongevityMap serves as a repository of genetic association studies of longevity and reflects our current knowledge of the genetics of human longevity.

Link: http://genomics.senescence.info/longevity/

A perfect world would include the means to prevent catastrophic failures of brain structure such as stroke from ever happening. One such means is a working implementation of the rejuvenation biotechnologies evisaged in detail in the SENS research plans. Strokes and other failures happen because tissue becomes damaged and frail. Remove that damage and the stroke risk of an old person would be that of a young person, which is to say very close to zero. Rejuvenation therapies lie a number of years in the future, however, where that number is very much determined by how much funding and support are dedicated to the right sort of research today. In the meanwhile, the present state of the art in medical technology, absent any way to greatly impact aging and the harm it causes, is to build better ways to clean up and restore more function after a stroke occurs.

The most promising lines of research in restorative therapies for stroke patients involve the manipulation and transplant of cells. Scientists are finding ways to spur native cells to greater feats of regeneration, or to bring in new cells that can do the job where native cells will not. I'm sure that you're all familiar with work on stem cell transplants of one form or another, for example, but there are many more strategies under development. On this topic a recent open access review notes the growth in clinical trials for stroke treatments in the past few years. At some point all of the promising work in the laboratory and all of the experience gained in treatments available via medical tourism will start to push its way into the highly regulated, expensive, slow-moving mainstream of clinical translation:

The Rise of Cell Therapy Trials for Stroke: Review of Published and Registered Studies

Stroke is responsible for 11.1% of all deaths, and is the second leading cause of death worldwide after ischemic heart disease. The injury produced by stroke is largely complete after 24-48 h, and neuroprotective therapies that must be administered within a time window such as 3-6 h are difficult to apply in clinical practice. Approximately 80% of all strokes are ischemic, and currently, tissue plasminogen activator (tPA) is the only pharmacological agent approved for treatment of acute ischemic stroke. However, tPA therapy has important limitations, notably the narrow therapeutic window of 4.5 h, which limits its use to a small minority (2% to 4%) of patients. Moreover, tPA prevents disability in only six patients per 1000 ischemic strokes, and does not reduce the mortality rate.

On the other hand, neurorestorative therapies, including cell therapies, seek to enhance regenerative mechanisms such as angiogenesis, neurogenesis, and synaptogenesis, and have been investigated extensively in the preclinical models of ischemia. Neurorestorative cell therapies can be grossly divided into endogenous or exogenous. Endogenous therapies are those that aim to stimulate, for example, bone marrow-cell migration to the blood stream, with pharmacological agents such as granulocyte-colony stimulating factor (G-CSF). The exogenous approach involves the injection of a variety of cells to produce structural or functional benefits. Although excellent reviews have been recently made on different aspects of cell therapies for stroke, there has been a dramatic increase in the number of published and registered trials in the past years that has not been comprehensively assessed.

Several preclinical studies have indicated that there is a structural and/or functional recovery after intracerebral, intra-arterial, and intravenous therapy with different cell types. Although clinical results with other ischemic diseases and preclinical studies for stroke are encouraging, there are still many questions regarding the possible mechanisms of action of the cells and the optimal treatment protocol. One of the main questions to be answered is related to the best cell type to be used in these patients. Further, aspects such as the mechanisms [that produce] improvements and the optimal treatment protocol are not yet fully understood and require further evaluation. Nevertheless, different clinical studies, the majority of them small, nonrandomized and uncontrolled, have now been reported and indicate that cell therapy seems safe, feasible, and potentially efficacious. The increasing number of ongoing studies, including large randomized double-blind studies, have the potential to determine the efficacy of cell therapy for stroke and to translate the preclinical findings into clinical practice.

Here is a commentary on what is known of the effects of calorie restriction in humans, and the prospects for determining whether or not it actually extends life in our species, from one of the foremost researchers in the field:

Calorie Restriction (CR) without malnutrition is the most powerful nutritional intervention that has consistently been shown to increase maximal and average lifespan in a variety of organisms, including yeasts, worms, flies, spiders, rotifers, fish and rodents. Far from merely stretching the life of an old, ill and weak animal, CR extends longevity by preventing chronic diseases, and by preserving metabolic and biological functions at more youthful-like state. In rodents, the CR-mediated preventive effects are widespread with major reductions in the occurrence and/or progression of cancer, nephropathy, cardiomyopathy, obesity, type 2 diabetes, neuro-degenerative disease, and several autoimmune diseases.

Whether or not CR without malnutrition will extend lifespan in humans is not known yet, but accumulating data indicate that moderate CR with adequate nutrition has a powerful protective effect against the development of obesity, type 2 diabetes, inflammation, hypertension and cardiovascular disease, which are major causes of morbidity, disability and mortality. In humans calorie restriction without malnutrition also results in a consistent reduction in circulating levels of growth factors, anabolic hormones, adipokines and inflammatory cytokines, which are associated with an increased risk of some of the most common types of cancer.

Moreover, CR in these individuals resulted in an amelioration of two well-accepted markers of cardiovascular aging, i.e. left ventricular diastolic function and heart rate variability. These data indicate that CR exerts direct systemic effects that counter the expected age-associated changes in myocardial stiffness and autonomic function so that LV diastolic function and heart rate variability indexes in CR individuals are similar to those of individuals 20 years younger on a typical Western diet. Consistently, we recently found that CR without malnutrition results in dramatic changes of the human skeletal muscle transcriptional profile that resemble those of younger individuals.

More studies are needed to understand how macro- and micro-nutrients, endurance exercise, and other environmental and psychological factors interact with CR in modulating metabolic and molecular pathways that regulate health and longevity. Randomized, CR-controlled, long-term survival studies in humans will never be performed because of obvious problems with long-term compliance and costs of such a long study. Nonetheless, we hope that by following the health status of individuals practicing long-term CR without malnutrition, in particular of those who are now in their 70s and 80s, we could gain soon some information about the effects of CR on successful aging and healthy longevity in humans as well. Because we have detailed information about their close relatives' disease and survival histories, if we observe that as the [CR practitioners] age, they don't develop any of the metabolic abnormalities and/or chronic diseases typical of their parents/siblings, and live substantially longer than their relatives, this will be the best available proof that CR works in humans.

Link: http://impactaging.com/papers/v5/n7/full/100581.html

Contrary to earlier research wherein scientists concluded that rapamycin extends life by slowing aging, here another group proposes that the extended life observed in laboratory animals results from cancer suppression, and aging isn't greatly impacted. Drugs that can slow aging are in any case a sideshow, a line of research that will require decades and billions but is incapable of producing ways to rejuvenate the old. Only SENS and similar repair-based research programs have the potential to result in therapies that will extend the healthy lives of the elderly and restore their lost vigor and youth. So if the scientific community is going to spend the few decades between now and my old age working on new medicine, I'd rather they ditched the old-style drug discovery pipeline in favor of a research strategy that is actually likely to benefit me. As to the debate on rapamycin:

Rapamycin is used in recipients of organ transplants, as it keeps the immune system in check and can consequently prevent rejection of the foreign tissue. In 2009, US scientists discovered another effect: Mice treated with rapamycin lived longer than their untreated counterparts. "Rapamycin was the first drug shown to extend maximal lifespan in a mammalian species. This study has created quite a stir. We wanted to address if rapamycin slows down aging in mice or, alternatively, if it has an isolated effect on lifespan - without broadly modulating aging."

"Our results indicate that rapamycin extends lifespan, but it has only limited effects on the aging process itself. Most aging traits were not affected by rapamycin treatment. Although we did observe positive effects on some aging traits, such as memory impairments and reduced red blood cell counts, our studies showed that similar drug effects are also seen in young mice, indicating that rapamycin did not influence these measures by slowing aging, but rather via other, aging-independent, mechanisms."

The researchers believe that such aging-independent drug effects also underlie rapamycin's effect on lifespan. "We assume that the lifespan of mice is extended because rapamycin inhibits tumor formation. This is a well-known rapamycin effect, which we were able to confirm. Cancer is the leading cause of death in the relevant mouse strains. Rapamycin, therefore, seems to have isolated effects on specific life-limiting pathology, but lacks broad effects on aging in mice."

"Generally speaking, our studies show that a number of different parameters have to be considered when assessing the efficacy of possible anti-aging interventions. The interpretation of the data depends heavily on the overall picture of findings. Lifespan measures alone are not a reliable indicator of anti-aging effects. This makes the search for anti-aging medicines tedious, but it is also very promising, because such substances could open up new possibilities for medicine. However, this is still some way off."

Link: http://www.dzne.de/en/about-us/public-relations/meldungen/2013/press-release-no-23.html

A growing number of celebrity figures publicly support the work on human rejuvenation carried out by the SENS Research Foundation. That work is nothing less than building therapies to treat, halt, and reverse degenerative aging. Researchers employed by and associated with the Foundation labor to create biotechnologies that can repair the known and identified causes of degenerative aging, the low-level forms of persistent damage that occur in and around our cells.

SENS stands for the Strategies for Engineered Negligible Senescence, the research plan to take us from describing known forms of biological damage all the way to the therapies that can repair that damage. At this point the SENS research programs are detailed and fully realized: they draw from existing work that has taken place over the past few decades in laboratories around the world, and in some cases just a few years of a dedicated, fully funded research program would be enough to produce the first demonstration of specific forms of biological repair of aging in mice. Other portions of SENS need much more work - but in all cases, it is very clear just what has to be done to get to the point of a working therapy. The only hurdles remaining are funding and public support.

Thus we come to the support of celebrities and public figures, people who tend to straddle the worlds of wealth and attention, the two line items that are needed to speed and expand work on SENS. The SENS Research Foundation showcases some of their celebrity supporters on the carousel page linked below, such as Edward James Olmos, Ray Kurzweil, and Peter Thiel:

SENS Research Foundation Celebrity Reimagine Aging Campaign

If you want to change the way you think about aging, you've come to the right place. This page features exclusive thoughts on the topic from leading actors, musicians, celebrities, and visionaries. You'll see how everyone's views on aging are different - and how the research that we're funding right now draws from the most positive aspects of them all.

Aging today is like tuberculosis at the dawn of the 20th century: a blight upon the human condition, a scourge to be eradicated, and the medical community beginning to head in the right direction to perform that eradication. As SENS Research Foundation supporter Peter Thiel says of aging:

Almost every human being who has ever lived is dead. Solving this problem is the most natural, humane, and important thing we could possibly do.

If you happen to be one of the celebrities or public figures in the Fight Aging! audience, allow me to point out that you could do some good here. Join the Reimagine Aging initiative, and lend your voice and influence to supporting the work of the SENS Research Foundation, still the only organization on the planet to have undertaken the vital role of coordination, funding, and advocacy for the development of rejuvenation biotechnology. The future of medicine, including ways to reverse aging and rejuvenate the elderly, will arrive at the pace it is developed. Speeding that pace is a matter of greater public awareness, understanding, and of course funding. The more help we all give to this cause, the more likely it is that we will live to see our old age abolished, our suffering alleviated, and our healthy, active lives restored - and to know that we aided in saving billions of lives from an early, slow death.

If we cannot accurately measure the progression of aging, then how do we establish whether a therapy under development meaningfully impacts aging? Animal studies will always precede human trials, and the necessary years will have been taken to measure changes in life span in short-lived species in the laboratory, but it is obviously out of the question to evaluate the effects on people by the wait-and-see method. A popular science piece here looks at the importance of the search for reliable ways to measure aging:

Don't look to online calculators of "biological age" for an answer. Those focus mainly on risk factors for diseases, and say little about normal aging, the slow, mysterious process that turns children to codgers. In fact, scientists are still hunting for biological markers of age that reliably register how fast the process is unfolding. Seemingly obvious candidates won't do. Wrinkles, for example, often have more to do with sun exposure than aging. Markers like age-related increases in blood pressure are similarly problematic, often confounded by factors unrelated to aging.

But recently researchers have identified some particularly good indicators of time's largely hidden toll on our bodies and how fast it's increasing. Experts on aging generally agree that acceptable biomarkers of aging should foretell the remaining life span of a middle-aged person more accurately than chronological age does. Further, they should offer a consistent picture of biological age. "Do those 50-year-olds with the best retention of immune function also tend to have the least cataracts, good sense of smell, least osteoporosis, lowest blood pressure and best memory?" Proposed biomarkers of aging haven't yet convincingly cleared these hurdles. But some provocatively telling ones have come to light.

Earlier this year [researchers] reported that a kind of molecular aging clock is embedded in our genomes whose speed can be measured via blood testing. The moving parts of the clock consist of chemical tags on DNA molecules that control whether genes are active in cells. The researchers found that the patterns of the tags, called epigenetic markers, predictably change with age. The scientists scrutinized around 485,000 of these tags in blood cells of 656 people aged 19 to 101. Some 70,387 tags were predictive of chronological age. Collectively these tags spell out "a signature for age that is largely not changed by disease or ethnic background." That means these markers may be less muddied by confounders than other factors tied to aging.

Link: http://www.nytimes.com/2013/07/23/health/meaningful-markers-of-aging.html

All sorts of maintenance processes operate in various parts of the cell. An important location is within the swarming herd of mitochondria, as damage there appears to be a significant cause of degenerative aging. Some forms of mitochondrial damage can evade the evolved means of repair and recycling, leading to dysfunctional mitochondria and dysfunctional cells that export harmful reactive compounds out into surround tissues. Can this process be slowed by boosting the operation of natural maintenance mechanisms, however? Arguably this is what happens in many of the methods demonstrated to extend life and slow aging in laboratory animals, such as calorie restriction, and here researchers are examining some of the relevant mechanisms in nematode worms:

NAD(+) is an important cofactor regulating metabolic homeostasis and a rate-limiting substrate for sirtuin deacylases. We show that NAD(+) levels are reduced in aged mice and Caenorhabditis elegans and that decreasing NAD(+) levels results in a further reduction in worm lifespan. Conversely, genetic or pharmacological restoration of NAD(+) prevents age-associated metabolic decline and promotes longevity in worms.

These effects are dependent upon the protein deacetylase sir-2.1 and involve the induction of mitonuclear protein imbalance as well as activation of stress signaling via the mitochondrial unfolded protein response (UPR(mt)) and the nuclear translocation and activation of FOXO transcription factor DAF-16. Our data suggest that augmenting mitochondrial stress signaling through the modulation of NAD(+) levels may be a target to improve mitochondrial function and prevent or treat age-associated decline.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23870130

In recent years a number of research groups have proposed that there exist populations of pluripotent stem cells in adult tissues, capable of forming any of the hundreds of different types of cell in the body. Different groups have different names for the cells they have found, but "very small embryonic-like stem cells" or VSELs is the name given by one of the more active researchers in this area. Greater confirmation or refutation of the existence of VSELs should also bias us one way or another for the various other researchers and their proposed pluripotent cell populations.

Why does this research matter? It is a matter of economics: if there is an easily accessible population of stem cells in every patient's skin that can be used to generate any type of cell in the body, then that will make a big difference to the pace at which regenerative therapies can be developed and deployed to the clinic, as well as making those therapies cheaper and faster. If, on the other hand, it turns out that adult tissues do not retain any sort of pluripotent stem cells, then it will require cell reprogramming to come to maturity in order to reach the same goals. All the other known and categorized stem cell populations in the adult body can be made to produce at best a couple of different types of cell, depending on their location and lineage.

Here, then, is a skeptical view on VSELs from researchers who have concluded that no such thing exists. Whenever you have a small number of researchers with differing opinions, the only thing to do is wait for more scientists to join in and produce further data:

A Wild Stem Cell Chase

The existence of very small embryonic-like stem cells (VSELs) has been hotly debated by scientists since they were first reported in mouse bone marrow in 2005. The cells were later identified in human blood and bone marrow as well, and have been proposed as a viable alternative to mouse and human embryonic stem cells (ESCs) in research and medicine. But a study published today [has] called the very existence of VSELs in question, with the senior author deeming them a "distraction."

Irving Weissman of Stanford University School of Medicine and his team set out to replicate the original finding of VSELs in mouse bone marrow, using the most rigorous protocols yet. They focused on identifying candidate VSELs by using the characteristics of size, phenotype, and pluripotency markers, but failed to find any cells that fit previous VSEL descriptions. The researchers found that the vast majority of events matching the estimated size of VSELs actually appeared to be artifacts, such as dead cells and debris. The team tested the remaining "exceedingly rare population" of cells that matched the VSEL profile for pluripotency markers without luck. "The claims about VSELs were not yet replicated by independent scientists. We redid the experiments as they have been described and could not confirm what was claimed."

Meanwhile, researchers continue to make progress on reprogramming of cells, but years lie between here and widespread use of therapies based on these technologies. The first early stage clinical trials using reprogrammed cells are only just starting now in Japan:

In the seven years since their discovery, induced pluripotent stem (iPS) cells have transformed basic research and won a Nobel prize. Now, a Japanese study is about to test the medical potential of these cells for the first time. Made by reprogramming adult cells into an embryo-like state that can form any cell type in the body, the cells will be transplanted into patients who have a debilitating eye disease. Masayo Takahashi, an ophthalmologist at the RIKEN Center for Developmental Biology in Kobe, Japan, plans to submit her application for the study to the Japanese health ministry next month, and could be recruiting patients as early as September.

A time-honored journalistic strategy is to put two interesting people with disparate views on their field in the same room to see what they have to say. In this case the subject is aging, longevity, and the prospects for extending healthy human life spans. The introductory blurb is quoted below, but the piece is long, with a lot of commentary from the participants - so click through and read the whole thing:

Bortz and de Grey have never met before, but they have a lot to talk about. I've asked them to come to the Tied House today - de Grey from eight blocks away, where his SENS (Strategies for Engineered Negligible Senescence) Research Foundation is headquartered; Bortz from nearby Stanford, where he teaches medicine - to discuss a subject that has obsessed both of them for decades: the process of aging, and how it may change in the decades ahead. Questions about the future of aging have been in the air lately. Are humans on the cusp of living to 120, 130, or more? What will aging look like in this new world of longevity? Will we just be adding 30, 40, 50 years to the end of life, or can we delay the process and lead normal lives to such advanced ages? Is 100 the new 60?

Neither Bortz nor de Grey is a stranger to publicity. A former co-chairman of the American Medical Association's Task Force on Aging and past president of the American Geriatrics Society, Bortz, a physician by training, is one of America's foremost experts on robust aging, having published more than 150 scientific articles on the subject. His "thesis," as he calls it, is that exercise is the key to extending the human life span. "We know enough to live 100 healthy years," Bortz says, "but we screw it up."

De Grey, meanwhile, has been a favorite subject for journalists since the early 2000s. As an undergraduate at Cambridge, he studied computer science; his specialty was artificial intelligence. But soon after graduation, he met and married Adelaide Carpenter, a Cambridge fruit-fly geneticist 19 years his senior, took over the genetics department's drosophila database, and immersed himself in the biology of aging. In 1999, de Grey published The Mitochondrial Free Radical Theory of Aging; a year later, Cambridge awarded him a Ph.D.

De Grey's new theories were grand. He believed that by dividing the diseases of old age into seven categories of cellular and molecular damage, and then by working to conquer each category through as-yet-undeveloped medical technologies, it would be possible to "cure" aging - not to stop it, or to slow it, but to repair and reverse it, the way one would restore an aging automobile, and to live indefinitely as a result. In 2000, de Grey co-founded the Methuselah Foundation, which awarded multimillion-dollar grants to scientists who extended the healthy life span of mice, and in 2009, the organization evolved into SENS, a nonprofit that sponsors and funds scientific rejuvenation research. Its major benefactor is Peter Thiel, the billionaire founder of PayPal.

Link: http://www.thedailybeast.com/newsweek/2013/07/24/you-can-live-forever-is-immortality-plausible-or-is-it-quack-science.html

Insulin-like growth factor 1 (IGF-1) is one of the better studied components of metabolic pathways and mechanisms linked to longevity. Despite the many researchers and numerous years of work involved metabolism is so complex that there is still a very long way to go yet before the research community can establish complete understanding of what is actually going on in long-lived mutant mice with different levels of IGF-1. The cost and very slow pace of progress in the face of this complexity is one of the reasons why trying to slow aging by altering metabolism is a terrible choice of strategy for human life extension - we should instead focus on what we do understand well, which is how to repair the low-level cellular damage that causes aging, and keep the metabolism we have already.

Here is an example of continuing work on IGF-1 in mice, a confirmation of extended life, which is the sort of thing that keeps the grant funds coming for further efforts to figure out what is going on under the hood:

Reduced signaling through the IGF type 1 (IGF-1) receptor increases life span in multiple invertebrate organisms. Studies on mammalian longevity suggest that reducing levels of IGF-1 may also increase life span. However, the data are conflicting and complicated by the physiology of the mammalian neuroendocrine system.

We have performed life-span analysis on mice homozygous for an insertion in the Igf1 gene. These mice produce reduced levels of IGF-1 and display a phenotype consistent with a significant decrease in IGF-1. Life-span analysis was carried out at three independent locations. Although the life-span data varied between sites, the maximum life span of the IGF-1-deficient mice was significantly increased and age-specific mortality rates were reduced in the IGF-1-deficient mice; however, mean life span did not differ except at one site, where mean life span was increased in female IGF-1-deficient animals. Early life mortality was noted in one cohort of IGF-1-deficient mice.

The results are consistent with a significant role for IGF-1 in the modulation of life span but contrast with the published life-span data for the hypopituitary Ames and Snell dwarf mice and growth hormone receptor null mice, indicating that a reduction in IGF-1 alone is insufficient to increase both mean and maximal life span in mice.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23873963

We age because damage accumulates at the lowest levels of our biological structures, in and around the protein machinery of our cells. But an individual is not a static structure: we are not like buildings or cars because our machinery can repair and replace itself to an impressive degree. Cells accumulate enormous numbers of defects in their proteins and large component parts - such as mitochondria - on a day to day basis, and garbage in the form of metabolic waste products and broken or proteins accumulates constantly. The vast majority of these issues are repaired and removed extremely quickly.

The real downward slope in aging occurs when the mechanisms governing repair and maintenance start to fade. The advocates of programmed aging would say that this decline is the result of an unfortunate continuation of genetic programs that were necessary or advantageous in early life, but now become harmful. But most of the research community think that it's all still damage - it's just that the dynamic relationship between damage and health in a self-repairing system is much more complex than it is in a static structure. Damage accumulates, and some forms of damage cause a breakdown in the systems that remove damage: hence you wind up with what is known as the garbage catastrophe.

Researchers can explain genetic degenerative diseases that only manifest after a few decades of life in terms of this failure of maintenance: an individual that suffers far more damage than others due to an errant gene has cells that can keep up the pace in youth, but which lose the battle earlier in the process of declining repair with age. Neurodegenerative conditions like Parkinson's disease can be framed in this way as garbage catastrophes: the genetic associations determine who is being more rapidly damaged in some cell populations and thus more quickly overwhelmed.

Processes of cellular repair, such as autophagy, are considered important in how metabolism determines longevity: most methods of extending life by slowing aging in laboratory animals involve increased levels of autophagy, implying cells and cellular mechanisms that are less damaged for longer periods of time. Calorie restriction, for example, boosts autophagy. Scientists have been looking into increased autophagy as the basis for therapies for some years, as in this recent example of ongoing research into the genetic condition of Huntington's disease:

NIH-funded study finds that quickly clearing away damaged proteins may help prevent neurodegenerative disorders

Researchers investigated how cells deal with different forms of huntingtin, the protein involved in Huntington's. The mutant version of huntingtin is longer, and contains three building blocks of the protein repeated an abnormal number of times. These repeats in huntingtin are what cause it to misfold, eventually leading to neuron death and the symptoms of the disease.

The researchers found that the amount of time the mutant protein remained in the cell predicted neuronal survival: shorter mean lifetimes of mutant huntingtin were associated with longer neuronal survival. A shorter mean lifetime indicates that a protein does not remain in the cell for a long time, and that proteostasis is working effectively to clear it away. This suggests that improving proteostasis in Huntington's brains may improve neuronal survival.

To test this idea, the researchers activated Nrf2, a protein known to regulate protein processing. When Nrf2 was turned on, the mean lifetime of huntingtin was shortened, and the neuron lived longer. "Nrf2 seems like a potentially exciting therapeutic target. It is profoundly neuroprotective in our Huntington's model and it accelerates the clearance of mutant huntingtin. One surprising finding from these experiments was the significance of single cells' ability to clear mutant huntingtin. It turned out that this ability largely predicted their susceptibility, whether that neuron came from the most vulnerable region of the brain - the striatum - or the cortex, which is less vulnerable."

The findings indicate that the toxicity of the damaged proteins may cause neurodegeneration by interfering with the proteostasis system, affecting how quickly they are cleared from neurons. The researchers explored potential mechanisms behind differences in proteostasis. One way that cells normally get rid of proteins is through autophagy - a process in which proteins are packed up into spheres and then broken down. Results in this paper suggested that neurons increased the rate of autophagy when they sensed that the mutant form of huntingtin was accumulating, indicating the autophagy system may be a drug target.

"These findings provide evidence that our brains have powerful coping mechanisms to deal with disease-causing proteins. The fact that some of these diseases don't cause symptoms we can detect until the fourth or fifth decade of life, even when the gene has been present since birth, suggests that those mechanisms are pretty good."

Nrf2 is involved in the beneficial hormetic response to low levels of damage associated with calorie restriction, exercise, and the like. Interestingly long-lived naked mole rats have more Nrf2 in their cells, and the same is true of other long-lived species that appear to share a more effective cellular repair and maintenance response than their shorter-lived peers. Research of this nature all suggests that greatly boosted autophagy is a good thing to aim for as the basis for a therapy of general application - it's something that everyone should have turned on all the time.

These days immortality is a lazy shorthand for vulnerable agelessness attained though medical technology: your body won't kill you while you have access to preventative therapies to treat aging, but falling pianos can still ruin your day. Aiming at the goal of indefinitely extended healthy lives is decried in some quarters, but the arguments marshaled against efforts to make the human condition better by eliminating the pain and suffering of degenerative aging have never looked all that coherent to me:

I was a bit perplexed, to say the least, when I read Big Think blogger John N. Gray's article "Immortality is a Waste of Time." His entire argument revolved around the notion that, because of unknown contingencies throughout life, the act of curtailing death's inevitability and infinity is thus a waste of time, money, thought and anxiety.

This is absurd. An absurdity flooded with fear-mongering imagery of our future, claiming the acts of planning for our possible deaths as being equivalent to "a society that is one of cryonic suspension, a freezer-centered society, a society in which we spend our thoughts, our desires, our passions, our incomes on tending freezers." Tending freezers, he says? Like we tend to our graveyards, our crematoriums, and mausoleums? Examples, I might add, to which wastes precious land to accommodate the bodies and/or ashes of our long-since-deceased (or soon-to-be-deceased) loved ones.

This notion that "history will go on," all while admitting that it "makes good sense to take care of your health, to try to remain healthy for as long as possible" and that "we should use the new technologies to enhance the mortal life we have," is contradictory and ahistorical. History most certainly went on, but then the goings-on of history were determined - not by a lack of care for what our future holds for us, but - by a global society who no longer saw it fit to merely live by age 30, or to go days without food, or to suffer from terrible diseases due to complete lack of medical aid and knowledge. Our society has spent centuries upon centuries fighting for a better world not just for themselves, but for those who'll come after them. Maybe our efforts won't lead to immortality in our lifetime. But then when is a good time to fight for it? Should we simply condemn our future relatives to a life - albeit one certainly going on - flooded with problems that could have been alleviated, if not addressed completely beforehand?

Link: http://ieet.org/index.php/IEET/more/murphy20130717

Calorie restriction is known to improve memory and slow the age-related decline of specific measures of brain health. Here is another example of research that reinforces the evidence for this benefit, as researchers start to spend more time on searching for differences in outcome in different implementations of calorie restriction:

Caloric restriction (CR) is argued to positively affect general health, longevity and the normally occurring age-related reduction of cognition. This issue is well examined, but most studies investigated the effect of short-term periods of CR. Herein, 4 weeks old female mice were fed caloric restricted for 4, 20 and especially for 74 weeks. CR mice received 60% of food eaten by their ad libitum (AL) fed littermates, and all age-matched groups were behaviorally analyzed.

The motor coordination, which was tested by rotarod/accelerod, decreased age-related, but was not influenced by the different periods of CR. In contrast, the age-related impairment of spontaneous locomotor activity and anxiety, both being evaluated by open field and by elevated plus maze test, was found aggravated by a lifelong CR. Measurement of cognitive performance with morris water maze showed that the working memory decreased age-related in AL mice, while a lifelong CR caused a better cognitive performance and resulted in a significantly better spatial memory upon 74 weeks CR feeding. However, a late-onset CR feeding in 66 weeks old mice did not ameliorate the working memory. Therefore, a lifelong CR seems to be necessary to improve working memory.

Link: http://dx.doi.org/10.1371/journal.pone.0068778

In statistical studies of health, considering the life histories, longevity, and mortality rates within a large group of individuals, researchers have found that calorie restriction and exercise have positive effects on long-term health that are large in comparison to all other positive influences measured to date. No widely available medical technology can yet grant even a sizable fraction of the additional healthy years of life that are available for free through the adoption of a better lifestyle. The most important goals in medicine - and all technology for that matter - for the next few decades involve making that last statement a thing of the past. That will involve finding ways to rejuvenate the old and extend healthy life far beyond what can be attained through today's technologies and techniques.

Meanwhile, the size of the influence of calorie restriction and exercise means that we have to eye every study in laboratory animals to see whether the researchers have accounted for differences between their groups. In human epidemiological studies, we have to ponder whether the researchers are correctly adjusting their results for these influences, or whether the associations that they identify between health or longevity and other characteristics are in fact just reflections of a deeper relationship with calorie intake or exercise.

In recent years a number of studies have claimed relationships between human mortality rates and various character traits. Researchers have standardized measures of personality, and those can be matched up with mortality in a range of different study data sets to show that some types of personality tend to live longer. One explanation is that this all comes to down to, say, ability to earn, and is thus just another facet of the standard issue correlation between wealth and longevity. Another theory is much the same, except replace wealth with conscientiousness and its effects on health maintenance.

But might it all be largely a matter of correlations with calorie intake? In a society in which calories are easy to come by, where in fact we need to actively refrain from eating more than is good for our long term health, the correlation between character and long term health might be much more pronounced than in past centuries. Yet this is only because calorie intake is such a strong determinant of the trajectory of health and mortality across a life span. So it is interesting to see people finding correlations between diet and personality:

Personality and Dietary Intake - Findings in the Helsinki Birth Cohort Study

We set out to study the associations between personality traits, resilience and food and nutrient intake in 1681 Finns in late adulthood. As hypothesized, neuroticism was associated with mainly poorer dietary quality as the intakes of fish and vegetables were lower and intake of soft drinks was higher, but this applied to women only. In line with our hypothesis, we observed extraversion being e.g. associated with a higher vegetable intake in women. Openness was associated with higher intakes of vegetables and fruits in both genders. Agreeable women showed favorable trends, as did conscientious women, the latter reporting e.g. a higher fruit intake. Some of these trends were further strengthened when testing subjects with resilient vs. non-resilient personality profiles; resilient women reported higher intakes of vegetables, fruits, fish, and dietary fiber and lower intake of alcohol. Our results were in line with our original study hypothesis and the associations were not due to age, educational attainment, or total energy intake.

Our result that neuroticism was associated with several unfavorable dietary intakes is consistent with two previous cross-sectional studies. One study in Japanese students found neuroticism to be associated with intakes of sweet and salty foods while a Scottish study found, high neuroticism to be associated with a traditional convenience diet (eating more tinned vegetables, meat pies, pasties and sausage rolls, puddings etc.) and low neuroticism to be associated with a Mediterranean-style diet. A recent Estonian study also found low neuroticism to be associated with a health aware dietary pattern. Our results are also in line with findings showing that high neuroticism is associated with obesity, metabolic syndrome and an increased risk for [cardiovascular_disease].

This study doesn't have anything to say about calorie level variations, but one might assume that where there is variation in constituents there will also be variation in calories.

Studies of human health are usually snapshots of a large population over a small fraction of their lives, gathering data so that researchers can use statistical methods to make inferences and identify correlations between lifestyles or genetics and health outcomes. There are many pitfalls here, not least of which is the tendency to lump together several groups with very different risks into one group, because the researchers didn't have the resources or the necessary data to dig deeper. For example, there is the business of risk levels between groups at various levels of alcohol consumption quoted below (wherein alcohol consumption habits are probably themselves strongly associated with lifestyle packages, wealth, conscientiousness, and other harder-to-measure line items that influence how well people tend to make use of medical services and how well they tend to take care of their health).

In an age of rapid progress in biotechnology, lifestyle choices like whether your drink a little or less than a little will soon become irrelevant to the general trajectory of your future health. Your future life span near-entirely depends on how fast rejuvenation therapies such as those featured in the Strategies for Engineered Negligible Senescence (SENS) proposals can be built. I point out this research by way of an example of one of the many systematic ways in which scientific work can be incomplete, misleading, or flawed, and encourage you think of it every time you look at another epidemiological study, so as to wonder what the authors there might be missing.

Multiple studies have shown that the likelihood of dying for people who drink increases as they consume more alcohol. Those same studies have shown that a person's mortality risk also increases at the other end of the spectrum - among people who choose not to drink at all - though the risk is still much less than for heavy drinkers. Some researchers have hypothesized that the increased mortality among nondrinkers could be related to the fact that light alcohol consumption - drinking, on average, less than one drink a day - might actually protect people from disease and reduce their stress levels.

But [other researchers] decided to examine whether characteristics of different subgroups of nondrinkers could explain the increased mortality risk. "Among nondrinkers, people have all sorts of background reasons for why they don't drink. We wanted to tease that out because it's not really informative to just assume that nondrinkers are a unified group." [The researchers] lied on data collected in 1988 by the National Health Interview Survey about the drinking habits of more than 41,000 people from across the United States. The researchers also had access to information about which respondents died between taking the survey and 2006. During the survey, nondrinkers were asked to provide their reasons for not drinking.

The research team divided nondrinkers into three general categories: "abstainers," or people who have never had more than 12 drinks in their lives; "infrequent drinkers," or people who have fewer than 12 drinks a year; and "former drinkers." Each category was further divided using a statistical technique that grouped people together who gave similar clusters of reasons for not drinking. The team then calculated the mortality risk for each subgroup compared with the mortality risk for light drinkers, and they found that the risks varied markedly.

Abstainers who chose not to drink for a cluster of reasons that included religious or moral motivations, being brought up not to drink, responsibilities to their family, as well as not liking the taste, had similar mortality risks over the follow-up period to light drinkers. Former drinkers, however, had the highest mortality risk of all nondrinkers. Former drinkers whose cluster of reasons for not drinking now included being an alcoholic and problems with drinking, for example, had a 38 percent higher mortality risk than light drinkers over the follow-up period. "So this idea that nondrinkers always have higher mortality than light drinkers isn't true. You can find some groups of nondrinkers who have similar mortality risks to light drinkers."

Link: http://www.sciencedaily.com/releases/2013/07/130719085257.htm

At this point the general consensus is that dietary supplementation of antioxidant compounds is of either no benefit or mildly harmful to long term health. The only methods of extending life via the introduction of antioxidant compounds involve careful targeting to the mitochondria, such that damaging oxidant molecules generated there are swept up, but the oxidant molecules used in signaling processes elsewhere in cells and tissues are not. The benefits of exercise, for example, rest upon slightly raised levels of reactive oxygen species which can be blocked by high levels of antioxidants in the diet:

In older men, a natural antioxidant compound found in red grapes and other plants - called resveratrol - blocks many of the cardiovascular benefits of exercise. What is emerging is a new view that antioxidants are not a fix for everything, and that some degree of oxidant stress may be necessary for the body to work correctly. This pivotal study suggests that reactive oxygen species, generally thought of as causing aging and disease, may be a necessary signal that causes healthy adaptations in response to stresses like exercise. So too much of a good thing (like antioxidants in the diet) may actually be detrimental to our health.

We studied 27 healthy, physically inactive men around 65 years old for 8 weeks. During the 8 weeks all of the men performed high-intensity exercise training and half of the group received 250 mg of resveratrol daily, whereas the other group received a placebo pill (a pill containing no active ingredient). The study design was double-blinded, thus neither the subjects nor the investigators knew which participant that received either resveratrol or placebo.

"We found that exercise training was highly effective in improving cardiovascular health parameters, but resveratrol supplementation attenuated the positive effects of training on several parameters including blood pressure, plasma lipid concentrations and maximal oxygen uptake. We were surprised to find that resveratrol supplementation in aged men blunts the positive effects of exercise training on cardiovascular health parameters, in part because our results contradict findings in animal studies. It should be noted that the quantities of resveratrol given in our research study are much higher than what could be obtained by intake of natural foods."

Link: http://www.eurekalert.org/pub_releases/2013-07/w-at071913.php

It is no big secret that connections make the world go round - though it certainly took me far too long to realize the primacy of networking over talent, hard work, and all the other virtues. You can be exceptional, but that contributes little to your chances of success in life if no-one knows about it. If you want to work at the best and most important tasks in your field, then you have to make connections with the people who are doing that already. No-one collaborates with random folk from out of the blue: they hire the people they know and they form companies with the people they know. It is routinely the case that connections will put you in the position to become good far more reliably than being good will put you in the position to make connections.

If you are a successful, motivated student in the medical life sciences, working in a field such as genetics, molecular biology, bioinformatics, and so on, then you are already good, a cut above the average. But are you setting yourself up for mediocrity and a hard time in your industry by virtue of failing to put yourself out there? Internships are one way to build the connections needed to get the choice opportunities that only come to those in the network, but don't wait to go through formal channels. There are no rules to these things. Do you like the work that a particular laboratory is doing? Then contact the people working on it and say something. Reach out and make the connection.

Even in an exciting, rapidly growing, changing, revolutionary industry like the intersection of biotechnology and medicine there are the doldrums and the bad jobs and the make-work and the dross. Molecular biologists with connections have the choice of filtering that out to attempt world-changing research in young companies or well-known laboratories - while the rest get to slog through the job market looking for something that is work, not a vocation.

My recommendation for today: the most important research of the next few decades revolves around rejuvenation, the repair of the causes of aging, and producing cures for age-related conditions that work in entirely new ways. At the center of all the myriad connections and relationships in this research community are the folk who work with the SENS Research Foundation. The Foundation is very interested in producing the molecular biology community of the future to expand work in this area and see it through to completion, and hence they offer many opportunities to students: internships, the opportunity to build connections, and so on. But to hell with the structure of it - that's just a suggestion, not a set of rules carved in stone. If you can read the Foundation's research reports, and look at the cutting edge work that they sponsor and be excited about it, then just open up a dialog. Reach out, let them know you exist and are interested: that already puts you far ahead of the rest of the field.

Becoming known to the SENS Research Foundation principals and researchers is something that you can make pay off: not just the chance to do things that are truly meaningful in medical research, but also to forge the connections that will allow you to have the career that you want to have, rather than the career that you have to settle for. The Foundation staff know everyone who is anyone in the life science fields and laboratories that are important to aging and future medicine to prevent and reverse aging.

So, look, let me point out exactly what I mean by all of this, by way of directing your attention to the outcome of a 2012 internship at the SENS Research Foundation:

Jennie received her B.A. with majors in Molecular Cellular and Developmental Biology, Integrative Physiology, and Neuroscience, from the University of Colorado at Boulder in May 2012. During her internship with SENS Research Foundation (SRF) in Mountain View, CA, Jennie attempted to identify genes involved in the Alternative Lengthening of Telomeres (ALT) Mechanism.

After completing her summer internship, Jennie was recruited by former SRF researchers in Central New York and co-founded Ichor Therapeutics, Inc. The company works to develop and commercialize research and clinical products in the field of regenerative medicine. She is listed as co-author on the company research and business proposal that landed a $450,000 seed grant from Life Extension Foundation. In addition to her work at Ichor, she is currently a laboratory assistant at the lab of Dr. Sarah E. Hall at Syracuse University's College of Arts and Sciences.

Other interns have similar stories of success and impressive placements. People do not get randomly recruited by startups, or randomly raise funds from the LEF - it happens because of who you know. The best opportunities only arise because of the people that you know, and because of the people who know that you exist. So make connections, and more to the point take the actions that will raise the odds of you being able to make high quality connections in your industry. If you are in molecular biology, bioinformatics, or a similar field, then you should talk to the SENS Research Foundation, take it from me. They have a very impressive network, and they are the ground floor of what will be the dominant medical industry of the 2020s and later decades.

The microRNA let-7 has been shown to be involved in maintenance of stem cell populations. It was mentioned in research in flies from last year: let-7 levels rise with aging, causing other changes in various proteins which result in a reduced number of stem cells that are active and maintaining tissues. Here researchers investigate let-7 in nematode worms in connection with the regenerative capacity of nerve tissue:

Like mammalian neurons, C. elegans neurons lose regeneration ability as they age, but it is not known why. C. elegans is a soil worm with its brain wiring diagram being mapped entirely - every connection between every nerve cell. Forty percent of genes identified in the worm genome have a counterpart in humans. Genes that allow neurons to connect with each other to form functional neuronal circuits and to regenerate themselves after injury are highly similar between worms and humans. Thus, what we learn in worms will likely be relevant to the development and regeneration of the human nervous system. The let-7 microRNA and its target, the LIN-41 tripartite motif protein, were recently shown to function as neuronal timers in worms to time the decline of the ability of neurons to regenerate as they age

Since let-7 and lin-41 genes are broadly expressed in different types of neurons, their roles in neuronal regeneration may be widespread. In addition to let-7, many microRNAs are also expressed in postmitotic neurons, raising the possibility that other microRNAs could also contribute to developmental decline in neuronal regeneration. In C. elegans, many aged neurons display a further decline in axon regeneration. In [at least some] aged neurons, a reduced let-7 remains able to enhance axon regeneration so it is likely that let-7 continues to contribute to the further decline in axon regeneration in aged neurons.

These discoveries have important implications in treating brain and spinal cord injury or neuro-degenerative diseases as they show that it may be possible to improve the ability of neurons in the adult brain to regenerate after injury through therapeutic inhibition of the let-7 microRNA, and thereby restore their youthful regenerative capacity. The idea of slowing down neuronal aging to promote axon regeneration after injury is an appealing possibility.

Link: http://www.impactaging.com/papers/v5/n7/full/100574.html

Exercise extends average life spans (but not maximum life spans) in laboratory animals and improves long term health. In human epidemiological studies it is associated with better health and greater life expectancy. Here is another of the many, many examples of this relationship:

In a study of more than 27,000 Americans, 45 years and older who were followed for an average of 5.7 years, researchers found: 1) One-third of participants reported being inactive, exercising less than once a week. 2) Inactive people were 20 percent more likely to experience a stroke or mini-stroke than those who exercised at moderate to vigorous intensity (enough to break a sweat) at least four times a week. 3) Among men, only those who exercised at moderate or vigorous intensity four or more times a week had a lowered stroke risk. 4) Among women, the relationship between stroke and frequency of activity was less clear.

"The stroke-lowering benefits of physical activity are related to its impact on other risk factors. Exercise reduces blood pressure, weight and diabetes. If exercise was a pill, you'd be taking one pill to treat four or five different conditions." The study - the first to quantify protective effects of physical activity on stroke in a large multiracial group of men and women in the United States - supports previous findings that physical inactivity is second only to high blood pressure as a risk factor for stroke.

Link: http://www.eurekalert.org/pub_releases/2013-07/aha-bas071513.php

A great deal of research into fundamental mechanisms associated with aging and the way in which metabolism determines variations in natural longevity has been carried out - and is still carried out - using yeast cells. The phenomenon of enhanced health and longevity with calorie restriction exists in yeast, for example, and involves similar mechanisms to those found in mammals. It is not the only common point of reference.

Yeasts are not animals, but rather forms of fungus, or at least belong to various branches of that large taxonomy. But what about the kingdom of plants? Plants age, and that fact can be investigated, and the mechanisms compared with those of mammals. Yet their cells are are arguably more different from ours than are those of yeast, so can the study of aging in plants be expected to yield anything that is of practical value when it comes to intervening in mammalian aging to extend healthy life? There are researchers who think so, and this open access paper serves as an overview of some of their arguments, with pointers to other papers in a recent issue of the Journal of Ecology:

Plants do not count... or do they? New perspectives on the universality of senescence

Surprisingly, little is known about the general patterns, causes and consequences of whole-individual senescence in the plant kingdom. There are important differences between plants and most animals, including modular architecture, the absence of early determination of cell lines between the soma and gametes, and cellular division that does not always shorten telomere length. These characteristics violate the basic assumptions of the classical theories of senescence and therefore call the generality of senescence theories into question.

Most classical theories of senescence were developed with an implicit general animal or explicit human bias in mind. In spite of taxonomic biases, understandably driven by an anthropocentric interest in delaying death and improving life quality at advanced ages, the claim has been made that senescence is universal. Hamilton stated that senescence should occur even 'in the farthest reaches of almost any bizarre universe'. His assertion is of broad interest to evolutionary biologists in general and plant ecologists in particular because (i) it suggests the existence of a universal rule of ecology and evolution that is yet to be tested, and (ii) it obviously suggests that plants are not immune from senescence.

The universality of senescence rests on the assumption that the wear-and-tear of life is cumulative and inescapable over an organism's life span because time flows only in one direction. Yet, plants show extreme plasticity, being able to retrogress to juvenile stages under specific conditions. Chen et al. recently showed that the genetic and physiological activity of grafted stems of Sequoia sempervirens is the same as that in juveniles and very distinct from that of ungrafted adults. Plants have been historically considered as populations of modules in a continuous state of renewal and replacement, allowing continuous whole-plant rejuvenation. The relationship between leaf senescence, module senescence and whole-plant senescence remains largely unexplored, and yet full of potential. For instance, many species (e.g. the orchid Spiranthes spiralis) completely renew their photosynthetic and below-ground storage tissues annually. These species are potentially in a state of 'perpetual somatic youth'.

The field of senescence is by historical inertia dominated by research on humans. The main emphasis of research into senescence to date has been on whether and how humans can slow it down, and even postpone it. We argue that there are at least three reasons why human demographers, animal ecologists and plant population ecologists should work together.

First, all three parties are currently asking the same questions, although perhaps with different terminology. Human demographers are interested in how cultural background and migration affect population dynamics and senescence rates, whereas animal and plant population ecologists are interested in maternal effects and dispersal.

Second, senescence is a phenomenon caused by evolutionary processes, and the comparative method has previously proved useful in ascertaining the ecological and physiological processes necessary for its evolution. Research that ignores taxonomic boundaries will advance our understanding of evolutionary senescence.

Thirdly, for decades, animal demographers have been developing robust statistical tools to explore the evolution of senescence that account for differences between individuals within populations with imperfect long-term data. All of these techniques could prove useful in the plant world too, particularly in the examination of long-lived species. Furthermore, we argue that the transfer of knowledge between these research factions should be tri-directional. For instance, the work by Caswell & Salguero-Gómez [introduces] a novel method for quantifying selection gradients on age and stage in plants that is equally applicable to the analyses of data from humans and the rest of the animal kingdom.

I would argue that continuous renewal seen in some plant species is similar in relevance to the exceptional regeneration of hydra, or the strange life cycle of the jellyfish Turritopsis Dohrnii - by which I mean interesting, but not of any great relevance to human aging. Plants and hydra and jellyfish all lack the complex structures that higher animals possess. We can't just regenerate everything or throw away the majority of our body or regress back to earlier life stages because we have minds and other systems that are bound to the physical structure and specific existing cells of our nerve and brain tissue. Becoming complex seems to have the attached cost of a loss of regenerative capacity, except when it comes to our germ cells and early embryos, which seem quite capable of rejuvenation when needed. But then they are not possessed of complex structures, and arguably have more in common with the hydra than with an adult individual.

Damaging reactive oxygen species (ROS) and other free radicals are generated within your cells, largely as a result of the day to day operations of mitochondria, the power plants of the cell that produce chemical energy stores used by cellular processes. Too many free radicals produce the state called oxidative stress, in which a cell struggles to keep up with the repair of its protein machinery. Oxidative stress increases with age: this is thought to be due to increasing dysfunction in mitochondria, and to be a root cause of degenerative aging.

It's not quite so simple, however, as the presence of oxidative molecules in our biology is vital to life. Evolution eagerly uses and reuses every cog, nut, and bolt that happens to be to hand, and so ROS are involved in a range of essential cellular mechanisms. Low levels of ROS are usually beneficial and necessary, while high levels are usually damaging and bad. (Unless you are a naked mole rat, in which case high levels seem to be business as usual and something to be shrugged off in the course of living for an exceedingly long time). Biology is a complex business, and it is always the case that the details matter: you can't just talk about ROS levels, but have to talk about where, when, how they change, and their interaction with other processes.

Under normal physiological conditions, reactive oxygen species (ROS) serve as 'redox messengers' in the regulation of intracellular signalling, whereas excess ROS may induce irreversible damage to cellular components and lead to cell death by promoting the intrinsic apoptotic pathway through mitochondria. In the aging process, accumulation of mitochondria DNA mutations, impairment of oxidative phosphorylation as well as an imbalance in the expression of antioxidant enzymes result in further overproduction of ROS. This mitochondrial dysfunction-elicited ROS production axis forms a vicious cycle, which is the basis of mitochondrial free radical theory of aging. In addition, several lines of evidence have emerged recently to demonstrate that ROS play crucial roles in the regulation of cellular metabolism, antioxidant defence and posttranslational modification of proteins.

We first discuss the oxidative stress responses, including metabolites redistribution and alteration of the acetylation status of proteins, in human cells with mitochondrial dysfunction and in aging. On the other hand, autophagy and mitophagy eliminate defective mitochondria and serve as a scavenger and apoptosis defender of cells in response to oxidative stress during aging. These scenarios mediate the restoration or adaptation of cells to respond to aging and age-related disorders for survival.

In the natural course of aging, the homeostasis in the network of oxidative stress responses is disturbed by a progressive increase in the intracellular level of the ROS generated by defective mitochondria. Caloric restriction, which is generally thought to promote longevity, has been reported to enhance the efficiency of this network and provide multiple benefits to tissue cells. In this review, we emphasize the positive and integrative roles of mild oxidative stress elicited by mitochondria in the regulation of adaptation, anti-aging and scavenging pathway beyond their roles in the vicious cycle of mitochondrial dysfunction in the aging process.

Link: http://dx.doi.org/10.1177/1535370213493069

Researchers here explore changes that occur in gut bacteria populations as a result of the practice of calorie restriction. The challenge for assigning causes to the extended longevity produced by a calorie restricted diet in laboratory species such as mice is that calorie restriction changes near every measurable aspect of metabolism: it is a system-wide and sweeping alteration of state. So we should not be surprised to see that populations of bacteria in the body also change - but is that an important effect in comparison to other fundamental alterations in cellular metabolism?

Calorie restriction has been regarded as the only experimental regimen that can effectively lengthen lifespan in various animal models, but the actual mechanism remains controversial. The gut microbiota has been shown to have a pivotal role in host health, and its structure is mostly shaped by diet. Here we show that life-long calorie restriction on both high-fat or low-fat diet, but not voluntary exercise, significantly changes the overall structure of the gut microbiota of C57BL/6 J mice.

Calorie restriction enriches phylotypes positively correlated with lifespan, for example, the genus Lactobacillus on low-fat diet, and reduces phylotypes negatively correlated with lifespan. These calorie restriction-induced changes in the gut microbiota are concomitant with significantly reduced serum levels of lipopolysaccharide-binding protein, suggesting that animals under calorie restriction can establish a structurally balanced architecture of gut microbiota that may exert a health benefit to the host via reduction of antigen load from the gut.

Link: http://dx.doi.org/10.1038/ncomms3163

This month's issue of Life Extension Magazine contains an interview with SENS Research Foundation cofounder Aubrey de Grey by Ben Best, a noted figure in the cryonics and longevity advocacy communities. The SENS Research Foundation runs a research program that aims to produce the foundation technologies to create human rejuvenation by means of repairing the low-level damage to cells and protein structures that causes aging.

As an aside, I should say that the Life Extension Foundation (LEF) and their Life Extension Magazine are a very mixed house: on the one hand the founders use some of the profits of their business to fund serious modern research, including improvements in cryonics, and through their magazine introduce a broader readership to some of the cutting edge work on the foundations of human rejuvenation presently taking place. On the other hand, this is all built upon the business of selling supplements, which is not something that can in any way greatly extend human life expectancy. The vast majority of the impact that the LEF has is to promote supplements as a way to extend life - and this simply isn't a viable path forward to the future. The world would be a far better place if everyone interested enough in long-term health to buy expensive supplements instead settled for a multivitamin and some fish oil and donated the rest of their supplement budget to medical research. The expectation value of doing that is somewhat greater than making a habit of ingesting anything you can purchase from a vitamin store.

So I have mixed feelings about these legacy organizations in the longevity advocacy community. Some are doing good by funding modern science and promoting SENS or similar research programs, but they also loudly propagate a great deal of what amounts to misinformation about what the average fellow can do, realistically, to impact the future of his aging process. At this point progress in new forms of medical science is the only thing that will significantly alter our future life spans: no combination of vitamins and supplements has been show to produce even a fraction of the benefits resulting from exercise and calorie restriction. But the existence of the LEF as an ongoing commercial concern depends upon denying this truth, vigorously and often.

The counterargument to this line of thinking is "so how much money have you donated to scientific research lately, Reason?" The answer to that question is "nowhere where as much as the Life Extension Foundation has." So who here is doing more good for whom?

But back to the interview, which I think you'll find is gratifyingly technical for a change, and covers some topics that haven't been touched on at all in past interviews - such as recent funding changes, opinions on mainstream research groups, and so forth:

Interview with Aubrey de Grey, PhD

LE: You recently inherited a large sum of money and chose to donate most of it to the SENS Foundation. Will you provide some details and explain your motives?

AdG: My mother died in May 2011 and I was her only child; the upshot is that I inherited roughly $16.5 million. Of that, I assigned $13 million to SENS (I won't bore you with the legal details, which were tedious in the extreme). It was pretty much a no-brainer for me: I've dedicated my life to this mission, and I dedicate all my time to it, so why not my money too? I retained enough to buy a nice house, but beyond that I have inexpensive tastes and I have no doubt that this is the best use of my wealth. It will accelerate research considerably, and also it will have indirect benefits in terms of helping us to put more resources into raising the profile of this work and garnering more support.

LE: Who are the other major donors to the SENS Foundation, and what proportion of the budget is covered by the money you donated?

AdG: My donation will be spent over a period of about five years, and it roughly doubles the budget we had previously, from $2 million annually to $4 million. The number one external donor remains our stalwart supporter Peter Thiel. Additionally, another internet entrepreneur, Jason Hope, has recently begun to contribute comparable sums.

LE: What will the SENS Foundation do when your donation money runs out?

AdG: It's hard to look ahead as far as five years, the projected duration of my donation, but we certainly have great confidence that our outreach efforts will bear fruit in that time. My hope is that five years from now we will be big enough that the expiry of my donation will go relatively unnoticed.

...

LE: What is advantageous and what is disadvantageous about the money spent on aging research by the National Institute on Aging (NIA, a branch of the US federal government's National Institutes of Health)?

AdG: It's pretty much all advantageous - just not nearly as advantageous as it could be. There is pitifully little money going into the search for interventions to postpone aging, and of what there is, pitifully little is focused on late-onset interventions.

LE: What do you think of the way the Ellison Medical Foundation spends money on aging research?

AdG: Exactly the same as for the NIA. The Ellison Foundation was set up with a remit to fund work that complemented the NIA, but I'm afraid to say that in practice it has merely supplemented it.

...

LE: How difficult would it be to eliminate lipofuscin (the cellular junk that particularly accumulates in neurons and heart muscle cells) compared to eliminating 7KC (an oxidized derivative of cholesterol that accumulates in atherosclerotic plaques) or A2E (a substance accumulating in the retina with age that causes macular degeneration and blindness) as a lysoSENS project? How much difference do you think elimination of lipofuscin would make in terms of rejuvenation?

AdG: This is a big question right now. We have a PhD student in our funded group at Rice University who is working on lipofuscin, but he is just starting. Lipofuscin is indeed harder, but what makes it harder is not the aging-versus-disease distinction but simply the nature of the substance. Lipofuscin is very heterogeneous in its molecular composition, and moreover it is mainly made of proteins, so it is hard to distinguish from material that we don't want to break down. I should note in passing that the material whose accumulation causes macular degeneration is often called lipofuscin but really should not be, because the only thing it has in common with bonafide lipofuscin is its subcellular location (the lysosome) and its fluorescence properties: its molecular composition is entirely different.

LE: In the 2011 report of the SENS Foundation, progress on mitoSENS (making copies of mitochondrial DNA in the nucleus to protect them from free-radicals generated by mitochondria) was restricted to 5 of the 13 protein-encoding mitochondrial genes. How confident are you that all 13 such genes can be copied into the nucleus in the foreseeable future? Are some of those genes more important than others, or are you simply going after the easier targets?

AdG: We're pretty confident. Some of the genes we've chosen to work on first are easy targets in the sense that other researchers have demonstrated some success with them already; other genes are chosen more because success would be high-impact, in that it would allow more clear-cut assays of efficacy. In the end, all 13 are equally important.

There's a lot more in that vein. Quite the number of people work with or for the SENS Research Foundation these days: it is at the center of a web of connections throughout the aging research community and related life science fields.

I should say that the large number of people who have criticized de Grey on various grounds in past years should all be eating their hats these days: I shouldn't have to say anything about just how admirable is his disposition of his own wealth. If de Grey didn't exist, we'd have had to invent him. Sometimes, rarely, it really is the case that one visionary arises to drag the rest of the world along into the future, kicking and screaming, long before the zeitgeist of the age would have produced a comparable figure in some other community. It is in many ways interesting to speculate on where we might be right now absent de Grey, or in a world in which he had chosen to continue to work in artificial intelligence rather than the life sciences, and I believe that the answer is that we'd probably still be waiting on a funded research program for radical life extension to emerge.

Today's nearest neighbors to the Strategies for Engineered Negligible Senescence (SENS) are either very recent and quite clearly inspired by it, such as the proposals put forward by some of SENS Research Foundation advisors and their allies, or are largely focused on strategies related to programmed aging, such as the materials of the Science for Life Extension Foundation and associated members of the Russian biogerontology community. In no case I'm aware of are these proposals funded to even the modest level that currently exists for SENS.

Further, it's clear that the activities of the SENS Research Foundation, and to a greater degree the Methuselah Foundation before it, have had an enormous positive effect over the past decade with respect to changing the culture of the research community. The aging research community of fifteen years past was one in which researchers could not openly talk about extending healthy human life span, or at least not if they wanted to retain their funding. The research community today is quite the opposite, and that goes a long way towards making it possible for competitors and allies for radical life extension programs to arise at all.

Any method to distinguish or interfere with cancer cells that is broadly applicable to a majority of cancer types will greatly reduce the threat of cancer in old age. Cancer is dangerous precisely because it is so very varied, both between types and between individual tumors. I remain confident that there must be numerous commonalities in the low-level mechanisms of cancer that reflect the commonalities in its behavior, however. There is, for example, the need for lengthening of telomeres that forms the basis of the SENS approach to eliminate cancer as a possibility in human biology.

Some other candidates are emerging, such as targeting CD47 with antibodies to strip cancer cells of a method they all appear to use to avoid destruction by the immune system. Here is news of another potentially actionable mechanism that might be shared by many cancer types:

Cancer cells grow and divide much more rapidly than normal cells, meaning they have a much higher demand for and are often starved of, nutrients and oxygen. We have discovered that a cellular component, eEF2K, plays a critical role in allowing cancer cells to survive nutrient starvation, whilst normal, healthy cells do not usually require eEF2K in order to survive. Therefore, by blocking the function of eEF2K, we should be able to kill cancer cells, without harming normal, healthy cells in the process. A treatment that could block this protein could represent a significant breakthrough in the future of cancer treatment.

Traditional chemotherapy and radiotherapy cause damage to healthy cells, and other more targeted treatments are usually only effective for individual types of cancer. Contrastingly, this new development does not damage healthy cells and could also be used to treat a wide variety of different cancers. [Researchers] are now working with other labs, including pharmaceutical companies, to develop and test drugs that block eEF2K, which could potentially be used to treat cancer in the future.

Link: http://www.eurekalert.org/pub_releases/2013-07/uos-sdg071113.php

One future path for medical technology is to augment the internal functions of our cells with artificial versions of natural organelles, membrane-enclosed sacks of protein machinery that do some form of useful work - such as produce therapeutic proteins, or remove harmful waste products that natural organelles struggle with.

The research noted below is one of a number of early experiments along these lines, but it isn't clear that it would be very beneficial as built. Neutralizing free radicals via the introduction of additional antioxidants is not generally beneficial: while they are damaging to protein machinery both inside and outside cells, they are also a part of numerous signaling systems, such as those relating to cellular maintenance and repair processes, or the benefits produced by exercise. Removing free radicals is only demonstrated to extend life and improve health over the long term when localized to the mitochondria of the cell, where it might not be practical to insert an entire new organelle.

[Researchers] have successfully developed artificial organelles that are able to support the reduction of toxic oxygen compounds. This opens up new ways in the development of novel drugs that can influence pathological states directly inside the cell. Free oxygen radicals are produced either as metabolic byproduct, or through environmental influences such as UV-rays and smog. Is the concentration of free radicals inside the organism elevated to the point where the antioxidant defense mechanism is overwhelmed, the result can be oxidative stress, which is associated with numerous diseases such as cancer or arthritis.

The aggressive molecules are normally controlled by endogenous antioxidants. Within this process, organelles located inside the cell, so-called peroxisomes, play an important part, since they assist in regulating the concentration of free oxygen radicals. [The] researchers developed a cell organelle based on polymeric nanocapsules, in which two types of enzymes are encapsulated. These enzymes are able to transform free oxygen radicals into water and oxygen. In order to verify the functionality inside the cell, channel proteins were added to the artificial peroxisome's membrane, to serve as gates for substrates and products. The results show that the artificial peroxisomes are incorporated into the cell, where they then very efficiently support the natural peroxisomes in the detoxification process.

Link: http://www.unibas.ch/index.cfm?uuid=E11708E2A1B6CA17E9F30BEA67B66F72&show_long=1

The sixth Strategies for Engineered Negligible Senescence (SENS) conference will be held in Cambridge, England this coming September. There's still time to register: a group of exceptional figures in aging research and related fields in medicine and the broader life sciences will gather to talk about how to greatly extend healthy human life, with the focus being on how to best move ahead in the implementation of the SENS proposals for rejuvenation biotechnology:

The purpose of the SENS conference series, like all the SENS initiatives, is to expedite the development of truly effective therapies to postpone and treat human aging by tackling it as an engineering problem: not seeking elusive and probably illusory magic bullets, but instead enumerating the accumulating molecular and cellular changes that eventually kill us and identifying ways to repair - to reverse - those changes, rather than merely to slow down their further accumulation. This broadly defined regenerative medicine - which includes the repair of living cells and extracellular material in situ - applied to damage of aging, is what we refer to as rejuvenation biotechnologies.

As usual, the conference has a great line up of speakers, and the range of abstracts for presentation is well worth reading if you'd like to get an idea as to what people are working on these days. Not all of it is directly relevant to SENS, but that's the way these things go: people come to learn and be swayed as much to present the work they're presently engaged in. The SENS Research Foundation staff are presently publishing a steady flow of speaker highlights for the forthcoming conference, and here are the latest in line:

SENS6 Speaker Highlight: Todd Rider

Dr. Rider's most recent efforts have led to a remarkable development within the PANACEA (Pharmacological Augmentation of Nonspecific Anti-pathogen Cellular Enzymes and Activities) project. This new treatment is known as DRACO, which stands for Double-stranded RNA Activated Caspase Oligomizer. Essentially, DRACO works by triggering apoptosis in cells that contain viral double-stranded RNA, an indicator that they have been infected by a virus. Non-infected cells, on the other hand, are not affected by the treatment. Based on the tests that have been performed so far, DRACO has the potential to be effective against nearly any virus. Trials done in vitro or in mice have shown that DRACO kills cells infected with the common cold, H1N1 influenza, dengue fever virus, a polio virus, and others. Meanwhile, the treatment has been shown to be nontoxic to all of the cell types tested, including those from humans.

SENS6 Speaker Highlight: Robin Franklin

Many diseases mirror some aspect of aging. Multiple sclerosis (MS), which is caused by the loss of the myelin coating that protects nerve cells in the brain and spinal cord, is one example: myelin is also lost and poorly replaced in normal aging. Scientists like Cambridge's Dr. Robin Franklin, a SENS6 speaker, are working hard to repair this damage.

To learn how the axons of nerve cells might best be remyelinated, Dr. Franklin has been studying the cellular and molecular aspects of the process. Stem cells in the brain differentiate into oligodendrocytes, which are responsible for remyelination. However, these stem cells have an increasingly difficult time differentiating in an aging brain. This low level of differentiation may also cause multiple sclerosis, such that true damage repair therapies for MS might also be effective against age-related neurodegeneration.

SENS6 Speaker Highlight: Alan Russell

Dr. Russell has founded several biotech companies, including Agentase, LLC and NanoSembly, LLC, and holds fourteen patents. His many honors include the R&D 100 Award, the National Academy of Engineering's Gilbreth lectureship, and the University of Manchester's Outstanding Alumnus Award. At SENS6, Dr. Russell's talk will focus on the disruptive potential of tissue engineering. He will discuss the great promise of growing new organs to replace failing ones, addressing the underlying cause of disease. He will also cover the problems that tissue engineering faces - among them, its lack of market adoption - and propose solutions. Finally, he will describe some of the research being conducted in his own leading laboratory. This includes work on engineering cell membranes, and using cytotactic surfaces to change the direction that cells roll.

A second group of researchers recently demonstrated that cancer patients have a lower risk of Alzheimer's disease, providing data that adds to the puzzling nature of this finding:

[Researchers] found that most types of cancer were associated with a reduced risk of Alzheimer's, which has no cure. Survivors of liver cancer had the most protection, a 51 percent reduced risk. Cancers of the pancreas, esophagus, lung, and kidney, as well as leukemia, also appeared to be "protective," reducing risk between 22 and 44 percent. The study, released just days after publication of a similar report from Italian researchers, is by far the largest to establish such a link.

Notably, the researchers also found that certain cancers apparently conferred no reduced Alzheimer's risk, including melanoma (a cancer of the skin), prostate, and colorectal cancers. Breast cancer was not studied because there were too few cases in the database the researchers analyzed of nearly 3.5 million veterans, 98 percent of them men, who received care between 1996 and 2011.

The scientists said the reduced risk of Alzheimer's was not simply because cancer patients die young, before they can develop the dementia. Cancer survivors lived long enough and even appeared to be at increased risk to develop other typical age-related diseases, including stroke, osteoarthritis, cataracts, and macular degeneration. And they found that most cancer survivors also had an increased risk for non-Alzheimer's dementia. The protective effect of most cancers seemed to extend only to Alzheimer's. [What] surprised the team was the other finding: Cancer patients treated with chemotherapy enjoyed a reduced Alzheimer's risk. They were 20 to 45 percent less likely to develop Alzheimer's than cancer survivors who were not treated with chemotherapy.

Link: http://www.bostonglobe.com/lifestyle/health-wellness/2013/07/15/cancer-and-chemotherapy-reduce-risk-alzheimer-boston-study-finds/W6odekQ4X5jTDlW9WMRUbP/story.html

This is an intriguing finding, and I have no suggestions for either possible underlying mechanisms or possibilities for systematic error in the research. So far as I am aware the common risk factors for cancer are also risk factors for Alzheimer's disease (AD), so one would not expect to see the correlations shown here:

This was a cohort study in Northern Italy on more than 1 million residents. Cancer incidence was derived from the local health authority (ASL-Mi1) tumor registry and AD dementia incidence from registries of drug prescriptions, hospitalizations, and payment exemptions. Expected cases of AD dementia were calculated by applying the age-, sex-, and calendar year-specific incidence rates observed in the whole population to the subgroup constituted of persons with newly diagnosed cancers during the observation period (2004-2009). The same calculations were carried out for cancers in patients with AD dementia. Separate analyses were carried out for the time period preceding or following the index diagnosis for survivors and nonsurvivors until the end of 2009 and for different types and sites of cancer.

The risk of cancer in patients with AD dementia was halved, and the risk of AD dementia in patients with cancer was 35% reduced. This relationship was observed in almost all subgroup analyses, suggesting that some anticipated potential confounding factors did not significantly influence the results. The occurrence of both cancer and AD dementia increases exponentially with age, but with an inverse relationship; older persons with cancer have a reduced risk of AD dementia and vice versa. As AD dementia and cancer are negative hallmarks of aging and senescence, we suggest that AD dementia, cancer, and senescence could be manifestations of a unique phenomenon related to human aging.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23843468

To live far longer in good health our best and first course of action is to build new and better medicinal technologies: ways to repair the known and enumerated root causes of aging, the forms of low-level cellular and molecular damage that accumulate with age and eventually kill us. How this might be achieved is outlined in the SENS proposals and currently the subject of a research program that deserves far more funding and attention.

Plenty of people have other ideas about how to engineer far longer life spans. One of the more popular involves discarding our biology to move minds into software or replace the brain with some form of more easily repaired and robust machinery. This is focus of the 2045 Initiative, for example. From where I stand, this looks a lot like replacing a hard problem with a harder problem - I can't envisage a scenario for the next 20 to 40 years in which building the foundation for artificial minds can outpace rejuvenation biotechnology in terms of offering more healthy life to old people. (And when I say "old people," I of course mean "us." Time waits on no man, and clock is ever ticking).

Nonetheless, the development of an artificial mind is a popular topic. It will only become more so as large-scale funding continues to move into efforts to simulate brains. Ultimately there will be people running on software and hardware that is not biological in origin. I just don't think that's going to happen soon enough for those of us in the later half of an old-style life span. With that in mind, let me point you to a couple more articles on the topic, to append to a fair number of the same that have appeared in recent months:

Transhumanism and Mind Uploading Are Not the Same

Having a positive view of mind uploading is neither necessary nor sufficient for being a transhumanist. Mind uploading has been posited as one of several routes toward indefinite human life extension. Other routes include the periodic repair of the existing biological organism (as outlined in Aubrey de Grey's SENS project or as entailed in the concept of nanomedicine) and the augmentation of the biological organism with non-biological components (Ray Kurzweil's [view]). Transhumanism, as a philosophy and a movement, embraces the lifting of the present limitations upon the human condition.

Dmitry Itskov's 2045 Initiative is perhaps the most prominent example of the pursuit of mind uploading today. [Is] Itskov's path toward immortality the best one? I personally prefer SENS, combined with nanomedicine and piecewise artificial augmentations of the sort that are already beginning to [occur]. Itskov's approach appears to assume that the technology for transferring the human mind to an entirely non-biological body will become available sooner than the technology for incrementally maintaining and fortifying the biological body to enable its indefinite continuation. My estimation is the reverse.

We Seek Not to Become Machines, But to Keep Up with Them

Too often is uploading portrayed as the means to superhuman speed of thought or to transcending our humanity. It is not that we want to become less human, or to become like a machine. For most Transhumanists and indeed most proponents of Mind Uploading and Substrate-Independent Minds, meat is machinery anyways. In other words there is no real (i.e., legitimate) ontological distinction between human minds and machines to begin with. Too often is uploading seen as the desire for superhuman abilities. Too often is it seen as a bonus, nice but ultimately unnecessary.

I vehemently disagree. Uploading has been from the start for me (and I think for many other proponents and supporters of Mind Uploading) a means of life extension, of deferring and ultimately defeating untimely, involuntary death, as opposed to an ultimately unnecessary means to better powers, a more privileged position relative to the rest of humanity, or to eschewing our humanity in a fit of contempt of the flesh. We do not want to turn ourselves into Artificial Intelligence, which is a somewhat perverse and burlesque caricature that is associated with Mind Uploading far too often.

The notion of gradual uploading is implicitly a means of life extension. Gradual uploading will be significantly harder to accomplish than destructive uploading. It requires a host of technologies and methodologies - brain-scanning, in-vivo locomotive systems such as but not limited to nanotechnology, or else extremely robust biotechnology - and a host of precautions to prevent causing phenomenal discontinuity, such as enabling each non-biological functional replacement time to causally interact with adjacent biological components before the next biological component that it causally interacts with is likewise replaced. Gradual uploading is a much harder feat than destructive uploading, and the only advantage it has over destructive uploading is preserving the phenomenal continuity of a single specific person. In this way it is implicitly a means of life extension, rather than a means to the creation of [strong artificial intelligence], because its only benefit is the preservation and continuation of a single, specific human life, and that benefit entails a host of added precautions and additional necessitated technological and methodological infrastructures.

An open access review paper here looks at some of the low-level processes involved in late-life neurodegeneration, the decline of brain functionality. If following a SENS-like viewpoint of the causes of degenerative aging, we would say that these are secondary processes, a loss in the ability of brain tissue and brain cells to maintain themselves due to forms of accumulated damage that occur at an even lower functional level in our biology.

The core point of the SENS proposals for rejuvenation biotechnology is that we don't need to understand the very complex middle layers of degeneration and maintenance in order to halt and reverse aging - we just need to fix the lowest-level causes of aging, which are presently well known. All have associated strategies that will lead to repair or reversal of their effects. Still, most of the research community continues to focus instead on generating a complete understanding of the exceedingly complex processes of aging, starting from the mid-layers and working out:

Most neurons are born with the potential to live for the entire lifespan of the organism. In addition, neurons are highly polarized cells with often long axons, extensively branched dendritic trees and many synaptic contacts. Longevity together with morphological complexity results in a formidable challenge to maintain synapses healthy and functional.

This challenge is often evoked to explain adult-onset degeneration in numerous neurodegenerative disorders that result from otherwise divergent causes. However, comparably little is known about the basic cell biological mechanisms that keep normal synapses alive and functional in the first place. How the basic maintenance mechanisms are related to slow adult-onset degeneration in different diseases is largely unclear.

In this review we focus on two basic and interconnected cell biological mechanisms that are required for synaptic maintenance: endomembrane recycling and calcium (Ca2+) homeostasis. We propose that subtle defects in these homeostatic processes can lead to late onset synaptic degeneration. Moreover, the same basic mechanisms are hijacked, impaired or overstimulated in numerous neurodegenerative disorders. Understanding the pathogenesis of these disorders requires an understanding of both the initial cause of the disease and the on-going changes in basic maintenance mechanisms. Here we discuss the mechanisms that keep synapses functional over long periods of time with the emphasis on their role in slow adult-onset neurodegeneration.

Link: http://www.molecularneurodegeneration.com/content/8/1/23

If the method of improving endurance in mice found by these researchers actually works in the way they think that it works, then it should also increase mouse life span:

The drug candidate, SR9009, is one of a pair of compounds [described] as reducing obesity in animal models. The compounds affect the core biological clock, which synchronizes the rhythm of the body's activity with the 24-hour cycle of day and night. The compounds work by binding to one of the body's natural molecules called Rev-erbα, which influences lipid and glucose metabolism in the liver, the production of fat-storing cells and the response of macrophages (cells that remove dying or dead cells) during inflammation.

In the new study, [researchers] demonstrated that mice lacking Rev-erbα had decreased skeletal muscle metabolic activity and running capacity. [They] showed that activation of Rev-erbα with SR9009 led to increased metabolic activity in skeletal muscle in both culture and in mice. The treated mice had a 50 percent increase in running capacity, measured by both time and distance. "The animals actually get muscles like an athlete who has been training. The pattern of gene expression after treatment with SR9009 is that of an oxidative-type muscle - again, just like an athlete."

The authors of the new study suggest that Rev-erbα affects muscle cells by promoting both the creation of new mitochondria (often referred to as the "power plants" of the cell) and the clearance of those mitochondria that are defective.

Link: http://www.eurekalert.org/pub_releases/2013-07/sri-dcd071013.php

Not so long ago a reader asked me about cell fusion in relation to repairing age-damaged cells, and I noted that while some work on cell fusion is taking place it seems far less researched as a basis for regenerative therapies than, say, straightforward stem cell transplants. I certainly don't see much on this topic in the course of my browsing.

Still, fusion of transplanted stem cells with local cells shows up in the recent work linked below, in which researchers demonstrate partial functional regeneration of damaged retinal tissue in mice - which is a pretty big deal as an outcome, and I can't imagine that the authors will have any trouble finding additional funds to move ahead with their work. It seems that the fusion process can effectively be used as a form of cell reprogramming, and fused cells go on to take useful actions that repair surrounding tissues to a degree that would otherwise not occur. Press materials on this research are doing the rounds:

A Step Forward in Neuronal Regeneration

Researchers from the Centre for Genomic Regulation (CRG) in Barcelona have managed to regenerate the retina thanks to neuronal reprogramming. There are currently several lines of research that explore the possibility of tissue regeneration through cell reprogramming. One of the mechanisms being studied is reprogramming through cell fusion. [Researchers] have used the cell fusion mechanism to reprogramme the neurones in the retina. This mechanism consists of introducing bone marrow stem cells into the damaged retina. The new undifferentiated cells fuse with the retinal neurones and these acquire the ability to regenerate the tissue.

Here is the open access paper for those who want to dig in deeper to the mechanisms involved and discussion of the work by the researchers:

Wnt/β-Catenin Signaling Triggers Neuron Reprogramming and Regeneration in the Mouse Retina

Cell-fusion-mediated somatic-cell reprogramming can be induced in culture; however, whether this process occurs in mammalian tissues remains enigmatic. Here, we show that upon activation of Wnt/β-catenin signaling, mouse retinal neurons can be transiently reprogrammed in vivo back to a precursor stage. This occurs after their spontaneous fusion with transplanted hematopoietic stem and progenitor cells (HSPCs). Moreover, we demonstrate that retinal damage is essential for cell-hybrid formation in vivo.

Newly formed hybrids can proliferate, commit to differentiation toward a neuroectodermal lineage, and finally develop into terminally differentiated neurons. This results in partial regeneration of the damaged retinal tissue, with functional rescue. We show that upon [induced] retinal damage, transplanted stem and progenitor cells (SPCs), such as mouse hematopoietic stem and progenitor cells (mHSPCs), human (h)HSPCs, retinal (R)SPCs, and embryonic stem cells, can fuse with retinal neurons in vivo with high efficiency. Importantly, we show that the fate of these hybrids is to embark upon apoptosis unless Wnt/β-catenin signaling is activated in the transplanted cells.

Indeed, the activation of the Wnt pathway induces reprogramming of retinal neurons back to precursor or embryonic stages after HSPC or ESC fusion, respectively. HSPC-derived reprogrammed hybrids can proliferate and in turn differentiate into ganglion and amacrine neurons, thereby contributing to retinal regeneration. Remarkably, multielectrode recordings of retinal explants showed functional rescue of ganglion neurons to light response in the regenerated retinas.

The next stage in this research is to improve the quality of the result, and demonstrate that the signs of restored function observed here translate into restored sight. We shall see how long that takes to arrive.

If asked yesterday, I'd have guessed that there wasn't a great deal of difference in the majority of the life history of people born ten years apart in the early 1900s in Europe: a small incremental improvement in adult life expectancy for those born later and a larger improvement in life expectancy at birth due to lowered infant mortality. Advances in medicine are weighted towards the recent past: progress is speeding up and practical improvements in medical technology - and patient outcomes - are presently arriving far more rapidly than, say, fifty or a hundred years ago. So the study noted below may be largely measuring improvements in medical care for the elderly that have taken place across the past few decades rather than anything that happened prior to that.

We compared the cognitive and physical functioning of two cohorts of Danish nonagenarians, born 10 years apart. People in the first cohort were born in 1905 and assessed at age 93 years (n=2262); those in the second cohort were born in 1915 and assessed at age 95 years (n=1584). Both cohorts were assessed by surveys that used the same design and assessment instrument, and had almost identical response rates (63%). Cognitive functioning was assessed by mini-mental state examination and a composite of five cognitive tests that are sensitive to age-related changes. Physical functioning was assessed by an activities of daily living score and by physical performance tests (grip strength, chair stand, and gait speed).

The chance of surviving from birth to age 93 years was 28% higher in the 1915 cohort than in the 1905 cohort (6.50% vs 5.06%), and the chance of reaching 95 years was 32% higher in 1915 cohort (3.93% vs 2.98%). The 1915 cohort scored significantly better on the mini-mental state examination than did the 1905 cohort, with a substantially higher proportion of participants obtaining maximum scores. Similarly, the cognitive composite score was significantly better in the 1915 than in the 1905 cohort. The cohorts did not differ consistently in the physical performance tests, but the 1915 cohort had significantly better activities of daily living scores than did the 1905 cohort. [These results suggest] that more people are living to older ages with better overall functioning.

Link: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(13)60777-1/fulltext

Scientists demonstrate the ability to make stem cells assemble into small inner ear structures in this research. This is a long way from building tissue masses that are easy to see with the naked eye, but it is progress nonetheless:

[Researchers] reported that by using a three-dimensional cell culture method, they were able to coax stem cells to develop into inner-ear sensory epithelia - containing hair cells, supporting cells and neurons - that detect sound, head movements and gravity. Previous attempts to "grow" inner-ear hair cells in standard cell culture systems have worked poorly in part because necessary cues to develop hair bundles - a hallmark of sensory hair cells and a structure critically important for detecting auditory or vestibular signals - are lacking in the flat cell-culture dish.

The team determined that the cells needed to be suspended as aggregates in a specialized culture medium, which provided an environment more like that found in the body during early development. The team mimicked the early development process with a precisely timed use of several small molecules that prompted the stem cells to differentiate, from one stage to the next, into precursors of the inner ear. But the three-dimensional suspension also provided important mechanical cues, such as the tension from the pull of cells on each other. "We were surprised to see that once stem cells are guided to become inner-ear precursors and placed in 3-D culture, these cells behave as if they knew not only how to become different cell types in the inner ear, but also how to self-organize into a pattern remarkably similar to the native inner ear."

Link: http://www.sciencedaily.com/releases/2013/07/130710141852.htm

The effort to understand how exactly metabolic processes determine longevity is a frustrating business. Researchers are at the stage in the game where they can increase or reduce longevity in many different ways through various genetic and epigenetic manipulations in mice, worms, flies, and other laboratory species. They can obtain mountains of data from these longer-lived or shorter-lived animals: gene expression patterns and any number of different measures of metabolism and the operation of organs and cells. Making sense out of all this data is the challenge.

For example, some interventions boost the free radical output of mitochondria and extend life. Others raise that free radical output and reduce life span. The interplay of different systems in the body is far too complicated for simple models of "more of X is bad" to survive for long. Extra damaging free radicals might a bad thing in one context, but in another they happen to trigger enough of an extra effort from cell maintenance processes to cause a net gain in robustness and longevity in the organism. More of a specific regulatory protein in circulation might be beneficial in one amount, harmful in a slightly greater amount, and those threshold levels will change depending on the levels of four or five other proteins. It's a complicated business.

Here is an example of a life-extending and memory-improving genetic alteration in mice that reduces mitochondrial function (generally thought to be a bad thing) and increases the output of damaging free radicals from the mitochondria (also generally thought to be a bad thing):

Decreased in vitro mitochondrial function is associated with enhanced brain metabolism, blood flow, and memory in Surf1-deficient mice

Recent studies have challenged the prevailing view that reduced mitochondrial function and increased oxidative stress are correlated with reduced longevity. Mice carrying a homozygous knockout (KO) of the Surf1 gene showed a significant decrease in mitochondrial electron transport chain Complex IV activity, yet displayed increased lifespan and reduced brain damage after excitotoxic insults.

In the present study, we examined brain metabolism, brain hemodynamics, and memory of Surf1 KO mice using in vitro measures of mitochondrial function, in vivo neuroimaging, and behavioral testing. We show that decreased respiration and increased generation of hydrogen peroxide in isolated Surf1 KO brain mitochondria are associated with increased brain glucose metabolism, cerebral blood flow, and lactate levels, and with enhanced memory in Surf1 KO mice. These metabolic and functional changes in Surf1 KO brains were accompanied by higher levels of hypoxia-inducible factor 1 alpha, and by increases in the activated form of cyclic AMP response element-binding factor, which is integral to memory formation.

It would be a good thing to have a brain that is a robust collection of artificial machinery when such a thing becomes possible, as the present evolved biological human brain is short-lived and frail in comparison to what could be achieved with a mature nanorobotics industry, capable of producing robust nanomachines that replicate cell functions. But how do you move from a biological to a machine brain without destroying or merely copying yourself? All of the obvious, easily envisaged methodologies are variations on the theme of destructive copying, in which you die and a copy of you continues.

This continuity of the self through an upgrade of the physical structure hosting your mind is a popular topic in the longevity advocacy community. Pretty much everyone has written on the subject at some point in time, despite the fact that it's definitely not the next thing up on deck in the march of technology - the first order of business is to develop the means to repair aging in our biology, to give us enough time to live into a future in which things like brain upgrades are possible.

Later in the piece quoted below the half-brain methodology is discussed. This is one of the earliest attempts to produce a physically realistic method of progressive brain replacement that is at least one step less fatal than all-in-one-go destructive copying. But I think that it is still undesirable: hauling out and replacing large chunks of the brain at a time is still functionally destructive to the self if the chunks are large enough. The safest approach is to scale down the replacement to the level of individual cells, proceeding at a pace similar to the natural processes of cell replacement in the brain.

I love life. And so the prospect of indefinite life extension is very attractive, IMO. Then again, seeing as how I wish to live much longer than my biologically-fixed clock dictates, to simply make a copy of myself to live forever, but not actually myself, just doesn't cut it. I would never destroy my brain and let someone else be me for me. If I'm to achieve indefinite life extension, then I want to do so with both my physical and functional continuity still in complete operation. Without one, the other is completely irrelevant.

What is physical and functional continuity? Functional continuity is basically the stream of consciousness which makes you...well...you. "Destroying" functional continuity wouldn't necessarily do anything to you, nor would it remain destroyed, per se. When we're going through REM sleep every night, our functional continuity fluctuates on and off, only to be completely restored the next morning. Yes, your consciousness before sleep was different from the consciousness you now acquire after sleep, but you remain yourself - you're still self-aware.

So what about physical continuity? Physical continuity is very important - much more important than functional continuity. Physical continuity - using as simple an understanding as possible - is essentially the brain and all of its synaptic operations. To destroy physical continuity would be to destroy the brain. Thus destroying everything, including the functional continuity which comes along with it. You can destroy your functional continuity and still have the chance to regain it so long physical continuity remains intact. The contrary, however, would be the end of yourself in its entirety.

Thus bringing us to our current dilemma of mind uploading. How are we to achieve mind uploading without destroying physical continuity in the process? To simply "download" everything within your brain and upload it into an artificial brain, while functional continuity is being streamed, physical continuity is being replicated, not maintained. Essentially you'd be partaking in a really cool process of cloning. That's it.

Link: http://ieet.org/index.php/IEET/more/murphy20130710

A machine-translated interview with Aubrey de Grey, cofounder of the SENS Research Foundation and author of the SENS proposals for developing biotechnologies to repair and reverse the root causes of aging:

Interviewer: Why should we stop aging?

de Grey: The fundamental reason why we should develop a drug against aging is that aging is bad for you. It makes people sick. There are many views on how people should live, but there is really no debate about the fact that people do not like being sick. That's the main reason. It is also important to emphasize that the human body is just a machine. It is a very complicated machine, but a machine after all, which means that if you can stop people becoming sick, then you're also avoiding the increased risk of death that comes with being sick. A person has a very low probability of dying anytime soon if he avoids becoming ill. There will be a side effect of increased longevity that comes with the medical defeat of aging, but it is only a secondary effect. I do not work on longevity, I work so that people will not become sick.

Interviewer: Who are the supporters of aging, the opponents of longevity research?

de Grey: Most people, I think, is little concerned when talking about the defeat of aging. The fear of the unknown overwhelms them. They forget that we have a problem today, and prefer not to think about the tremendous costs of Alzheimer's disease or heart problems and the like. They instead remain concerned about the kinds of hypothetical disadvantages envisaged for a post-aging world such as overcrowding, dictators living forever or inability to pay pensions, or whatever it might be. I find this extremely frustrating because it is a complete abandonment of any sense of proportion. I find it extraordinary that people are willing to enjoy this kind of denial. But it is not extraordinary from a psychological point of view because until recently - until I came along - it was perfectly reasonable to consider that the defeat of aging was a long way distant because many people had tried and failed.

Interviewer: What question would you like to be asked more often?

de Grey: "How big do you want the check to be?" What I do is work on the science behind the development of anti-aging treatments. This requires three things. The first is that it requires a solid scientific basis. So the reason why we can make predictions about the future, although speculative, is that we can describe in detail what already exists and where we go from there. So a good level of precursor technology must exist. The second is that people who are better placed to further develop this technology should be excited about it. They must be aware of the potential applicability of the work of others for the defeat of old age. The third is that you have to have the resources to make this happen.

I realized about fifteen years ago that we now have the technological foundations in place, and it was then when I developed the SENS concept. The second case is something I've been working on, meeting with the world's scientific leaders in the relevant fields. We do not lack people who know what they are doing. So the only missing link is the number three, the financial resources to do the job.

Link: http://translate.google.com/translate?u=www.misionescuatro.com/ampliar.php?id=47248

There has been an injection of greater rigor into mainstream mouse studies of longevity in recent years, possibly prompted by a growing realization that many studies of past decades were fatally undermined by a failure to consider the possibility of inadvertent calorie restriction, among other issues. So even well-trafficked areas such as the biology of long-lived lineages like Ames dwarf and growth hormone receptor knockout (GHRKO) mice presently see a steady progression of new and ever more careful studies of the basics. Not that there is any shortage of new ground to cover in something as complex as the biology of a mammal. There are unknowns enough to last for decades at the present pace of discovery.

These two papers take a new look at how some of the long-lived mouse breeds react to calorie restriction and the similar method of alternate day fasting, both of which are shown to extend life in ordinary non-engineered laboratory mice. There is far more evidence for the benefits of calorie restriction than there is for forms of intermittent fasting, as it has been studied for longer and by more research groups. Interestingly, some studies have shown alternative day fasting to extend life to some degree even when the overall level of calories consumed is not reduced. Other studies show that calorie restriction and alternate day fasting produce notably different patterns of gene expression - sets of overlapping but different changes.

The end goal behind this sort of work is to pin down the shared mechanisms by which life is extended, and thereby do a better job of identifying exactly what they are and how they work. If you find two methods of life extension that don't stack - as appears to be the case for GHRKO and calorie restriction - then that's a good place to start looking for these shared root causes.

Metabolic Alterations Due to Caloric Restriction and Every Other Day Feeding in Normal and Growth Hormone Receptor Knockout Mice

Mutations causing decreased somatotrophic signaling are known to increase insulin sensitivity and extend life span in mammals. Caloric restriction and every other day (EOD) dietary regimens are associated with similar improvements to insulin signaling and longevity in normal mice; however, these interventions fail to increase insulin sensitivity or life span in growth hormone receptor knockout (GHRKO) mice.

To investigate the interactions of the GHRKO mutation with caloric restriction and EOD dietary interventions, we measured changes in the metabolic parameters oxygen consumption (VO2) and respiratory quotient produced by either long-term caloric restriction or EOD in male GHRKO and normal mice.

GHRKO mice had increased VO2, which was unaltered by diet. In normal mice, EOD diet caused a significant reduction in VO2 compared with ad libitum (AL) mice during fed and fasted conditions. In normal mice, caloric restriction increased both the range of VO2 and the difference in minimum VO2 between fed and fasted states, whereas EOD diet caused a relatively static VO2 pattern under fed and fasted states. No diet significantly altered the range of VO2 of GHRKO mice under fed conditions. This provides further evidence that longevity-conferring diets cause major metabolic changes in normal mice, but not in GHRKO mice.

Metabolic adaptations to short-term every-other-day feeding in long-living Ames dwarf mice

Restrictive dietary interventions exert significant beneficial physiological effects in terms of aging and age-related disease in many species. Every other day feeding (EOD) has been utilized in aging research and shown to mimic many of the positive outcomes consequent with dietary restriction. This study employed long living Ames dwarf mice subjected to EOD feeding to examine the adaptations of the oxidative phosphorylation (OXPHOS) and antioxidative defense systems to this feeding regimen.

Every other day feeding lowered liver glutathione (GSH) concentrations in dwarf and wild type (WT) mice but altered GSH biosynthesis and degradation in WT mice only. The activities of liver OXPHOS enzymes and corresponding proteins declined in WT mice fed EOD while in dwarf animals, the levels were maintained or increased with this feeding regimen. Antioxidative enzymes were differentially affected depending on the tissue, whether proliferative or post-mitotic. Gene expression of components of liver methionine metabolism remained elevated in dwarf mice when compared to WT mice as previously reported however, enzymes responsible for recycling homocysteine to methionine were elevated in both genotypes in response to EOD feeding.

The data suggest that the differences in anabolic hormone levels likely affect the sensitivity of long living and control mice to this dietary regimen, with dwarf mice exhibiting fewer responses in comparison to WT mice. These results provide further evidence that dwarf mice may be better protected against metabolic and environmental perturbations which may in turn, contribute to their extended longevity.

Being sedentary has a cost: your health will most likely be worse, and your life expectancy shorter. One of the metabolic dysfunctions that arises with increasing age is a reduction in insulin sensitivity, most often associated with excess fat tissue and the descent into type 2 diabetes, but lack of exercise is also an important contributing factor. Here researchers look into some of the low-level biological mechanisms involved in the relationship between exercise and insulin metabolism:

Both aging and physical inactivity are associated with increased development of insulin resistance whereas physical activity has been shown to promote increased insulin sensitivity. Here we investigated the effects of physical activity level on aging-associated insulin resistance in myotubes derived from human skeletal muscle satellite cells. Satellite cells were obtained from young (22 yrs) normally active or middle-aged (56.6 yrs) individuals who were either lifelong sedentary or lifelong active.

Human myotubes in culture obtained from middle-aged sedentary individuals have differences in insulin stimulated glucose metabolism that would be expected to be seen due to secondary aging in vivo, including impaired insulin-stimulated glucose uptake. Interestingly, physical activity throughout life seems to protect myotubes from these aspects of secondary aging potentially through adaptations including increased expression of GLUT4 and MYH2.

Additionally, lifelong physical activity exerts positive effects on muscle metabolism (including enhanced GSK3 phosphorylation and GLUT4 expression) when compared to the same parameters in myotubes from young, recreationally active, healthy controls. Life-long physical activity, such as seen in elite athletes, has shown that 60 year old athletes have the same glucose and insulin levels during an oral glucose tolerance test as 26 year olds. It is therefore unlikely that deterioration in insulin sensitivity is an inevitable consequence of aging and is maintained by regular physical activity.

Link: http://dx.doi.org/10.1371/journal.pone.0066628

Enhanced longevity associated with changes in the insulin/IGF-1 pathway is one of the most studied areas of the genetics of longevity in laboratory animals. Metabolism is complex enough that researchers are still building the picture of how alterations like this work to extend life. The open access research quoted below suggests that broad reductions in rate of creation of proteins from DNA blueprints are involved, and thus a related boost in the level of autophagy as the body seeks to recycle more proteins.

This shows up elsewhere in processes related to longevity - for example in dietary methionine restriction, as methionine is required for the assembly of all proteins. Increased levels of the housekeeping processes of autophagy appear in many forms of metabolic alteration that extend life, and most likely work by consistently reducing the levels of cellular damage that contribute to degenerative aging over the long term.

To date, the biological processes underlying Insulin/IGF-1-mediated longevity remain studied predominantly at the gene level. However, organismal phenotypes are far more dependent on protein function. An initial quantitative proteomics study of Insulin/IGF-1 pathway confirmed the role of stress-protective pathways during longevity signalling. Additionally, it uncovered several compensatory pathways involved in longevity, underscoring the potential of this approach to identify novel longevity pathways. However, this analysis was restricted to a subset of the nematode proteome, involving mainly cytoplasmic and non-membrane bound proteins.

In this study, a more stringent and non-biased proteomics approach of the whole nematode using TMT proteomics was employed. This recently developed quantification method was used to identify novel processes and pathways involved in Insulin/IGF-1-mediated longevity. The obtained results confirmed the previously reported alteration of several proteins in daf-2(e1370) nematodes, including an increased representation of stress-resistance enzymes and a decrease in chaperone proteins. However, our results go on to reveal a severe and previously overlooked reduction in ribosomal proteins and concomitant translational activity. In addition, reduced expression of proteins involved in mRNA processing, translation, and the ubiquitin-proteasome system (UPS) was observed. Functional assays confirmed reduced mRNA levels and 20S proteasomal activity while at the same time total protein content of the mutants compared with wild-type nematodes remained unchanged. Moreover, the importance of these processes for lifespan extension is demonstrated using RNA interference (RNAi)-mediated knockdown of identified candidates.

All together, we propose a model for Insulin/IGF-1-mediated longevity that, in addition to an enhanced stress response, relies on protein metabolism coupled to the reduction in de novo protein synthesis and a shift from the UPS of degradation to recycling of proteins via autophagy.

Link: http://dx.doi.org/10.1038/msb.2013.35

A few improvements to the Fight Aging! site have emerged in recent days, and seem worth mentioning.

All Traffic is Encrypted

As you might have noticed, traffic to and from Fight Aging! is now all running over Secure Sockets Layer (SSL) connections. Page requests and page contents are encrypted from end to end between the server and your browser. So while all of that traffic is apparently being copied and archived by various powers that be, along with everything else that crosses the internet, it's not as though any of the listeners between you and Fight Aging! can easily find out what you post or what you read.

This is a trivial gesture in the grand scheme of things, but the more sites that uniformly encrypt all traffic the better: it creates a background of data that is expensive to analyze, and which cannot easily be used as a part of any scheme of automation to profile every internet citizen. Over the next year or two the generally available mechanisms of encryption for browsers and web servers will improve with the addition of perfect forward secrecy, so that even though there are (or will be) multiple eternal archives of all internet traffic, every individual session will have to be cracked and decrypted separately. There are no shortcuts that attackers can take, such as by secretly obtaining a backup of the Fight Aging! server and it's encryption key from the hosting provider. This will push out the time horizon and difficulty for people mining your past quite considerably.

All outgoing links to Wikipedia in Fight Aging! posts, of which there are many, are also now using SSL by default.

If you are making use of Fight Aging! feeds or otherwise using machinery to automatically read the content here, make sure that your tools and code are smart enough to follow the automatic redirects from http:// URLs to https:// URLs that are now issued by the Fight Aging! server. If you don't know whether you should be concerned about this, then you shouldn't be concerned about this - it's most likely not going to be an issue for you. The vast majority of applications will do the right thing and go to the encrypted feed at an https:// URL even if sent to the plain http:// URL.

No More Google Analytics Tracking

In the same vein, there is no more tracking of visitors to Fight Aging! via the Google Analytics product. It's not too hard to run my own local analytics software on page request records when I feel the urge to know more about the number of visitors and what they're reading. I generally don't keep more than a few weeks those records on the server at any given point in time; more is just clutter.

Abandoning Indentation

For the past nine and a half years of Fight Aging! quoted text in posts has always been indented. The size of that indentation has diminished over time, but even when it is small it is a break in the flow of reading - it makes the eyes skip, requires the brain to take notice, and is generally an irritation. I'm not the best person to be noticing this, however: by the time quoted text is in a post and indented, I've read it a couple of times and I'm not reading it again. I don't read my own posts in the same way that a visitor does, so I don't tend to experience the same issues.

Not that this is much of an excuse for taking nearly a decade to conclude that perhaps, just maybe, repetitive indentation in long columns was a dumb design choice to begin with. Regardless, indentation is now gone and I think you'll find that this change greatly improves the readability of both individual posts and the wall of text that is the site home page. (If you can't see the change, you might try clearing your browser cache and reloading the page to pick up the slight but significant style alterations).

Reliability theory can be used to model aging in terms of progressive failure of component subsystem, just as occurs in electronic equipment and other systems prone to complex forms of decay. One of the predictions that results from this method is that we are born with a preexisting level of damage, and so we should expect to see correlations between aspects of newborn biology and later aging.

On a similar note it has been determined in recent years that at least some species adjust the metabolism of their descendants in reaction to environmental factors such as availability of food. Calorie restriction, for example, doesn't just change the metabolism of the individuals that are living on fewer calories, but also results in different patterns of gene expression that show up in their offspring.

Here is an example of a correlation between early life metabolism and later life progression of aging in humans, which might be considered in the context provided by the above points:

Scientists have found that key metabolites in blood - chemical 'fingerprints' left behind as a result of early molecular changes before birth or in infancy - could provide clues to a person's long-term overall health and rate of ageing in later life.

One particular metabolite - C-glyTrp - is associated with a range of age-related traits such as lung function, bone mineral density, cholesterol and blood pressure. Its role in ageing is completely novel. Crucially, researchers found it was also associated with lower weight at birth when they compared the birth weights of identical twins. This finding suggests that levels of this novel metabolite, which may be determined in the womb and affected by nutrition during development, could reflect accelerated ageing in later adult life.

Scientists have known for a long time that a person's weight at the time of birth is an important determinant of health in middle and old age, and that people with low birth weight are more susceptible to age related diseases. So far the molecular mechanisms that link low birthweight to health or disease in old age had remained elusive, but this discovery has revealed one of the molecular pathways involved. "This unique metabolite, which is related to age and age related diseases, was different in genetically identical twins that had very different weight at birth. This shows us that birth weight affects a molecular mechanism that alters this metabolite. This may help us understand how lower nutrition in the womb alters molecular pathways that result in faster ageing and a higher risk of age-related diseases fifty years later."

Link: http://www.eurekalert.org/pub_releases/2013-07/kcl-r070813.php

Researchers are making progress on the construction of cell structures that look very much like naturally formed nerve tissue, and may thus be useful substitutes for the current practice of nerve grafting:

Regeneration of nerves is challenging when the damaged area is extensive, and surgeons currently have to take a nerve graft from elsewhere in the body, leaving a second site of damage. Nerve grafts contain aligned tissue structures and Schwann cells that support and guide neuron growth through the damaged area, encouraging function to be restored.

[Researchers have now] reported a way to manufacture artificial nerve tissue with the potential to be used as an alternative to nerve grafts. Pieces of Engineered Neural Tissue (EngNT) are formed by controlling natural Schwann cell behaviour in a three-dimensional collagen gel so that the cells elongate and align, then a stabilisation process removes excess fluid to leave robust artificial tissues. These living biomaterials contain aligned Schwann cells in an aligned collagen environment, recreating key features of normal nerve tissue.

Building the artificial tissue from natural proteins and directing the cellular alignment using normal cell-material interactions means the EngNT can integrate effectively at the repair site. "We previously reported how self-alignment of Schwann cells could be achieved by using a tethered collagen hydrogel, which exploited cells' natural ability to orientate in the appropriate direction by using their internal contraction forces. Our current research shows that cell-alignment in the hydrogel can be stabilised using plastic compression. The compression removes fluid from the gels, leaving a strong and stable aligned structure that has many features in common with nerve tissue."

Link: http://www.sciencedaily.com/releases/2013/07/130708102938.htm

I recently noticed a two-part interview with researcher Vladimir Skulachev on a Russian language medical news site. Long-time readers will recognize the name in connection with work on plastoquinone-based mitochondrially targeted antioxidants: Skulachev's group produces the SkQ series of compounds that in recent years have been shown to generate benefits and extend life in mice. These are noteworthy for working though dietary intake, rather than requiring injection like the SS class of mitochondrially targeted antioxidants.

Mitochondrially targeted antioxidants are thought to work by soaking up a usefully large portion of the reactive oxygen species (ROS) produced by mitochondria in cells at their source, before they can cause harm to cellular structures - and especially before they can damage mitochondrial DNA. Progressively accumulated oxidative damage to mitochondrial DNA is widely considered to be an important contribution to degenerative aging, per the mitochondrial free radical theory of aging.

Like many Russian biogerontologists, Skulachev is on the programmed aging side of the fence, seeing aging as more of an evolved genetic program that causes damage rather than as a matter of accumulated damage that causes systems to change as they head down the path toward failure. This is far from a trivial difference, as it informs the strategies that researchers adopt in attempts to remove degenerative aging from the human condition - the wrong choice leads down an expensive and largely ineffective path. For my part, I think that the evidence points towards damage rather than programs.

As always I should note that automated translation of Russian has a way to go yet: we can put men on the moon and make stem cells dance to our tune, but moving a few verbs around remains beyond us. Thus the quoted materials below have been tidied up with guesswork and interpolation; errors are probably mine where they appear:

Can I live a few hundred years?

Interviewer: Is there a limit to growth? How long, in principle, a person can expect to live?

Skulachev: I think that there is no limit, and sooner or later people will come to practical immortality. Before, I was afraid to say so, because it sounded too provocative, but now, perhaps, it is already possible. The development of biology is such fantastic pace, after 100 years it will be completely realistic to talk of changing human nature ... This, of course, will never be immortality in its idealized form - when a person, for example, is beneath a falling concrete slab, we will not have a way to return him to his former state. But if we exclude such an absolute disaster, it is possible to assume the reality of a Methuselah-like near future, the life of a few centuries.

In principle we have not reached a point where people could die from wear and tear of the body. So far, I'm sure that people die because of orders received from the genome - for evolution it is enough to live and then give a place to others. This is a purely evolutionary mechanism, not necessary for modern man who has ceased to adapt to the environment and began to adapt the environment to his needs. How it will end and how dangerous this situation is - that is another question.

Interviewer: If everyone would live like Methuselah, does not have the resources ...

Skulachev: A typical error. In fact, there are a lot of resources and those resources are growing in proportion to human knowledge. But I would again like to emphasize that our goal is not immortality. We set ourselves a much simpler task: to transfer humans from the category of aging organisms into the category of non-aging organisms. Non-aging organisms exist in nature, both animal and plant. But perhaps the most striking example is the naked mole rat: they do not suffer from cancer, cardiovascular and infectious diseases, and their life expectancy is extremely high for small rodents - more than 30 years. So, the recent work of biochemists show that naked mole rats turn off a number of regulatory systems that are active in genetically close relative species. And it is very likely that as a result they have interrupted signals that trigger the mechanism of aging.

Abolish age

Last year, the Russian market launched a brand new ophthalmic drug based on SkQ1 for the treatment of dry eye syndrome - an old man's disease is considered incurable. Droplets containing SkQ1 as active ingredient, resulted in the disappearance of disease symptoms in 60% of patients after three weeks of treatment. Now research is ongoing in eight clinics in Russia and two in Ukraine. There is reason to think that the positive effect of a more prolonged use SkQ1 can be even greater.

It can treat some cancers, we have found in animal experiments. But no evidence of carcinogenicity caused by SkQ has been received. There are two aspects to this result. First, the very low therapeutic concentrations of SkQ - thanks to the targeted effect the substance is effective in minute doses. And the second - it quickly breaks down in the body.

Now begins the process of registering our medicines in the United States. Because the clinical trials that need to be carried out in America are very expensive we started with the orphan disease of uveitis. This will reduce the number of participants and therefore costs. Uveitis is an extremely unpleasant condition in which the tissues of the eye are being targeted by the patient's own immune system. It is treated by large doses of steroid hormones with very serious adverse consequences. Now three independent labs in Minneapolis, Andover and Sunny Vale (USA) have already confirmed our experiments previously carried out on animals in Russia.

We have already completed clinical trials on glaucoma and cataracts, which took place in Russia. The results are being published. In the near future are going to get the permission of Ministry of Health to study SkQ1 for the treatment of macular degeneration. It is hoped to complete this process in the winter of this year. It should be noted that initially the Ministry met our project with great skepticism. Too unusual results ... But, fortunately, we are guided by the principles of evidence-based medicine, and can always explain how and why our product works.

So all in all it looks like we'll be seeing the use of mitochondrially targeted antioxidants to treat numerous conditions over the next decade. Given that the substances are going through clinical trials, it seems unlikely that they'll be easily available - regulated and controlled as drugs, with harsh penalties for anyone using them outside the system. Still, broader usage can only result in it becoming easier for DIYbio and home chemistry amateurs to synthesize their own supplies should they feel so inclined, and should the evidence warrant making the effort versus just giving the funds to the SENS Research Foundation instead.

Growth hormone receptor knockout (GHRKO) mice are smaller, age more slowly, and live considerably longer than their unaltered peers. Researchers have yet to create a longer-lived mouse lineage. Interestingly, and perhaps unfortunately for the prospects of slowing aging in our species, similar human mutants do not appear to live longer than the rest of us. Much the same is true of the practice of calorie restriction: long-lived mice, tremendous health benefits in both mice and humans, but no signs of greatly extended life in humans.

Aging more slowly, either through disruption of growth hormone metabolism or through calorie restriction, means that all measures of degeneration are impacted - such as the frailty and muscular weakness examined by these researchers:

Neuromusculoskeletal (physical) frailty is an aging-attributable biomedical issue of extremely high import, from both public health and individual perspectives. Yet, it is rarely studied in nonhuman research subjects and very rarely studied in animals with extended longevity. In an effort to address this relatively neglected area, we have conducted a longitudinal investigation of the neuromusculoskeletal healthspan in mice with two senescence-slowing interventions: growth hormone (GH) resistance, produced by GH receptor "knockout" (GHR-KO), and caloric restriction (CR).

We report marked improvements in the retention of strength, balance, and motor coordination by the longevity-conferring GHR/BP gene disruption, CR regimen, or a combination of the two. Specifically, GHR-KO mice exhibit superior grip strength, balance, and motor coordination at middle age, and CR mice display superior grip strength at middle age. The advantageous effects established by middle-age are more pronounced in old-age, and these robust alterations are, generally, not gender-specific. Thus, we show that genetic and/or dietary interventions that engender longevity are also beneficial for the retention of neuromusculoskeletal health and functionality. The translational knowledge to be gained from subsequent molecular or histological investigations of these models of preserved functionality and decelerated senescence is potentially relevant to the efforts to reduce the specter of fear, falls, fracture, and frailty in the elderly.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23824747

It is a myth that dietary antioxidant supplementation can reliably extend life or even reliably do good things for general health. The weight of evidence strongly suggests that the results are either negligible or harmful. Oxidant molecules have many beneficial roles in addition to being damaging in large volumes, and most likely being involved in the progression of aging. They are used as signals in our tissue to spur maintenance processes essential in generating the benefits derived from exercise, for example.

It is possible to reliably extend life with antioxidants, but they have to be carefully designed molecules that target themselves to the mitochondria in our cells, where the most damaging and least necessary oxidants are generated. The types of antioxidant that you can buy in the store, such as those used in this study, don't go to where they can do some good in tissues and instead interfere with useful processes everywhere else:

While oxidative damage owing to reactive oxygen species (ROS) often increases with advancing age and is associated with many age-related diseases, its causative role in ageing is controversial. In particular, studies that have attempted to modulate ROS-induced damage, either upwards or downwards, using antioxidant or genetic approaches, generally do not show a predictable effect on lifespan.

Here, we investigated whether dietary supplementation with either vitamin E (α-tocopherol) or vitamin C (ascorbic acid) affected oxidative damage and lifespan in short-tailed field voles, Microtus agrestis. We predicted that antioxidant supplementation would reduce ROS-induced oxidative damage and increase lifespan relative to unsupplemented controls.

Antioxidant supplementation for nine months reduced hepatic lipid peroxidation, but DNA oxidative damage to hepatocytes and lymphocytes was unaffected. Surprisingly, antioxidant supplementation significantly shortened lifespan in voles maintained under both cold (7 ± 2°C) and warm (22 ± 2°C) conditions. These data further question the predictions of free-radical theory of ageing and critically, given our previous research in mice, indicate that similar levels of antioxidants can induce widely different interspecific effects on lifespan.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23825087

Higher organisms like we humans are made of cells, of several hundred distinct types if you exclude all of the symbiotic bacterial species that we carry along with us. The vast majority of cells have short finite life spans: they stop reproducing and self-destruct or become senescent after a number of reproductive divisions. You might be familiar with the Hayflick limit in relation to this topic: it is the number of times a cell divides before it removes itself from the cell cycle to a fate of destruction or senescence. Similarly you have probably heard of telomeres, the repeating DNA sequences at the end of our chromosomes. The length of telomeres shortens with each cell division, forming a sort of countdown clock, and too-short telomeres is one of mechanisms by which cell division is halted.

The reality on the ground is much more complex than this simple view of a cell division countdown. Some cells don't divide and last you a lifetime, such as many of those in the central nervous system. Other cells, such as stem cell populations, have their telomeres repeatedly extended by the enzyme telomerase. Different cells in different parts of the body have very different life spans, and the complex array of processes that determine those life spans is highly variable, reacting to the environment and to each other.

None of this really has much direct bearing on the life span of an organism, however. You can't just wave a wand that would extend the life of all cells, and expect to see a similar extension of life in the organism - whether that happens or not depends on the intricate details of how cells relate to organs and systems. The life span of cells is all the way down there in the depths of the machine, details internal to low-level components that are decoupled from how the machine behaves in aggregate. There is no particular reason for cell life spans to have anything to do with how long the machine as a whole can last. Some of our tissues are designed to cycle through and replace all of their cells very rapidly, in a matter of days. Other cells are never replaced and live as long as we do.

Cell behavior is subordinate to the needs of the organ or system that they are a part of. The cells of a given type evolved to have their present behavior and typical life spans because, when acting as a system in conjunction with other cell types, they produce a working organ or system that provides some evolutionary advantage. If that can be done with lots of cell turnover and short cell life spans, it will be. If it can be done with little cell turnover and long cell life spans, it will be also - but either path can produce a long-lived and reliably functional organ. This point is one that a recent article comes to eventually, after a tour of the Hayflick limit and telomere biology:

Lust for life: Breaking the 120-year barrier in human aging

It is true that as we get older our telomeres shorten, but only for certain cells and only during certain times. Most importantly, trusty lab mice have telomeres that are five times longer than ours but their lives are 40 times shorter. That is why the relationship between telomere length and lifespan is unclear.

Apparently using the Hayflick limit and telomere length to judge maximum human lifespan is akin to understanding the demise of the Roman empire by studying the material properties of the Colosseum. Rome did not fall because the Colosseum degraded; the Colosseum degraded because the Roman Empire fell.

Within the human body, most cells do not simply senesce. They are repaired, cleaned or replaced by stem cells. Your skin degrades as you age because your body cannot carry out its normal functions of repair and regeneration.

The processes that cause degenerative aging occur at the level of cells and specific protein machinery within cells, harming their ability to perform as they should. Old, damaged cells produce more old, damaged cells when they divide. Old, damaged stem cells simply fail to keep up with their tasks of tissue maintenance. Long-lived cells become progressively more damaged and incapable, or die back, either of which causes very visible issues when it happens in the nervous system and brain.

Aging is simply a matter of damage. But how that damage translates into system failure is not a straightforward matter of cells living longer or cells dying sooner - except when it is for some long-lived cell types. Every tissue fails through the same general processes, but those processes produce a very wide range of failure modes, depending on the character of the tissue and the cells that make it up. Go beyond the comparative simplicity of the root causes of aging, and everything becomes progressively ever more complex as you move towards describing the highly varied biology of fatal age-related diseases. This is why intervening in the root causes is absolutely the best and most cost-effective strategy, the only one likely to produce meaningful progress towards human rejuvenation in our lifetimes.

As a final note, for my money, I'd wager that forms of amyloidosis are the present outermost limiting condition on human life span. The evidence suggests that this is what ultimately kills supercentenarians, the resilient individuals who have made it past the age of 110, avoiding or surviving all of the fatal age-related medical conditions that claimed their peers.

As these authors note, progress towards heart regeneration via stem cell therapies is ongoing. Numerous important steps forward in the control and manipulation of heart cells and stem cells have been demonstrated in the laboratory in recent years:

Damage in cardiac tissues from ischemia or other pathological conditions leads to heart failure; and cell loss or dysfunction in pacemaker tissues due to congenital heart defects, aging, and acquired diseases can cause severe arrhythmias. The promise of successful therapies with stem cells to treat these conditions has remained elusive to the scientific community. However, recent advances in this field have opened new opportunities for regenerative cardiac therapy.

Transplantation of cardiomyocytes derived from human pluripotent stem cells has the potential to alleviate heart disease. Since the initial derivation of human embryonic stem cells, significant progress has been made in the generation and characterization of enriched cardiomyocytes and the demonstration of the ability of these cardiomyocytes to survive, integrate, and function in animal models.

The scope of therapeutic potential from pluripotent stem cell-derived cardiomyocytes has been further expanded with the invention of induced pluripotent stem cells, which can be induced to generate functional cardiomyocytes for regenerative cardiac therapy in a patient specific manner. The reprogramming technology has also inspired the recent discovery of direct conversion of fibroblasts into cardiomyocyte-like cells, which may allow endogenous cardiac repair. Regenerative cardiac therapy with human pluripotent stem cells is now moving closer to clinic testing.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23819949

This study was mentioned in a recent review of treatment options currently under development for osteoporosis, the systematic loss of bone mass and strength with age:

Bone regeneration by systemic transplantation of mesenchymal stem cells (MSCs) is problematic due to the inability to control the MSCs' commitment, growth and differentiation into functional osteoblasts on the bone surface. Our research group has developed a method to direct the MSCs to the bone surface by conjugating a synthetic peptidomimetic ligand (LLP2A) that has high affinity for activated α4β1 integrin on the MSC surface, with a bisphosphonates (alendronate) that has high affinity for bone (LLP2A-Ale), to direct the transplanted MSCs to bone.

Our in vitro experiments demonstrated that mobilization of LLP2A-Ale to hydroxyapatite accelerated MSC migration that was associated with an increase in the phosphorylation of Akt kinase and osteoblastogenesis. LLP2A-Ale increased the homing of the transplanted MSCs to bone as well as the osteoblast surface, significantly increased the rate of bone formation and restored both trabecular and cortical bone loss induced by estrogen deficiency or advanced age in mice. These results support LLP2A-Ale as a novel therapeutic option to direct the transplanted MSCs to bone for the treatment of established bone loss related to hormone deficiency and aging.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23818248

Back in 2008 or so, a group of researchers crunched the numbers to argue that most of the variation in longevity between mammal species (which spans the range from small rodents that live a couple of years to whales that live a couple of centuries) is largely determined by resting metabolic rate and variations in mitochondrial DNA. Our mitochondria are the power plants of the cell, the descendants of symbiotic bacteria with their own DNA, and they toil to produce chemical energy stores to power the rest of the cell machinery. They occupy a central role in our biology, and this is one of many papers that point to the significance of mitochondria in aging.

For an introduction on why mitochondria and their composition are important, you might look back in the Fight Aging! archives, or investigate the membrane pacemaker hypothesis of aging. The short version of the story is that mitochondria produce damaging reactive byproducts in the course of their operation: anything that can react with protein machinery and disrupt its operation is harmful to a cell, though most such incidences are quickly repaired. The cell components that suffers the brunt of the damage are of course the mitochondria themselves, which only makes the situation progressively worse. Some species are better at soaking up the reactive compounds with natural antioxidant proteins, while others have mitochondria and cell structures that are more resistant to damage, some can better repair damaged mitochondria, and yet more have more efficient mitochondria that emit fewer damaging molecules - all of these things tend to lead to a longer life when present.

While engineering humans to have better mitochondria is going to happen sooner or later, there are also other and arguably better near term options for dealing with the issue. A number of research groups are working towards ways to repair or replace mitochondria in living tissue, and thus removing their contribution to degenerative aging. This is a very necessary part of the rejuvenation toolkit of future medicine, but like much of the present work in this field it is poorly funded and proceeding far more slowly than it might be.

The researchers mentioned above, who investigated correlations between metabolic rate and longevity, recently published this open access paper in which there is some more number crunching to probe associations between various measures and species maximum life span (MLS):

Telomere length and body temperature - independent determinants of mammalian longevity?

We have previously shown that body mass (BM) or resting metabolic rate alone explain around 40-50% of the variation in mammalian longevity, whereas their combination with mitochondrial DNA (mtDNA) GC content could explain over 70% of the MLS variation. Consequently, we hypothesized that other putative players in MLS determination should have relatively small contribution or their effects should be mediated by the above factors.

Recent finding by Gomes et al. (2011) demonstrating a strong negative correlation between telomere length and MLS in 59 mammalian species calls for re-evaluation of this hypothesis. Indeed, the coefficient of MLS determination calculated using the data in their paper indicates that the telomere length could alone explain more than 1/3 of the variation in the lifespan of mammals. Here, we explore whether the telomere length has an independent impact on mammalian longevity or its effect is attributed to co-variation with other determinants of MLS, such as BM and mtDNA GC content.

Partial correlation and multivariate analyses showed that the telomere length has an independent impact on longevity determination. The partial correlation analysis allows eliminating the co-variation effects. We found that the correlative links between telomere length and BM or mtDNA GC do not significantly alter its association with longevity. That is, the telomere length could explain part of the variation in the mammalian longevity which is not explained by the BM and mtDNA GC.

In attempt to discover [other possible] still unaccounted factors, we further included in the analysis an additional variable closely related but not identical to the metabolic rate - body temperature (Tb). Gomes et al. (2011) hypothesized that the evolution from exothermic to homeothermic organisms was accompanied by telomere shortening as a tumor protective adaptation to an enhanced mutation load caused by high Tb. Yet, within mammalian species we did not observe any significant correlation between the telomere length and typical Tb.

Unexpectedly, we found that Tb [may] explain some cases of considerable deviations from the MLS predicted by BM, mtDNA GC, and telomere length. For example, the naked mole-rat (Heterocephalus glaber) and North American pika (Ochotona princeps) have similar values of BM, mtDNA GC content and telomere length, yet the naked mole-rat lives 4.4 times longer. This apparent "discrepancy" could be largely attributed to the difference in Tb which, in the sample analyzed, is the lowest for the naked mole-rat (32.1°C) and the highest for the North American pika (40.1°C).

Last year Japanese scientists published on their work in growing small amounts of liver tissue from stem cells. Here is more on this line of research:

The researchers found that a mixture of human liver precursor cells and two other cell types can spontaneously form three-dimensional structures dubbed "liver buds." In the mice, these liver buds formed functional connections with natural blood vessels and perform some liver-specific functions such as breaking down drugs in the bloodstream. It's possible the technique will work with other organ types, including the pancreas, kidney, or lungs. The study is the first demonstration that a rudimentary human organ can be produced using induced pluripotent stem (iPS) cells. These iPS cells are made by converting mature cells such as skin cells into a state from which they can develop into many other cell types.

The researchers took a creative approach to building the proto-liver [by] co-mingling three different cell types: liver cell precursors derived from human iPS cells, blood vessel precursors called endothelial cells, and connective tissue precursor cells called mesenchymal stem cells. Both the blood vessel and connective tissue precursor cells were harvested from umbilical cords.

To demonstrate the therapeutic potential of the liver bud method, [the researchers] transplanted a dozen liver buds into the abdomen of mice whose natural liver function was shut down with a drug. The liver bud transplants kept these mice alive for the month they were watched. The liver buds did not achieve all the functions of a mature liver. For instance, the buds did not form a bile duct system. However, in ongoing research, the team has found that by transplanting the buds into an existing liver, the body seems to make use of the existing bile system.

One potential therapeutic use of the method could involve delivering microscopic liver buds to human patients through a large vein that connects to the liver to improve survival after liver failure. [The researchers are] optimistic that as much as 30 percent of liver function could be restored through this method, [but] estimated that such a treatment is at least 10 years away. In the meantime, the method must be improved so that the liver buds can be produced much more efficiently.

Link: http://www.technologyreview.com/news/516706/a-rudimentary-liver-is-grown-from-stem-cells/

Decellularization is the process of taking a donor organ and stripping its cells, leaving behind the extracellular matrix and all its chemical cues. The organ can then be repopulated with a patient's cells, producing working tissue for transplant that will not be rejected. The donor organ doesn't even have to be human: decellularization greatly improves the prospects for xenotransplantation, such as obtaining hearts or kidneys from pigs. So far decellularization has only been used in human medicine for comparatively simple tissue structures, such as the trachea, but researchers are not very many years away from trials for decellularized hearts and other major organs. This article goes into detail on the challenges still to be surmounted at every step of the way:

The strategy is simple enough in principle. First remove all the cells from a dead organ - it does not even have to be from a human - then take the protein scaffold left behind and repopulate it with stem cells immunologically matched to the patient in need. Voilà! The crippling shortage of transplantable organs around the world is solved. In practice, however, the process is beset with tremendous challenges. Researchers have had some success with growing and transplanting hollow, relatively simple organs such as tracheas and bladders. But growing solid organs such as kidneys or lungs means getting dozens of cell types into exactly the right positions, and simultaneously growing complete networks of blood vessels to keep them alive. The new organs must be sterile, able to grow if the patient is young, and at least nominally able to repair themselves. Most importantly, they have to work - ideally, for a lifetime.

The leading techniques for would-be heart builders generally involve reusing what biology has already created. Suspended by plastic tubes in a drum-shaped chamber made of glass and plastic is a fresh human heart. Nearby is a pump that is quietly pushing detergent through a tube running into the heart's aorta. The flow forces the aortic valve closed and sends the detergent through the network of blood vessels that fed the muscle until its owner died a few days before. Over the course of about a week [this] flow of detergent will strip away lipids, DNA, soluble proteins, sugars and almost all the other cellular material from the heart, leaving only a pale mesh of collagen, laminins and other structural proteins: the 'extracellular matrix' that once held the organ together.

Through trial and error, scaling up the concentration, timing and pressure of the detergents, researchers have refined the decellularization process on hundreds of hearts and other organs. It is probably the best-developed stage of the organ-generating enterprise, but it is only the first step. Next, the scaffold needs to be repopulated with human cells. 'Recellularization' introduces another slew of challenges. "One, what cells do we use? Two, how many cells do we use? And three, should they be mature cells, embryonic stem cells, iPS [induced pluripotent stem] cells? What is the optimum cell source?" Using mature cells is tricky to say the least. "You can't get adult cardiocytes to proliferate. If you could, we wouldn't be having this conversation at all" - because damaged hearts could repair themselves and there would be no need for transplants.

Link: http://www.nature.com/news/tissue-engineering-how-to-build-a-heart-1.13327

Deathism is a label of convenience for any philosophy or outlook that regards death as a good thing. These worldviews also tend to be in favor of both degenerative aging and the involuntary nature of death - that we are forced to die regardless of what we might think on the subject. A deathist is someone who holds such a viewpoint. One of the more sensible comments I've seen on deathism in general is this:

Such is human nature, that if we were all hit on the head with a baseball bat once a week, philosophers would soon discover many amazing benefits of being hit on the head with a baseball bat: It toughens us, renders us less fearful of lesser pains, makes bat-free days all the sweeter. But if people are not currently being hit with baseball bats, they will not volunteer for it. Modern literature about [death and the prospects for radical life extension through medical science] is written primarily by authors who expect to die, and their grapes are accordingly sour.

One of the hoary old arguments put out by near everyone in favor of unavoidable death is that "death gives life meaning." The conceit here is that life is somehow meaningless until you can draw a line under it and assess, or perhaps that no-one would do anything if they didn't have a timer counting down their own personal extinction. I've never been able to grasp the essence of the first point, which just seems so much nonsense to me: why draw the line on death? Why not somewhere else? The past at any point is fixed and up for evaluation, but why draw lines at all for that matter?

The second point can be thrown out on the grounds that humans with an adult life expectancy of 80 behave remarkably similarly to humans with an adult life expectancy of 40-something, as any exploratory expedition through the better-recorded sections of Roman history will demonstrate. Where differences exist they certainly don't involve people lazying around as the expectation of additional years grows, but are rather changes in the nature of the tasks that people busy themselves with. A longer time horizon means that you can undertake better, more ambitious, more profitable projects by virtue of having longer in which to complete them. Competition if nothing else drives that process.

Since various deathists persist in arguing that involuntary death (without or without the suffering and pain of aging) is necessary to give life meaning, there is a steady flow of articles from the radical life extension advocacy community to point out just how ridiculous the deathist position is. Here is one of the more recent examples:

Death is Dumb!

One common argument against indefinite lifespans is that a definitive limit to one's life - that is, death - provides some essential baseline reference, and that it is only in contrast to this limiting factor that life has any meaning at all. In this article I refute the argument's underlying premises, and then argue that even if such premises were taken as true, its conclusion - that eradicating death would negate the "limiting factor" that legitimizes life - is also invalid, because the ever-changing state of self and of world can constitute such a limiting factor just as well as death can, which can be seen lucidly in the simple fact that opportunities once here are now gone, and that it is not death but life itself that is responsible for that.

Culture is in constant upheaval, with new opportunity's opening up(ward) all the time. Thus the changing state of culture and humanity's upheaved hump through time could act as this "limiting factor" just as well as death or the changing self could. What is available today may be gone tomorrow. We've missed our chance to see the Roman Empire at its highest point, to witness the first Moon landing, to pioneer a new idea now old. Opportunities appear and vanish all the time.

Indeed, these last two points - that the changing state of self and society, together or singly, could constitute such a limiting factor just as effectively as death could - serve to undermine another common argument against the desirability of limitless life: boredom. Too often is this rather baseless claim bandied about as a reason to forestall indefinitely-extended lifespans - that longer life will lead to increased boredom. That self and society are in a constant state of change means that boredom should become increasingly harder to maintain.

Bone weakens with age, a condition known as osteoporosis. Like many aspects of aging it appears that this can be partially slowed by means of calorie restriction, but prevention is going to require new medical technology. Patching over the underlying causes, such as by interfering in the behavior of cells that create and destroy bone tissue, is the focus of the research mainstream. The better approach is to repair the underlying damage that causes aging, as detailed in the SENS proposals, and thereby eliminate the changes in our cell populations that cause bone to weaken.

One of the interesting aspects of presently available treatments for osteoporosis is the outcome of bisphosphonate use: one study showed an unusually large increase in life expectancy for patients undergoing biphosphonate therapy, and I've been waiting to see if this is replicated in other data. Here is a review article that surveys the present and near future options for treating osteoporosis:

Osteoporosis is caused by an uncoupling of bone resorption from bone formation such that the activities of osteoclasts far outweigh those of the osteoblasts. Peak bone mass is achieved in early adulthood and, following this point, both women and men lose bone with increasing age. As a stepping stone to determining a genetic link in osteoporosis, twin and family studies have shown that up to 85% variation in bone mass density (BMD) can be attributed to genes. Although initially genome-wide scans revealed no significant association to individual genes due to low sensitivity, later genome-wide association studies showed single nucleotide polymorphisms (SNPs) associated with variation in BMD. Many of these genes are associated with regulation of bone mineral homeostasis.

Bisphosphonates are the most commonly used drugs for the treatment of osteoporosis. They avidly bind to bone and are internalized by osteoclasts to inhibit resorption. They are administered both orally and intravenously and are divided into two classes - the low potency non-nitrogen containing bisphosphonates and the potent nitrogen-containing bisphosphonates. These two classes have distinct intracellular targets and molecular mechanisms of action that lead to inhibition of osteoclast-mediated bone resorption. As bisphosphonates have an apparent half-life of more than 10 years due to selective adherence to the bone surface, successive treatment over years would not only have a cumulative effect, but may actually be detrimental for bone health by preventing the cyclical changes required to maintain normal bone architecture.

Over recent years, stem cell therapy in musculoskeletal research has exploded, and there is a wide range of possible clinical applications for such technologies, many focusing on tissue repair following damage, including bone fractures, cartilage lesions, or ligament and tendon injuries. One hurdle in the development of therapies exploiting endogenous mesenchymal stem cells (MSCs) is their lack of capacity to home to bone surfaces. A recent study indicated the possibility of directing endogenous MSCs to the bone surface using piggyback technology in which LLPA2, the ligand for integrin α4β1 expressed by MSCs, is administered in vivo, piggybacked onto [an existing bisphosphonate treatment for osteoporosis]. When LLPA2 binds to MSCs, the bisphosphonate directs those stem cells to the bone surface where osteoblastic differentiation and subsequent bone regeneration takes place.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3686324/

You might recall that in some ways muscle tissue shows a surprising lack of degeneration associated with aging. Not every measure and biological mechanism declines greatly. It's not all that comforting, as evidently we're all still aging into frailty regardless, but it does suggest that perhaps a larger fraction of muscle aging than previously thought is under our control, the result of poor lifestyle choices such as sedentary behavior.

While the general understanding of muscle regenerative capacity is that it declines with increasing age due to impairments in the number of muscle progenitor cells and interaction with their niche, studies vary in their model of choice, indices of myogenic repair, muscle of interest and duration of studies.

We focused on the net outcome of regeneration, functional architecture, compared across three models of acute muscle injury to test the hypothesis that satellite cells maintain their capacity for effective myogenic regeneration with age. Muscle regeneration in extensor digitorum longus muscle (EDL) of young (3 mo-old), old (22 mo-old) and senescent female mice (28 mo-old) was evaluated for architectural features, fiber number and central nucleation, weight, collagen and fat deposition.

Histological analyses revealed successful architectural regeneration following [injury] with negligible fibrosis and fully restored function, regardless of age. In comparison, the regenerative response to injuries that damaged the neurovascular supply [was] less effective, but similar across the ages. The focus on net regenerative outcome demonstrated that old and senescent muscle has a robust capacity to regenerate functional architecture.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23807088

There are a good many organizations that advocate for aging research and extended healthy lives. You can find some of them listed in the resources section here at Fight Aging! There is only one organization in the world, however, that (a) is presently meaningfully focused on creating the means of human rejuvenation, (b) has the support of a broad range of researchers and philanthropists, and (c) to which folk like you and I can donate, in the secure knowledge that even small donations will go towards directly speeding the development of specific, planned, plausible therapies to repair and reverse aging.

That organization is the SENS Research Foundation, which over the past few years has moved from strength to strength in expanding its budget and convincing more and more of the aging research community to become allies and supporters of ambitious goals in longevity science. At a $3 million yearly budget, the Foundation's reach is no longer a group that you can fit into a small photograph: there are small laboratories in a number of research establishments around the world, a bunch of folk in the Bay Area, and a broad network of advisors, just to start with.

You all recognize the SENS Research Foundation cofounder Aubrey de Grey, of course, but there are many more people working away on the foundations of rejuvenation biotechnology and they deserve their time in the spotlight. So the Foundation is running a series of profiles at the moment: funded researchers, interns, volunteers, advocates, conference speakers, advisors, and others - people who are working to ensure that you and I have a shot at living much longer healthy lives while evading the pain and suffering caused by untreated aging. I linked to some of these profiles a few weeks ago, and here are more in the same vein:

SENS6 Speaker Highlight: Dr. George Church

The SENS6 conference's keynote address will be delivered by Dr. George Church, a researcher widely considered a luminary in modern biotechnology with over 300 publications to date. Dr. Church may be best known for his key role in the Human Genome Project, which he helped initiate and drive. His genomic sequencing innovations have led him to be involved with most of the companies in that field, either as a co-founder, advisor, or provider of licensed technology.

At SENS6, Dr. Church's presentation will address his cutting-edge work on bringing CRISPR-associated systems, an adaptive immune defense of some single-celled organisms that uses short strands of RNA, to human cells. He will also discuss the latest sequencing technologies, and the need to supplement genomic information with environmental and trait data.

SENS6 Speaker Highlight: Dr. Felipe Sierra

Dr. Felipe Sierra stands out for his unifying vision and deep involvement in aging research. [He is] the head of the National Institute on Aging's Division of Aging Biology (DAB). The DAB studies the aging process itself; the remits of its various branches are genetics and cell biology, the effects of cellular and molecular changes on tissue function, and animal models of human aging. Instead of funding work about the mechanisms or progression of age-related diseases, the DAB supports work that elucidates why exactly it is that older adults suffer from these diseases while younger ones do not.

At SENS6, Dr. Sierra will give a presentation about [the Geroscience Interest Group] and the fundamental process that underlies the diseases of aging. He will be joined at the conference by many other top scientists, including Harvard's George Church, the Mayo Clinic's Jan van Deursen, Carnegie Mellon's Alan Russell, and MIT's Todd Rider.

Intern Sam Curran: IDing Senescent Cell Secretion Potentially Implicated In Age-Related Decline Of Immune System Function

Senescent cells [contribute to] pathologies associated with old age, such as tissue degeneration. Is there a way to target and treat the afflicted cells responsible [here]? This is the question being addressed [by] Sam Curran. In the summer of 2012 as part of the SENS Research Foundation Summer Internship Program, Sam joined Dr. Judith Campisi's laboratory at the Buck Institute for Research on Aging to work on a project dealing with the senescence phenotype of mesenchymal stem cells.

After the success of his summer project, Sam was invited by the Campisi lab to continue his research for a year of full-time funding by the SENS Research Foundation. Since his summer internship ended, Sam has made a number of novel discoveries. For instance, the senescence-associated secretory phenotype (SASP) of MSCs may be different than other cells due to their immunosuppressive secretions. Sam has already identified one senescence-associated immunosuppressive factor that may be implicated in two important biological phenomenon: the ability of senescent cells to evade immune-surveillance and age-related decline of immune system function. Sam hopes to identify additional immunosuppressive MSC SASP factors with yet another year of funded research in the Campisi lab before pursuing a Ph.D. in bioengineering in the fall of 2014.

Haroldo Silva: Lead OncoSENS Scientist Researches Telomere Lengthening and Cancer Pathways

I was a doctoral student at the University of California, Berkeley, in the department of Bioengineering. My dissertation laboratory at UC Berkeley is known for cutting-edge aging research and that was one of the reasons I joined that group in the first place. I also attended a seminar at Berkeley given by Aubrey de Grey which really opened my eyes about the real possibilities of a novel perspective on aging research transforming the world in our lifetime.

I am the lead scientist of the OncoSENS team at SRF. Our group seeks to uncover the genetic pathways and mechanisms that enable cancer cells to acquire unlimited cellular division. One of the major hurdles cancer cells need to overcome is how to keep the ends of their chromosomes (i.e., telomeres) from shortening with each cell division. A major pathway exploited by cancer cells to elongate their telomeres is upregulation of an enzyme called telomerase. However, about 10-15% of cancers do not have any detectable telomerase activity and thus operate via another pathway called Alternative Lengthening of Telomeres (ALT). The goal of our research team is to find out which specific genes are responsible for ALT activity in these cancers. Therefore, in theory, removal of both telomerase and ALT genes from the genome should eradicate cancer completely.

Connie Wang: Microglia, Aging and Alzheimer's

During her time at Caltech, Connie has engaged in a variety of research interests. She has conducted plant genetics research to determine whether a strain of Mimulus was a distinct subspecies and also helped design an optical coherence tomography (OCT) system for use in retinal surgery.

In 2012, she participated in the SENS Research Foundation Summer Internship Program. During her time at the SRF Research Center in Mountain View, California, she developed microglial cell assays that helped lay the groundwork for studying the relationship between microglia, aging, and Alzheimer's Disease. This summer, Connie is working with the Reichert lab at Duke University to develop an angiogenesis-promoting system for glucose sensors planted under the skin with the goal of making them a viable long-term solution for insulin-dependent diabetics. She will return to Caltech in the fall to begin her final year of study before applying to graduate school in 2014.

Supporters of radical life extension research are organizing a conference in Washington, DC, this coming September 22nd:

ImmortalLife.info is presenting a conference in the capitol of the USA on September 22. Space is limited to 300 seats. "Radical LIfe Extension - Are You Ready to Live 1,000 Years?" is co-sponsored by LongeCity and Maximum LIfe Foundation. LongeCity is an international, not-for-profit, membership-based organization (501-3-c status in the United States). It's mission is "to conquer the blight of involuntary death". LongeCity is providing ImmortalLife.info with airfare for speakers. Maximum Life Foundation, led by David A. Kekich, intends to "Reverse Aging by 2029." Maximum Life Foundation serves as ImmortalLife.info's fiscal sponsor.

We will have 11 speakers discussing Immortality / Life Extension from a wide variety of perspectives: scientific, political, social, poetic, religious, atheistic, economic, demographic, moral, etc. Everyone who preregisters for the event will receive a free e-book titled "Human Destiny is to Eliminate Death - essays and rants on immortalism." Many of the 35 articles that it includes are written by speakers at our event.

Immortality is a potent word with many associations, as well as being the first resort of the lazy press when talking about longevity science, and there are those in the advocacy community who don't like it being slung around. Success in advocacy is accompanied by a move to moderation in message and a distancing from more radical opinions, for example, and this is just as true in aging research as anywhere else. But there is definitely a role for people willing to plant a flag out there and argue for the most extreme plausible proposal no matter how much it rocks the boat: without someone pushing the bounds of the conversation, how will there be progress?

Link: http://immortallife.info/articles/entry/tickets-on-sale-now-for-immortal-event-in-washington-dc1

Cryonics is the low-temperature preservation of the brain and body on death, so as to preserve the tissue structures that hold the data of the mind. This offers a chance of future restoration to life via advanced medical technologies, which is more than can be said for the other post-mortem options presently available to us. Here is an interview with Max More of the Alcor Life Extension Foundation, one of the two long-established cryonics providers in the US:

Somebody might opt to be placed into biostasis at the end of their natural life [for] the same reason that a person might choose to have open heart surgery or an experimental cancer treatment. Essentially, we see cryonics as an extension of critical care medicine. If you were unlucky enough to go into cardiac arrest whilst walking down the street 50 years ago, you would probably have been pronounced dead at the scene. Nowadays, paramedics routinely use defibrillators and cardiopulmonary resuscitation (CPR) to revive patients who would simply have died in the past.

Cryonicists recognise that what we call 'dead' is somewhat arbitrary; it depends largely on the level of medical technology that is available at a particular point in time. When today's doctors declare a person clinically dead, they are not saying that that person is biologically dead. They are not saying that all of their brain cells have exploded or disappeared. They are simply stating that the person in question has become non-functional in a way that they are unable, or unwilling, to fix. So, why give up on that person? They're still potentially there; their brain is intact. As cryonicists, we are looking towards the future. We can do things today that weren't possible 50 years ago. It's clearly going to be the case that in 50 years' time, we will be capable of achieving things that are not possible today. In the future, we will be able to fix many things that we cannot fix at present. Hopefully, this will include the ageing process itself.

If you look deeper into cryonics, you will begin to recognise how it is connected to other sciences. Organ donation, for example, is a current research area that shares several commonalities with cryonics. The initial procedures that we conduct in order to maintain biological viability are much the same as those carried out when preserving a donor organ. Moreover, there is plenty of evidence to suggest that what we are doing is working. Electron microscope studies have demonstrated that when we place a person into biostasis, the connections between their brain cells persist. Given what we know about human memory, this indicates that the person is still potentially there.

Cryonics is beginning to make sense within the context of medical advances that are taking place across a range of sectors. People are putting the pieces together and arriving at their own conclusions. Nobody knows whether or not cryonics will ultimately succeed, but it certainly isn't crazy. In fact, it looks a whole lot more plausible today than it did in the past.

Link: http://www.scienceomega.com/article/1221/exploring-cryonics-could-science-offer-new-life-after-death

The vast majority of animals undergo degenerative aging: it is evident, easy to measure, and well recorded. The remaining tiny minority may undergo degenerative aging, but due to a combination of insufficient study and individual robustness throughout life researchers can't yet accurately determine the outer limits to their life spans, or how fast they age, or definitively how and why their aging is different from ours.

Lobsters fall into this category (though possibly not for very much longer), as do hydra, some clams and mussels, and a handful of others. It's probably worth remarking on the fact that if naked mole rats were much less studied, they might also be on the list - but since researchers have colonies of thousands of naked mole rats in laboratories and are intensely focused on their peculiar biology we have a much more comprehensive idea as to how they age, what their maximum life span is, and so on. Conversely if all those naked mole rats were instead arctic quahog clams, then I'd wager clams wouldn't be on the list above. To a certain degree the list of potentially ageless animals is as much a list of ignorance as it is of interesting and resilient species.

The vast majority of animals age because aging is a necessary evolutionary strategy for success in a changing world, or at least that is the common view:

When conditions change, a senescent species can drive immortal competitors to extinction. This counter-intuitive result arises from the pruning caused by the death of elder individuals. When there is change and mutation, each generation is slightly better adapted to the new conditions, but some older individuals survive by random chance. Senescence can eliminate those from the genetic pool.

From the perspective of individuals this is a race to the bottom, wherein lineages that result in more harm to their own members prosper and spread at the expense of those that do not. Successful it may be, and no doubt the bone mountain of history is a necessary precondition for you and I to be standing here today, but that doesn't mean it is a good thing here and now. In particular, in the decades ahead you and I will suffer decades of pain and privation leading up to an ignominious, undignified death assuming nothing is done about the situation. This is an age of biotechnology, however: now that we can do something about it, we should be doing our utmost to get rid of degenerative aging, and the suffering and death it causes, and take the reins of the future into our own hands.

Today I noticed a slightly different way of looking at the near-universality of aging as an outcome of evolutionary selection. It comes from an author who is very much in the programmed aging camp when it comes to how and why aging progresses in an individual, but for the purposes of this argument about the evolution of aging that doesn't matter all that much:

The Demographic Theory of Aging

If it weren't for aging, the only way that individuals would die would be by starvation, by diseases, and by predation. All three of these tend to be "clumpy" - that is to say that either no one is dying or everyone is dying at once. Until food species are exhausted, there is no starvation; but then there is a famine, and everyone dies at once. If a disease strikes a community in which everyone is at the peak of their immunological fitness, then either everyone can fend it off, or else everyone dies in an epidemic. And without aging, even death by predation would be very clumpy. Many large predators are just fast enough to catch the aging, crippled prey individuals. If this were not so, then either all the prey would be vulnerable to predators, or none of them would be. There could be no lasting balance between predators and prey.

Without aging, it is difficult for nature to put together a stable ecosystem. Populations are either rising exponentially or collapsing to zero. With aging, it becomes possible to balance birth and death rates, and population growth and subsequent crashes are tamed sufficiently that ecosystems may persist. This is the evolutionary meaning of aging: Aging is a group-selected adaptation for the purpose of damping the wild swings in death rate to which natural populations are prone. Aging helps to make possible stable ecosystems.

Aging as a damping function introduced into population dynamics is an interesting way of looking at it. Starting from that purely mechanistic perspective it makes one wonder why aging came to near-universally dominate as the source of that damping function - why are there no other viable alternatives to achieve that result in the natural world?

From the perspective of aging as a process caused by an accumulation of cellular and molecular damage, rather than a process caused by evolved genetic programming, longevity evolves when evolutionary success is predicated by living longer, so that better repair and maintenance mechanisms are favored. In this view, aging was a given from day one of the first evolving organism, as all complex systems suffer damage in the course of operation. Even bacteria age, putting the origins of aging far, far back in the deep past: when the first multicellular organisms emerged the fact of degenerative aging was already baked into the mix. The only question from there forward was whether and how evolutionary circumstances would lead to biological mechanisms that mitigated or repaired the damage that causes aging.

NF-κB shows up in a range of research on longevity and aging. It's one of a number of central pieces of biological machinery that appear to be altered by methods of extending life in laboratory animals, but which influence (usually indirectly) so very many processes and mechanisms that understanding how it all fits together becomes an enormous task. In this open access paper researchers look at NF-κB in the context of the immune system failure and systematic chronic inflammation that occurs with aging:

Chronic inflammation is a major biological mechanism underpinning biological ageing process and age-related diseases. Inflammation is also the key response of host defense against pathogens and tissue injury. Current opinion sustains that during evolution the host defense and ageing process have become linked together.

An excessive activation of NF-κB signaling pathway characterizes the entropic ageing process, responsible of inflammageing and SASP phenotype, and the consequent onset of several age-related diseases. This is plausible since nearly all insults enhancing the ageing process are well-known activators of NF-κB signaling system.

Thus, the large array of defense factors and mechanisms linked to the NF-κB system seem to be involved in ageing process. This concept leads us in proposing inductors of NF-κB signaling pathway as potential ageing biomarkers. On the other hand, ageing biomarkers, represented by biological indicators and selected through apposite criteria, should help to characterize biological age and, since age is a major risk factor in many degenerative diseases, could be subsequently used to identify individuals at high risk of developing age-associated diseases or disabilities. In addition, we also suggest [these biomarkers] as targets for the development of new therapeutic strategies against ageing and age-related diseases.

In the programmed view of aging, targeting things like the NF-κB signaling pathway is the logical first step, as aging is thought by that school to be caused by changes in gene expression and behavior of signaling pathways. In the more mainstream view of aging as caused by accumulated cellular and molecular damage, however, altering gene expression and pathway behavior is only a patch on the real problem. Those changes are a reaction to various forms of molecular damage in and between cells, and changing the response to damage rather than repairing that damage is only of limited benefit. It's a little like changing the oil in your car and hoping rather than replacing worn engine components.

Unfortunately despite the fact that most of the research community supports damage-based theories of aging, scientists still largely pursue research that better fits the programmed view of aging - i.e. that seeks only to alter biological reactions to the cause of aging rather than directly addressing the damage that is the cause. Only by repairing the damage, such as by implementing the SENS proposals for rejuvenation therapies, can we create truly effective therapies for aging.

Link: http://www.immunityageing.com/content/10/1/24

OXYS rats are a laboratory breed engineered to show accelerated aging. They exhibit higher levels of oxidative free radicals than other rats, and degenerate more rapidly. Animal lineages are engineered this way to reduce the cost and duration of exploratory studies of aging or specific conditions of aging.

Here researchers show that rapamycin, demonstrated to extend life in mice in recent years, can partially reverse accelerated degeneration in OXYS rats. This is an expected result given the range of other work on rapamycin to date. It is, however, worth noting that enthusiasm for rapamycin is driven as much by the fact that it is already an FDA-approved drug as for its merits as a basis for treatments. The cost of obtaining new drug approval is very high and takes a long time, so that funding sources are steered towards favoring the development of marginal new uses for existing drugs rather than better forms of entirely new medicine:

Cellular and organismal aging are driven in part by the MTOR (mechanistic target of rapamycin) pathway and rapamycin extends life span in C elegans, Drosophila and mice. Herein, we investigated effects of rapamycin on brain aging in OXYS rats. Previously we found, in OXYS rats, an early development of age-associated pathological phenotypes similar to several geriatric disorders in humans, including cerebral dysfunctions. Behavioral alterations as well as learning and memory deficits develop by 3 months.

Here we show that rapamycin treatment decreased anxiety and improved locomotor and exploratory behavior in OXYS rats. In untreated OXYS rats, MRI revealed an increase of the area of hippocampus, substantial hydrocephalus and 2-fold increased area of the lateral ventricles. Rapamycin treatment prevented these abnormalities, erasing the difference between OXYS and Wistar rats (used as control). All untreated OXYS rats showed signs of neurodegeneration, manifested by loci of demyelination. Rapamycin decreased the percentage of animals with demyelination and the number of loci.

Levels of Tau [were] increased in OXYS rats (compared with Wistar). Rapamycin significantly decreased Tau and inhibited its phosphorylation in the hippocampus of OXYS and Wistar rats. We conclude that rapamycin in low chronic doses can suppress brain aging.

Link: http://impactaging.com/papers/v5/n6/full/100573.html