Fight Aging!

Most cancers kill through metastasis. It isn't the initial malignant tumor but rather the spread of its cells throughout the body to seed more growths that outpaces today's medical toolkit. Absent metastasis, most cancers would be far more controllable and far less deadly, and even last generation treatments like chemotherapy could be made more localized and less taxing on the patient. Thus while a way to block metastasis in a majority of cancers is not a cure, it is a worthwhile stepping stone to aim for. Many of the same considerations come into play as for research aimed at destroying cancer cells: are there common mechanisms involved in the dispersal of malignant cancer cells into the blood system; do these migrating cells have any common surface molecules or other distinguishing traits; how plausible is it to interfere in their activities without impacting normal tissues; and so forth.

Cancer research is well funded in comparison to other fields of medical science. While there is a lot of dead wood and waste, as is always the case given the large amounts of public funding, the field as a whole is heading in the right direction towards a robust suite of next generation treatments. For those of us not expecting a high chance of dealing with cancer for another couple of decades at least, the odds are good that we will have a comparatively smooth ride of it. It will be expensive and unpleasant in comparison to, say, avoiding cancer entirely, but targeted immunotherapies with few side effects and that work to produce cures in near every patient will be the order of the day. Metastatic cells will be sabotaged one way or another - either interrupted in their attempts to escape the primary tumor or chased down by targeted cell killers in the bloodstream. All in all it will be a far cry from today's late detection of cancer, standard treatments of radiotherapy and chemotherapy, and the poor odds faced by many patients.

These two items give a decent view into the sort of investigations into metastasis taking place today. Greater understanding and better tools are emerging as researchers search for ways to intervene in the underlying processes driving metastasis so as to prevent cancers from spreading:

Decoding the emergence of metastatic cancer stem cells

Researchers have mapped how information flows through the genetic circuits that cause cancer cells to become metastatic. The research reveals a common pattern in the decision-making that allows cancer cells to both migrate and form new tumors. Researchers say the commonality may open the door to new drugs that interfere with the genetic switches that cancer must flip to form both cancer stem cells and circulating tumor cells - two of the main players in cancer metastasis. "Though some of the circuits for metastasis have been mapped, this is the first study to examine how cancer uses two of those circuits, in concert, to produce not just cancer stem cells, but also dangerous packs of hybrid stem-like-cells that travel in groups to colonize other parts of the body."

The switch that many cancer cells use to become metastatic is the circuit that governs the epithelial-to-mesenchymal transition, or EMT. The EMT, an important feature in embryonic development and wound healing, allows cells to revert back along their developmental path and take on certain stem-like features that allow them to form new tissues and repair tissue damage. [Researchers examined] the interaction between the three-way EMT switch and a second, well-documented genetic switch that gives rise to cancer stem cells (CSCs). The research showed that the CSC circuit also operates as a three-way switch. In addition, the study found "significant correspondence" between the operation of the two switches, which suggests a mechanism that would confer "stemness" on hybrid E-M cancer cells that are known to travel in packs called circulating tumor cells (CTCs).

The coupling between the two switches shows that two seemingly independent and distinct cellular programs - one that drives migration and a second that drives adaptation and tumorigenesis - are linked. "The existence of a link suggests that we may be able to simultaneously target both processes with innovative new therapies."

Viewing Cancer on the Move: New Device Yields Close-up Look at Metastasis

[Researchers] reported on successful tests that captured video of human breast cancer cells as they burrowed through reconstituted body tissue material and made their way into an artificial blood vessel. "There's still so much we don't know about exactly how tumor cells migrate through the body, partly because, even using our best imaging technology, we haven't been able to see precisely how these individual cells move into blood vessels. Our new tool gives us a clearer, close-up look at this process."

Researchers were able to record video of the movement of individual cancer cells as they crawled through a three-dimensional collagen matrix. This material resembles the human tissue that surrounds tumors when cancer cells break away and try to relocate elsewhere in the body. This process is called invasion. [The researchers] also collected video of single cancer cells prying and pushing their way through the wall of an artificial vessel lined with human endothelial cells, the same kind that line human blood vessels. By entering the bloodstream through this process, called intravasion, cancer cells are able to hitch a ride to other parts of the body and begin to form deadly new tumors.

"Cancer cells would have a tough time leaving the original tumor site if it weren't for their ability to enter our bloodstream and gain access to distant sites. So it's actually the entry of cancer cells into the bloodstream that allows the cancer to spread very quickly." Knowing more about this process could unearth a key to thwarting metastasis.

Some people do seem to like to jump straight to talking about immortality as soon as the topic of extending human life comes up. Immortality here is meant in the sense of complete resistance to aging through medical technology capable of repairing the cellular and molecular damage that causes degenerative aging and all its symptoms and conditions. Near perfect repair is a long way out into the future - we'll get there by degrees, with prototype rejuvenation treatments that are steadily expanded and improved step by step over decades or centuries. Each new advance will allow us to live long enough to benefit from the next. We don't even have the prototypes yet, however, and most of the research community is not heading in the right direction to produce them. So there is a lot to be done yet in order to produce any meaningful benefits for those who are old and suffering, and that includes persuading the surprisingly large majority who think that aging and all the pain and death it causes should be left untouched:

The dream to live forever has captivated mankind since the beginning. We see this in religion, literature, art, and present day pop-culture in a myriad of ways. But all along, the possibility that we'd actually achieve such a thing never quite seemed real. Now science, through a variety of medical and technological advances the likes of which seem as far fetched as immortality itself, is close to turning that dream into a reality. This hour we talk with experts who are on the cutting edge of this research about the science and implications of ending aging.

What exactly is aging anyway? A natural process which is best, albeit unfortunately, left to itself? Or should we think of it more like a fatal disease - something to be cured at all costs like cancer or Ebola? And why not think of it as such? The fact is that aging kills more people and causes more suffering than all other sources combined. Does not the Hippocratic oath therefore compel medical experts to find its cure if they can? Or should the guiding principle, do no harm, more appropriately be applied to those who'll suffer the consequences if we were to actually end aging?

Whether you love life or simply fear death, chances are you've imagined what it would be like to live forever. What would you do with all that time? How would the world around you change? And speaking of the world around you, could it even sustain an immortal population? With densely packed mega-cities and resource shortages plaguing us already, how would society manage the extra burdens incurred by radical life extension? Some believe that longer life spans would lead to increased productivity and innovation; enough so to hedge against the burdens it would create. Others see longer life spans as a sure fire way to make an already challenging resource management problem even worse.

Link: http://wnpr.org/post/achieving-immortality-how-science-seeks-end-aging

Dementia can result from age-related damage to the white matter in the brain, known as leukoaraiosis or white matter hyperintensities. Here researchers look at the source of this damage:

Approximately 50 per cent of older individuals have evident white matter damage on their medical imaging scans. For most patients, these changes are harmless but when this damage is severe, it can cause impairment. Previous studies have already established that the more white matter disease there is in the brain, the more likely patients are to have symptoms of dementia such as cognitive impairment or changes in behaviour. What was not understood is why this white matter disease develops - the traditional assumption was that it might be the result of the natural aging process.

The researchers conducted an intensive study to observe the development of this white matter disease over a short period of time, rather than on an annual basis - the interval at which previous studies have performed repeat brain imaging. The study involved 5 patients with white matter disease undergoing detailed MRI scanning of their brains every week for 16 consecutive weeks. The weekly MRI scans revealed new tiny spots arising in the brain's white matter that were, based on their MRI appearance, characteristic of small new strokes (cerebral infarcts). The lesions had no symptoms but, with time, came to resemble the existing white matter disease in the subjects' brains. In the study's random sampling, the majority of subjects had this phenomenon: Tiny strokes occurring without symptoms, and developing into the kind of white matter disease that causes dementia.

"The findings suggest that the tiny, silent strokes are likely much more common than physicians previously appreciated, and these strokes are likely a cause of the age-related white matter disease that can lead to dementia. We don't yet know whether these small strokes are responsible only some or most of the white matter disease seen in older patients. But in those where it is the cause, the detection of white matter disease on brain imaging should trigger physicians to treat patients aggressively when managing stroke risk factors such as high blood pressure, diabetes, high cholesterol, cigarette smoking and lack of exercise not only to prevent further strokes, but also to reduce the development of cognitive impairment over time."

Link: http://www.uhn.ca/corporate/ForMedia/PressReleases/Pages/researchers_discover_possible_cause_dementia.aspx

Immune cells play an important role in regeneration, though this is yet another aspect of the immune system as a whole that is understood in outline but the all-important details remain a big blank space in the middle of the map. The interactions between the immune system and the rest of our biochemistry are very complex, to say the least, and cataloging them will no doubt keep hundreds of researchers busy for a few decades yet. There are many good reasons to dig into these details, and one of them is that immune cells and their behavior may have a lot to do with the very large differences in regenerative capabilities observed both between species and between embryonic and adult regeneration in the same species. It is quite possible that enhanced regeneration of organs in mammals might be obtained through nothing more than manipulation of immune cells, though it remains to be seen just how far this approach can take us.

Salamanders and zebrafish are both studied for their ability to regenerate entire organs, such as the heart and limbs. In both cases, the immune cells called macrophages have been shown to play a necessary role in this exceptional regeneration. Without them, lost tissue scars as it does in mammals rather than regenerating to form new replacement tissue structures. Some mammals have demonstrated enhanced regeneration with similarities to salamander regeneration, however, such as the genetically engineered MRL mice that lack the p21 gene. Given the connections between the immune system and tissue regrowth it is tempting to speculate on whether enhanced regeneration in the MRL mouse lineage has anything to do with p21's immune regulation roles. Sadly there is still too little data here to do more than speculate.

Below you'll find a more recent study that demonstrates immune cells to be responsible for a portion of the differences between mammalian embryonic and adult heart tissue regeneration. As you might be aware, the heart doesn't regenerate well at all in adults, but it's a whole different story in embryos. That's true for a range of tissues, in fact, but this work just covers the heart:

Heart's own immune cells can help it heal

The heart holds its own pool of immune cells capable of helping it heal after injury. Most of the time when the heart is injured, these beneficial immune cells are supplanted by immune cells from the bone marrow, which are spurred to converge in the heart and cause inflammation that leads to further damage. In both cases, these immune cells are called macrophages, whether they reside in the heart or arrive from the bone marrow. Although they share a name, where they originate appears to determine whether they are helpful are harmful to an injured heart. In a mouse model of heart failure, blocking the bone marrow's macrophages from entering the heart protects the organ's beneficial pool of macrophages, allowing them to remain in the heart, where they promote regeneration and recovery.

Researchers have known for a long time that the neonatal mouse heart can recover well from injury, and in some cases can even regenerate. If you cut off the lower tip of the neonatal mouse heart, it can grow back. But if you do the same thing to an adult mouse heart, it forms scar tissue. This disparity in healing capacity was long a mystery because the same immune cells appeared responsible for both repair and damage. Until recently, it was impossible to distinguish the helpful macrophages that reside in the heart from the harmful ones that arrive from the bone marrow.

The investigators found that the helpful macrophages originate in the embryonic heart and harmful macrophages originate in the bone marrow and could be distinguished by whether they express a protein on their surface called CCR2. Macrophages without CCR2 originate in the heart; those with CCR2 come from the bone marrow, the research showed. [The researchers] asked whether a compound that inhibits the CCR2 protein would block the bone marrow's macrophages from entering the heart. "When we did that, we found that the macrophages from the bone marrow did not come in. And the macrophages native to the heart remained. We saw reduced inflammation in these injured adult hearts, less oxidative damage and improved repair. We also saw new blood vessel growth. By blocking the CCR2 signaling, we were able to keep the resident macrophages around and promote repair. We have identified similar immune cell subtypes that are present in the human heart. We need to find out more about their roles in heart failure in patients and understand more about how macrophages that reside in the heart promote repair."

Alzheimer's disease is the name given to the end state of rising amyloid levels in the brain: it is the stage at which the patient has a lot of amyloid and is severely impacted by it. But we will all suffer increased levels of amyloid to some degree, and we will all be negatively affected by it to some degree. This is similarly the case for the other protein aggregate involved in Alzheimer's disease, tau, that precipitates into tangles in brain tissue. Rising levels are a shared manifestation of aging, it is just that some people arrive at the pathological level much earlier. One of the objectives of repair based treatments that fix damaged clearance mechanisms or remove protein aggregates from tissues is to make this difference irrelevant - everyone should undergo the therapies every so often, and then no-one would have to worry about a future involving degeneration of the mind:

We recommend a new term, "primary age-related tauopathy" (PART), to describe a pathology that is commonly observed in the brains of aged individuals. Many autopsy studies have reported brains with neurofibrillary tangles (NFTs) that are indistinguishable from those of Alzheimer's disease (AD), in the absence of (Aβ) plaques. For these "NFT+/Aβ-" brains, for which formal criteria for AD neuropathologic changes are not met, the NFTs are mostly restricted to structures in the medial temporal lobe, basal forebrain, brainstem, and olfactory areas (bulb and cortex).

Symptoms in persons with PART usually range from normal to amnestic cognitive changes, with only a minority exhibiting profound impairment. Because cognitive impairment is often mild, existing clinicopathologic designations, such as "tangle-only dementia" and "tangle-predominant senile dementia", are imprecise and not appropriate for most subjects. PART is almost universally detectable at autopsy among elderly individuals, yet this pathological process cannot be specifically identified pre-mortem at the present time.

Improved biomarkers and tau imaging may enable diagnosis of PART in clinical settings in the future. Indeed, recent studies have identified a common biomarker profile consisting of temporal lobe atrophy and tauopathy without evidence of Aβ accumulation. For both researchers and clinicians, a revised nomenclature will raise awareness of this extremely common pathologic change while providing a conceptual foundation for future studies.

Link: http://dx.doi.org/10.1007/s00401-014-1349-0

The first stage of success in tissue engineering of any specific organ is to produce small sections of tissue that are close enough to the real thing to be used in research. Given a methodology to reliably produce these tissue sections from the starting point of a cell sample, they can be used in drug testing, to investigate the detail mechanisms of genetic diseases and aging, and similar applications. It is also possible that even small amounts of tissue can be the basis for some treatments, as patches for localized injuries that are resistant to regeneration:

Three-dimensional "mini-stomachs" have been created from human stem cells. The tiny organs measure about 3 millimeters in diameter and can be used as models for the infections that are often precursors to peptic ulcers and stomach cancer. "This represents the first in vitro model of the human stomach, and it's not a cute little term - they really do look like 'mini stomachs.'"

When the researchers first tried to grow these tissues, they did so using embryonic stem cells - cells that originate from a human embryo. The growth process, from start to finish, took about a month, [and] the end product was a small organ that contained human stomach tissue made of at least eight different cell types. But before the researchers could celebrate, they had to make sure the technique could be deployed using cells from adults as well, a critical step in ensuring that the technique can be tailored to fit a specific patient. It worked in those cells too.

[The researchers] have started exploring whether this tissue could be used to patch ulcers in mice. Stomach ulcers are essentially defects in the lining of the organs; in severe cases, they can be "patched" to avoid pain and internal bleeding. Right now, patching ulcers involves growing gastric tissues from a sample removed during a biopsy. [But] growing tissues from stem cells would allow researchers to bypass that step altogether, because they could start with cells taken from a patient's blood. "I think if our animal trials go well we could certainly scale up and start patching ulcers within the next ten years."

Link: http://www.theverge.com/2014/10/29/7086031/tiny-human-stomachs-created-from-stem-cells

I don't normally point out funding press materials, preferring to focus on the other end of the research process, but this one, drawn to my attention by the Healthspan Campaign newsletter, contains a good overview of the current state of knowledge regarding the persistent herpesvirus called cytomegalovirus (CMV) and its role in immune aging. CMV is actually just about as innocuous and prevalent as herpesviruses get: most people are infected by the time they reach old age, and near all of them suffered no obvious and immediate consequences of that infection. Given the readership demographics here, I'd give even odds that you have CMV lurking in your tissues as you read this.

No obvious consequences is not the same as no consequences: the results of CMV infection are very real, just slow to appear. Like other herpesviruses, CMV can remain latent in the body and cannot be permanently cleared by the efforts of the immune system. One thesis on how it contributes to degeneration of the immune system is that ever more of the immune system's limited cohort of cells become specialized to attack CMV, with no resulting gain in that unending fight, leaving ever fewer cells able to tackle all of the other necessary tasks. In effect this is a sort of progressive misconfiguration of a programmable system, and a problem that might in the near future be addressed by selectively destroying these specialized cells. Some experiments conducted in recent years strongly suggest that this will spur the generation of replacement immune cells, and consequently a restoration of some lost functionality in the immune system.

This is a pretty compelling hypothesis given the evidence to date, but as for so much of everything that involves the immune system it is yet to be proven beyond a doubt. As for many of these sorts of things my preferred approach to investigation would be to fix the damage, here meaning removal of the CMV-specialized memory T cells, such as by adopting one of the targeted cell destruction technologies in the late stages of development in the cancer research community, and see what happens afterwards in tissue and animal studies. That of course is not the way things are done in the mainstream of research, where the tendency is to be much more conservative in adopting hypotheses for experimentation, and the first focus is on developing as complete an understanding as possible before building potential treatments. That may all lead to the same place in the end, or it may not - we shall see.

Impact of Lifelong Cytomegalovirus Infection on Aging and the Immune System Focus of UA Research

A virus that infects us when we're young and then hides in our cells throughout our lives without causing symptoms may weaken the ability of our immune system to defend against influenza, West Nile or other viruses as we age. "It is critically important to understand the causes and consequences of lifelong CMV infection for immunity and aging. CMV is present in 70 to 90 percent of people over 65, which by 2050 will translate into 70 million people in the United States and more than 1 billion people in the world." CMV has been associated with impaired immunity, increased morbidity due to cardiovascular diseases, and reduced lifespan and health span - the length of life spent in good health.

"Our research group recently showed that infection with only CMV, and no other acute or persistent viruses, causes defects in immune responsiveness to other infections and causes alterations in the naïve T cell receptor repertoire and impaired effector T cell responses. But the precise mechanism by which CMV affects naïve T cell responses remains incompletely understood. Our study seeks to define the cost, if any, of persistent CMV infection on immune function as we age and to begin to define ways to intervene against the negative effects of CMV in aging."

The adverse impact of lifelong CMV infection on the aging of T cells - a type of white blood cell essential to the functioning of the immune system - and the development of new immune responses could be due to a number of factors. "Improved control of CMV and/or reduction of CMV-specific [memory T cell] accumulation could be beneficial for immune defense, such as immune responsiveness to vaccination. But it is also possible that the virus actually helps the immune system in the younger age, while impairing it in older adults. The immune system works hard to keep the dormant CMV in check. We hypothesize that efficient CMV control will correlate with strong and successful responses to vaccination in humans and that individuals who use vast resources to control CMV will be less likely to respond well to vaccination."

One of the root causes of degenerative aging is the accumulation of sugary metabolic wastes known as advanced glycation end-products that are in some cases very hard to for our evolved biochemistry to break down. Some types can form cross-links, gluing together important proteins such as those making up the supporting extracellular matrix scaffold. The properties of elastic tissues such as skin and blood vessel walls derive from the particular structure of the extracellular matrix, and cross-links degrade that structure, preventing it from functioning correctly. Their presence contributes to blood vessel stiffening with age and all the problems that result from that, for example, but there are plenty of other affected tissues.

The SENS approach to this contributing cause of aging is to build the necessary tools to work with the most common cross-link compound in human tissues, glucosepane. It is hoped that other research groups will pick up the work once they no longer have to start by building the very fundamental tools for the job. As things stand few research institutions are willing to start from scratch when there are so many other lines of research presently available that do not need a complete tool infrastructure built before anything can be accomplished.

Advanced age is associated with increases in muscle passive stiffness, but the contributors to the changes remain unclear. Our purpose was to determine the relative contributions of muscle fibers and extracellular matrix (ECM) to muscle passive stiffness in both adult and old animals. Passive mechanical properties were determined for isolated individual muscle fibers and bundles of muscle fibers that included their associated ECM, obtained from tibialis anterior muscles of adult (8-12 mo old) and old (28-30 mo old) mice. Maximum tangent moduli of individual muscle fibers from adult and old muscles were not different at any sarcomere length tested. In contrast, the moduli of bundles of fibers from old mice was more than twofold greater than that of fiber bundles from adult muscles at sarcomere lengths of more than 2.5 μm.

Because ECM mechanical behavior is determined by the composition and arrangement of its molecular constituents, we also examined the effect of aging on ECM collagen characteristics. With aging, muscle ECM hydroxyproline content increased twofold and advanced glycation end-product protein adducts increased threefold, whereas collagen fibril orientation and total ECM area were not different between muscles from adult and old mice. Taken together, these findings indicate that the ECM of tibialis anterior muscles from old mice has a higher modulus than the ECM of adult muscles, likely driven by an accumulation of densely packed extensively crosslinked collagen.

While looking at this research it is worth bearing in mind that short lived rodents have a different cross-link biochemistry in comparison to we long-lived humans. Early attempts to develop cross-link-breaking drugs floundered on this issue: promising results in rats didn't translate to human medicine at all. The overall picture of how this degeneration proceeds and why it happens is very similar, so there is much that can be learned, but the types of cross-link are different in ways that matter greatly for the development of treatments.

Link: http://dx.doi.org/10.1152/japplphysiol.00256.2014

Researchers are digging in to some of the proximate mechanisms that lead to menopause, and making some progress by the looks of it. This is a good example of the general approach to aging taken by the research community: start at the end stage manifestation of dysfunction, such as menopause, and work backwards through layers of metabolic changes in search of causes. These changes are reactions to cellular and molecular damage that is fairly well described at this time. Researchers have a good catalog of the fundamental differences between old tissues and young tissues, but for most outcomes in aging there is no good understanding in detail of exactly how this damage spirals out to produce the observed late stage results.

So how to go about filling this gap in understanding? Instead of trying to fix the damage and working forwards to see the results, researchers follow a strategy of working backwards from the end stages. The final state of knowledge will be the same, but this approach is far less likely to produce meaningful treatments: applications of partial knowledge of the late stages of disease leads to efforts to manipulate the operation of a complex system in order that it runs less poorly when damaged. It is patching a failing machine, hard, expensive and doomed to failure. Compare that with treatments that remove the damage: much simpler, and more likely to be effective. If your engine rusts, you remove the rust every now and again, not rebuild the engine to work slightly better while rusting into uselessness.

Some women can have successful pregnancies at the age of 50, whereas other are unable to get pregnant when they are 30. Researchers are not yet able to fully explain such differences. One factor is that the onset of menopause is influenced by the point at which the uterus runs out of eggs to release. A recent [study] sheds light on the mystery of the biological clock that governs fertility. Just as newborn infants require nurturance in order to survive, eggs in the uterus need nourishment and support from the granulosa cells of the primary follicle. According to the latest [discovery] a signaling pathway in these cells plays a key role in enabling immature eggs to survive.

The mTOR signaling pathway in the granulosa cells is necessary for activating expression of the kit ligand growth factor, which subsequently binds to the c-kit receptors of eggs and determines their fate. "This mechanism permits the granulosa cells to decide when eggs will begin to grow and when they will die. In that sense, they serve as a kind of biological clock that monitors the onset of menopause." Researchers believe that the discovery will point the way to interventions that stimulate the growth of eggs that have been unable to mature.

Link: http://science.gu.se/english/News/News_detail//-identifying-the-biological-clock-that-governs-female-fertility.cid1242454

We live in an age of rapidly advancing biotechnology, and research communities are on the verge of developing actual, real, working rejuvenation treatments. Given the funding there are lines of research under way today that might take the ills of aging and turn them back. Yet most people really don't care all that much, and are even troubled by the idea that they might be able to live for decades longer in good health. Those who do spend time thinking on it are largely bedeviled by a profound lack of ambition, and spend their time talking about dietary modifications, lifestyle choices, and supplements mined from the natural world that cannot possibly achieve any meaningful difference in human life span.

A few years here and there, sure. Anyone can do that - just eat less. But adding decades to life can only come from future advances in medicine that are a radical departure from the present methods of treating age-related conditions. Rejuvenation will arise from repair of the root causes of aging, removing wastes and broken molecules within and around cells. This needs new gene therapies, new classes of drug that can interact with metabolic wastes that have gone largely neglected to date, and much more.

For those of us aware of what might be possible were much greater effort focused on repair of the cellular and molecular damage of aging, infographics such as the one linked below are somewhat depressing. Researchers could be figuring out how to revert the molecular damage in cells that causes age-related frailty and disease, with the goal of entirely eliminating these causes of pain and suffering from the human condition, but the public at large are hesitant to step beyond recommendations on whether or not to drink coffee or exercise a little more. Their boundaries of the possible are so narrow as to exclude any meaningful change through medical science. It is almost as though they don't want success:

A Handy Guide to Longer Living Through Science!

The grail of longevity research remains that elusive drug, food, personality trait or lifestyle change that will prolong robust, healthy life. It's not here yet.

You'll see analogous sentiments in the economic arena, a fear of change and an underlying echo of the belief that financial traditions and edifices are in some way more important than human life. Longevity is cast as bad news for no reason other than things must change, and bad decisions and bad entitlements will have to be unwound:

Americans Are Living Longer Than Ever. And That May Kill Your Pension

For the first time, both boys and girls born today can expect to see at least 90 years of age, according to revised mortality tables published on Monday by the Society of Actuaries. Middle age and old age have also stretched out. Half a century ago reaching age 65 meant automatic retirement and imminent infirmity. Today, millions of 65-year-olds aren't just in the workforce - they are reinventing themselves and looking for new pursuits, knowing they have many good years ahead. What is good news for humanity, though, sends tremors through the pension world. Every few extra years of life expectancy come with a price tag. Already, many private and public pension funds are woefully underfunded - and the new tables essentially mean they are even further behind.

All this noted, a great deal of progress in advocacy has in fact occurred in the past decade. Nonsense and low expectations are not universal, and discussion of rejuvenation and radical life extension is more commonplace than it was. The research community is in the early stages of a great tectonic shift in research strategy, moving from treating only the manifestations of aging to treating the underlying processes - and accepting that the goal is extension of healthy life spans, not just treating diseases. So some people are willing to look for more and call out those who are short-sighted, trapped in parochial visions of what is possible and plausible:

Why I Want to Live Past 75

The best thing about Ezekiel Emanuel's "Why I Hope To Die at 75" is that it calls attention to the most consequential development of our time, the aging of the American and global population. His argument is colorful and contrarian, but also based on 20th century assumptions. And, it is as misguided as it is unimaginative. For Emanuel's thesis to make sense, we must accept that "the miracle of longevity," which has been brought about by innovation, invention and human imagination, has run out of gas. In other words, his argument presupposes that what has enabled longevity has run its course and we're done making progress.

Let's recognize Dr. Emanuel's piece for what it is - a sweeping declaration of 21st century impossibility framed by what was achieved in the 20th century. It's a static view of the human condition, which is his basic mistake. Rather, human imagination that will fuel invention and innovation can continue to propel us to a healthier and more active life as we live to be 100 as a matter of course.

Cell therapies and tissue engineering benefit from being able to use a patient's own cells as a starting point. If the patient is old, as is the case for most potential uses of regenerative medicine, cells are tissues are damaged and dysfunctional. To what degree is this an issue in the construction of treatments? It is clearly killing the patient by degrees, but one of the more promising signs for the near future of stem cell treatments in recent years has been that old stem cells appear to be capable of youthful action given the right cues. The cellular and molecular damage of aging is there, however, and other uses for a patient's own tissues are indeed impacted. This is why the stem cell research field is on a trajectory to understand and reverse aspects of aging in old tissues; they have to do this in order to ensure that the majority of possible treatments will work effectively:

Adipose tissue-derived microvascular fragments are promising vascularisation units for applications in the field of tissue engineering. Elderly patients are the major future target population of such applications due to an increasing human life expectancy. Therefore, we herein investigated the effect of aging on the fragments' vascularisation capacity. Microvascular fragments were isolated from epididymal fat pads of adult (8 months) and aged (16 months) C57BL/6 donor mice. These fragments were seeded onto porous polyurethane scaffolds, which were implanted into dorsal skinfold chambers to study their vascularisation.

Scaffolds seeded with fragments from aged donors exhibited a significantly lower functional microvessel density and intravascular blood flow velocity. This was associated with an impaired vessel maturation, as indicated by vessel wall irregularities, constantly elevated diameters and a lower fraction of CD31/α-smooth muscle actin double positive microvessels in the implants' border and centre zones. Additional in vitro analyses revealed that microvascular fragments from adult and aged donors do not differ in their stem cell content as well as in their release of angiogenic growth factors, survival and proliferative activity under hypoxic conditions. However, fragments from aged donors exhibit a significantly lower number of matrix metalloproteinase 9-positive perivascular cells. Taken together, these findings demonstrate that aging is a crucial determinant for the vascularisation capacity of isolated microvascular fragments.

Link: http://www.ecmjournal.org/journal/papers/vol028/vol028a20.php

Researchers here uncover an interesting role for one of the forkhead box (FOX) proteins, and the potential basis for a treatment for pulmonary hypertension:

An estimated 100 million people worldwide suffer from pulmonary hypertension. The disease is characterised by progressive narrowing of the pulmonary arteries. The reduced diameter of the vessels leads to poor perfusion. The right ventricle tries to compensate by increasing its pumping action. This, in turn, increases the blood pressure in the pulmonary arteries. In the course of time, chronic overload damages the heart. The result is cardiac insufficiency, also known as congestive heart failure. Several forms of treatment developed in recent years aim mainly to alleviate the symptoms and relieve strain on the heart. Pulmonary hypertension, however, is still incurable, not least of all due to insufficient knowledge of what causes the disease at the molecular level.

[Scientists] have now achieved a major advance. In transcription factor FoxO1 they have identified a key molecule that plays a decisive role in the regulation of cell division in vascular wall cells and the lifespan of the cells. "The vessel walls of pulmonary arteries are constantly being renewed. A complex interplay of many factors normally ensures that the ratio between dividing and dying cells is balanced." The researchers found an important clue about the central role of FoxO1 in tissue samples from pulmonary hypertension patients: "In these patients, FoxO1 is not sufficiently active, so that the activity of various genes is not properly controlled. If we switch off FoxO1 by means of genetic or pharmacological intervention, the vascular wall cells divide more frequently." Consequently, pulmonary hypertension develops.

Reduced FoxO1 activity is therefore an important factor in the development of pulmonary hypertension. In further experiments it was found that certain growth factors and chemical messengers are responsible for reduced FoxO1 activity. Accordingly, pathological cell division in pulmonary vessel walls normalized when the researchers boosted FoxO1 activity. "Rats suffering from pulmonary hypertension were essentially cured." Based on these positive findings, the scientists are optimistic that the study findings can be used to develop a novel therapeutic approach.

Link: http://www.mpg.de/8721341/PullamsettiFoxO1

Citations in an academic paper have some similarities to links in the web, or at least in the case where those links are a result of human choice and consideration. Considered in the abstract, a citation is a vote of attention rather than an opinion on the contents of the cited paper. To find out what the author actually thinks you'd have to read and understand the paper, something that is largely beyond today's expert systems software. If you want to systematically analyse academic sentiment in a field, however, even one as comparatively small as aging research, software is nonetheless what you will be using. There are too many people making too many citations to go about this in any other way.

The group of researchers quoted below took a hybrid approach to the challenge of a more rigorous determination of the consensus position of what comes next for aging research. They used the web of citations to find a handful of the most cited papers - a very simple piece of automated analysis - and then processed the contents of those papers with the Mark I Human Brain. This is the present best of both worlds: take advantage of the tasks that computers find easy and the tasks that we humans find easy and merge the work somewhere in the middle. The processing cycles of graduate students, much like those of modern computers, are cheap and widely available these days.

If you make a habit of following my litany of complaints about the state of the field of aging research then the results of this analysis of the mainstream focus will come with few surprises attached. It is all about gently slowing aging through manipulation of metabolism, establishing greater knowledge of the fine details of metabolic changes with aging, use of stem cells, telomere biology, and and some items relating to present day treatment strategies for the most common age-related conditions, such as type 2 diabetes and heart disease. The class of aging research I favor, repairing the cellular damage that causes aging after the SENS model, is still barely gaining a foothold as a coherent strategy in the bigger picture. That is the only path towards true rejuvenation of the old and prevention of age-related disease, however, as present approaches are merely going to make the old slightly less impacted by the processes of damage accumulation that are eating them alive.

Of modern medical research, stem cell research, cancer research, and probably immunology are about the only fields with sizable factions that are heading more or less in the right direction, working on classes of treatment that might actually be considered damage repair. That's two and half distinct damage processes out of seven and a half or so that make up aging, depending on who is counting. A lot more has to be accomplished yet.

Aging and energetics' 'Top 40' future research opportunities 2010-2013

Energetics can be defined as the study of the causes, mechanisms, and consequences of the acquisition, storage, and utilization of metabolizable energy by biological organisms. The United States - indeed the world - is currently undergoing a crisis of excess energy storage, sometimes called the obesity epidemic. A consistent finding from ecology, basic laboratory science, and epidemiologic research is that aspects of energetics, including the perceived and actual availability of food, the ingestion of food, the composition of the food consumed, the amount of body energy accreted and expended, affect disease and disability, senescence, mortality rate, and longevity.

To identify research priorities and opportunities in the domain of aging and energetics as advocated in the 40 most cited papers related to aging and energetics in the last 4 years. The investigators conducted a search for papers on aging and energetics in Scopus, ranked the resulting papers by number of times they were cited, and selected the ten most-cited papers in each of the four years that include 2010 to 2013, inclusive.

Ten research categories were identified from the 40 papers. These included: (1) Calorie restriction (CR) longevity response, (2) role of mTOR (mechanistic target of Rapamycin) and related factors in lifespan extension, (3) nutrient effects beyond energy (especially resveratrol, omega-3 fatty acids, and selected amino acids), 4) autophagy and increased longevity and health, (5) aging-associated predictors of chronic disease, (6) use and effects of mesenchymal stem cells (MSCs), (7) telomeres relative to aging and energetics, (8) accretion and effects of body fat, (9) the aging heart, and (10) mitochondria, reactive oxygen species, and cellular energetics.

The paper is open access and contains a very readable overview of each of these areas. It is worth a look as a matter of interest. This is after all a fair cross-section of the work being funded today, to a first approximation, and which must largely be supplanted in the near future by damage repair approaches if we are to see significant gains in health human life span and meaningful treatments for age-related degeneration in the old within our lifetimes.

Mitochondria are the bacteria-like power plants of the cell, thousands to each cell, and each mitochondrion bearing its own DNA separate from that in the cell nucleus. Damage to this DNA is important in aging, and in a variety of diseases. Mitochondrial disease and mitochondrial contributions to degenerative aging are two very different things, however, for all that they both involve damage to mitochondrial DNA. In mitochondrial disease most of a patient's mitochondria have the same form of mutational damage, inherited from the mother or generated very early in embryonic growth. In aging the damage is random between cells, but there are certain forms of mutational damage that become amplified because they make a damaged mitochondrion more likely to survive and replicate in comparison to its undamaged peers.

Here is an interesting, albeit minority view on mitochondrial damage and how cells respond to it. It is of more relevance to mitochondrial disease, but there are aspects of it that might be informative with respect to cells in old tissues overtaken by damaged, dysfunctional mitochondria:

The new research shows that small changes in the ratio of mutant to normal mitochondrial DNA within the thousands of mitochondrial DNAs inside each cell can cause abrupt changes in the expression of numerous genes within the nuclear DNA. "By showing that subtle changes in the cellular proportion of the same mitochondrial DNA mutation can result in a wide range of different clinical manifestations, these findings challenge the traditional model that a single mutation causes a single disease. The research offers key insights into understanding the underlying cause of metabolic and neurodegenerative disorders such as diabetes, Alzheimer, Parkinson and Huntington disease, as well as human aging. The discrete changes in nuclear gene expression in response to small increases in mitochondrial DNA mutant level are analogous to the phase changes that result from adding heat to ice. As heat is added, the ice abruptly turns to water and with more heat, the water turns abruptly to steam."

[Researchers investigated] levels of a pathogenic mutation in one particular base of mitochondrial DNA. Researchers already knew that if 10 to 30 percent of a person's mitochondrial DNA has this mutation, a person has diabetes, and sometimes autism. Individuals with an mtDNA mutation level of 50 to 90 percent have other multisystem diseases, particularly MELAS syndrome, a severe condition which involves brain and muscle impairments. Above the 90 percent level, patients die in infancy. In the current study, conducted in cultured human cells, [the researchers] analyzed cells with different levels of this pathogenic mtDNA mutation to determine the effects on the gene expression of the cell. The researchers measured variations in cellular structure and function, nuclear gene expression, and production of different proteins.

The gene expression profile - the pattern of gene activity seen at the level at which mtDNA mutations trigger brain disorders - parallels the profiles found in Alzheimer, Parkinson and Huntington diseases. "The findings in this study provide strong support for the concept that common metabolic diseases such as diabetes and obesity, heart and muscle diseases, and neurodegenerative diseases have underpinnings in energy deficiencies from malfunctioning mitochondria. Thus this concept brings together a cluster of diseases previously considered to be separate from one another."

Link: http://www.chop.edu/news/steadily-rising-increases-mitochondrial-dna-mutations-cause-abrupt-shifts-disease

Given a donor blood vessel, researchers can strip it of its cells to leave just the extracellular matrix structure. This can then be repopulated with a patient's own cells, making it possible to transplant the blood vessel without risk of rejection. This is one of a number of applications of decellularization demonstrated in human trials in recent years:

Our study is a proof-of-concept clinical report of the successful recellularisation of two decellularised human blood vessels with autologous whole peripheral blood, which were subsequently used for a bypass procedure in two patients with portal vein thrombosis without the need for immunosuppression. The work is important conceptually because it provides early evidence for generating clinically useful personalized blood vessels using a simple blood sample from the patient.

Vascular diseases are increasing health problems affecting more than 25 million individuals in westernized societies. Such patients could benefit from transplantation of tissue-engineered vascular grafts using autologous cells. One challenge that has limited this development is the need for cell isolation, and risks associated with ex vivo expanded stem cells. Here we demonstrate a novel approach to generate transplantable vascular grafts using decellularized allogeneic vascular scaffolds, repopulated with peripheral whole blood (PWB) in vitro in a bioreactor. For clinical validation, two autologous PWB tissue-engineered vein conduits were prepared and successfully used for by-pass procedures in two pediatric patients. These results provide a proof of principle for the generation of transplantable vascular grafts using a simple autologous blood sample, making it clinically feasible globally.

In the present and other currently ongoing studies we have successfully recellularized veins using blood from individuals and patients in the age range of 4-55 years. However, it is reported that the numbers of circulating stem/precursor cells is decreased in patients with diabetes and end-stage renal diseases. So it remains to be tested whether this method would work in such patients. We did not detect any HLA antibodies after transplantation indicating satisfactory decellularization of the blood vessels. Both patients have been transplanted on compassionate grounds and therefore optimization of the technique has been on a "patient to patient" basis. We are currently seeking permits to carry out a clinical trial, which will include a larger number of patients to determine the efficacy of grafting tissue-engineered veins as vascular replacement therapy.

Link: http://dx.doi.org/10.1016/j.ebiom.2014.09.001

Cryonics involves the low-temperature preservation of the recently deceased, and as an industry it has been around for some decades. Using modern techniques and if the preservation is accomplished with speed, this can result in a good preservation of the fine structure of the brain, and thus of the data that makes up the mind. There is a lot more to it than just the technology, however. Like all major medical procedures it requires considerable organization, legal, financial, and logistical, and much of the focus of a cryonics provider is on the work needed make such a one-time event, occurring on an unpredictable schedule and subject to the legal scrutiny of numerous government bodies, run as smoothly as possible.

A preserved individual has all the time in the world to wait on future advances in technology that will required for the task of restoring a preserved brain to new life in a new body. This isn't fantastical: it requires a mature molecular nanotechnology industry capable of producing and controlling complex medical nanorobot swarms, alongside the sort of control over cellular biology that we would expect to emerge later this century. A lot of serious scientific thought over the decades has gone into foreseeing exactly what would be needed for this task, and the only real issue is that this technology doesn't yet exist. People who are cryopreserved get to wait around for that to happen. People who go to the grave do not: they are lost and gone beyond all help, and it is a tragedy of staggering proportions that we live in a world in which cryonics is little thought of.

It was recently brought to my attention that the two cryonics providers in the US, the Cryonics Institute and the Alcor Life Extension Foundation, publish attractive modern business websites these days. In Alcor's case that is a recent update. If you want to find out more about cryonics, now is a good time:

We wanted to bring the appearance of alcor.org up to date and make it more appealing. We also wanted to improve engagement with visitors. This revision is a major cosmetic facelift. We will follow up with significant changes to the content, designed to help visitors find the information most important to them. We have also added a chat function. In just the first couple of days, this is proving to be a valuable tool for engaging website visitors and answering their questions. Take a look!

This is a sign of the times perhaps: cryonics as an industry remains out of sight and out of mind for most people, but it nonetheless receives more positive attention these days than it has in the past. The people involved in running providers and research groups in the industry are ever looking to move beyond the non-profit and grassroots origins of the cryonics community over the past 40 years to become more professional and more businesslike. The underlying technologies, such as vitrification of tissues, will become used more broadly in medicine for long-term organ preservation and similar needs in the years ahead, and the transformation of the industry from community effort to ongoing businesses will speed up.

That said, this remains a niche market, albeit one that in a just world would be much larger. Service providers are a hybrid form of company, one third a membership society with aspects in common with life insurance businesses, another third the provision of medical services for members that has a lot in common with acute critical care and all of its complexities, and the remaining third a specialist long-term biomedical storage facility. That is a mix that doesn't occur in too many other places in the business community: some hospitals, perhaps, but few other places.

The open access paper quoted below provides some insight into increasing sophistication of the work involved in identifying longevity-related genes and proteins in mammals. Many of these have been discovered over the past twenty years, leading to numerous ways to alter the operation of metabolism in order to slow aging and thus extend healthy life. This should probably be considered a part of the bigger picture of progress towards a better understanding of the fine details of biochemistry, however, and not a stepping stone to longer lives for you and I. Slowing aging by building a better metabolism is not a great strategy at this point in time in comparison to working on repair of damage. Researchers know much more about the damage that causes aging than they do about metabolism, so the choice is between easier and more promising lines of research versus much harder work that will produce far less useful results.

Unfortunately for us, since scientists are in the business of gaining knowledge rather than changing the world, most research is in fact directed towards the harder work that will do little to produce meaningful treatments for aging. That is why we need advocacy and grassroots fundraising programs and organizations aimed at changing the strategic direction of aging research.

Longevity is correlated with stress resistance in many animal models. However, previous efforts through the boosting of the antioxidant defense system did not extend life span, suggesting that longevity related stress resistance is mediated by other uncharacterized pathways. We have developed a high-throughput platform for screening and rapid identification of novel genetic mutants in the mouse that are stress resistant. Selection for resistance to stressors occurs in mutagenized mouse embryonic stem (ES) cells, which are carefully treated so as to maintain pluripotency for mouse production.

Initial characterization of these mutant ES cells revealed mutations in Pigl, Tiam1, and Rffl, among others. These genes are implicated in glycosylphosphatidylinositol biosynthesis, NADPH oxidase function, and inflammation. These mutants: (1) are resistant to two different oxidative stressors, paraquat and the omission of endogenous reactive oxygen species (ROS), (3) are capable of generating live mice, and (4) transmit the stress resistance phenotype to the mice. This strategy offers an efficient way to select for new mutants expressing a stress resistance phenotype, to rapidly identify the causative genes, and to develop mice for in vivo studies.

Link: http://journal.frontiersin.org/journal/10.3389/fgene.2014.00310/full

The evolution of cell therapies will most likely be towards treatments that alter cell type and behavior in place, drawing from the existing pool of cells and changing them to suit the needs of the patient. Given sufficient control over cell activities and cell state old cells might be repaired and entire organs could be regenerated through this approach. Present efforts in tissue engineering and transplants are a stepping stone to this more sophisticated future of regenerative medicine. Here is an early example of this trend underway:

Recent success in restoring visual function through photoreceptor replacement in mouse models of photoreceptor degeneration intensifies the need to generate or regenerate photoreceptor cells for the ultimate goal of using cell replacement therapy for blindness caused by photoreceptor degeneration. Current research on deriving new photoreceptors for replacement, as regenerative medicine in general, focuses on the use of embryonic stem cells and induced pluripotent stem (iPS) cells to generate transplantable cells. Nonetheless, naturally occurring regeneration, such as wound healing, involves awakening cells at or near a wound site to produce new cells needed to heal the wound.

Here we discuss the possibility of tweaking an ocular tissue, the retinal pigment epithelium (RPE), to produce photoreceptor cells in situ in the eye. Unlike the neural retina, the RPE in adult mammals maintains cell proliferation capability. Furthermore, progeny cells from RPE proliferation may differentiate into cells other than RPE. The combination of proliferation and plasticity opens a question of whether they could be channeled by a regulatory gene with pro-photoreceptor activity towards photoreceptor production. Studies using embryonic chick and transgenic mouse showed that indeed photoreceptor-like cells were produced in culture and in vivo in the eye using gene-directed reprogramming of RPE cells, supporting the feasibility of using the RPE as a convenient source of new photoreceptor cells for in situ retinal repair without involving cell transplantation.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4074479

The development of accurate and cheap biomarkers of biological age is an important goal for the research community. The issue at hand is this: short of sitting back and waiting for years or decades, how should one test a supposed rejuvenation treatment? How to evaluate whether it works and how successful it is? If you have to wait and see, as is presently the case, then even mouse studies take years and cost millions of dollars apiece. If you could instead wait a month and take some blood samples, then suddenly a whole lot more research can be accomplished with that money.

Consider proposed SENS treatments that involve the clearance of age-related cross-link compounds such as glucosepane that harm tissue flexibility and integrity, for example. It is clearly the case that researchers will be able to tell how well they achieve that immediate goal, as they will measure cross-link levels in tissues beforehand and afterwards - a simple and straightforward test of effectiveness. Researchers can also assess secondary measures that are considered important in aging and known to correlate with the presence of cross-links, such as blood pressure, blood vessel elasticity, skin elasticity, and so forth. In theory these should all improve; if not, well that would be an unexpected setback. But if it works, and all these measures move back towards the values typical of a youthful individual, is that actually rejuvenation? Has this patient's biological age been reduced?

At the moment that question is impossible to answer without sitting back and waiting for decades. One group of researchers is well on the way to demonstrating the reliable use of specific patterns of changing DNA methylation as a measure of biological age, however, and so far their methodology seems like a promising candidate for a biomarker of aging. Where there is one such measure, we should expect there to be others. Everything in our biochemistry interacts with everything else, after all. Thus here researchers make the first steps towards the possibility of assembling a biomarker of aging from some combination of circulating microRNA levels. It is quite intriguing that their research demonstrates patterns that are characteristic of age, yet independent of health status in the case of their chosen group of patients:

Circulating MicroRNAs as Easy-to-Measure Aging Biomarkers in Older Breast Cancer Patients: Correlation with Chronological Age but Not with Fitness/Frailty Status

MicroRNA's (miRNAs) are short, non-coding and highly stable RNA's that are involved in post-transcriptional regulation of gene expression. They are known as fine-tuning mediators of a wide variety of normal physiological pathways, developmental processes and pathological conditions; it is thus plausible that they also play a role in cellular senescence and tissue/body aging.

Circulating miRNAs actually are attractive candidate biomarkers for clinical use, because of their easy accessibility and outstanding stability in serum/plasma. Here, we describe the potential use of microRNA signatures expressed in serum/plasma for the assessment of biological age in breast cancer patients. We compared a panel of 175 different microRNAs, known to be among the most relevant in serum/plasma, between older and young breast cancer patients and validated the findings of this initial exploratory screening in an independent breast cancer cohort. At least 5 circulating microRNAs emerged from this study that are worth to be further explored as potential aging biomarkers in larger cohorts of young versus old fit versus old frail individuals, both within and beyond a cancer background.

Plasma levels of miR-20a-3p, miR-30b-5p, miR106b, miR191 and miR-301a were confirmed to show significant age-related decreases. The remaining miRNAs included in the validation study (miR-21, miR-210, miR-320b, miR-378, miR-423-5p, let-7d, miR-140-5p, miR-200c, miR-374a, miR376a) all showed similar trends as observed in the exploratory screening but these differences did not reach statistical significance. Interestingly, the age-associated miRNAs did not show differential expression between fit/healthy and non-fit/frail subjects within the older breast cancer cohort of the validation study and thus merit further investigation as true aging markers that not merely reflect frailty.

Telomerase extends telomeres, the protective ends of chromosomes. A portion is lost with each cell division, and this mechanism forms part of a clock regulating the replicative life span of ordinary cells. Stem cells maintain long telomeres and when active work to introduce into tissues a continual supply of new daughter cells with long telomeres. Average telomere length declines with illness or age most likely largely because of disturbances to this process of tissue maintenance: as the creation rate of new cells with long telomeres falls, the average telomere length in tissue will also fall.

Telomerase is vital to most cancers, in which individual cells maintain long lives and act more like unlimited stem cells than the ordinary cells they are descended from. A fair amount of modern research into telomeres and telomerase is conducted by the cancer research community. Ways to selectively block the activity of telomerase would be a potent cancer therapy.

One of the possible reasons why artificially increased levels of telomerase extends life in mice is that it improves stem cell function in this way. Extending telomeres is not the only function of telomerase, however. Evolution tends to produce systems in which components are promiscuously reused in many processes. For example, telomerase has been shown to improve mitochondrial function, and mitochondria are important in the aging process:

Telomerase activity is essential for human cancer cells in order to maintain telomeres and provide unlimited proliferation potential and cellular immortality. However, additional non-telomeric roles emerge for the telomerase protein TERT that can impact tumourigenesis and cancer cell properties. This review summarises our current knowledge of non-telomeric functions of telomerase in human cells, with a special emphasis on cancer cells.

Non-canonical functions of telomerase can be performed within the nucleus as well as in other cellular compartments. These telomere-independent activities of TERT influence various essential cellular processes, such as gene expression, signalling pathways, mitochondrial function as well as cell survival and stress resistance. Emerging data show the interaction of telomerase with intracellular signalling pathways such as NF-κB and WNT/β-catenin; thereby contributing to inflammation, epithelial to mesenchymal transition (EMT) and cancer invasiveness. All these different functions might contribute to tumourigenesis, and have serious consequences for cancer therapies due to increased resistance against damaging agents and prevention of cell death.

In addition, TERT has been detected in non-nuclear locations such as the cytoplasm and mitochondria. Within mitochondria TERT has been shown to decrease ROS generation, improve respiration, bind to mitochondrial DNA, increase mitochondrial membrane potential and interact with mitochondrial tRNAs. All these different non-telomere-related mechanisms might contribute towards the higher resistance of cancer cells against DNA damaging treatments and promote cellular survival. Understanding these different mechanisms and their complexity in cancer cells might help to design more effective cancer therapies in the future.

Link: http://dx.doi.org/10.2174/1381612820666140630095606

Mitochondria, the cell's power plants, contain their own DNA. This is a legacy of their origin as symbiotic bacteria, but it makes them vulnerable to damage. Mitochondrial DNA is not as well protected and maintained in comparison to nuclear DNA, and it sits right next to an energetic biochemical process that generates plenty of potentially harmful reactive oxygen species. More serious mutational damage such as deletions are thought to contribute to aging by creating mitochondria that lack the proteins needed for proper function. Here, however, researchers speculate that other types of mutation that alter the produced proteins rather than block their production can contribute to the development of autoimmune disease:

Autoimmune disease is a critical health concern, whose etiology remains enigmatic. We hypothesized that immune responses to somatically mutated self proteins could have a role in the development of autoimmune disease. IFN-γ secretion by T cells stimulated with mitochondrial peptides encoded by published mitochondrial DNA was monitored to test the hypothesis. Human peripheral blood mononuclear cells (PBMCs) of healthy controls and autoimmune patients were assessed for their responses to the self peptides and mutated-self peptides differing from self by one amino acid.

None of the self peptides but some of the mutated-self peptides elicited an immune response in healthy controls. In some autoimmune patients, PBMCs responded not only to some of the mutated-self peptides, but also to some of the self peptides, suggesting that there is a breach of self-tolerance in these patients. Although PBMCs from healthy controls failed to respond to self peptides when stimulated with self, the mutated-self peptide could elicit a response to the self peptide upon re-stimulation in vitro, suggesting that priming with mutated-self peptides elicits a cross-reactive response with self. The data raise the possibility that DNA somatic mutations are one of the events that trigger and/or sustain T cell responses in autoimmune diseases.

Link: http://dx.doi.org/10.1016/j.humimm.2014.06.012

Some family lineages produce far more long-lived individuals than others with the same background: similar region, culture, wealth, and era. From that we can conclude that some natural genetic variations provide a greater chance of living longer in good health. The present high level view of genetics and aging is that outside of rare and catastrophic mutations, genetic variation has comparatively little influence on survival prior to old age: it's all about lifestyle choices, and to a first approximation those boil down to smoking, exercise, excess fat tissue, and how much you eat. After age 70 or so this changes, and genetic variation plays an ever larger role. Centenarians, those who reach age 100 or more, typically are less impacted by aging at any given age than their less fortunate peers. Aging is damage, they are less damaged, and their genetics has a role in this.

This is the logic that leads a great many researchers to investigate the biochemistry and genetics of centenarians and long-lived families in search of knowledge that can be turned to treatments to slow aging. This is little different to work on calorie restriction mimetics in terms of expected utility, however. It is hard work, a slow, expensive investigation of extremely complex systems that are at present poorly understood. The end result will not be any way to turn back aging, but at best to slow it. Genetic variations that show up more often in centenarians are not a guarantee of comparative longevity, they only swing the odds. There are many people with these genes, and very, very few of them live to be 100 or older. It's just that if you don't have that biochemistry the odds are even more terrible.

I don't want the future of aging research to be an expensive, slow scrabble for ways to slightly slow aging, or to make it slightly more possible to be burdened by a high load of cellular and molecular damage and yet remain alive. The future should be the targeted exploitation of what is known of the root causes of aging, so as to build repair and rejuvenation therapies that can maintain health and youth, and effectively cure age-related conditions in the old. That is the path to meaningful results in terms of more years lived in good health: repair the damage in the system you have, as this is a much more efficient approach in comparison to changing the system to slow its decay.

That doesn't mean that centenarian research is uninteresting, however. It is fascinating stuff. Just bear in mind that it most likely isn't a path to much of use other than greater knowledge of the fine details of the biology of aging. This is knowledge that we arguably have little need of in order to move a long way towards a cure for aging based on repair its known root causes.

Can Enhanced Autophagy be Associated with Human Longevity? Serum Levels of the Autophagy Biomarker Beclin-1 are Increased in Healthy Centenarians

Autophagy is a major clearance mechanism that degrades organelles and large protein aggregates to maintain cell survival and protein homeostasis. Although induction of autophagy can promote longevity in experimental models, the question as to whether increased basal levels of autophagy can be associated with human longevity remains open. In this pilot study, we investigated the association between serum concentrations of beclin-1, a key regulator of autophagy, and human exceptional longevity.

Serum beclin-1 was measured in three study groups: 79 healthy centenarians (39 males, aged 100-104 years); 178 non-diabetic patients who had experienced an acute myocardial infarction at a young age (101 males, 28-39 years); and 180 age- and sex-matched healthy young volunteers (103 males, 27-39 years). Healthy centenarians had significantly higher beclin-1 levels compared with both young patients with myocardial infarction and healthy controls, whereas no significant difference was observed between the two groups of young subjects. Our preliminary data suggest that elevated basal levels of autophagy as reflected by high serum beclin-1 levels may be a biomarker of healthy human exceptional longevity.

Disease variants in genomes of 44 centenarians

To identify previously reported disease mutations that are compatible with extraordinary longevity, we screened the coding regions of the genomes of 44 Ashkenazi Jewish centenarians. We identified 130 coding variants that were annotated as "pathogenic" or "likely pathogenic" based on the ClinVar database and that are infrequent in the general population. These variants were previously reported to cause a wide range of degenerative, neoplastic, and cardiac diseases with autosomal dominant, autosomal recessive, and X-linked inheritance. Several of these variants are located in genes that harbor actionable incidental findings, according to the recommendations of the American College of Medical Genetics. In addition, we found risk variants for late-onset neurodegenerative diseases, such as the APOE ε4 allele that was even present in a homozygous state in one centenarian who did not develop Alzheimer's disease. Our data demonstrate that the incidental finding of certain reported disease variants in an individual genome may not preclude an extraordinarily long life. When the observed variants are encountered in the context of clinical sequencing, it is thus important to exercise caution in justifying clinical decisions.

Factors affecting the survival probability of becoming a centenarian for those aged 70, based on the human mortality database: income, health expenditure, telephone, and sanitation

The survival probability of becoming a centenarian (SPBC) is defined as an estimate of the production of centenarians by a population. The SPBC (70) is the survival probability of becoming a centenarian for those aged 70. Significant positive correlations were found between the SPBC (70), and the socioeconomic factors of gross national income (GNI), public expenditure on health as a percentage of gross domestic product (PEHGDP), fixed and mobile telephone subscribers (FMTS) as the standard of living, and improved sanitation facilities (ISF).

It is always good to see more researchers talking openly about the prospects for treating aging, reversing dysfunction, and extending life. This review is open access, but the full paper is only available in PDF format at the moment:

Until recently, the aging process - the gradual detrimental effect of time on an organism that leads to death - was considered irreversible. However, research over the last 30 years has challenged this assumption, providing compelling evidence that the aging process can be affected by several factors, including the genetic composition of the organism, as well as the experiences the organism has with its environment. These findings indicate that aging is not a deterministic process, but is instead plastic, potentially availing itself to manipulation by means available to the fields of biology and medicine. The malleability of the aging process raises the exciting possibility that harnessing this plasticity may provide a means to slow or even reverse the aging process itself and rejuvenate physiological systems.

[This is] particularly evident in the loss of plasticity and cognitive abilities occurring in the aged central nervous system (CNS). However, it is becoming increasingly apparent that extrinsic systemic manipulations such as exercise, caloric restriction, and changing blood composition by heterochronic parabiosis or young plasma administration can partially counteract this age-related loss of plasticity in the aged brain. In this review we discuss the process of aging and rejuvenation as systemic events. We summarize genetic studies that demonstrate a surprising level of malleability in organismal lifespan, and highlight the potential for systemic manipulations to functionally reverse the effects of aging in the CNS.

Based on mounting evidence, we propose that rejuvenating effects of systemic manipulations are mediated in part by blood-borne 'pro-youthful' factors. Thus systemic manipulations promoting a younger blood composition provide effective strategies to rejuvenate the aged brain. As a consequence, we can now consider reactivating latent plasticity dormant in the aged CNS as a means to rejuvenate regenerative, synaptic and cognitive functions late in life, with potential implications even for extending lifespan.

Link: http://dx.doi.org/10.1111/jnc.12969

There is plenty of evidence to link regular exercise with specific aspects of better health, such as measures of functionality in the brain and cardiovascular system. Here, however, researchers produce data to suggest that some of the protective effects of exercise decline in later old age. This may well be the case, but it is worth noting that this is a small study, and that other past studies have indicated that exercise at any age is beneficial:

Physical exercise in old age can improve brain perfusion as well as certain memory skills. This is the finding of [neuroscientists] who studied men and women aged between 60 and 77. In younger individuals regular training on a treadmill tended to improve cerebral blood flow and visual memory. However, trial participants who were older than 70 years of age tended to show no benefit of exercise. Thus, the study also indicates that the benefits of exercise may be limited by advancing age.

The 40 test volunteers were healthy for their age, sedentary when the study commenced and divided into two groups. About half of the study participants exercised regularly on a treadmill for 3 months. The other individuals merely performed muscle relaxation sessions. In 7 out of 9 members of the exercise group who were not more than 70 years old, the training improved physical fitness and also tended to increase perfusion in the hippocampus - an area of the brain which is important for memory function. The increased perfusion was accompanied by improved visual memory: at the end of the study, these individuals found it easier to memorize abstract images than at the beginning of the training program. These effects were largely absent in older volunteers who participated in the workout as well as in the members of the control group.

Physical exercise is known to have considerable health benefits: the effects on the body have been researched extensively, the effects on brain function less so. An increase in brain perfusion through physical exercise had previously only been demonstrated empirically in younger people. The new study shows that some ageing brains also retain this ability to adapt, even though it seems to decrease with advancing age. Furthermore, the results indicate that changes in memory performance resulting from physical exercise are closely linked to changes in brain perfusion.

Link: https://www.dzne.de/en/about-us/public-relations/meldungen/2014/press-release-no-13.html

The mainstream of the aging research community, or at least that fraction of it that is interested at all in increasing healthy longevity by intervening in the aging process, is almost entirely focused on the use of drugs to alter metabolism to slightly slow the onset of frailty and ill-health in later life. There isn't even much effort to find new drugs: candidates are largely existing drugs. Many of these researchers exclusively discuss compression of morbidity, the goal of extending healthy life without extending overall life span. There is still an aversion in many circles to any talk of extending overall human life spans, no matter how realistic the prospects, and the boundaries of the possible for these folk stops at slowing aging modestly. These are researchers who look ahead to another twenty years of research and development that looks exactly like the last fifty: a slow mining of the natural world in search of compounds that can be used as drugs to alter the operation of the human body to produce marginal benefits. No revolution, no great advances, just a continuation of the present trends.

This is an exceedingly narrow horizon, a box even. These researchers believe it will be challenging and expensive and slow to generate benefits, and if standard issue drug development after the 1970s model that is still with us today is all they plan to do, then that seems about right. Despite great advances in biotechnology, the research community is still only in the initial stages of of mapping the complexities of metabolism, epigenetics, and their changes with aging. There is little in the way of a clear path forward to actually slow aging in humans, and where there are potentially promising areas of study, such as calorie restriction, large amounts of funding and time have so far failed to produce meaningfully beneficial therapies based on calorie restriction mimetics.

This dismal situation is why we need a disruption of the entire field in favor of research approaches that might actually work to greatly extend healthy and overall human life, that have much more in the way of straightforward and defined research plans leading to therapies, and wherein the scientists involved are not afraid to stand up and state that the end of frailty and disease in aging, indeed the end of aging itself, is the goal. The present mainstream is not getting the job done: their primary focus is on gaining knowledge of metabolism and the fine details of aging, not of taking all that is known so far and building the best therapies possible.

The Strategies for Engineered Negligible Senescence (SENS) approach typifies the sort of reaction to the mainstream you'll find among more visionary researchers who see that much more can be done about aging in the near future. There are much better paths to a future of longer lives than the tired road of drug development. If all that happens over the next twenty years is more messing with metabolism in the vague hope that small and expensive benefits will be realized, than that will be a waste of a great opportunity. Enough is known to make real progress in treatments for aging today - the only thing missing is large-scale funding and widespread public support.

The open access paper quoted below provides a very clear and detailed look at the viewpoint of those who think that only marginal gains are possible, and that researchers shouldn't talk about or try to achieve extension of overall human life span. You should compare it with a reading of the introduction to the SENS research program. On the one hand a manifesto that has as an important strand of work digging through existing drugs in search of something, anything, that might do more good than harm. On the other, a call for taking the best of present knowledge to deliberately target the known root causes of aging with the aim of turning back the progression towards disability and disease. Night and day.

Translational Geroscience: Emphasizing function to achieve optimal longevity

Investigators working in fields related to the biology and biomedicine of aging ("Geroscientists") are among those at the forefront for creating solutions to the impending impact of global aging. Several strategies have been identified, the most well-known of which is the "compression of morbidity" paradigm advanced by Fries over 30 years ago. This approach is based on the idea that because most illness today is in the form of chronic diseases, if the onset of these disorders can be delayed to an older age, and the delay is greater than any associated increase in life expectancy, then illness, disability and their sequelae can be restricted to a shorter period at the end of life.

The key issue is how to best achieve compression of morbidity. Presently there is considerable support for the tactical approach of slowing the fundamental biological processes of aging, as opposed to treating (or even preventing) individual chronic diseases. Much of the momentum for this approach has been created by the tremendous advances made over the last 25 years in what is now the routine manipulation of lifespan in model systems such as Drosophila or C. elegans. The idea is that targeting specific 'upstream' pathways, originally identified in model systems, holds promise for delaying the age of onset of multiple age-associated comorbidities as a group, whereas delaying the clinical manifestation of a particular disease may simply result in some other age-related disorder "backfilling" the consequent reduction in risk. Slowing aging at the molecular and cellular levels would, theoretically, increase "healthspan", i.e., the period of life free from serious chronic diseases and disability, thus compressing morbidity and facilitating attainment of optimal longevity.

In the area of promising dietary and pharmacological strategies, the National Institute on Aging (NIA) Interventions Testing Program (ITP) has become a highly successful source of potential treatments to reduce age-associated pathologies and extend lifespan in mice. Moreover, independent laboratories working in basic aging biology recently have produced a remarkable number of potential targets and associated target-modulating treatments worthy of translational consideration. Overall, it seems likely that identification of candidate therapies from preclinical models will not be the major limitation for establishing effective interventions to slow the effects of aging and delay the onset of age-associated co-morbidities.

One of the main obstacles for translation of treatments to improve function with aging lies in the initial steps from assessments in animal models to testing for safety and efficacy in human subjects (phase I and II clinical trials). The process for bringing new prescription agents targeting aging to market has been described in detail by Kirkland, and the steps, time lines and costs involved are extensive. However, development of drugs for older patients with geriatric syndromes such as frailty, as well as clinical disorders that are antecedents of these syndromes, clearly is an important goal and area of interest for the pharmaceutical industry.

Complementary options to new proprietary prescription drug development also exist, and may represent, in some cases, a nearer-term source for new therapies with function-enhancing effects for older adults. For example, widely used FDA approved drugs with established safety and efficacy for treating age-associated clinical disorders such as cardio-metabolic diseases (e.g., metformin, statins, renin-angiotensin system inhibitors, recent generation beta-blockers) could undergo repurposing for treatment of at risk older adults or patients with aging syndromes. Although such agents could be prescribed presently for their off-label effects in cases in which the existing evidence supports likely efficacy, broad use of these drugs likely will require new trials with appropriate subject groups and clinical endpoints recognized by drug regulatory authorities.

On the one hand it is good that ever more of the research community and its supporters are waking up to the idea of treating aging and speaking in public on that topic, rather continue with the past course of patching its consequences in silence. On the other hand, the specific research and development strategies advocated by most factions are just not good at all. They will produce knowledge, certainly, but nothing in the way of treatments that might be expected to add even a decade to human life spans. We can and should do far better than this, and the way to do so is via SENS and other repair-based approaches to the damage of aging. Only repair can lead to a future of actual rejuvenation and the prospect of unlimited healthy life spans.

Here is recent news of an approach to spinal injury that has produced benefits in one patient. It is worth tempering optimism until larger trials are attempted, however, as nerve regeneration has proven to be highly variable between individuals. The published paper on the results is open access, but very slow to load at the moment.

A paralysed man has been able to walk again after a pioneering therapy that involved transplanting cells from his nasal cavity into his spinal cord. Darek Fidyka, who was paralysed from the chest down in a knife attack in 2010, can now walk using a frame. The treatment used olfactory ensheathing cells (OECs) - specialist cells that form part of the sense of smell. OECs act as pathway cells that enable nerve fibres in the olfactory system to be continually renewed. In the first of two operations, surgeons removed one of the patient's olfactory bulbs and grew the cells in culture. Two weeks later they transplanted the OECs into the spinal cord, which had been cut through in the knife attack apart from a thin strip of scar tissue on the right.

They had just a drop of material to work with - about 500,000 cells. About 100 micro-injections of OECs were made above and below the injury. Four thin strips of nerve tissue were taken from the patient's ankle and placed across an 8mm (0.3in) gap on the left side of the cord. The scientists believe the OECs provided a pathway to enable fibres above and below the injury to reconnect, using the nerve grafts to bridge the gap in the cord.

Before the treatment, Mr Fidyka had been paralysed for nearly two years and had shown no sign of recovery despite many months of intensive physiotherapy. Mr Fidyka first noticed that the treatment had been successful after about three months, when his left thigh began putting on muscle. Six months after surgery, Mr Fidyka was able to take his first tentative steps along parallel bars, using leg braces and the support of a physiotherapist. Two years after the treatment, he can now walk outside the rehabilitation centre using a frame. He has also recovered some bladder and bowel sensation and sexual function.

Link: http://www.bbc.com/news/health-29645760

Deafness due to noise exposure is apparently due in part to destruction of specific forms of synapses linking hair cells and nerve cells. Researchers are here manipulating cells in search of ways to boost the regrowth of these synapses:

NT3 is crucial to the body's ability to form and maintain connections between hair cells and nerve cells, the researchers demonstrate. This special type of connection, called a ribbon synapse, allows extra-rapid communication of signals that travel back and forth across tiny gaps between the two types of cells. "It has become apparent that hearing loss due to damaged ribbon synapses is a very common and challenging problem, whether it's due to noise or normal aging. We began this work 15 years ago to answer very basic questions about the inner ear, and now we have been able to restore hearing after partial deafening with noise, a common problem for people. It's very exciting."

After determining that inner ear supporting cells supply NT3, the team turned to a technique called conditional gene recombination to see what would happen if they boosted NT3 production by the supporting cells. The approach allows scientists to activate genes in specific cells, by giving a dose of a drug that triggers the cell to "read" extra copies of a gene that had been inserted into them. For this research, the scientists activated the extra NT3 genes only into the inner ear's supporting cells.

The genes didn't turn on until the scientists wanted them to - either before or after they exposed the mice to loud noises. The scientists turned on the NT3 genes by giving a dose of the drug tamoxifen, which triggered the supporting cells to make more of the protein. Before and after this step, they tested the mice's hearing using an approach called auditory brainstem response - the same test used on humans. The result: the mice with extra NT3 regained their hearing over a period of two weeks, and were able to hear much better than mice without the extra NT3 production.

Link: http://www.eurekalert.org/pub_releases/2014-10/uomh-srh102014.php

Following on from the recent Rejuvenation Research 2014 conference, the SENS Research Foundation staff have released their latest annual report. The Foundation is perhaps the only organization to presently focus entirely on advancing repair-based approaches to the development of treatments for aging: take the known root causes, the fundamental forms of damage that distinguish old tissues from young tissues, and build ways to fix them. Unlike other possible approaches to treating aging, there is a clear path forward, as all the forms of damage are identified and one or more potential strategies for developing effective forms of repair exists.

Unfortunately, the SENS approach to aging is still the disruptive, growing newcomer in the research community. The vast majority of longevity research efforts focus on altering the operation of metabolism in order to slow the pace of damage accumulation in aging. This is a part of the field in which there is no clear technical path forward, however. More than a billion dollars have been spent over the past decade with little to show for it but incrementally greater knowledge, and even if results were obtained in the decades ahead, they would be of little use to old people. There isn't much you can do with a way to slow aging if you are already so old and damaged as to be close to death. In time this present state of affairs will change, and SENS will take over the mainstream by virtue of producing better results and at a far lower cost.

This process of disruptive bootstrapping requires greater public support and greater funding than presently exists, however, which is why our help and our donations are so important. A great deal has already been achieved over the past decade as a small community of supporters and scientists took SENS from initial idea to ongoing research program that enjoys the support of many noted figures in the scientific community. Success is always just a starting point for the work of tomorrow, and much more lies ahead if we are to achieve the goal of an end to disease and frailty in aging. The times are changing:

SENS Research Foundation Annual Report 2014 (PDF)

The landscape of aging research is changing. At the Bethesda meeting of the NIH's Geroscience Interest Group it was clear that the walls between gerontological and disease research were beginning to come down. SENS Research Foundation was there. At the G8 Dementia Summit in London, Prime Minister David Cameron spoke of the UK government's vision of an aging society completely free from Alzheimer's. SENS Research Foundation was there.

This is a dialogue which reflects large, multinational efforts. It is a dialogue which goes beyond our own work at the Foundation, but in which we have played our part, affecting its direction at every opportunity. And now, 'big pharma' and nimble start-ups are beginning to change the public discourse, as they make statements about their intentions to address aging directly. This reimagining of what it means to age resonates with a growing global community of politicians, academics and industrialists.

The combined efforts of all these groups, together with regulatory and financial institutions, will be needed to end age-related disease. But it will also require an approach capable of delivering effective interventions against these diseases, interventions which cure rather than alleviate, which prevent rather than delay. That's why we do what we do: we are unique in our mission to ensure that these interventions - cures based on the damage-repair approach we call rejuvenation biotechnology - are developed. As part of that mission we are committed to ensuring that our voice and the voices of our wider community are heard in the arenas where they can effect real progress.

The present budget for the Foundation is modest for a research center or for an advocacy organization. At around $4 million for 2013 it is a tenth of the size of a major independent institution in the field such as the Buck Institute for Research on Aging. You might also compare it with the grants of a few million dollars apiece made by the Glenn Foundation for Medical Research over recent years to establish a network of aging research laboratories. In general aging research is the poor cousin in the broader field of medical research, and you'll see ten times these amounts floating around the cancer and stem cell research communities on a regular basis. That too is something that must change.

In 2012 SENS Research Foundation received a restricted grant from SENS Foundation EU, resulting from the settlement of the de Grey family trust. The total value of this grant, $13.1 million, was recorded as revenue in 2012 and added to our current assets as a pledge receivable. The terms of the grant allow SENS Research Foundation to use a specified amount of the total grant each year on research, education and outreach. In 2013 we used $2,381,952 of the grant in the furtherance of our mission. The generosity of our many supporters generated additional revenue of $1,721,904 in 2013.

The Foundation funds research programs in more than a dozen labs at the present time, and you'll find notes on all of them in the later pages of the report. You should of course read the whole thing:

SENS Research Foundation supports a global research effort. Our own scientists are based in our Mountain View, California facility and we fund researchers at field-leading institutions around the world. As we age, we accumulate decades of unrepaired damage to the cellular and molecular structures of our bodies. The types of damage are few in number - we count seven, currently - but cause a great many diseases of aging, including cancer, Alzheimer's and atherosclerosis. Rejuvenation biotechnologies target this underlying damage, restoring the normal functioning of our bodies' cells and essential biomolecules. As preventative interventions they halt the harmful accumulation of damage, stopping disease before it ever starts.

Cell Therapy for the Intestinal Tract, Wake Forest Institute for Regenerative Medicine

At WFIRM, SENS Research Foundation is funding a project to restore intestinal structure and function. The central goal is the development of a regenerative medicine approach to treating inflammatory bowel disease (IBD), an autoimmune disorder that devastates the cells lining the intestine. Though IBD is not a disease of old age, therapies that repopulate the cells of the gut are critical to the development of a new generation of cancer therapies, as these therapies are likely to depopulate the stem cell reserves of several tissues (and replace the missing cells with fresh, cancer-protected stem cells).

Clearance of Macrophage Oxysterols Driving Atherosclerosis, Rice University

The SENS Research Foundation-funded team at Rice University is working to tackle two intracellular aggregates driving age-related disease and dysfunction: macrophage oxysterols (the core lesion underlying heart disease, via foam cell formation) and lipofuscin (a potential factor in multiple degenerative aging processes).

Chemistry Toward Cleavage of Advanced Glycation Crosslinks, University of Cambridge, Yale University

Advanced glycation end-products (AGEs) are a class of compounds that accumulate in our tissues as part of the degenerative aging process. The Yale AGE team is working on new tools for the detection of AGEs and their precursors. The program will synthesize glucosepane, currently thought to be the single largest contributor to tissue AGE crosslinking, and the understudied crosslink pentosinane. The team will then to use these compounds to develop new antibodies and reagents to enable rejuvenation research. Ongoing experiments in collaboration with SENS Research Foundation's Cambridge research center are focused on developing antibodies against CML (a common reactive glycation product) and MGH. These efforts will be expanded once glucosepane constructs are prepared.

Investigating the Nature of Academia-Industry Interaction in the Translation of Gene Therapies, University of Oxford, Centre for the Advancement of Sustainable Medical Innovation

The recent clinical success of gene therapy has increased the visibility of the field, attracting interest from industry. It faces commercialization challenges which differ from conventional therapeutics due to complex manufacturing procedures, record-breaking price tags, and the potential for truly personalized approaches. The first stage of the project analyzes the features of researchers and research at the University of Oxford which have led to support from industry. Surveys of industry partners aim to identify how these features are perceived, and why they influence the allocation of industry funds. This project also examines the mechanisms by which collaborations form in preclinical research. The second stage of the project considers the critical role of academia-industry collaboration in the translation of these novel high-risk, high-cost technologies. This collaboration is critical in bringing these therapies to patients.

Optimizing the Quality and Effectiveness of Risk, University of Oxford, Centre for the
Advancement of Sustainable Medical Innovations

There is declining productivity in biomedical research and development in terms of new product approvals, in part due to an inherently risk averse regulatory pathway for novel healthcare innovations. This is despite major achievements and opportunities in novel technological platforms. The portfolio of risk:benefit methodologies have been applied inconsistently and often conflated with cost-effective analysis. This yields results that do not effectively inform clinical practice or strategies for biomedical innovation. This investigation aims to assess risk:benefit appraisal methodologies in the analysis of published randomized controlled trials for pre-licensure biomedical.

Targeting the Senescence-Associated Secretory Phenotype, Buck Institute for Research on Aging

Senescent cells also develop resistance to signals for apoptosis (cellular suicide) and secrete inflammatory signaling molecules and protein-degrading enzymes into their local environment. This last phenomenon is called the senescence-associated secretory phenotype (SASP). SASP is thought to play a role in the chronic inflammation that is widespread in aging tissues, which in turn promotes the progression and propagation of age-related frailty and the many diseases of aging. With SENS Research Foundation funding, the Buck Institute SASP project has been screening small molecules for their effects on fibroblasts (a kind of skin cell) that have been rendered senescent by ionizing radiation, with the aim of identifying agents that could either selectively kill senescent cells, or interrupt the SASP and prevent its harmful effects.

Maximally-Modifiable Mouse, Applied StemCell, Inc.

The goal of the Maximally Modifiable Mouse (MMM) project is to generate mouse models allowing easy genetic modification at any time point during the mouse's lifespan, thus hastening the process of testing potential interventions against age-related disease. The MMM project aims to generate a new line of transgenic mice with "docking sites" for a high-precision targeting system for gene insertion that are not typically found in mammals engineered into their genomes. The docking site will then be ready for the insertion of new therapeutic transgenes at any time during the mice's lifespan, allowing for the testing of candidate therapies.

Rejuvenation of the Systemic Environment, University of California, Berkeley

The experimental technique of heterochronic parabiosis, in which the circulation of an aged animal is joined to that of a young one, exposes the aged organism's tissues to a youthful systemic environment (and vice-versa). The UC Berkeley systemic environment team is exploring the influence of the systemic environment on aging processes using a novel computer-controlled technological platform and specialized hardware made from off-the-shelf and custom 3-D printed parts. This platform enables the group to easily and safely extract blood from small animals, process what they extract in any of several ways, and either return it to the original animal or exchange it with that of an oppositely-aged animal. Plasma contains the soluble signaling molecules of interest in parabiosis experiments, and the use of plasma instead of whole blood enables scientists to disentangle the effects of an old animal having access to the young animal's blood cells and organs from the effects of the factors found circulating in the systemic environment.

Clearance of RPE Aggregates Driving Macular Degeneration, SENS Research Foundation Research Center

Our cells contain vesicles called lysosomes that use enzymes to recycle cellular wastes. Some stubborn wastes, however, are beyond the lysosome's evolved capacity to break down. These products accumulate in the cell's main body or in the lysosome, and may even make their way outside the cell. In the eye, extracellular garbage called drusen gradually accumulates in a portion of the retina called the macula. Drusen accumulation is an indicator for age-related macular degeneration (ARMD), the leading cause of blindness in persons over the age of 65. The SRF-RC RPE aggregate team is working to identify enzymes capable of degrading recalcitrant wastes and restoring lysosomal activity in RPE cells, which could enable ongoing maintenance of macular photoreceptors and prevent the appearance of drusen and the development of ARMD.

Tissue-Engineered Thymus, Wake Forest Institute for Regenerative Medicine

The thymus engineering group at WFIRM is working to produce new thymus tissue with a rejuvenated ability to produce T-cells, helping to restore the immune system's youthful strength. The scientists are using the powerful "decellularized scaffold" approach. Researchers begin with a donor organ and strip it of its original cells, leaving a "scaffold" of extracellular matrix (ECM) onto which cells derived from the transplant recipient can be seeded.

Allotopic Expression of Mitochondrially-Encoded Proteins, SENS Research Foundation Research Center

The accumulation of cells harboring deletion-mutation-containing mitochondria is a significant consequence of aging, and is implicated in age-related disease. The SRF-RC mitochondrial mutations team is working to develop engineered mitochondrial genes that could be stored safely in the cell's nucleus and function as "backup copies" for cells whose mitochondria harbor deletion mutations. They are currently working to realize the potential of a new method for targeting these engineered nuclear-encoded genes to the mitochondria, and to optimize the precision of this targeting.

Diagnostic and Therapeutic Antibodies against Transthyretin Amyloids, University of Texas-Houston Medical School, Harvard University

A key driver of age-associated ill health is a form of molecular damage in which certain proteins in the body lose their native structure and bind together with one another, forming harmful aggregates. One less-known amyloid disease is senile systemic amyloidosis (SSA), a disorder caused by aggregation of a hormone-transporter protein called transthyretin (TTR). With SENS Research Foundation support, the UTHMS TTR amyloid team is working to develop engineered catalytic antibodies ("catabodies") targeting misfolded TTR as a rejuvenation biotechnology for prevention and treatment of TTR amyloidosis. These "catabodies" combine the specificity of conventional antibodies with the catalytic power of enzymes, giving a single catabody molecule the ability to permanently degrade large amounts of target amyloid.

Identification of the Genetic Basis of ALT, SENS Research Foundation Research Center

To survive, all cancers must develop a mechanism to re-lengthen their telomeres. Many cancers do this by hijacking the genes involved in regulation of the enzyme telomerase, which are only supposed to be expressed by certain specific cell types under very tight control. 10-15% of cancers, meanwhile, employ a telomerase-independent mechanism known as alternative lengthening of telomeres (ALT). The SRF-RC ALT group has has developed a fast, high-throughput assay method and will use the new, faster ALT assays to hunt for genes that might be involved in the ALT machinery, and screen libraries of drugs to identify new candidate treatments that would shut down ALT cancer cells.

Epimutations: Targets or Bystanders for Rejuvenation Biotechnology? Albert Einstein College of Medicine

Just as our genes can suffer mutations that damage the instructions cells use to make their encoded proteins, so too our cells can suffer damage to the "epigenetic" structures that help to regulate whether a particular gene is turned on or off in a particular kind of cell at a particular time. These epimutations therefore cause cells to turn the expression of particular genes on or off aberrantly. The Albert Einstein College of Medicine (AECOM) epimutations team is investigating the possibility that epimutations could be contributing to age-related disease. Numerous cells in a tissue could, in this scenario, be engaging in aberrant gene expression, leading over time to tissue dysfunction and eventual pathology.

Probably indicative of the Calico Labs strategy for the foreseeable future, here is a piece of news from last month that I missed at the time. The initiative will be taking over funding of an established drug development program aimed at increasing neural plasticity, trying to find ways to spur the brain to generate more new neurons to compensate for damage. Like much of what goes on in modern medical research for age-related conditions, this is a compensatory approach, addressing proximate rather than root causes of degeneration. For many conditions, this may be useful and possibly even sufficient - Parkinson's disease, for example, affects a mechanical part of the brain that has little to do with the structure of the mind, and the cells there could in theory be replaced wholesale over and again as needed.

Generally, however, we want a research community that works to repair and prevent the root causes of aging, rather than one focused on trying to patch up late stage age-related damage after the fact, or worse, trying to alter the operation of metabolism to make it run slightly better when damaged. If the Calico Labs leadership intend to build an establishment rapidly over the next few years by adopting promising research programs, then the less optimal paths are largely what they'll be funding, however:

This week, UT Southwestern researchers published a new paper about the molecular target of P7C3 compounds, a class that has been shown to help in various animal models of neurodegeneration. UT Southwestern previously licensed the P7C3 compounds to Dallas-based 2M Companies. 2M and Calico have now entered into a new license agreement under which Calico will take responsibility for developing and commercializing the compounds resulting from the research program. Under the agreement, Calico will fund research laboratories in the Dallas area and elsewhere to support the program.

Death of nerve cells is the key mechanism in many devastating neurological diseases for which there are currently inadequate treatment options. [The UT Southwestern researchers] have collaborated since 2007 to find novel drugs that promote the growth of new nerve cells in the brain, a process known as "neurogenesis." The P7C3 compounds discovered by the team have previously been shown to be effective in animal models of age-related neurocognitive impairment, Parkinson's disease, amyotrophic lateral sclerosis (ALS), and depression. New research [shows] that these drugs activate a cellular enzyme involved in energy metabolism, known as NAMPT (short for nicotinamide phosphoribosyltransferase), which is critical to the proper functioning and survival of cells. A separate [study] shows that the P7C3 compounds protect against brain dysfunction when given to rodents following traumatic injury.

Link: http://www.calicolabs.com/news/2014/09/11/

Researchers are making progress towards a methodology for growing intestinal tissues from a patient's cells. As is usually the case in this sort of work, the first results are not intended for use in therapies, but will instead provide raw materials that can help to speed further research:

Researchers have successfully transplanted "organoids" of functioning human intestinal tissue grown from pluripotent stem cells in a lab dish into mice. Through additional translational research the findings could eventually lead to bioengineering personalized human intestinal tissue to treat gastrointestinal diseases. "This provides a new way to study the many diseases and conditions that can cause intestinal failure, from genetic disorders appearing at birth to conditions that strike later in life, such as cancer and Crohn's disease. These studies also advance the longer-term goal of growing tissues that can replace damaged human intestine."

The scientists used induced pluripotent stem cells (iPSCs) - which can become any tissue type in the body - to generate the intestinal organoids. The team converted adult cells drawn from skin and blood samples into "blank" iPSCs, then placed the stem cells into a specific molecular cocktail so they would form intestinal organoids. The human organoids were then engrafted into the capsule of the kidney of a mouse, providing a necessary blood supply that allowed the organoid cells to grow into fully mature human intestinal tissue. The researchers noted that this step represents a major sign of progress for a line of regenerative medicine that scientists worldwide have been working for several years to develop.

Mice used in the study were genetically engineered so their immune systems would accept the introduction of human tissues. The grafting procedure required delicate surgery at a microscopic level, according to researchers. But once attached to a mouse's kidney, the study found that the cells grow and multiply on their own. Each mouse in the study produced significant amounts of fully functional, fully human intestine.

Link: http://www.cincinnatichildrens.org/news/release/2014/lab-grown-intestines-10-19-2014/

The body is a life support system, carriage, and collection of useful accessories for the brain. Insofar as you as an individual are concerned, you are your brain. The rest of the body is only indispensable because we don't have other ways to provide the same capabilities. That will change, though likely not in any easily predicted way: the decades ahead are a time of great uncertainty in technological details because the pace of change is so rapid. Small differences in research today are magnified over the years leading up to future applications of that science. We might set out to draw a smooth line of progression between today's prosthetics - artificial limbs with simple nervous system interfaces, bioartificial dialysis devices, vision substitutes for the blind via implanted electrode grids, and so forth - and the integrated artificial brain carriage of tomorrow, a collection of technologies and capabilities that will bear roughly the same relationship to the natural human body and biological systems as a car bears to a horse. Some people, such as those involved in the 2045 Initiative see this as a goal to be pursed more aggressively and directly than is presently the case. But I suspect that the line will be anything but smooth and direct.

Prosthetics are just one approach to tackling the results of disability, disease, and the damage of aging, after all. If the goal is function where function is lost, then prosthetics are in competition with regenerative medicine. The two sides will tend to ebb and flow in funding for any of the thousands of potential applications as they do better or worse than one another in providing the ability to regain what was lost. My suspicion is that prosthetics will fade as as an active line of development in the decades ahead due to progress in tissue engineering and regenerative medicine. Artificial limbs, perhaps the least complex of all possible prosthetics, will soon be potentially better than the real thing in a range of capabilities. Yet I imagine that the average fellow short a limb would nonetheless jump at the chance of regrowing a biological replacement in the fashion of a salamander if that was a possibility, as it may well be twenty years from now.

Meanwhile, however, it is interesting to watch progress in this field. Some of the work on prosthetics is potentially applicable to augmentation devices such as wearable exoskeletons that might provide the frail elderly with far greater freedom of action. But again, this is no substitute for the creation of repair biotechnologies that might restore lost capabilities and health. Much of today's prosthetics development is a matter of substitution and compensation; increasingly useful, and the only game in town until there is more progress in medicine, but a phase of technology that will pass, or transition to augmentation of those without disability. Perhaps it will return in earnest at the end of the biological period of medicine when "prosthetics" will mean producing discrete systems of diamondoid nanomachinery to replace slices of our biology: artificial immune cells; artificial oxygen stores in blood; artificial ATP-producing nanofactories to augment mitochondria. All of these are machines that we can consider and design in theory today, and that might be hundreds of times more efficient than our evolved biology. Building an industry to create and maintain such things lies a few steps beyond present endeavors in medicine and materials science, however. It or something similar might be the new new thing for the 2040s and later.

Returning to the present day, here are a few articles noting the present state of work on limb prosthetics. Perhaps the most interesting aspect of this is work on integration with the nervous system. That is a technology that has wide-ranging applications beyond prosthetics, and we'll be seeing a lot more of in the years ahead.

Is This the Future of Robotic Legs?

"When you view the human being in terms of its locomotory function, some aspects are quite impressive," Herr said. "Our limbs are very versatile: We can go over very rough terrain, we can dance, we can stand still. But...our muscles, when they do positive work, 75 percent is thrown out as heat and only a quarter is mechanical work. So we're pretty inefficient, we're pretty slow and we're not terribly strong. These are weaknesses we can fix."

The next frontier for bionics, Herr believes, is neurally controlled devices. For now, the BiOM [prosthetic foot] works independently from the brain, with an algorithm and a processor governing the prosthetic's movement. But Herr is working on sensors that can tap into the body's nervous system - eventually we could see a prosthetic controlled by the brain, muscles and nerves.

Mind-controlled prosthetic arms that work in daily life are now a reality

The novel osseointegrated (bone-anchored) implant system gives patients new opportunities in their daily life and professional activities. "We have used osseointegration to create a long-term stable fusion between man and machine, where we have integrated them at different levels. The artificial arm is directly attached to the skeleton, thus providing mechanical stability. Then the human's biological control system, that is nerves and muscles, is also interfaced to the machine's control system via neuromuscular electrodes. This creates an intimate union between the body and the machine; between biology and mechatronics."

The patient is also one of the first in the world to take part in an effort to achieve long-term sensation via the prosthesis. Because the implant is a bidirectional interface, it can also be used to send signals in the opposite direction - from the prosthetic arm to the brain. This is the researchers' next step, to clinically implement their findings on sensory feedback.

"Reliable communication between the prosthesis and the body has been the missing link for the clinical implementation of neural control and sensory feedback, and this is now in place. So far we have shown that the patient has a long-term stable ability to perceive touch in different locations in the missing hand. Intuitive sensory feedback and control are crucial for interacting with the environment, for example to reliably hold an object despite disturbances or uncertainty. Today, no patient walks around with a prosthesis that provides such information, but we are working towards changing that in the very short term."

Amputees discern familiar sensations across prosthetic hand

The system, which is limited to the lab at this point, uses electrical stimulation to give the sense of feeling. But there are key differences from other reported efforts. First, the nerves that used to relay the sense of touch to the brain are stimulated by contact points on cuffs that encircle major nerve bundles in the arm, not by electrodes inserted through the protective nerve membranes. Second, to provide more natural sensations, the research team has developed algorithms that convert the input from sensors taped to a patient's hand into varying patterns and intensities of electrical signals. The sensors themselves aren't sophisticated enough to discern textures, they detect only pressure.

The different signal patterns, passed through the cuffs, are read as different stimuli by the brain. The [researchers believe] that everyone creates a map of sensations from their life history that enables them to correlate an input to a given sensation. "I don't presume the stimuli we're giving is hitting the spots on the map exactly, but they're familiar enough that the brain identifies what it is."

Here is a short article from earlier this month in a popular science magazine. SENS, the Strategies for Engineered Negligible Senescence, is a research and development program that aims to repair aging by reverting the known root causes. These are forms of cellular and molecular damage cataloged by the research community over the past century; it has been three decades since the last was discovered, so there is a fair degree of confidence that the list is completely enough for now. For each of these types of damage there is a clear path towards the production of treatments:

Aubrey de Grey wants to save lives. He wants to save as many as he possibly can, as soon as he can, and to do it he is going to fix ageing. The prominent scientist and futurologist is on a crusade to beat ageing and when he does it will mean that we stay healthy and live longer - possibly for up to hundreds of years. But, as de Grey emphasises, his primary goal is not just making people live longer; he wants us to live healthily, he wants to restore us to a state of health that is "fully functional in every way". The ability to live for hundreds of years is just a side effect. The work carried out by de Grey and his colleagues at the SENS Research Foundation will ultimately raise new challenges that need to be tackled, both in medicine and society, but there is no scientific reasoning why the body, with the right treatment, cannot be healthy for much longer.

The idea of treating disease and the disabilities of old age will not be treated by one breakthrough de Grey says. It has to be broken down into a series of manageable tasks. "We don't really think there is going to be one particular technique that will do the job. We believe that the process of ageing has to be recognised as a chaotic somewhat uncoordinated set of processes such that a truly effective treatment of it is going to involve a divide and conquer approach, essentially sub-dividing the problem into a variety of types of damage that accumulate and figuring out therapies that can address each of them."

In a world where getting old is no longer an issue, concerns will arise about population levels and resources that the planet can provide. But this view does not give credit to other technologies that are developing at a faster implementation rate than anti-ageing, and people can have a blinkered view about this. "They just don't look at the problem properly, so for example one thing that people hardly ever acknowledge is that the other new technology is going to be around a great deal sooner than [SENS rejuvenation biotechnology], or at least sooner than [SENS] will have any demographic impact. For example we will have [a much lower] carbon footprint because we will have things like better renewable energy and nuclear fusion and so on, so that it will actually be increasing the carrying capacity of the planet far faster than the defeat of ageing could increase the number of people on the planet."

Link: http://www.factor-tech.com/health-augmentation/8475-aubrey-de-grey-longer-lives-wont-mean-overpopulation/

The heat shock factor HSF-1 is involved in the processes of cellular maintenance relating to ensuring correct protein folding and clearing out misfolded proteins. Protein shape is vital to the operation of cellular machinery, and the presence of misfolded proteins should be considered a form of damage. It has been demonstrated that more HSF-1 extends life and improves tolerance to damage-inducing stress in laboratory animals, and thus a number of research groups are interested in producing treatments based on this effect.

For 35 years, researchers have worked under the assumption that when cells undergo heat shock, as with a fever, they produce a protein that triggers a cascade of events that field even more chaperones to refold unraveling proteins that could kill the cell. The protein, HSF-1 (heat shock factor-1), does this by binding to promoters upstream of the 350-plus chaperone genes, upping the genes' activity and launching the army of chaperones, which originally were called "heat shock proteins."

Injecting animals with HSF-1 has been shown not only to increase their tolerance of heat stress, but to increase lifespan. Because an accumulation of misfolded proteins has been implicated in aging and in neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's diseases, scientists have sought ways to artificially boost HSF-1 in order to reduce the protein plaques and tangles that eventually kill brain cells. To date, such boosters have extended lifespan in lab animals, including mice, but greatly increased the incidence of cancer.

[Researchers] found in experiments on the nematode worm C. elegans that HSF-1 does a whole lot more than trigger release of chaperones. An equal if not more important function is to stabilize the cell's cytoskeleton, which is the highway that transports essential supplies - healing chaperones included - around the cell. "We are suggesting that, rather than making more of HSF-1 to prevent diseases like Huntington's, we should be looking for ways to make the actin cytoskeleton better."

[The researchers compare] a cell experiencing heat shock to a country under attack. In a war, an aggressor first cuts off all communications, such as roads, train and bridges, which prevents the doctors from treating the wounded. Similarly, heat shock disrupts the cytoskeletal highway, preventing the chaperone "doctors" from reaching the patients, the misfolded proteins. "We think HSF-1 not only makes more chaperones, more doctors, but also insures that the roadways stay intact to keep everything functional and make sure the chaperones can get to the sick and wounded warriors." The researchers found specifically that HSF-1 up-regulates another gene, pat-10, that produces a protein that stabilizes actin, the building blocks of the cytoskeleton. By boosting pat-10 activity, they were able to cure worms that had been altered to express the Huntington's disease gene, and also extend the lifespan of normal worms.

Link: http://newscenter.berkeley.edu/2014/10/16/new-front-in-war-on-alzheimers-other-protein-folding-diseases/

To suffer a stroke is one the uglier and more abrupt system failures of aging. A vital blood vessel in the brain is either blocked by the biological debris of clots and fatty deposits on blood vessel walls, or more rarely the blood vessel suffers a structural failure of its walls due to forms of cellular and molecular damage that weaken, restructure, and stiffen this tissue. The higher blood pressure that accompanies age, for a collection of reasons that are only mostly avoidable, raises the odds of disaster. Thus a part of the brain is either deprived of oxygen or flooded with blood, and in either case cells die and a fragment of the brain - and the mind it hosts - is lost or greatly impaired, often permanently.

The ultimate objective of rejuvenation biotechnology after the SENS model of is to remove the root causes that lead to stroke, as for all age-related conditions. Break down the metabolic waste that stiffens blood vessels and indirectly raises blood pressure; restore stem cell populations to more aggressive repair of failing tissues; and more besides. Among the "more besides," is it the case that stroke has immune dysfunction among its noteworthy contributing causes? The immune system fails in characteristic ways with aging, among them a growth in chronic inflammation: even as the immune system becomes unable to adequately police the body in search of pathogens and rogue cells, it is constantly overactive, in a state of inflammation. This progression towards dysfunction is termed inflammaging, but there may be comparatively straightforward ways to turn it back at least some of the way. This might be achieved by crudely rebalancing the internal configuration of the immune system, destroying one class of cells that serve little useful purpose, but have grown too numerous. Their numbers block the generation of effective new immune cells, but if winnowed that would change.

Open access papers in the latest issue of Aging and Disease argue for the immune dysfunction contribution to stroke, mediated by inflammation:

Ischemic Stroke: A Consequence of a Diseased Immune System?

Stroke is a leading cause of long-term disability and the second leading cause of death globally. Approximately 795,000 strokes are reported each year in the US, 87 percent of which are ischemic. The direct medical cost associated with stroke in 2009 was approximately $22.8 billion, with an additional $13.8 billion in indirect costs associated with lost productivity, unemployment, rehabilitation, and follow-up care.

It is interesting to consider whether a common mechanism of immune dysfunction underlies many complex diseases, such as stroke, heart disease, myocardial infarction, and atherosclerosis. While it is possible that the immune system is similarly altered, gene-environment interactions may control the timing or severity of the dysfunction, and epigenetic modifications may provide a common molecular mechanism to link the immune response among different disease states. Our knowledge of the epigenetic control of the immunological consequences of ischemic stroke is limited and requires a new approach to clinical and pre-clinical studies.

The Immune Response to Acute Focal Cerebral Ischemia and Associated Post-stroke Immunodepression: A Focused Review (PDF)

It is currently well established that the immune system is activated in response to transient or focal cerebral ischemia. This acute immune activation occurs in response to damage, and injury, to components of the neurovascular unit and is mediated by the innate and adaptive arms of the immune response. The initial immune activation is rapid, occurs via the innate immune response and leads to inflammation. The inflammatory mediators produced during the innate immune response in turn lead to recruitment of inflammatory cells and the production of more inflammatory mediators that result in activation of the adaptive immune response.

Under ideal conditions, this inflammation gives way to tissue repair and attempts at regeneration. However, for reasons that are just being understood, immunosuppression occurs following acute stroke leading to post-stroke immunodepression. This review focuses on the current state of knowledge regarding innate and adaptive immune activation in response to focal cerebral ischemia as well as the immunodepression that can occur following stroke.

Cytokines: Their Role in Stroke and Potential Use as Biomarkers and Therapeutic Targets (PDF)

The complex, multifaceted cascade of events that results from brain deprivation of oxygen, glucose, and other essential nutrients to the brain causes dysfunction. During ischemia, glutamate stored within brain cells is released when cells are hyperactive or die. Furthermore, brain and immune cells produce reactive oxygen species (ROS), and restoration of blood flow in the occluded vessel generates additional ROS. ROS activate endothelial cells and cause oxidative stress. Oxidative stress and the induction of the inflammatory cascade leads to the breakdown of the blood-brain barrier allowing activated blood-borne immune cells such as neutrophils and T-cells to infiltrate and accumulate in the ischemic brain tissue. Along with the accumulation of activated immune cells, microglia in the brain become activated after cerebral ischemia. Activated microglia secrete pro-inflammatory mediators such as cytokines.

As cells die and brain tissue is damaged, molecular danger signals further potentiate the inflammatory response by activating more microglia and infiltrating leukocytes in a feed-forward response producing more deleterious pro-inflammatory cytokines. These inflammatory changes after ischemia lead to an increase in neuronal cell death resulting in a larger infract volume and worse neurological outcome. Inflammation is a key player in brain damage during cerebral ischemia; however, inflammation aiding in repair and recovery after cerebral ischemia can be beneficial.

It is clear that cytokines play an important role in the pathophysiology of stroke, and the loss in balance between pro-inflammatory and anti-inflammatory cytokines after stroke affects infarct size and functional outcome. Thus, focusing on one cytokine only as a potential biomarker or a therapeutic target likely will not be advantageous in stroke. Future work needs to elucidate the temporal profile of cytokines in the periphery in human and experimental stroke studies to determine which cells contribute to the elevation of cytokines in the brain and blood and to understand how they work in concert to provide neuroprotection or increase neurotoxicity.

The crosstalk between the immune system and the brain is still not well understood. Using cytokines as biomarkers or therapeutic targets may be beneficial to understand the post-ischemic immune response and its effects on outcome clinically and to modulate the post-ischemic immune response to limit tissue damage. However, modulation of the immune response can also be detrimental after stroke; thus, it is imperative that further clinical and experimental studies be pursued to better understand the complex interaction between the immune system and the brain after stroke.

The brain attempts to repair itself following damage such as that caused by a stroke, and researchers continue to discover more about these processes, many of which are still comparatively poorly understood. The near term goal here is to manipulate the underlying biochemistry in order to spur much greater regeneration, possibly not just following injury, but also as a way to offset some of the impact of aging on the brain:

A previously unknown mechanism through which the brain produces new nerve cells after a stroke has been discovered. A stroke is caused by a blood clot blocking a blood vessel in the brain, which leads to an interruption of blood flow and therefore a shortage of oxygen. Many nerve cells die, resulting in motor, sensory and cognitive problems. The researchers have shown that following an induced stroke in mice, support cells, so-called astrocytes, start to form nerve cells in the injured part of the brain. Using genetic methods to map the fate of the cells, the scientists could demonstrate that astrocytes in this area formed immature nerve cells, which then developed into mature nerve cells.

The scientists could also identify the signalling mechanism that regulates the conversion of the astrocytes to nerve cells. In a healthy brain, this signalling mechanism is active and inhibits the conversion, and, consequently, the astrocytes do not generate nerve cells. Following a stroke, the signalling mechanism is suppressed and astrocytes can start the process of generating new cells. "Interestingly, even when we blocked the signalling mechanism in mice not subjected to a stroke, the astrocytes formed new nerve cells. This indicates that it is not only a stroke that can activate the latent process in astrocytes. Therefore, the mechanism is a potentially useful target for the production of new nerve cells, when replacing dead cells following other brain diseases or damage."

"One of the major tasks now is to explore whether astrocytes are also converted to neurons in the human brain following damage or disease. Interestingly, it is known that in the healthy human brain, new nerve cells are formed in the striatum. The new data raise the possibility that some of these nerve cells derive from local astrocytes. If the new mechanism also operates in the human brain and can be potentiated, this could become of clinical importance not only for stroke patients, but also for replacing neurons which have died, thus restoring function in patients with other disorders such as Parkinson's disease and Huntington's disease."

Link: http://www.lunduniversity.lu.se/article/mechanism-that-repairs-brain-after-stroke-discovered

A trial has been running in leukemia patients using immune cells modified to express a variety of chimeric antigen receptors. This allows the immune cells to recognize and attack cancer cells with a high degree of specificity, and the early results in the trial were impressive. Here is a more recent update:

The blood cells of cancer patients, reprogrammed by doctors to attack their leukemia and re-infused back into the patients' veins, led to complete remissions in 27 of 30 people. That's especially exciting because those patients had failed all conventional treatments. Not all of the remissions lasted. Nineteen patients in the study remain in remission 2 to 24 months later, and 15 of them didn't need any additional treatment. Seven patients relapsed between 6 months and 9 months after their infusion; those included three people whose cancers spread beyond the blood cells the new treatment targets. Five patients left the study for alternative therapy. The numbers are remarkable because these patients had cancer return as many as four times before they joined the study, including some whose cancer had returned after stem cell transplants.

For this method, the researchers harvest a patient's T cells using a process like blood transfusion. Then the lab [performs] a gene transfer, to teach the T cells to target a protein found on the surface of B cells, another type of blood cell that's affected in leukemia. The T cells are then transplanted back into the patient, where they hunt and kill anything with the protein attached to it. That means all B cells, not just the cancerous ones, are killed. Tests of all treated patients showed that their normal B cells had been killed along with the tumors. Because B cells are responsible for creating antibodies, which hunt any viruses or bacteria circulating in the blood stream, the solution isn't ideal; patients usually receive immunoglobulin replacement to help boost their immune systems to healthy levels. Living without B cells isn't perfect, but it's better than dying of cancer.

Absence of B cells is a situation that should be possible to fix with today's cell technologies. In past years researchers have destroyed and recreated the immune system in patients with autoimmune disease, so repopulating B cells should be a very plausible goal.

Link: http://www.theverge.com/2014/10/15/6985201/lab-made-blood-cells-hunt-cancer-leading-to-remissions

There are traditional wisdoms in the study of the evolutionary origins of aging. For example that greater extrinsic mortality due to predation or an otherwise harsh environment selects for shorter life spans, producing species whose individual members are optimized to reproduce rapidly and age rapidly, as health assurance mechanisms that create longer reproductive and overall life spans are either lost or never evolve in the first place. This and other consensus theories initially emerged from simple models that have nonetheless largely continue to do fairly well over the years, but all simple models are eventually challenged. With the falling cost and vast increase in available computing power ever more sophisticated evolutionary modeling has taken place, and researchers are finding that there can be exceptions to almost every hypothesis in the field.

Here is an interesting paper in which researchers propose that under some circumstances high extrinsic mortality can result in species with longer lives, not shorter lives, and further that aging may have evolved because it actually increases lifespan in a species living in a high mortality environment. These are not the only researchers producing models in which this sort of thing happens. The argument here is that aging and improved youthful ability are linked: the evolution of capabilities that improve survival and reproductive success in the face of adversity in early life goes hand in hand with an inability to maintain tissues and metabolism over the long term. Thus individuals better survive their hostile environment and live longer on average, but age as a consequence.

Interaction Mortality: Senescence May Have Evolved because It Increases Lifespan

Given an extrinsic challenge, an organism may die or not depending on how the threat interacts with the organism's physiological state. To date, such interaction mortality has been only a minor factor in theoretical modeling of senescence. In general, it holds that mortality does not affect evolution if it affects all organisms equally. The intuitive reason for this is that evolution favors a phenotype (strategy) if it is better at propagation than other strategies. If all strategies are affected equally, no strategy improves relative to others, and selection gradients remain unchanged.

Mortality that does not distinguish between individuals is often called 'extrinsic mortality' and modeled as an age-independent parameter in the mortality function of age-structured models. In these models, extrinsic mortality is a discounting factor in the survival function that cannot be molded in any way by the (fictitious) organism that is studied. However, whether environmental threats result in mortality depends on the interaction of those threats with an organism's physiological state. By adjusting its state, an organism can influence death from environmental causes.

To investigate mortality-environment interactions from a theoretical perspective, we model a trade-off between an age-independent and an age-dependent mortality term. As an example of a biological rationale for such a model, [it has been] suggested that it could be beneficial from an evolutionary standpoint to attain a state that is unmaintainable by its very nature, causing mortality to be low at young ages, but to increase over time [as senescence takes hold]. As a result, death can be postponed to later ages, depending on the magnitude of initial reduction relative to the ensuing increase in mortality with age.

We find that depending on the physiological constraints, any outcome is possible in any environment, be it 'no senescence' or 'high rate of senescence'; that the highest optimal rate of senescence emerges for an intermediate physiological constraint; and that the optimal rate of senescence as a function of the environment is driven by the way the environment changes the effect of the organism's state on mortality. We conclude that predicting the outcome requires knowledge about the interaction of the environment and the organismal physiology: separately, these have little predictive power.

We propose, perhaps paradoxically, that senescence may have evolved because it extends lifespan. Lifespan is equal to the inverse of average mortality. If mortality increases over age, but [for a senescent species] starts off from a much lower level than would otherwise be the case [for a non-senescent species], average mortality may go down, implying lifespan extension.

Sepsis is a serious threat to the old, but researchers are developing new forms of blood cleansing devices that more effectively target the causes of this condition by removing pathogens from the blood. Looking ahead, one can imagine an evolution of this technology into long-term implants that could augment immune system function for everyone, providing far greater resistance to many threats to health:

A microfluidic device filled with magnetic nanometer-sized beads that bind a plethora of pathogens and toxins was able to clear these invaders from the blood of rats with sepsis, improving their outcomes. The design of the extracorporeal device was inspired by the small vessels and sinusoids within the spleen, through which blood "trickles slowly, almost like in a wetlands, efficiently capturing pathogens".

The device has two interconnected channels, one for the flowing blood and another containing a saline solution that traps and removes the pathogens. Magnetic nanobeads coated with a genetically engineered version of the mannose binding lectin (MBL) protein - which has a natural proclivity for foreign toxins and bugs, and normally functions as part of the mammalian innate immune system - are injected into the flowing blood before it enters the device.

Extracorporeal blood cleansing is not a novel concept for treating sepsis. An antibiotic-coated column called Toraymyxin that is approved in Japan and Europe - currently in a Phase 3 clinical trial in the U.S. - can remove endotoxins from the blood and has been shown to improve outcomes for sepsis patients. Other dialysis-like devices have been developed to mitigate the symptoms of sepsis, and these have included hemofiltration of the inflammatory molecules that are the root of the so-called cytokine storm that spurs organ damage in sepsis patients. But previous approaches did not target the cause of the storm - pathogens.

"Some already available blood-cleansing technologies have negative side effects like depletion of platelets, white blood cells, or other proteins along with the deleterious elements. What I like a lot about this approach is that it appears safe and there is no blood coagulation or altering of the blood composition - that is really important."

Link: http://www.the-scientist.com/?articles.view/articleNo/40979/title/Next-Generation--Blood-Cleansing-Device/

There are signs of progress in the use of cell therapies to restore vision. A small trial involving patients suffering from forms of degenerative blindness caused by loss of retinal cells is reporting better results than expected:

The study involved patients suffering from age-related macular degeneration and Stargardt's macular dystrophy, the two leading causes of adult and juvenile blindness in the developed world. The diseases destroy a person's central vision. Working with Advanced Cell Technology Inc. [researchers] took human embryonic stem cells and turned them into the kind of cells that are killed by these diseases - retinal pigment epithelial cells. Then, they infused between 50,000 and 150,000 cells into the retinas of the patients. "What we did is put them into patients who have a disease where those particular cells are dying; and we replaced those dying tissues with new tissue that's derived from these stem cells. In a way it's a retinal transplant."

No one expected the cells to help any of these patients see better, because the study was designed mostly just to see if doing this was safe. Researchers were concerned the cells could destroy whatever vision was left or lead to tumors in the volunteers' eyes. So [they] picked patients whose eyes were so far gone that they weren't risking losing any vision. That also meant that there was little hope the cells could help either.

Surprisingly, many of the patients did start to see better. Ten of the 18 patients can see significantly better. One got worse, but the other seven either got better or didn't lose any more vision. The researchers stress that the findings must be considered preliminary because the number of patients treated was relatively small and they have only been followed for an average of less than two years. But the findings are quite promising. The patients had lost so much vision that there was no expectation that they could benefit.

Link: http://www.npr.org/blogs/health/2014/10/14/346174070/embryonic-stem-cells-restore-vision-in-preliminary-human-test

The aging research community might be divided into two camps. The much larger camp sees aging as a process of damage accumulation and reactions to that damage. There is a lot of argument over which forms of damage are more important and how they lead to the observed age-related changes in biochemistry, but the primary forms of damage are well described and that list has existed in its present form for more than thirty years. The smaller camp in the research community sees aging as an evolved genetic program of changes that cause damage. So we have a cart and a horse and debate over which is which. For my part I see the balance of evidence as leaning strongly towards aging as damage.

It can be the case that researchers well understand the fundamental damage of aging but yet argue over whether it is a cause or a consequence because metabolism - the day to day operation of our biochemistry, and the way in which it reacts to circumstances - is fantastically complex. Even in this age of advanced biotechnology and large-scale computation we stand a long, long way from a full model of its operation. So it seems likely that settling the debate over aging as damage versus aging is program will occur when the first damage repair treatments are rolled out and trialed in mice. They should be very effective if aging is in fact the results of damage. If aging is a program, well, they will be much less effective and the results transient. The cost of performing this grand experiment is very low in comparison to the cost of trying to build a complete understanding of metabolism. At this point in time it requires hundreds of millions of dollars and a decade of work to chase down answers in the roles of just a few genes and proteins out of the thousands of noteworthy types of molecule involved in metabolism: just look at sirtuin research as an example. In the world of SENS rejuvenation research, hundreds of millions of dollars would buy most of a rejuvenation toolkit for laboratory mice and the proof as to whether it works or not.

We live in a world that isn't all that rational, however, as illustrated by the fact that damage repair approaches like SENS are not well funded. Despite the fact that a majority in the research community work from the hypothesis that aging is caused by cellular and molecular damage in tissues, they work on treatments that make much more sense for the programmed aging school of thought. Generally research focuses on the end stages of age-related conditions, working backwards to identify proximate causes of pathology. Scientists identify the next to last changes before the end, which of course are very rarely the same thing as the primary forms of damage that are thought to cause aging. Only in some diseases, such as macular degeneration, is there a very short chain of steps from fundamental damage (build up of metabolic waste products called lipofuscin) to disease process (death of retinal cells), and that chain is well understood.

So instead of root causes, researchers are far more often studying the details of metabolic disarray in late stage disease. Simple causes spiral out into highly complex dysfunction in a system, our metabolism, that is researchers are still figuring out piece by piece as they go. Since genetic and epigenetic studies are becoming popular - they are newly cheap and funding is easily raised - the proximate causes latched onto are often epigenetic changes. These are consequences, reactions to damage, if you think that aging is damage, and primary causes of damage if you think that aging is programmed. So we have researchers who are firmly in the aging as damage camp nonetheless working hard to create treatments that should, by their own hypotheses, have only marginal benefits. Treatments that won't in any way deal with the underlying problem, but rather are attempts to force a dysfunctional metabolism to work better under a high load of damage. This is patching the problem, and will be expensive and provide little in comparison to the results that damage repair could achieve.

But anyway, there are plenty of examples to point out. Most research into treating aging is as I've described above, and the "repair the damage" approach of SENS is still the disruptive minor newcomer. It's strange, given that the majority of the field considers aging to be a process of damage. Here is one example in which researchers pick out an epigenetic change that occurs in aging, resulting in altered levels of one particular protein, and discuss the prospects for altering it in order to adjust the operation of metabolism. Read the open access paper, and bear in mind that this is what the ultimately futile path looks like, the way forward that will not greatly help us when we are old:

GHK and DNA: Resetting the Human Genome to Health

During human aging there is an increase in the activity of inflammatory, cancer promoting, and tissue destructive genes plus a decrease in the activity of regenerative and reparative genes. The human blood tripeptide GHK possesses many positive effects but declines with age. It improves wound healing and tissue regeneration (skin, hair follicles, stomach and intestinal linings, and boney tissue), increases collagen and glycosaminoglycans, stimulates synthesis of decorin, increases angiogenesis, and nerve outgrowth, possesses antioxidant and anti-inflammatory effects, and increases cellular stemness and the secretion of trophic factors by mesenchymal stem cells.

GHK was discovered during studies comparing the effect of human plasma from young persons (age 20-25) to plasma from older persons (age 50-70) on the functioning of incubated slices of human hepatic tissue. The younger plasma more effectively induced a profile associated with youth by suppressing fibrinogen synthesis. The active factor was found to be GHK. Since then numerous studies over the course of four decades demonstrated that this simple molecule improves wound healing and tissue regeneration.

Even though numerous and diverse beneficial effects of GHK have been known for decades, it was not clear how one simple molecule could accomplish so much. The use of gene expression data greatly extends our understanding of GHK's effects and its potential treatments of some of the diseases and biochemical changes associated with aging. As a potential therapeutic agent GHK has a clear advantage over many other active chemicals that may also show promising results in gene profiling experiments, its gene modulating effects correspond to findings from in vivo experiments. When GHK is administered internally to an animal, it induces actions throughout the body.

There is still not enough information to translate gene profiling data into biological effects. However, based on the documented activity of GHK in vivo, we can predict [various] beneficial actions from our gene profiling data. Most current theories and therapies to treat disease tend to target only one biochemical reaction or pathway. But for human aging, our data suggests that we must think of simultaneously resetting hundreds to thousands of genes to protect at-risk tissues and organs. GHK may be a step towards this gene resetting goal.

The cost of aging is enormous, far greater than any other single cause of pain, suffering, and death. Approximately two thirds of all deaths are due to aging and its consequences: more than 100,000 lives are lost to aging each and every day. These are rarely pleasant or easy ends. Aging progressively raises the chance of suffering a range of fatal or disabling medical conditions: cardiovascular disease, amyloidosis, dementia, and many others. Hundreds of millions of people live with ever worsening chronic pain, disability, and suffering as a result of aging.

The overwhelming majority of all medical expenditure goes towards treating the consequences of aging or providing palliative care for the aged. Further, there is an enormous opportunity cost to aging: those who become frail and unable to work might have otherwise gone on to continue earning and creating value. The amounts involved are staggering: the cost of the most common chronic medical conditions in the US alone amounts to ~$280 billion in expenditures and ~$1 trillion in lost productivity each and every year. The overwhelming majority of that is due to aging.

Yet it remains unusual for anyone to point out that this is happening, or that we need to address it by striking at the root cause of all this pain, suffering, death, and loss:

Humanity faces a major problem (what I refer to here simply as the Problem) this century. And given the nature of the Problem it will most likely be a significant problem for all future generations as well, unless we seriously tackle this problem. The Problem is one of the most significant problems we have ever faced. Sadly not very many people realize how big of a problem the Problem is, and few believe there is anything we can do to remedy the Problem. Thus people do not pressure their governments to take action to address the Problem.

There is an extremely strong scientific consensus concerning the likelihood that the Problem will impose unprecedented levels of suffering, disease and disability on people in both rich and poor countries. Indeed this is a certainty if we do nothing to prevent the Problem. Furthermore, the Problem threatens to undermine the economic prosperity of all nations, rich and poor alike. So if you hadn't yet guessed it, the Problem is global aging. Civilization has become so successful at preventing early and mid-life mortality - thanks to public health measures like the sanitation revolution, immunizations, antibiotics, changes in behaviour and increases in material prosperity - that our populations now age.

Some claim we should just focus on "adaptation" to minimize the harms of the Problem. Those taking this position doubt we can do anything to directly alter the certainty and severity of the problem. And yet many of the scientists with expertise on the nature of the Problem believe we can directly manipulate the factors responsible for the Problem. Numerous scientific experiments have demonstrated that the biological processes involved in senescence (aging) can be modulated, thus slowing down the rate of molecular and cellular decline.

Given the rapid rise of chronic disease that has already occurred, and will dramatically rise this century as populations age, what can be done? The strategy of adaptation is one that simply takes the biology of aging we have inherited from our species life and evolutionary history as a given, and looks for ways to minimize the harmful effects of aging. So promoting exercise, or tackling specific diseases of aging by funding medical research on cancer or Alzheimer's disease, or redesigning cities to better promote the mobility of aging populations.

A more ambitious and rational strategy would be to aspire to modulate aging itself. Retarding human aging could dramatically increase the health span and reduce the period of time humans will suffer chronic disease. Such an intervention could be something all future generations benefit from as well. There are hardly any global problems as pressing and significant as tackling aging is today.

Link: http://colinfarrelly.blogspot.com/2014/10/the-problem.html

It was only comparatively recently that researchers developed a potential measure of biological age using patterns of DNA methylation, a collection of epigenetic alterations that are in some cases similar between different individuals of the same age. It makes sense that there should be age-related patterns to find in our biochemistry, as we all age due to the same root causes: degenerative aging is the consequence of a few forms of cellular and molecular damage, and since the damage is the same, some of the reactions to that damage should also be the same.

Researchers have now had enough time to apply the new DNA methylation measure in larger studies and process the data. I imagine we'll be seeing more results like this one over the next few years. In this case the data adds to the voluminous support for the negative impact of excess fat tissue on long-term health:

Scientists have found, for the first time, that obesity significantly quickens the aging process of the liver and have revealed that carrying excessive weight can negatively impact certain human tissues. The researchers used an 'epigenetic clock' [based on] a naturally occurring process called methylation, which is a chemical modification of the DNA molecule. To reach their findings in this study and examine the connection between increased body weight and epigenetic acceleration, the [scientists] worked with and used [the] aging clock method on almost 1,200 human tissue samples, 140 of which were liver samples.

The researchers found that the aging clock was quite accurate and was able to match the biological age with the chronological age of liver tissue samples taken from subjects with little body fat. On the other hand, the scientists found that liver tissues taken from subjects who were obese had a tendency of having a higher biological age than their chronological age. While they found that obesity has no affect the epigenetic age of human tissues such as fat, muscle or blood, [the] epigenetic age of the liver, on average, increased by 3.3 years for every 10 units of Body Mass Index (BMI). "This does not sound like a lot, but it is actually a very strong effect. For some people, the age acceleration due to obesity will be much more severe, even up to 10 years older."

Link: http://blogs.voanews.com/science-world/2014/10/13/obesity-found-to-age-the-liver-faster/

On October 1st we kicked off this year's grassroots matching fundraiser in support of SENS Research Foundation programs. Earlier this year a group of us raised a $100,000 matching fund to encourage donations: each $1 donated to the SENS Research Foundation before the end of the year draws an additional $2 from the fund. The Foundation is a 501(c)(3) charity, and your tax-deductible donations help to expand ongoing research programs that aim to produce the necessary foundation biotechnologies for therapies to repair the causes of degenerative aging. We have a chance at avoiding frailty and age-related disease, but if we want to attain that goal in time enough to matter then we must all do our part. New medical technologies don't fund themselves, and the future we get is the future we choose to invest in.

As of last Friday more than 200 people from the futurist and broader longevity science community stepped up to donate a total of $6,600. Thus with matching from our fund these first donors have ensured that nearly $20,000 will go to support rejuvenation research organized by the Foundation in 2015. We have a way to go yet to draw down the rest of the fund, however - and all help is appreciated.

A big part of this process is people and discussion, not money. It is about building a larger community of supporters, reaching new audiences who have yet to give serious thought to just what might be accomplished in the next twenty years if the right approach to therapies for aging wins out. To most people rejuvenation is an impossible pipe dream, but then most people don't pay any attention to the ins and outs of medicine in practice, let alone medical research still in progress, until they need to. We must do our part to change this state of affairs, to make aging research more like cancer research in the public eye: support, a clear vision for a cure, and an eagerness for progress.

To implement a comprehensive suite of first generation rejuvenation treatments in mice, of the damage repair variety as outlined in the SENS proposals, the research community will need a large amount of resources, perhaps as much as Big Pharma devotes to guiding a single new drug through research and development. That funding largely arrives from institutions and companies with millions to spend on each grant or project, but they never become involved in any line of research that lacks prototype treatments resulting from early stage research, and widespread recognition and support.

The way you raise tens of millions or more for medical research from a few select groups is by first raising tens of thousands from hundreds of grassroots supporters, while thousands more are talking about your work, and tens of thousands are reading about it in the press. You use that modest funding to conduct the low-cost early stage research to produce prototypes and prove your case: producing clinical treatments remains very expensive, but progress in the tools of biotechnology has made early stage medical research very cheap in comparison to past decades.

That is how bootstrapping works, whether for research, biotech startups, or any human endeavor for that matter. But can we do it for SENS rejuvenation research? Of course we can. In fact, we've done it already: SENS started out fifteen years ago or so with a few tens of thousands of dollars here and there raised from hundreds of supporters. As those numbers grew, deeper pockets then provided most of the probably $20-30 million devoted to SENS research programs to date. They did this only because crowds were already making modest donations and talking in support of SENS. The overall funding for SENS is a number hard to pin down nowadays: there is a fair amount of relevant work taking place that is not funded by the SENS Research Foundation or even coordinated by the Foundation, and in some cases it's a tough call as to whether to include it or not in any estimate.

So what are we doing here with this fundraiser? The answer to that question is this: the same proven-to-work strategy, except with more money and faster progress than the early days. The grassroots who make modest donations are the very people who lead the way and light the path for later large-scale funding, and when the grassroots grows that funding will be larger than the present support for SENS. You can help us to make this happen by reaching out to the communities you know: people that haven't heard from us. It's a simple message:

• Do you want to grow sick and frail with age, or for that to happen to your friends and parents? We don't.
• We live in an age of science and progress. Medical researchers can now work to prevent the disability and degeneration of aging, with your support.
• The pains and suffering of aging are not inevitable forever. All ill health was once incurable, but cures were made by dealing with the root causes of ill health. The same can can also be accomplished for the frailty and sickness of old age.
• The state of research and the detailed knowledge of what must be done is presently much more advanced than you might imagine.
• If supporting cancer research looks good, why not also give to support research to treat the root causes of all age-related disease?
• It makes sense. Later, when we are old, we will get the medicine that we supported today.

An interesting interview with a tissue engineer can be found at the Methuselah Foundation blog. It covers one view of the path from today's research to the clinical availability of complete engineered livers constructed to order, among other subjects:

[The most significant challenge] definitely has to do with scaling up our cell sources, because the liver is such a large organ, and you just need an enormous volume of cells. We can take fat-derived bone marrow stem cells and turn them into pretty much any cell that we want, but we need such large quantities that we may have to combine cells from different populations in order to get enough. [So] we're going back to how we tackled it for the small bowel, which was to use clusters of cells known as organoid units rather than single cells alone. For the bowel, what that cluster looks like is an epithelial cell - the specialized stem cell of the intestine - with a little ball of cells gathered around it. One of the beauties of these organoid units is that because all of the cells are together, they've already got their natural architecture in place. When you're working with single cells, they have the unfortunate habit of changing into other cells that you don't want. And the more you can keep them together, the happier they are. So these already existing cell architectures turned out to be very useful to us.

Likewise, with the liver, rather than using single cells alone and therefore having to figure out how to mass produce them in order to get enough, we're exploring whether or not we can use these organoid units instead and get them to expand and coalesce into functional tissue. It's kind of like giving the whole process a head start. Instead of saying, "Okay, two cells need to get together and start talking," we're saying, "Can we put 10 cells together and get them to talk to another 10 cells?"

Down the line, we're still going to have to figure out where these cells will come from. With pigs, I can take the liver from one pig and turn it into a scaffold, and then take another pig and break down its liver in order to get a bunch of little organoid units out of it, which I can then seed back into the scaffold. That's great, but it's not clinically translatable. I can't really go to a human patient and just take out little bits of their liver and start chopping them up, because they need their liver to survive. So it's a bit of a Catch-22 at the moment.

In the end, I wonder whether we may have to figure out how to harvest a smaller portion of organoid units from small biopsies of a patient's liver, seed them into a scaffold alongside other stem cells, and then somehow get those organoid units to turn the adjacent stem cells into liver cells. We do have a little bit of lab evidence that this could work, because we've taken bone marrow stem cells, co-cultured them together with epithelial cells from the bronchi, and these stem cells have shown signs of turning into epithelial cells themselves. But this still needs to be explored in a lot more detail.

In general, we'd eventually like to be able to say to you, "Here's a fully seeded new liver, and you can have a full transplant." Before we get to that point, however, it may also be possible to use a partial tissue-engineered liver to make some kind of dialysis machine, much like we do for the kidney. This would give us the opportunity, step by step, to offer an intermediate form of treatment that would give your liver a chance to regenerate a little bit and regain some of its function.

Based on the work we're doing now, I think we'll need another four to five years at least before we're ready to find our first human patient and do a serious pre-clinical GLP study, which is the completely audited study that the regulators would approve of. And that's for the dialysis treatment. Once you got the dialysis up and running, from there it may just be a case of scaling it up to full engineered organ transplants. I don't know how long that will take.

Link: http://mfoundation.org/blog/?p=213

Most of the research community proceeds under the assumption that amyloid, deposits of misfolded proteins that form in tissues, is a causative agent in Alzheimer's disease. Amyloid levels rise with age, probably due to progressive failure of clearance mechanisms. Definitive proof of the role of amyloid has been slow in coming, however, for all that the weight of evidence is strong. From a biochemical point of view Alzheimer's is a very complex condition, and there has been plenty of room for alternate theories to flourish, especially given the slow progress towards meaningful treatments based on removing amyloid.

Researchers are here claiming confirmation of the amyloid hypothesis, which is news, though that might be overstating the case:

An innovative laboratory culture system has succeeded, for the first time, in reproducing the full course of events underlying the development of Alzheimer's disease. Using the system they developed, [investigators] now provide the first clear evidence supporting the hypothesis that deposition of beta-amyloid plaques in the brain is the first step in a cascade leading to the devastating neurodegenerative disease.

"Originally put forth in the mid-1980s, the amyloid hypothesis maintained that beta-amyloid deposits in the brain set off all subsequent events - the neurofibrillary tangles that choke the insides of neurons, neuronal cell death, and inflammation leading to a vicious cycle of massive cell death. One of the biggest questions since then has been whether beta-amyloid actually triggers the formation of the tangles that kill neurons. In this new system that we call 'Alzheimer's-in-a-dish,' we've been able to show for the first time that amyloid deposition is sufficient to lead to tangles and subsequent cell death."

[The researchers] realized that the liquid two-dimensional systems usually used to grow cultured cells poorly represent the gelatinous three-dimensional environment within the brain. Instead the [team] used a gel-based, three-dimensional culture system to grow human neural stem cells that carried variants in two genes - the amyloid precursor protein and - known to underlie early-onset familial Alzheimer's Disease (FAD).

After growing for six weeks, the FAD-variant cells were found to have significant increases in both the typical form of beta-amyloid and the toxic form associated with Alzheimer's. The variant cells also contained the neurofibrillary tangles that choke the inside of nerve cells causing cell death. Blocking steps known to be essential for the formation of amyloid plaques also prevented the formation of the tangles, confirming amyloid's role in initiating the process. The version of tau found in tangles is characterized by the presence of excess phosphate molecules, and when the team investigated possible ways of blocking tau production, they found that inhibiting the action of an enzyme called GSK3-beta - known to phosphorylate tau in human neurons - prevented the formation of tau aggregates and tangles even in the presence of abundant beta-amyloid and amyloid plaques.

Link: http://www.sciencedaily.com/releases/2014/10/141012134838.htm

The future elimination of menopause through medical advances to treat aging has been in the news of late. Menopause is an undesirable thing that happens during aging, and the ultimate objective of rejuvenation research projects is to indefinitely postpone all of the undesirable things that happen during aging. Degenerative aging is a combination of primary damage, spiraling secondary forms of damage, and the evolved reactions of still-functioning systems to that damage. The best way forward to deal with all of this is that of the SENS research programs, among other lines of research: repair the damage. Don't try to compensate for damage, or alter the operation of biology to work better when damaged, as that is an expensive and futile undertaking. It is very hard to try to maintain a system on verge of failure due to damage. Instead work to remove the cause of the problems, giving our biology the chance to repair and restore itself. Our tissues can perform that task very proficiently when not operating in a damaged environment.

The media, and possibly the public, often seem to be far more taken with the possibilities of rejuvenation that don't matter than with those that do. Things like regrowth of lost hair, for example. This seems like a trivial thing. Aging cripples us and kills us: it takes away to ability to walk, to think, to live without constant pain. Yet the trivial, the hair and the wrinkles, captures all of the attention. This is just one of many ways in which it might be argued that we are not a particularly rational species. From where I stand, menopause is not all that much better as a focus for attention: it is far from the worst thing that will happen to any given aging woman.

Nonetheless, a recent interview in which Aubrey de Grey of the SENS Research Foundation mentioned in passing the prospect of the elimination of menopause was widely noted. That comment - out of all the things said - became the focus of dozens of press articles. Why don't people get this worked up about actually fatal age-related conditions like heart disease and dementia? Nonetheless, it should be the case that a woman of the future who has regular access to a comprehensive suite of repair therapies built after the SENS model, reverting the damage to cells and tissues that causes aging, will not suffer menopause. She will have tissues and systems that are the same as those of a young woman no matter her current chronological age. That is the goal, and no more menopause is a side-effect of keeping her healthy.

Over at the SENS Research Foundation you'll find a good science-heavy article on the end of menopause to counterbalance the near-complete absence of scientific details that is the status quo for the popular press. The excerpts below are just small excerpts - you should read the whole thing:

Rejuvenation Biotechnology: Toward the Indefinite Postponement of Menopause

SENS Research Foundation works to catalyze the development of rejuvenation biotechnology: a new class of medicines that will keep us young and healthy and forestall the disease and debility that currently accompany a long life, by targeting the root causes of age-related ill health. Menopause shares much in common with major age-related health problems, inasmuch as they all result from the accumulation of cellular and molecular damage in our tissues over time. Because this damage takes our tissues' microscopic functional units offline, aging damage gradually degrades each tissue's capacity to carry out its normal function with time. When enough of this damage accumulates in a particular tissue, specific diseases and disorders of aging characteristic of that tissue emerges, whether it's in the brain (Alzheimer's and Parkinson's disease), or the heart and circulatory system (atherosclerosis and heart failure), or the machinery controlling cellular growth (cancer) - or the ovaries (menopause). The corollary of this is that by removing and repairing this damage, rejuvenation biotechnology will restore the proper structure of the cellular machinery that keeps our tissues functioning, restoring their ability to keep us alive and with the good health that most of us enjoy at earlier ages.

So maintaining a woman's fertility and postponing or eliminating menopausal symptoms comes down to a mixture of repairing and replacing damaged cells (notably egg cells) and tissues (follicles) whose age-related degradation leads to menopause in the first place, bringing the whole system back to its youthful, functional norm. Today, researchers are pursuing several "damage-repair" approaches to realize this goal, and that's what we'll discuss in this article.

Cell Therapy

You're probably familiar with the promise of stem cells and other cell therapies to treat a variety of diseases and disorders involving cell loss, particularly diseases of aging. Cell therapy is an straightforward way to counteract the loss of viable egg cells with age, particularly in restoring a woman's fertility. To give a woman a new supply of eggs that matches her original genetics will require that those new egg cells begin with her own cells. Scientists are now mastering a couple of ways whereby a person's ordinary, mature cells can have their developmental clocks reset.

Tissue Engineering

This approach is similar to cell therapy, but focuses on the larger-scale goal of replacing an entire organ or tissue instead of replacing specific, critical cell types. In an exciting study, Stanford scientists have reported the ability to generate new follicles from ovarian tissue from women with primary ovarian insufficiency, in which a woman's ovaries stop producing new eggs before the age of 40 and she enters early menopause.

Awakening "Oogonial Stem Cells"

But maybe we don't need to actually give women new ovarian tissue to revive ovarian function. Since the 1950s, it's been the dogma that women are born with a fixed supply of early-stage egg cells that are produced during embryonic development. But this widely-accepted view has been strongly challenged in the last decade, [offering] the potential that "oogonial stem cells" (OSC) may lie dormant in aging women, waiting to be revitalized with the right cocktail of cells or signaling factors.

Cell Encapsulation

The rejuvenation biotechnologies we've explored so far involve replacing egg cells, or whole follicles, or even whole ovaries with new tissue, which would restore both fertility and normal, youthful hormone production. But the disruption of the hormonal system that drives the symptoms of menopause is only indirectly related to the actual release of egg cells. The two cell populations involved in the production and release of release sex hormones [are] part of the follicle itself, and their release is not directly tied to ovulation. If these cells could be replaced and maintained in the ovaries, they could potentially carry on producing sex hormones and maintain the normal system of feedback between the ovaries, those hormones, and the regulatory centers in the brain, even with no egg cell replacement.

Women Age as Whole People

But of course, a woman is more than a womb, and her aging is more than the aging of her reproductive system. Aging affects every organ, every tissue, every cell. And while specific diseases and disorders arise most recognizably when the burden of cellular and molecular damage to some particular tissue crosses a "threshold of pathology," no organ ages in isolation. We age as whole people, with stiffening arteries damaging our kidneys and brains, failing eyesight impairing our intellectual work, and a rising burden of tissue damage across the entire body forcing all of our cells operate in a haze of oxidative stress and inflammation. In the end, women will be truly free of menopause when and only when we are all free of the entire degenerative aging process: when a comprehensive panel of rejuvenation biotechnologies is developed to remove, repair, replace, or render harmless the full range of the damage of aging, and all of our tissues are made new.

To be clear, type 2 diabetes is a self-inflicted harm for the majority of sufferers, caused by too much food and too much fat tissue carried over the years. It is a condition that can be turned back even in comparatively late stages by nothing more than weight loss and a much reduced diet. Nonetheless it is a prevalent condition and a great deal of research effort is focused on finding more sophisticated methods of treatment.

Here researchers consider the role of cellular senescence in the loss of active pancreatic beta cells involved in the condition: to what degree is type 2 diabetes age-related because of the trend towards increasing weight gain and lack of exercise versus the rising numbers of senescent cells in older tissues? Cells become senescent, removing themselves from the cell cycle, in response to damage or tissue conditions and a signaling environment that implies damage lies ahead. Senescent cells accumulate with age and are a meaningful contribution to the aging process, playing a role in the pathology of many age-related conditions. Given the trials showing that lifestyle choices can reverse type 2 diabetes, however, I am skeptical that cellular senescence is an important factor in most of the cases seen these days:

The incidence of type 2 diabetes significantly increases with age. The relevance of this association is dramatically magnified by the concomitant global aging of the population, but the underlying mechanisms remain to be fully elucidated. Here, some recent advances in this field are reviewed at the level of both the pathophysiology of glucose homeostasis and the cellular senescence of pancreatic islets. Overall, recent results highlight the crucial role of beta-cell dysfunction in the age-related impairment of pancreatic endocrine function.

Alterations of glucose homeostasis increase with age and represent leading causes of morbidity and mortality, mainly linked to both the complications associated with type 2 diabetes and the increased risk for several other age-related diseases. The classical pathophysiological factors responsible for this age-related failure of glucose homeostasis (insulin resistance and decreased secretory capability of beta cells) are quite well characterized, but new mechanisms have recently been revealed. Central to this new development is the key concept that loss or dysfunction of pancreatic beta cells plays a crucial role in the pathogenesis of type 2 diabetes. Since the predominant mechanism of beta-cell generation seems to be self-renewal, the senescence-associated cell cycle dysregulation and the consequent proliferative arrest assume a particular relevance.

Link: http://journal.frontiersin.org/Journal/10.3389/fendo.2014.00138/full

Nicotinamide adenine dinucleotide cycles between two forms, NAD+ and NADH, in the course of participating in important cellular processes such as the mitochondrial respiration whose dysfunction is implicated as a cause of aging. Earlier this year researchers showed that NAD levels decline with age and restoring them can improve measures of health in old mice. Here the same research group notes that NAD mechanisms are required for most of the health and longevity benefits produced by the practice of calorie restriction, and their data suggests that this has a lot to do with changing the operation of mitochondria. Alterations to mitochondrial function show up time and again in considerations of aging and longevity, and are a factor in most of the known ways to slow aging in laboratory animals:

Interventions that slow aging and prevent chronic disease may come from an understanding of how dietary restriction (DR) increases lifespan. Mechanisms proposed to mediate DR longevity include reduced mTOR signaling, activation of the NAD+-dependent deacylases known as sirtuins, and increases in NAD+ that derive from higher levels of respiration. Here, we explored these hypotheses in Caenorhabditis elegans using a new liquid feeding protocol.

DR lifespan extension depended upon a group of regulators that are involved in stress responses and mTOR signaling, and have been implicated in DR by some other regimens [DAF-16 (FOXO), SKN-1 (Nrf1/2/3), PHA-4 (FOXA), AAK-2 (AMPK)]. Complete DR lifespan extension required the sirtuin SIR-2.1 (SIRT1), the involvement of which in DR has been debated. The nicotinamidase PNC-1, a key NAD+ salvage pathway component, was largely required for DR to increase lifespan but not two healthspan indicators: movement and stress resistance. Independently of pnc-1, DR increased the proportion of respiration that is coupled to ATP production but, surprisingly, reduced overall oxygen consumption.

We conclude that stress response and NAD+-dependent mechanisms are each critical for DR lifespan extension, although some healthspan benefits do not require NAD+ salvage. Under DR conditions, NAD+-dependent processes may be supported by a DR-induced shift toward oxidative metabolism rather than an increase in total respiration.

Link: http://onlinelibrary.wiley.com/doi/10.1111/acel.12273/full

Mitochondria are bacteria-like organelles within cells responsible for, among other things, generating the adenosine triphosphate (ATP) molecules used as a chemical energy stores to power cellular activities. This process produces a varying flux of reactive oxygen species (ROS), molecules that can cause significant damage to molecular machinery when present in large numbers. Large and complex molecules participating in vital cellular processes are fragile things in the face of a horde of small reactive molecules trying to form bonds and bend their partners out of shape. Many aspects of cellular metabolism react to raised levels of ROS, especially those playing a part in housekeeping activities such the prompt removal of damaged proteins and repair of DNA. This dance is a regular part of life: it happens every time you exercise, for example, and is an important part of the way in which exercise produces health benefits. ROS flux in this case is a signal resulting in reactions at the cellular level that lead to improved tissue function at the higher level.

Mitochondria have their own DNA, a legacy of their evolutionary past as symbotic bacteria. It is stuck right next door to the intricate structures that generate both ATP and potentially harmful reactive molecules. Damage to mitochondrial DNA occurs on an ongoing basis, possibly due to the flux of ROS they themselves generate, and possibly during the many, many times mitochondria divide to make up their numbers in a cell. Some of this DNA damage is inconsequential and essentially random: it doesn't spread among mitochondria, and it doesn't appear to cause any great harm. There are mouse lineages artificially weighed down with point mutations in mitochondrial DNA, for example, that seem to suffer no ill effects as a result. However some forms of more drastic mutation, such as deletions, can remove one or more necessary genes from mitochondrial DNA, causing that mitochondrion to fall into a dysfunctional state that can spread. This particular type of dysfunction leads to preferential survival for the malfunctioning mitochondria and they quickly take over the cell, causing it to malfunction also. This is one of the causes of degenerative aging.

Mitochondria within a cell are far from being a static population of structures: mitochondria replicate by division like bacteria, and there are processes watching mitochondria for damage or dysfunction, culling the herd of faulty organelles. Mitochondria are also quite capable of swapping proteins and parts between themselves, or even fusing together. All of this complicates any attempt to watch the progress of damage to mitochondrial DNA in cells: it is evidently rapid, as researchers never find cells in mid-transition between some mitochondria exhibiting harmful DNA damage and all mitochondria in a cell exhibiting that damage.

The way to address this contribution to the aging process is through some form of repair. The Strategies for Engineered Negligible Senescence (SENS) approach is to work around the damage by placing copies of mitochondrial DNA in the cell nucleus. Mitochondrial DNA mutation is only a problem if mitochondria must rely on their DNA to produce needed protein machinery: if there is another source, then the damage is irrelevant. There are numerous other possible approaches, however: repair the DNA directly and periodically, introduce whole new mitochondria into tissues, and so forth. All too few researchers are working on this, however. While it is generally agreed that mitochondria are very important in the aging process, the mainstream position is to work on gathering more data rather than work to fix the damage - though to my eyes this is one of many areas in which it is probably more cost effective to enact a repair therapy and see what happens.

In this research the opposite approach is taken: create damage to mitochondrial DNA and watch the results in mice. This sort of thing is very rarely as educational as we would like it to be, however. It is too easy to break biology in ways that shorten life, and the breaking changes have no necessary connection to aging or ways to lengthen life even when they take place in related areas of molecular biology. Mitochondrial dysfunction of a variety of forms that don't occur in aging cause disease and shorter life spans, and so the details matter greatly, here as everywhere else. Not all mitochondrial DNA mutations are equal, and an experiment of this nature is one where it takes a real specialist in the field to comment on its relevance to aging:

Mom's Mitochondria Affect Pup Longevity

The new study shows that mitochondrial DNA mutations in the mother's eggs can shorten her pups' lives by approximately one third. The mice that inherited mutant mitochondrial DNA showed an average lifespan of 100 weeks compared with 141 weeks for control mice. What is not yet known is how mitochondrial DNA mutations shorten lifespan. Dysfunctional mitochondria could impair cellular metabolism and lead to a variety of problems, such as the accumulation of damaging reactive oxygen species, reduced vitality of stem cells, and reduced DNA repair, leading to the accumulation of damage to the genome in the nucleus. "Aging is a complex process and involves so many different facets, so maybe it's a little bit of everything that together keeps on beating down the organism a little at a time."

Maternally transmitted mitochondrial DNA mutations can reduce lifespan

The accumulation of mitochondrial DNA (mtDNA) mutations resulting in mitochondrial dysfunction has been heavily implicated in the aging process as well as various age-related disorders and diseases. Replication of the mitochondrial genome continues in mitotic and meiotic cells, as well as in non-dividing cells, with an ~10-fold higher mutation rate than nuclear DNA. Thus, mutations can occur in the maternal germline and be transmitted to offspring. Despite the presence of protective mechanisms that eliminate deleterious mtDNA mutations, evidence indicates inheritability of low levels of heteroplasmy in humans; however, the influence of such mutations on health and lifespan has been largely unclear.

To determine the extent to which inherited mtDNA mutations may contribute to the rate of aging, we designed a series of mouse mutants and previously demonstrated that germline mtDNA mutations can induce and augment aging phenotypes. We also unexpectedly found that a combination of inherited and somatic mtDNA mutations cause stochastic brain malformations. These results suggest that starting life with healthy mitochondria might be important for the maintenance of health during aging. This suggests that the rate of aging may be set early in life before reproduction ends. We now present evidence to demonstrate that the presence of low levels of germline-transmitted mtDNA mutations during development can have life-long consequences not only by causing premature aging phenotypes, but also by shortening lifespan.

Our previous and present findings allow us to conclude that inherited mtDNA mutations alone or in combination with somatic mtDNA mutations, augments the rate of aging and shortens lifespan. These results also provide additional evidence for the hypothesis that certain determinants of aging are present prior to conception and during development. It would be interesting to understand if the rate of aging, determined early during life, can be altered.

That all individuals start life with an initial damage load is supported by the reliability theory of aging, a model of system failure over time in which an organism is considered as a collection of redundant breakable components. This turns out to be a fairly robust and useful way of thinking about the aging of biological organisms at a high level. It has nothing to say about mechanisms, but it does help to steer thinking as to what the plausible mechanisms of aging might be.

Many cell transplants have been shown to produce no long-lasting cells in the recipient. In stem cell treatments, for example, it is frequently the case that the stem cells have a short-term effect on the signaling environment that boosts regeneration by changing the behavior of native cell populations, but the transplanted cells do not take up residence and are gone within a few days to a few weeks. The research noted here lies at the opposite end of the spectrum, however, and confirms that dopamine-generating neurons transplanted to replace those lost to the mechanisms of Parkinson's disease last for a very long time indeed:

To determine the long-term health and function of transplanted dopamine neurons in Parkinson's disease (PD) patients, the expression of dopamine transporters (DATs) and mitochondrial morphology were examined in human fetal midbrain cellular transplants. DAT was robustly expressed in transplanted dopamine neuron terminals in the reinnervated host putamen and caudate for at least 14 years after transplantation.

The transplanted dopamine neurons showed a healthy and nonatrophied morphology at all time points. Labeling of the mitochondrial outer membrane protein Tom20 and α-synuclein showed a typical cellular pathology in the patients' own substantia nigra, which was not observed in transplanted dopamine neurons. These results show that the vast majority of transplanted neurons remain healthy for the long term in PD patients, consistent with clinical findings that fetal dopamine neuron transplants maintain function for up to 15-18 years in patients.

Link: http://dx.doi.org/10.1016/j.celrep.2014.05.027

Amyloid-β is one of the forms of misfolded protein that accumulate in tissues with age, precipitating to form solid clumps and fibrils. This one forms in the brain and is associated with Alzheimer's disease. Amyloid levels are fairly dynamic, and their growth with age appears to be a slow failure of clearance mechanisms rather than a gradual accumulation. One of those discussed here in the past is the choroid plexus, a filtration system for cerebrospinal fluid. Here, however, is consideration of another failing mechanism, one that is more tightly bound to the degeneration of blood vessel tissues.

This is of interest because Alzheimer's risk is strongly correlated to blood vessel health. Further, the process of age-related degeneration in blood vessels is one for which the links to forms of cellular and molecular damage that cause aging are fairly well understood at this time: cross-links formed by metabolic waste degrade blood vessel elasticity, for example. Ways to effectively remove those cross-links, such as those envisaged as the end result of work underway at the SENS Research Foundation, should be broadly beneficial to brain health as well as other tissues.

In Alzheimer's disease, amyloid-β (Aβ) accumulates as insoluble plaques in the brain and deposits in blood vessel walls as cerebral amyloid angiopathy (CAA). The severity of CAA correlates with the degree of cognitive decline in dementia. The distribution of Aβ in the walls of capillaries and arteries in CAA suggests that Aβ is deposited in the perivascular pathways by which interstitial fluid drains from the brain. Soluble Aβ from the extracellular spaces of gray matter enters the basement membranes of capillaries and drains along the arterial basement membranes that surround smooth muscle cells toward the leptomeningeal arteries. The motive force for perivascular drainage is derived from arterial pulsations combined with the valve effect of proteins present in the arterial basement membranes.

Factors that affect cerebrovascular health, such as age and APOE genotype, alter both the structure of the blood vessels and the expression of the basement membrane proteins such that the efficiency of perivascular drainage of Aβ is reduced. As increasing amounts of Aβ become entrapped within the drainage pathways, it causes damage to the underlying vasculature, further reducing the functionality of the vessel and creating a feedforward mechanism by which increasing amounts of Aβ accumulate as CAA. Finally, diffusion of soluble Aβ and interstitial fluid through brain tissue is blocked by insoluble Aβ in the extracellular spaces, levels of soluble Aβ and other metabolites in brain parenchyma rise and dementia ensues.

The failure of perivascular clearance of Aβ may be a major factor in the accumulation of Aβ in CAA and may have significant implications for the design of therapeutics for the treatment of Alzheimer's disease.

Link: http://onlinelibrary.wiley.com/doi/10.1111/bpa.12159/full

Methionine is one of the essential amino acids for mammals, a molecule necessary for synthesis of proteins but which our biochemistry cannot manufacture from scratch. Thus we have to obtain methionine from our diets, and without it we will die. But eating less than we might choose to has the opposite effect: the evidence to date strongly suggests that a large fraction of the beneficial effects on health and longevity produced by calorie restriction actually stem from methionine restriction: eat less food overall and you eat less methionine, since comparatively few foodstuffs have low methionine content. The operation of inroads are being made. It is also a great deal more difficult to organize as a lifestyle in comparison to calorie restriction, intermittent fasting, and the like, as the data on methionine levels is comparatively poor and there are few options when it comes to assembling meal plans. Most dietary staples are rich in methionine. If you want to obtain the benefits of an optimal metabolism, the old fashioned way is still best supported by evidence: regular moderate exercise and calorie restriction.

Beyond less food and less methionine there are many ways to manipulate the operation of metabolism in order to modestly slow aging and extend life in laboratory animals such as mice and flies. The most effective at present involve gene therapy to disable growth hormone or its receptor: the longest lived growth hormone receptor knockout (GHRKO) mice are dwarfs with life spans as much as 60-70% longer than their unmodified peers. Unfortunately that isn't likely to translate into extension of human life spans. The small population of mutants with Laron Syndrome have a similarly impacted growth hormone metabolism, and while it is possible that they are more resistant to some common age-related diseases, they don't live markedly longer than the rest of us.

There has been some interest in mixing and matching various means of slowing aging as a way to better identify which of them are just different ways of altering the same root mechanisms. It is probably the case that while there exist dozens of genetic alterations that extend life in laboratory animals, only a few underlying important changes in metabolism actually determine variations in longevity. Cells are machine shops in which everything connects to everything else: evolution produces promiscuous reuse of parts, and any given protein usually has multiple roles to play in quite diverse processes. It is impossible to change anything in isolation in the biochemistry of the cell.

Hence here is an open access paper in which researchers try methionine restriction for long-lived growth hormone mutant mice, and find that the mutants don't benefit from it at all. This strongly implies that whatever is turned on by methionine restriction is already turned on in the growth hormone mutants, and thus these are just different windows onto the same room. Growth hormone disruption is just another way to trigger something that looks like the calorie restriction response. That in turn reinforces the present consensus that both calorie restriction and disruption of growth hormone metabolism are not going to perform miracles for human longevity: we have too many examples in which that is not the case. The evolutionary explanation for calorie restriction is that it is an adaptation to seasonal famine, and thus short-lived animals evolve a much more plastic life span in response to that circumstance. A season is a large fraction of a mouse life span, but not so for humans.

Growth hormone signaling is necessary for lifespan extension by dietary methionine

Growth hormone significantly impacts lifespan in mammals. Mouse longevity is extended when growth hormone (GH) signaling is interrupted but markedly shortened with high-plasma hormone levels. Methionine metabolism is enhanced in growth hormone deficiency, for example, in the Ames dwarf, but suppressed in GH transgenic mice. Methionine intake affects also lifespan, and thus, GH mutant mice and respective wild-type littermates were fed 0.16%, 0.43%, or 1.3% methionine to evaluate the interaction between hormone status and methionine. All wild-type and GH transgenic mice lived longer when fed 0.16% methionine but not when fed higher levels. In contrast, animals without growth hormone signaling due to hormone deficiency or resistance did not respond to altered levels of methionine in terms of lifespan, body weight, or food consumption. Taken together, our results suggest that the presence of growth hormone is necessary to sense dietary methionine changes, thus strongly linking growth and lifespan to amino acid availability.

Ames dwarf and GHRKO mice lived a similar length of time as their wild-type controls when fed the 0.16% MET. Importantly, this finding reflects both a lack of response to low MET by the GH signaling-deficient mice and a significant extension of lifespan by their respective wild-type mice. On higher levels of MET, both the GHRKO and Ames mice outlived (median) their wild-type counterparts by 7-8 and 11-12 months, respectively. Maximal longevity did not differ between GHRKO or Ames mice, regardless of diet.

Here, we show that active GH signaling is necessary for mice to respond to changes in dietary methionine in terms of lifespan, body weight, and food consumption. The survival curves of mice with normal or excess plasma GH levels appeared similar. In contrast, the lifespans of Ames dwarf and GHRKO mice indicate that without GH signaling, the system is unable to detect or sense changes in dietary methionine. Thus, the underlying genotype effects that result in a lack of GH signaling are not apparent when animals consume low MET diets. In cases of either GH or MET deficiency, metabolic reprogramming occurs possibly shifting resources away from growth toward more protective mechanisms, resulting in lifespan extension.

Many of the varied genes and proteins that can be manipulated to extend longevity in lower animals are associated with mitochondrial function, and specifically the pace at which mitochondria generate reactive oxygen species (ROS) in the course of performing the task of generating adenosine_triphosphate, a chemical energy store used to power cellular processes. Cells react to the levels of ROS produced by their mitochondria, such as by dialing up their housekeeping and repair efforts when ROS output increases during exercise. More extended periods of increased cellular housekeeping lead to extended longevity for all the obvious reasons, as damaged molecular machinery and metabolic wastes are given less time to cause further damage.

Thus it isn't too surprising given current knowledge to find links between genes and proteins involved in cellular housekeeping and the behavior of mitochondria, and further between those involved in nutrient sensing and immune system regulation. Researchers interested in the intersection of metabolism and aging are exploring a network of interacting machines and feedback loops, in which every change causes reactions and adaptations elsewhere in the grand collection of machinery we call a cell:

Reactive oxygen species (ROS) have long been thought to cause aging and considered to be toxic byproducts generated during mitochondrial respiration. Surprisingly, recent studies show that modestly increased ROS levels lengthen lifespan, at least in the roundworm Caenorhabditis elegans. It was unclear how the levels of potentially toxic ROS are regulated and how ROS promote longevity. Here we demonstrate that ROS activate two proteins, AMP-activated kinase (AMPK) and hypoxia-inducible factor 1 (HIF-1), to promote longevity by increasing immunity.

Here, we show that a modest increase in ROS increases the immunity and lifespan of C. elegans through feedback regulation by HIF-1 and AMPK. We found that activation of AMPK as well as HIF-1 mediates the longevity response to ROS. We further showed that AMPK reduces internal levels of ROS, whereas HIF-1 amplifies the levels of internal ROS under conditions that increase ROS. Moreover, mitochondrial ROS increase resistance to various pathogenic bacteria, suggesting a possible association between immunity and long lifespan. Thus, balancing ROS at optimal levels appears to be crucial for organismal health and longevity. AMPK and HIF-1 may control immunity and longevity tightly by acting as feedback regulators of ROS.

Link: http://dx.doi.org/10.1073/pnas.1411199111

Mitochondria are the cell's power plants, swarming in bacteria-like herds to create chemical energy stores. They bear their own DNA, distinct from that in the cell nucleus. This mitochondrial DNA can become damaged in aging and some forms of this damage create harmful, malfunctioning mitochondria that overtake their cell and cause it to export damaging reactive compounds into surrounding tissues. One possible cause of this mitochondrial DNA damage is the fact that generating chemical energy stores results in the creation of reactive oxygen species (ROS) as a byproduct. This flux of ROS influences cellular activities in many ways, such as by spurring greater or lesser levels of housekeeping activity, and by causing damage directly through reactions with important molecular machinery.

In past years researchers have demonstrated benefits resulting from the delivery of targeted antioxidant compounds to the mitochondria, with the assumption that they produce benefits by soaking up more of the ROS before they can cause harm. One approach here is to use genetic engineering to increase levels of the natural antioxidant catalase: some studies have shown extension of life in mice via this method, while others have not. The delivery of artificial mitochondrially targeted antioxidants as drugs has been studied more closely, in comparison, and the results there are generally more consistent, showing small effects on life span and enough of a benefit to health for some conditions to make it worth building treatments.

Age-related muscle weakness has major adverse consequences on quality of life, increasing the risk of falls, fractures, and movement impairments. Albeit an increased oxidative state has been shown to contribute to age-dependent reduction in skeletal muscle function, little is known about the mechanisms connecting oxidation and muscle weakness. We show here that genetically enhancing mitochondrial antioxidant activity causes improved skeletal muscle function and voluntary exercise in aged mice.

Here we tested the effects of increased mitochondrial antioxidant activity on age-dependent skeletal muscle dysfunction using transgenic mice with targeted overexpression of the human catalase gene to mitochondria (MCat mice). Aged MCat mice exhibited improved voluntary exercise, increased skeletal muscle specific force and tetanic Ca2+ transients, decreased intracellular Ca2+ leak and increased sarcoplasmic reticulum (SR) Ca2+ load compared with age-matched wild type (WT) littermates.

Overall, these data indicate a direct role for mitochondrial free radicals in promoting the pathological intracellular Ca2+ leak that underlies age-dependent loss of skeletal muscle function. This study harbors implications for the development of novel therapeutic strategies, including mitochondria-targeted antioxidants for treatment of mitochondrial myopathies and other healthspan-limiting disorders.

Link: http://dx.doi.org/10.1073/pnas.1412754111

The practice of calorie restriction, consuming fewer calories while still obtaining optimal levels of dietary micronutrients, has been demonstrated to greatly improve measures of health in humans and slow the progress of near every measure of degenerative aging in numerous species in the laboratory. It extends life by up to 40% or so in mice and similarly in other short-lived species, but the effects on life span in comparatively long-lived primates appears to be more limited. Yet the health benefits and alterations to the operation of metabolism are very similar in mice and primates, providing a puzzle that will keep researchers occupied for some years to come, I expect.

Calorie restriction has been shown to slow the accumulation of DNA damage measured in aging, and evidence suggests that this is due to changes in the very complex array of DNA repair mechanisms hard at work in our cells. Calorie restriction also slows the pace at which senescent cells gather in tissues, and short-term calorie restriction can even modestly reduce the numbers of those cells present in older tissues. Senescent cells are those that have removed themselves from the cell cycle in reaction to damage or signals in the tissue environment associated with risk of damage, such that causes by excess heat and toxins. Some forms of DNA damage such as double-strand breaks can trigger cellular senescence; this process is considered to be an evolutionary adaptation to suppress the risk of cancer arising from just such damaged cells. However there are also harmful consequences, as senescent cells degrade surrounding tissues, spurring their neighbors to also become senescent. The growing presence of these cells directly contributes to many of the degenerative conditions of aging.

The research linked below uncovers a link between low nutrient environments in tissues, such as those created by calorie restriction, and more proficient DNA repair. It is no doubt far from the only contributing mechanism to the benefits of calorie restriction for DNA repair. The response to calorie restriction is enormously complex, touching on near every major area of research into metabolism, and as yet no complete model exists for even the better studied parts of the process:

A Diet for the Cell: Keeping the DNA Fit with Fewer Calories

Cells harbour genetic material in the form of DNA, which contains all the information required for the cell to function. Every time a cell divides this information has to be precisely copied so that the newly made cell receives a perfect replica in order that it, too, can function properly. The inheritance of damaged DNA, however, must be inhibited. In order to recognise altered DNA and prevent it from getting passed on to daughter cells, cells have developed surveillance mechanisms, or checkpoints. Checkpoints stop cells from dividing; thereby allowing more time for the cell to repair damaged genetic material. In some cases, however, the DNA cannot be efficiently repaired even though the checkpoints have been activated. If DNA damage persists for a very long time the cells may eventually turn the checkpoints off without waiting for the DNA to get repaired. This process, referred to as adaptation, may initially seem advantageous to the cell because it can finally grow again. "However, for the whole organism, adaptation is often dangerous, as the unrepaired DNA may lead to diseases such as cancer."

Molecular biologists have found a way to prevent cells from turning off the checkpoint and therefore increase the time available for repair, while at the same time preventing damaged DNA from getting passed to newly made cells. The researchers discovered that the amount of nutrients in the cellular environment is a major factor influencing this process. When cells with DNA damage are exposed to low levels of nutrients, they do not adapt and instead remain fully arrested with an active checkpoint. The same effect was observed when cells with DNA damage were treated with the drug "rapamycin", which inhibits metabolic signalling and therefore mimics nutrient starvation. "The cells that are in low nutrient conditions end up being much more viable, likely because they have waited for the damaged DNA to be repaired before starting to divide again. We believe that high nutrients are pushing cells to grow and proliferate even when the cells should not, e.g. with damaged DNA. Low nutrient conditions likely ensure that cells will only 'risk' dividing when the DNA has been completely repaired."

High Nutrient Levels and TORC1 Activity Reduce Cell Viability following Prolonged Telomere Dysfunction and Cell Cycle Arrest

Cells challenged with DNA damage activate checkpoints to arrest the cell cycle and allow time for repair. Successful repair coupled to subsequent checkpoint inactivation is referred to as recovery. When DNA damage cannot be repaired, a choice between permanent arrest and cycling in the presence of damage (checkpoint adaptation) must be made. While permanent arrest jeopardizes future lineages, continued proliferation is associated with the risk of genome instability.

We demonstrate that nutritional signaling through target of rapamycin complex 1 (TORC1) influences the outcome of this decision. Rapamycin-mediated TORC1 inhibition prevents checkpoint adaptation via both Cdc5 inactivation and autophagy induction. Preventing adaptation results in increased cell viability and hence proliferative potential. In accordance, the ability of rapamycin to increase longevity is dependent upon the DNA damage checkpoint. The crosstalk between TORC1 and the DNA damage checkpoint may have important implications in terms of therapeutic alternatives for diseases associated with genome instability.

Amyloids are formed from handful of types of misfolded proteins that interact to form insoluble deposits in tissues. The presence of amyloid grows with aging, and eventually causes the serious, fatal disruption of tissue function found in the family of amyloidosis conditions. The best approach to dealing with amyloid is to simply remove it, such as by using immune therapies of the sort currently in early stage trials for Alzheimer's disease. These are treatments that aim to use the immune system to break down harmful amyloid aggregates, and success should lead to a general technology platform that can be turned against any form of amyloid.

There is a way to go towards this goal, however, and in the meanwhile the present state of drug-based therapies for various forms of fatal amyloidosis is better than nothing but leaves a lot to be desired. As is still the case for many forms of cancer, the mainstream focus is on improving survival on a scale of adding additional months or a few years to remaining life, and reuse of existing drugs is always the first thing to be tried rather than the development of entirely new technologies:

The outcomes and responses to treatment remain poorly studied among patients with systemic AL amyloidosis who require further treatment following prior novel agent-based therapy. We report here treatment with lenalidomide-dexamethasone in 84 AL amyloidosis patients with relapsed/refractory clonal disease following prior treatment with thalidomide (76%) and/or bortezomib (68%).

On an intention-to-treat (ITT) basis, the overall haematological response rate was 61%, including 20% complete responses. The median overall survival (OS) has not been reached; 2-year OS and progression-free survival (PFS) was 84% and 73%, respectively. Achieving a free light chain (FLC) response was an independent good prognostic factor for OS in multivariate analysis. There was no impact of prior thalidomide or bortezomib therapy on response rate, OS or PFS. 16% achieved an organ response at 6 months, with a marked improvement in organ responses in patients on long term therapy (median duration 11 months) and 55% achieving renal responses by 18 months.

Lenalidomide/dexamethasone therapy achieves good haematological responses in patients with AL amyloidosis with relapsed/refractory clonal disease. The rate of renal responses among patients who received prolonged treatment was unexpectedly high, raising the possibility that immunomodulatory effects of lenalidomide therapy might enhance the otherwise slow natural regression of amyloid deposits.

Link: http://dx.doi.org/10.1111/bjh.12973

Women live longer than men, and while there is no shortage of theories as to why this is the case, the research community has yet to convincingly demonstrate which of them are correct. Adding an additional twist that will need to be explained, these researchers suggest that the size of the mortality rate advantage enjoyed by women diminishes considerably in late old age:

Although increased survival longevity among females is observed throughout much of adult life, supporting evidence among the oldest old is lacking. [Here, we] examine the hypothesis that gender differences in longevity [and] survival diminish with advancing age. The Jerusalem Longitudinal Study follows a representative cohort born 1920-21, comprehensively assessed at ages 70, 78, 85, and 90. Mortality data were collected from 1990-2013. Kaplan-Meier survival curves and Mortality Hazards Ratios were determined, adjusting for gender, marital status, education, loneliness, self-rated health, physical activity, functional status, neoplasm, diabetes mellitus, hypertension, ischemic heart disease.

Survival between ages 70-78 was 77.3%, 78-85 was 68.9%, 85-90 years was 71.1%, and 90-93 years was 80.5%. With advancing age, the survival advantage among females vs. men declined: at ages 70-78 (85.6% vs. 71%), 78-85 (74% vs. 63%), 85-90 (74% vs. 67.5%), and 90-93 (80% vs. 81%). Compared to females, the male mortality adjusted hazard ratio from ages 70-78 was 2.93; ages 78-85 was 2.1; ages 85-90 was 1.6; and ages 90-93 was 1.1. Our findings confirm the hypothesis that the increased longevity observed among females at age 70 gradually diminishes with advancing age, and disappears beyond age 90.

Link: http://dx.doi.org/10.1089/rej.2014.1587

BioWatch News is a market analysis venture focused on biotechnology, especially medical research and development. This is a fairly common business model: find a niche and help to explain it to investors. People with a lot of money at stake in the market will pay a proportionally greater price for good articles and analysis. Biotechnology is a field that is changing so fast and for which the course of the near future is so very unpredictable that there is considerable demand for vision, knowledge, and explanation on the part of those who know more about what is going on than your average fund manager.

Interestingly, investors - even large-scale investors - are the small fry among those people concerned about uncertainty in the future of medical development. The pension, medical insurance, and life insurance industries are far bigger and will destroy themselves if they bet the wrong way on whether or not radical life extension will happen in the decades ahead. The existing trends, if extended, predict only mild life extension, the addition of less than a year of adult life with each passing decade. These trends are based on the medicine of the past, however, and more importantly on an approach to aging and age-related disease that is both inefficient and changing. Up until this decade researchers made little to no effort to tackle the causes of aging directly, while going forward they will be doing exactly that, in numerous different ways. The trend in adult life expectancy will break upwards, a great discontinuity as lifespans suddenly leap due to the implementation of treatments to reverse the few forms of cellular and molecular damage that causes various aspects of degenerative aging.

When will this happen? That depends on how much funding is devoted to SENS-like repair strategies for aging, and how soon that funding arrives. Timelines and amounts are highly uncertain, as repair of the root causes of aging is still a disruptive new approach in its early growth phase. Small choices on the part of funding sources at this stage make a large difference to the future course of development. This sort of uncertainty gives financial managers heartburn, but even those who have never heard of SENS can see the currently riotous degree of debate and change in aging research. It is a field in the slow roil of scientific revolution. That in turn creates reports from professional actuaries that add ever greater uncertainty to future predictions of life expectancy, the all-important numbers upon which the strategy of financial giants turns. Times are changing.

As I'm sure you recall, the SENS Research Foundation recently hosted the Rejuvenation Biotechnology 2014 conference. This was one part of what will be a years-long strategy to build the necessary bridges with industry to ensure a smooth hand-off from laboratory to developer for future repair treatments aimed at the causes of aging. While we'd all like to think that a way to revert atherosclerosis or cut age-related loss of blood vessel and skin elasticity by half would wake the dead and cause funding to fall from the sky like golden rain, in reality it requires considerable organization to transition even an obvious, amazingly effective prototype treatment into a development program for clinical translation. Thus building bridges and making connections is a very necessary part of the future of rejuvenation research.

The BioWatch crew put out a special issue of their magazine for Rejuvenation Biotechnology 2014, in which there are interviews with Jerri Barrett and Aubrey de Grey of the SENS Research Foundation, Adina Mangubat of Spiral Genetics, and noted researcher George Church. There is also a great deal of commentary on where things are going and what needs to be done. You can download the PDF version at the SENS Research Foundation website. This is a 40-page magazine from industry watchers devoted to the concept of founding a rejuvenation biotechnology industry; you should read the whole thing:

BioWatch Complementary SENS Edition (PDF)

In holding RB2014, we hope to create an environment where we might foster cross-fertilization between disease researchers. Why? Because all of these diseases share at least one common causal factor: aging. What we are seeing is that sometimes a treatment designed for one disease of aging will also have a positive effect on another disease of aging. For example, much of the work that has been done in cancer has been adapted and is also being used in the treatment of Alzheimer's disease. This is exciting, and we see it as an opportunity to create an industry that is focused on the development of these treatments.

What makes this conference unique is that it is not just a scientific conference; we're also bringing in economists, regulatory experts, and venture capitalists. Rejuvenation biotechnology is not just business as usual in the biotech arena. These emerging new treatments mean that a lot of how we do business needs to adapt and change as well.

When Aubrey de Grey founded SENS Research Foundation, he had a vision to address the different kinds of cellular damage and how that cellular damage leads to the diseases of aging. Because of this vision, SRF is currently funding research for 18 different projects - three of them here at our headquarters in Mtn. View, and many others at different locations around the world.

Within the walls of SRF, we frequently talk about the fact that nothing can be accomplished in a vacuum. Using the example of Alzheimer's disease, a research team in one part of the world may be focused on one type of damage and making great strides; but unfortunately, without addressing the other two types of damage, they alone will not cure the disease. Let's say, however, that in another part of the world there are two other teams who are addressing the two other types of damage; If you break down silos and create an environment where these three teams can work together, there is a greater possibility of eradicating the disease.

Traditionally, SENS Research Foundation conferences have tended to be very academic and research focused; but we are recognizing that if we are actually going to create forward momentum in facilitating these changes, and bringing actual cures to the public, or to the patient world; then we have to take a step back and look at the much larger picture.

The war on the diseases of the aging is not a third world problem; nor is it confined to one particular country, or one particular race, or one particular gender. The war on the diseases of aging is global; affecting every continent, culture, society, and economy on earth today. Tackling this problem will require a paradigm shift in the usual pharmaceutical method of operation when it comes to bringing therapies to market. We must be willing to break down our silos and learn to collaborate with one another, taking advantage of the wisdom of the global collective of ingenuity, so that true invention and breakthrough can be achieved.

To this end, we give the SENS Rejuvenation Biotechnology Conference (RB2014) a great big around the world and back again, thumbs up. SENS Research Foundation has already stepped out in front to lead the way in breaking down research silos; they have locations all over the world working together, sharing research, collaborating together for true CURES to the diseases of aging. RB2014 is the first conference of its kind to offer further breaking down of silos between other researchers, and breaking down silos between regulatory personnel, investors, other professionals in the industry and even the public. The entire conference has been meticulously planned in the hopes of setting the stage for all of these people to work together and to have a real input into the formation of this emerging market.

Researchers have a found a way to selectively interfere with inflammatory processes in blood vessel walls so as to slow the onset of atherosclerosis:

Normally, the lining of blood vessels, or endothelium [ignores] the many cells and other factors rushing by in the bloodstream. But in response to inflammatory signals, as well as other stimuli, endothelial cells change suddenly and dramatically - sending out beacons to attract inflammatory cells, changing their surface so those cells can stick to and enter tissues, and initiating a complex cascade of responses essential to fighting infection and dealing with injury. Unfortunately, these same endothelial responses also promote atherosclerosis, the build-up of plaque in arteries that cause heart attacks, strokes, and other inflammatory diseases.

A [new study] is the first to demonstrate that BET bromodomain-containing proteins help execute inflammation in the endothelium while inhibition of BET bromodomain can significantly decrease atherosclerosis in vivo. "BET bromodomain-containing proteins have been studied in cancer for some time, where they are in therapeutic trials, but now we have mechanistic evidence for how BETs and their inhibition can impact endothelial inflammation and atherosclerosis."

In preclinical models, the researchers found that activating NF-kB, a canonical mediator of inflammation, rapidly redistributed the BET protein known as BRD4 to chromosomal sites where super enhancers driving expression of nearby inflammatory genes are located. Bromodomains are amino acid regions that bind to specifically modified sites on histones, the proteins around which DNA is coiled. By binding to these amino acid regions, BET bromodomain inhibitors block the assembly of protein complexes that drive expression of certain genes. In these studies, inhibiting BET bromodomains turned off an inflammatory program in human endothelial cells, decreased white blood cells adhering to endothelial cells, and decreased atherosclerosis in mice.

Link: http://news.harvard.edu/gazette/story/2014/09/a-way-to-inhibit-inflammation-of-blood-vessel-linings/

Artificial vision for the blind lies ahead, and this research and development proceeds in competition with regeneration medicine approaches that aim to reverse degeneration and damage in the eye. Some of the most advanced prototype devices presently in use take the approach of linking a camera to an electrode grid embedded in the retina, building a moving picture of glowing dots. But this isn't the only way forward:

Blindness is still one of the most debilitating sensory impairments, affecting close to 40 million people worldwide. Many of these patients can be efficiently treated with surgery or medication, but some pathologies cannot be corrected with existing treatments. In particular, when light-receiving photoreceptor cells degenerate, as is the case in retinitis pigmentosa, or when the optic nerve is damaged as a result of glaucoma or head trauma, no surgery or medicine can restore the lost vision. In such cases, a visual prosthesis may be the only option. Similar to cochlear implants, which stimulate auditory nerve fibers downstream of damaged sensory hair cells to restore hearing, visual prostheses aim to provide patients with visual information by stimulating neurons in the retina, in the optic nerve, or in the brain's visual areas.

In a healthy retina, photoreceptor cells - the rods and cones - convert light into electrical and chemical signals that propagate through the network of retinal neurons down to the ganglion cells, whose axons form the optic nerve and transmit the visual signal to the brain. Prosthetic devices work at different levels downstream from the initial reception and biochemical conversion of incoming light photons by the pigments of photoreceptor rods and cones at the back of the retina. Implants can stimulate the bipolar cells directly downstream of the photoreceptors, for example, or the ganglion cells that form the optic nerve. Alternatively, for pathologies such as glaucoma or head trauma that compromise the optic nerve's ability to link the retina to the visual centers of the brain, prostheses have been designed to stimulate the visual system at the level of the brain itself.

While brain prostheses have yet to be tested in people, clinical results with retinal prostheses are demonstrating that the implants can enable blind patients to locate and recognize objects, orient themselves in an unfamiliar environment, and even perform some reading tasks.

Link: http://www.the-scientist.com/?articles.view/articleNo/41052/title/The-Bionic-Eye/

Steve Aoki is a successful musician, but also, of late at least, an advocate for transhumanist goals for the near future that include rejuvenation research after the SENS model. This scientific paradigm is a path towards radical life extension: not just a mere few years gained, but decades at first and soon thereafter indefinite healthy life spans, as the ability of medical technologies to repair us overtakes the ability of aging to damage us.

Advocacy is not a profession. It isn't something you plan on, go to school for, follow a laid-out career. When it hits you that a particular goal is important enough to talk about, to take the people of the world by the shoulders and shake them - and it still amazes me that the slow and painful death of everyone you know is a non-issue to most people - then you speak to the audience you have and with the tools you have to hand. For my part, I'm a technologist. Whatever I chose to do in life was probably going to involve web sites: it's hard to avoid being swept up by the biggest wave in your field. So here I am, and here you are, reading what I write.

In Aoki's case, there is a much flashier platform and an entirely different audience: electronic music and young club-goers. I think this is a good thing, and I'm encouraged by the existence of individuals who choose to speak about rejuvenation research in ways and to listeners entirely unrelated to whatever I, the online futurist community, the aging research establishment, and others are ever likely come up with. Many approaches means many chances to reach more people, and thus persuade more people to materially support the cause of defeating all age-related disease. That's really all any grand and sweeping change requires: just a little persuasion, and each mention of the subject raises the water level just a little more, leading to a more receptive public. Many quarters of the science fiction community, for example, have for decades forged a path to set down the seeds that later grew into early support for the defeat of aging. All of this has value to my eyes, though of course it is very hard to directly measure the results of any particular instance of a spread of ideas through popular culture. The more that people talk about using medicine to directly tackle aging the better off we all, I say, and if that message is first seen in fiction or music, what does it matter for so long as it still leads some people in the right direction?

An Interview With Steve Aoki

Although Steve Aoki is best known for his shameless EDM anthems and unusual habit of covering his fans with cake, the L.A. DJ is also a cunning label head and enthusiastic techno-futurist. His latest album [is] a 10-song journey into a world when humans merge with technology, live forever and party even harder than they do now. Google engineer and The Age of Spiritual Machines author Ray Kurzweil speaks on the intro and Ending Aging wiz Aubrey de Grey riffs over the New Age closer.

"I started reading books on singularity and the progress of science and technology, and that was all really exciting to me because, being a science-fiction nut growing up and reading comic books. When you start seeing that some of the science-fiction - some of these ideas are actually real trajectories that are going to happen in our lifetime - at least notable writers and people doing research that you trust and respect, then my interest starts lighting up. Then when you start finding information all you want to do is share that information.

"Extending our lives, extending our creativity, opening up the mysteries of the brain. All those things that are really exciting - that's kind of the basis of [the album], and that's why I interviewed Ray Kurzweil and Aubrey de Grey. I'm also doing a companion set [where] I'm interviewing different scientists, authors, writers - interesting people who have written books that have inspired me."

In the years ahead we'll be seeing ever more of this sort of thing as the tipping point of public support for longevity science comes closer. More people are persuaded, more people are thinking on the topic, and ever more of them will work in fields and communities that are very distant from the audiences of today's supporters and advocates.

Many measurable differences in human ability and life course correlate with long-term health, age-related dysfunction, and mortality. Intelligence, social standing, and wealth are some of the more easily measured line items, but the reasons why these things correlate with better health and life expectancy remain to be proven. We can all suggest that more intelligent people will obtain access to and make better use of medical resources, as well as take better care of their general health, but demonstrating that this is in fact the mechanism using data from human populations is a whole different story. The issue is confounded by the fact that intelligence, social standing, and wealth all correlate strongly with one another as well, and there is even some evidence to suggest that greater intelligence and a more robust metabolism might have a biological connection in mechanisms of stress resistance.

On this subject, here is an interesting correlation pulled from historical epidemiological records, showing that young cognitive ability predicts future function of the respiratory system:

Poor pulmonary function is associated with mortality and age-related diseases, and can affect cognitive performance. However, extant longitudinal studies indicate that early cognitive ability also affects later pulmonary function. Despite the multifaceted nature of pulmonary function, most longitudinal studies were limited to a single index of pulmonary function: forced expiratory volume in 1 s (FEV1). In this study, we examined whether early adult cognitive ability predicted five different indices of pulmonary function in mid-life.

Mixed modelling tested the association between young adult general cognitive ability (mean age=20), measured by the Armed Forces Qualification Test (AFQT), and mid-life pulmonary function (mean age=55), in 1019 men from the Vietnam Era Twin Study of Aging. Pulmonary function was indexed by per cent predicted values for forced vital capacity (FVC%p), FEV1%p, maximum forced expiratory flow (FEFmax%p), and maximal voluntary ventilation (MVV%p), and by the ratio of FEV1 to FVC (FEV1/FVC), an index of lung obstruction.

After adjusting for smoking, pulmonary disease, occupation, income and education, age 20 AFQT was significantly associated with mid-life FVC%p, FEV1%p, FEFmax%p, and MVV%p, but was not significantly associated with FEV1/FVC. [Thus], early adult cognitive ability is a predictor of multiple indices of aging-related pulmonary function 35 years later, including lung volume, airflow and ventilator capacity. Cognitive deficits associated with impaired aging-related lung function may, thus, be partly pre-existing. However, results also highlight that early life risk factors may be differentially related to different metrics of later-life pulmonary health.

Link: http://dx.doi.org/10.1136/jech-2014-204143

The recently announced Palo Alto Longevity Prize is split into two parts, with the second to be awarded for a demonstration that restores metabolic homeostasis in an aging mammal to that of a young mammal. The prize administrators picked heart rate variability as the surrogate measure of homeostasis, which is an interesting choice.

Here one of the longevity science advocates from the Russian aging research community suggests that heterochronic parabiosis could be a winning approach for this portion of the prize. This involves linking the circulatory systems of two animals, usually mice, one old and one young. In recent years this has been used to identify some of the changes in circulating proteins that are key to the behavior of stem cells and other aspects of our biology that change with age.

One of the most productive paradigms of aging suppression is based on rejuvenation of blood-borne systemic regulatory factors. Parabiosis, which is characterized by a shared blood supply between two surgically connected animals, may provide such experimental paradigm. We propose to use heterochronic parabiosis, the parabiotic pairing of two animals of different ages, for old mouse rejuvenation. Heterochronic parabiosis also provides an experimental system to identify systemic factors influencing the aging process of the old mouse and promoting its longevity. The probability of the proposed study to demonstrate significant improvement of the heart rate variability marker is extremely high, because parabiosis was already shown to promote functional parameters of the nervous and cardiovascular systems.

The optimum rejuvenation effect of heterochronic parabiosis can be achieved using genetically identical animals. Genetically identical non-model organisms of different age can only be obtained by cloning. Interestingly, that there are no investigations of heterochronic parabiosis of cloned animals. Heterochronic parabiosis experiments indicate that blood-borne signals from a young circulation can significantly impact the function of aging tissues. The implication of these findings is that old tissues might make their function almost as well as young tissues if, by means of systemic influences, the molecular pathways could be 'rejuvenated' from an old state to a young state.

At first we will perform cloning of adult (1-year-old) mice using technique for improved success cloning rate. The parabiosis will be established at the age of 18 months for old partners and 2 month for the young ones. The detailed life span assay will reveal the influence of heterochronic parabiosis with the young clone on cardiovascular, nervous, respiratory, skeletal and muscular systems. The lifespan assay will how the young clone parabiosis impact on longevity of older partner. In addition, systemic factors, which influence the aging process of the old mouse and promote its longevity and rejuvenation, will be revealed.

Link: http://mariakonovalenko.wordpress.com/2014/10/03/how-to-win-the-palo-alto-longevity-prize/

Short term inflammation is a vital part of the immune response, necessary to keep us healthy in the face of life's many slings and arrows. Chronic inflammation is a different story, however, as it is a potent source of damage to tissues and bodily systems over the course of a lifetime. Numerous research groups are focused on developing a better understanding of how and why rising levels of chronic inflammation goes hand in hand with aging and dysfunction of the immune system. They see this as a characteristic process of degenerative aging, and in recent years have taken to calling it inflammaging.

To pick one example of the mechanisms involved in inflammaging, chronic inflammation is one important factor in the correlation between more visceral fat tissue, shorter life expectancy, and higher risk of suffering all of the common age-related diseases. Visceral fat is metabolically active and its interaction with immune cells is unhealthy, causing inflammation. That has meaningful consequences for health and mortality if you happen to carry a lot of fat tissue around with you.

Fat or no fat, the immune system becomes steadily more dysfunctional with age, however. The fat just makes it worse. An aged immune system is less effective at its tasks of defense and elimination of potentially dangerous damaged cells, but also overactive at the same time, fallen into a state of chronic inflammation in its disarray. The recently published research quoted below suggests that increased inflammation is such an important component of this degenerative process that even very crude tools that suppress inflammation can provide benefits. This suggests that more sophisticated approaches may also be worth pursuing even through they would most likely be only stepping stones on the way to real immune rejuvenation. Present means of suppressing age-related chronic inflammation don't address the root causes, the damage and misconfiguration of the aged immune system. Future treatments that tackle root causes should be far more effective.

Making Old Lungs Look New Again

The researchers compared lung cells from old and young mice and found that in the old mice, genes that make three classic pro-inflammatory proteins, called cytokines, were more active in the lungs of old mice. The cytokines are interleukin-1 (IL-1), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-a). In addition, immune system cells called macrophages in the lungs from old mice were in an advanced state of readiness to fight an infection - a status that signals inflammation. Macrophages in young mouse lungs were in a normal, resting state.

In test tubes, the scientists exposed mouse lung macrophages to tuberculosis (TB) bacteria. The macrophages from old mouse lungs were quicker to absorb the bacteria than were immune cells from young mice, but that initial robust immune response from the cells of old mice could not be sustained. "A primed macrophage in an old mouse has lots of receptors on its surface that can bind to TB, taking it up and trying to kill it. But what it lacks is the ability to increase the response further. A resting macrophage in a young mouse takes up TB and then can be activated to do something even more effective at killing the bacteria."

Though some elements of the elderly response to TB remain a mystery, this finding suggested that the inflammation in the lungs of elderly mice had the direct effect of reducing the long-term effectiveness of their immune response to TB infection. The researchers gave old and young mice ibuprofen in their food for two weeks and then examined their lung cells. After this diet modification, several pro-inflammatory cytokines in the lungs of old mice had been reduced to levels identical to those in the lungs of young mice, and the macrophages in old mouse lungs were no longer in a primed state. "There's a trend toward reduced inflammation. Essentially, ibuprofen made the lungs of old mice look young. Putting young mice on ibuprofen had no effect because they had no lung inflammation, which implies the ibuprofen reduced the inflammation and changed the immune response in the old mice."

Characterization of lung inflammation and its impact on macrophage function in aging

Systemic inflammation that occurs with increasing age (inflammaging) is thought to contribute to the increased susceptibility of the elderly to several disease states. The elderly are at significant risk for developing pulmonary disorders and infectious diseases, but the contribution of inflammation in the pulmonary environment has received little attention.

In this study, we demonstrate that the lungs of old mice have elevated levels of proinflammatory cytokines and a resident population of highly activated pulmonary macrophages that are refractory to further activation by IFN-γ. The impact of this inflammatory state on macrophage function was determined in vitro in response to infection with Mycobacterium tuberculosis (M.tb). Macrophages from the lungs of old mice secreted more proinflammatory cytokines in response to M.tb infection than similar cells from young mice and also demonstrated enhanced M.tb uptake and P-L fusion.

Supplementation of mouse chow with the NSAID ibuprofen led to a reversal of lung and macrophage inflammatory signatures. These data indicate that the pulmonary environment becomes inflammatory with increasing age and that this inflammatory environment can be reversed with ibuprofen.

Most of that portion of the aging research community interested in intervening in the aging process to extend healthy life focus on near term drug discovery and reuse. They recognize that the gains here will be small and the process, like all drug development, will be enormously expensive. They are trying to alter the operation of metabolism in order to slow down the pace at which it damages itself, but the ongoing interactions of metabolism and aging form an enormously complex and still poorly understood system. Researchers still don't have a full understanding of the easily replicated and widely studied life extension produced by calorie restriction in most species, for example. Even if drugs can be produced to recapture some of this alteration without meaningful side-effects, that will result in only a small gain in human life span, and it will do little to help the old. What use is a drug to slightly slow down the damage of aging when you are already so damaged as to be near death?

In short, the traditional approach of drug development to alter the operation of our biochemistry is a terrible way forward to extend healthy life. It is an expensive path to a mediocre result, and the research community is doing the worst thing that it could do: aiming very low and digging through drugs that already exist rather than building new technologies. But this is the mainstream today, and that is something that must change. The need for change is why I support disruptive next-generation research programs such as those of the SENS Research Foundation, where the focus is on evading the complexities of metabolism to focus on repair of clearly understood damage. Clean up the damage in the machinery, rather than try to change the whole machine to slow down the pace of damage. It's a much better path forward, and the only one likely to produce actual rejuvenation in the old.

Millions of people are taking anti-ageing drugs every day - they just don't know it. Drugs to slow ageing sound futuristic but they already exist in the form of relatively cheap medicines that have been used for other purposes for decades. Now that their promise is emerging, some scientists have started using them off-label in the hope of extending lifespan - and healthspan. "We are already treating ageing. We have been doing ageing research all along but we didn't know it. We can develop effective combinations for life extension right now using available drugs."

One of the most promising groups of drugs is based on a compound called rapamycin. It was first used to suppress the immune system in organ transplant recipients, then later found to extend lifespan in yeast and worms. In 2009, mice were added to the list. This led to an explosion of research into whether other structurally similar compounds - called rapalogs - might be more potent. Now the first evidence has emerged of one such drug having an apparent anti-ageing effect in humans. A drug called everolimus, used to treat certain cancers, partially reversed the immune deterioration that normally occurs with age in a pilot trial in people over 65 years old.

Other familiar drugs might also fit the bill. Low-dose aspirin and statins are widely taken by healthy people to reduce their risk of heart disease. Both extend lifespan in animals and seem to have anti-inflammatory effects. Inflammation is one of the proposed mechanisms behind ageing, so aspirin and statins could be effective heart drugs in part because they slow ageing.

The fact that common mechanisms seem to be behind the major diseases of ageing, like heart disease, stroke and dementia, is good news, as it suggests we should be able to extend our lifespan while also extending healthspan. Indeed, it would be difficult to imagine an effective longevity agent that worked without alleviating or delaying such conditions. Rapamycin, for instance, has been found to reduce the cognitive decline that accompanies ageing in animals.

Link: http://www.newscientist.com/article/mg22429894.000-everyday-drugs-could-give-extra-years-of-life.html?full=true

Here is a recent article from the SENS Research Foundation, a review of recent work in the broader research community relating to the development of neuroprotective drugs and proteins, ways to help brain cells resist the damage of aging:

The aging brain is characterized by the accumulation of a variety of proteinaceous aggregates, high levels of which constitute the distinctive neuropathological hallmarks and (in the consensus view) the underlying drivers of the neurodegenerative diseases of aging. Removal of these aggregates from the brain is therefore a central damage-repair strategy to prevent and arrest the course of "normal" cognitive aging and its diagnostically-specified extreme manifestations. Happily, this subfield of rejuvenation research has been advanced further toward medical availability than any other, with new strategically-positioned trials of Aβ immunotherapies and of a first-in-class α-synuclein vaccine.

Another pillar of comprehensive neurorejuvenation is cell therapy for the aging brain. However, cell therapy to preserve and restore the neuronal circuitry underlying higher-order cognitive functions in the aging brain is a much more formidable undertaking. Unlike with other major organs such as the heart or kidneys - or even the repair of dopaminergic brain circuitry as exhibited prominently in Parkinson's disease - wholesale replacement of brain functional units is undesirable, due to the structural basis of memory and identity. Thus, a more sophisticated and gradualist approach is required, in which existing circuits are rebuilt and reinforced by ongoing integration of transplanted neurons and precursors, in such a way as to maintaining their existing architecture.

Neuroprotective agents offer a potential stopgap, to hold the therapeutic window open in the period between the availability of aggregate-clearing immunotherapies and the development of neuronal replacement techniques. From first principles, one might anticipate that in a scenario in which therapeutic clearance of some aggregate had been achieved, the most effective neuroprotective agents would be those that target mechanisms of neurodegeneration that are not directly downstream of these aggregates. However, it is also likely that in the earliest iterations of these therapies, their specificity, range of action, therapeutic index, pharmacokinetics, or other properties may limit the scope and magnitude of clearance that can be achieved in a given round of application, so that even agents that allow vulnerable neurons to survive the downstream effects of these aggregates may yet deliver some neuroprotective benefit.

Link: http://www.sens.org/research/research-blog/neuroprotectors-dilemma-potential-neuroprotective-agent-janus-face

It is that time again, and our 2014 matching fundraiser starts today, October 1st 2014. From now until the end of the year, December 31st 2014, we will match the first $50,000 donated to the SENS Research Foundation with $2 for every $1 given. These funds will help to speed progress in ongoing scientific programs conducted in US and European research centers, their ultimate aim being to repair and reverse the causes of frailty and age-related disease.

• Donate directly: http://sens.org/donate

The SENS Research Foundation is a 501(c)(3) charity and all US donations are tax-deductible. Donations from most European Union countries are also tax-deductible, though the details vary by location. Please contact the SENS Research Foundation to find out more.

The Matching Fund Founders Ask You to Join Us

Who are we? We are Christophe and Dominique Cornuejols, David Gobel of the Methuselah Foundation, Dennis Towne, Håkon Karlsen, philanthropist Jason Hope, Michael Achey, Michael Cooper, and Reason of Fight Aging! We are all long-time supporters of SENS research aimed at rejuvenation through repair of the known root causes of aging. The few types of cellular and molecular damage that accumulate in all of our tissues cause progressive dysfunction and eventual death for everyone - unless something is done to stop it. This cause is important enough for everyone to do their part, and for us that means putting up a $100,000 matching fund we want you to help draw down: for every dollar you donate, we will match it with two of our own.

Even Small Donations Make a Meaningful Difference

Early stage medical biotechnology research of the sort carried out at the SENS Research Foundation costs little nowadays in comparison to the recent past. The cost of tools and techniques in biotechnology has plummeted in the past decade, even while capabilities have greatly increased. A graduate student with $20,000 can accomplish in a few months what would have required a full laboratory, years, and tens of millions of dollars in the 1990s. All of the much-lamented great expense in modern medicine lies in clinical translation, the long and drawn out process of trials, retrials, marketing, and manufacturing that is required to bring a laboratory proof of concept into clinics as a widely available therapy.

The SENS Research Foundation is focused on early stage research, following a plan that leads to technology demonstrations in the laboratory. With a proof of concept rejuvenation therapy the world will beat a path to their doorstep in order to fund clinical translation. The real challenge is here and now, raising the funds to get to that step. A few tens of thousands of dollars means the difference between a significant project delayed indefinitely or that project completed.

To pick one example, last year the community raised $20,000 to fund cutting edge work in allotopic expression of mitochondrial genes, a potential cure for the issue of mitochondrial damage in aging. That was enough to have a skilled young researcher work on the process for two of the thirteen genes of interest over a period of months. It really is that cheap given an existing group like the SENS Research Foundation with diverse connections and access to established laboratories.

Your donations make a real difference.

Spread the Word, Tell Your Friends

Don't forget to tell your friends about this fundraiser. Talk to your community, online and offline. Consider running local events to help meet our goal of raising $50,000 from a grassroots community of supporters. The more people who know about the prospects for near future therapies resulting from rejuvenation research of the sort carried out by the SENS Research Foundation, the easier it becomes to raise funds and obtain institutional support for these research programs in the future.

Launched at /r/Futurology and in Conjunction with Longevity Day

Take a look at the generous spirit displayed at /r/Futurology, the futurist Reddit community, when given the chance to help. Scores of people there have already donated modest sums to the cause in response to our fundraiser: many thanks to you all!

The 1st of October marks the launch of this fundraiser, but it is also the International Day of Older Persons, and the International Longevity Alliance would like this to become an official Longevity Day. This year, just like last year, groups of futurists around the world will be holding events to mark the occasion, and this includes the scientists and advocates present at the 2014 Eurosymposium on Healthy Aging.

Download the 2014 Fundraiser Posters

The full size graphics here are large enough for 24 x 36 inch posters, but are also suitable for page-sized fliers. The original Photoshop files are available on request, but are a little large to put up here. Make as much use of these as you like - please help to spread the word and help this fundraiser to meet its target.

Color design, 3600 x 5600 pixels suitable for 24 x 36 inch posters, 11.3MB
Color design, 2400 x 3600 pixels suitable for letter size, 6.3MB

Blue design, 7200 x 10800 pixels suitable for 24 x 36 inch posters, 13.1MB
Blue design, 2400 x 3600 pixels suitable for letter size, 3.8MB

One of the several possible approaches to address the important issue of mitochondrial damage in aging, wherein cells are overtaken by malfunctioning mitochondria and cause harm to surrounding tissues as a result, is some combination of destroying the damaged mitochondria and replacing them with whole new mitochondria infused into the body. Conveniently, it turns out that cells will of their own initiative take up and adopt new mitochondria introduced into the nearby environment. A number of demonstrations of this process have been carried out in recent years, and here is another one:

In eukaryotic cells, mitochondrial dysfunction is associated with a variety of human diseases. Delivery of exogenous functional mitochondria into damaged cells has been proposed as a mechanism of cell transplant and physiological repair for damaged tissue.

We here demonstrated that isolated mitochondria can be transferred into homogeneic and xenogeneic cells by simple co-incubation using genetically labelled mitochondria, and elucidated the mechanism and the effect of direct mitochondrial transfer. Isolated homogeneic mitochondria were transferred into human uterine endometrial gland-derived mesenchymal cells in a dose-dependent manner. Moreover, mitochondrial transfer rescued the mitochondrial respiratory function and improved the cellular viability in mitochondrial DNA-depleted cells and these effects lasted several days.

Finally, we discovered that mitochondrial internalization involves macropinocytosis. In conclusion, these data support direct transfer of exogenous mitochondria as a promising approach for the treatment of various diseases.

Link: http://onlinelibrary.wiley.com/doi/10.1111/jcmm.12316/full

There is primary aging and there is secondary aging. The former is a side-effect of the operation of metabolism, an accumulation of damage about which little is done at present. The latter is the consequence of an unhealthy lifestyle, which at the most obvious end of the spectrum includes the metabolic syndrome and type 2 diabetes caused by becoming sedentary and fat. Over the years numerous studies have shown that some of the declines of aging taken as inevitable are in fact self-inflicted by our own indulgences in this age of comparative leisure and low-cost calories. There is a modest difference to be made here, it is true, but you can't do much about primary aging. That requires new medical technologies capable of repairing the cellular and molecular damage that causes primary aging.

Here researchers demonstrate that the modest difference of a good lifestyle extends to the progression of early stage Alzheimer's disease, which is probably not surprising given the established risk factors for this condition include lack of exercise and being overweight. The methodology employed in this study included mild calorie restriction and exercise, which have been shown to improve pretty much anyone's general health at even advanced ages. Given the size of the effects of those two items demonstrated in past studies of health, I suspect the rest of the regimen is all window dressing. I'd like to see this run again with just the exercise and calorie restriction, and I'd wager the results would be much the same.

Overall this should be taken as a reminder that letting health maintenance slip in later years has a measurable cost, and in an era so close to the development of ways to treat primary aging, every year counts:

In the first, small study of a novel, personalized and comprehensive program to reverse memory loss, nine of 10 participants, including the ones above, displayed subjective or objective improvement in their memories beginning within 3-to-6 months after the program's start. Of the six patients who had to discontinue working or were struggling with their jobs at the time they joined the study, all were able to return to work or continue working with improved performance. Improvements have been sustained, and as of this writing the longest patient follow-up is two and one-half years from initial treatment. These first ten included patients with memory loss associated with Alzheimer's disease (AD), amnestic mild cognitive impairment (aMCI), or subjective cognitive impairment (SCI; when a patient reports cognitive problems). One patient, diagnosed with late stage Alzheimer's, did not improve.

[The] approach is personalized to the patient, based on extensive testing to determine what is affecting the plasticity signaling network of the brain. As one example, in the case of the patient with the demanding job who was forgetting her way home, her therapeutic program consisted of some, but not all of the components involved with [the] therapeutic program, and included:

(1) eliminating all simple carbohydrates, leading to a weight loss of 20 pounds; (2) eliminating gluten and processed food from her diet, with increased vegetables, fruits, and non-farmed fish; (3) to reduce stress, she began yoga; (4) as a second measure to reduce the stress of her job, she began to meditate for 20 minutes twice per day; (5) she took melatonin each night; (6) she increased her sleep from 4-5 hours per night to 7-8 hours per night; (7) she took methylcobalamin each day; (8) she took vitamin D3 each day; (9) fish oil each day; (10) CoQ10 each day; (11) she optimized her oral hygiene using an electric flosser and electric toothbrush; (12) following discussion with her primary care provider, she reinstated hormone replacement therapy that had been discontinued; (13) she fasted for a minimum of 12 hours between dinner and breakfast, and for a minimum of three hours between dinner and bedtime; (14) she exercised for a minimum of 30 minutes, 4-6 days per week.

Link: http://www.buckinstitute.org/buck-news/Memory-loss-associated-with-Alzheimers-reversed