Fight Aging!

Transplants of adult stem cells with the aim of spurring regeneration from injury and age-related dsyfunction have been a going concern for some years now, at first only available through medical tourism. It was that state of affairs that finally pressured US regulators to begin permitting these treatments to take place inside the US. Absent the widespread use of stem cell transplants throughout the rest of the world, I'm sure that the FDA would be requesting more data and more studies still, while forbidding clinical applications of stem cell science. The bureaucrats there exist to put roadblocks in place, as they derive only risk from actually permitting any new treatment to move forward. Only when they are made to look backwards and foolish is there enough of a counterbalancing risk to enable significant movement. As for all entrenched systems of government regulation it is a shameful, squalid, and petty situation: this would be laughable if not for the great harms it causes through ensuring that medical progress is far slower and more expensive than it should be.

In any case, while adult stem cell therapies are a going concern, the same is far from true for the use of embryonic stem cells as a source of cells for therapeutic use. That line of work was quite effectively sabotaged by a combination of politics and inherent difficulty and is only now reaching milestones envisaged a decade ago. Much of the early energy and enthusiasm passed instead to research into cellular reprogramming, such as that involved in the creation of induced pluripotent stem cells that can be used to generate any type of cells on demand.

Nonetheless there are research groups working with human embryonic stem cells as the basis for regenerative medicine. Here is an example of heart cells sourced from embryonic stem cells producing regeneration in primate hearts:

Stem cell therapy regenerates heart muscle in primates

Stem cell therapy can regenerate heart muscle in primates. The scientists on this and related projects are seeking way to repair hearts weakened by myocardial infarctions. This all-too-common type of heart attack blocks a major artery and deprives heart muscle of oxygen.

People who survive a severe episode often continue their lives in poor health because their hearts no longer work properly. The researchers hope eventually to restore such failing hearts to normal function. Their approach uses heart cells created from human embryonic stem cells. The researchers tested the possibility of producing enough of these cardiac muscle cells to remuscularize damaged hearts in a large animal whose heart size and physiology are human-like.

Human embryonic-stem-cell-derived cardiomyocytes regenerate non-human primate hearts

Pluripotent stem cells provide a potential solution to current epidemic rates of heart failure by providing human cardiomyocytes to support heart regeneration. Studies of human embryonic-stem-cell-derived cardiomyocytes (hESC-CMs) in small-animal models have shown favourable effects of this treatment. However, it remains unknown whether clinical-scale hESC-CM transplantation is feasible, safe or can provide sufficient myocardial regeneration.

Here we show that hESC-CMs can be produced at a clinical scale (more than one billion cells per batch) and cryopreserved with good viability. Using a non-human primate model of myocardial ischaemia followed by reperfusion, we show that that cryopreservation and intra-myocardial delivery of one billion hESC-CMs generates extensive remuscularization of the infarcted heart.

In contrast to small-animal models, non-fatal ventricular arrhythmias were observed in hESC-CM-engrafted primates. Thus, hESC-CMs can remuscularize substantial amounts of the infarcted monkey heart. Comparable remuscularization of a human heart should be possible, but potential arrhythmic complications need to be overcome.

The future of cancer treatment will be based upon a wide range of methodologies that selectively target cancer cells to deliver payloads that destroy only those cells. The end result will be highly effective treatments that can eliminate even metastatic cancer with minimal side effects. Here is an example of work in progress:

Biomedical engineers and neurosurgeons report that they have created tiny, biodegradable "nanoparticles" able to carry DNA to brain cancer cells in mice. "In our experiments, our nanoparticles successfully delivered a test gene to brain cancer cells in mice, where it was then turned on. We now have evidence that these tiny Trojan horses will also be able to carry genes that selectively induce death in cancer cells, while leaving healthy cells healthy."

[The researchers produced] tiny, round particles made up of biodegradable plastic whose properties can be optimized for completing various medical missions. By varying the atoms within the plastic, the team can make particles that have different sizes, stabilities and affinities for water or oil. For this study, [they] created dozens of different types of particles and tested their ability to carry and deliver a test sequence of DNA - specifically a gene for a red or green glowing protein. By assessing the survival of the cells that engulf the particles and measuring the levels of red or green light that they emitted, the researchers determined which formulation of particles performed best, then tested that formulation in mice with human brain cancer derived from their patients.

They injected the particles directly into mice with an experimental human brain cancer, and into the brains of healthy mice for use as comparison. Surprisingly, healthy cells rarely produced the glowing proteins, even though the DNA-carrying particles were entering tumor cells and non-tumor cells in similar numbers. "This is exactly what one would want to see, cancer specificity, but we are still researching the mechanism that allows this to occur. We hope our continued experiments will shed light on this so that we can apply what we learn to other scenarios."

The particles can be freeze-dried and stored for at least two years without losing their effectiveness. "Nanoparticles that remain stable for such a long time allow us to make up formulations well in advance and in large batches. This makes them easy to use consistently in experiments and surgeries; we add water to the particles, and they're good to go."

Link: http://www.eurekalert.org/pub_releases/2014-04/jhm-btc042914.php

Researchers hope that continued study of salamanders and other species with exceptional regenerative capabilities will yield results that can inform the development of regenerative treatments for humans:

We have known for hundreds of years that newts and other types of salamanders regenerate limbs. If you cut off a leg or tail, it will grow back within a few weeks. "To our surprise, if you surgically remove part of the heart, (the creature) will regenerate a new heart within just six weeks or so. In fact, you can remove up to half of the heart, and it will still regenerate completely!"

Before the research team dove deeper into this finding, [they] had to determine how a salamander could even live with a partial heart. It turns out that a clot forms at the surgical site, acting much like the cork in a wine bottle, to prevent the amphibian from bleeding to death. What is the cork made of? In part, stem cells. Stem cells have unlimited potential for growth and can develop into cells with a specialized fate or function. Embryonic stem cells, for example, can give rise to all of the cells in the body and, thus, have promising potential for therapeutics.

As it turns out, stem cells play an important role in regeneration in newts. "We discovered that at least some of the stem cells for heart regeneration come from the blood, including the clot." This finding could have exciting implications for therapies in humans with heart damage. By finding the genes responsible for regeneration in the newt, researchers may be able to identify pathways that are similar in newts and people and could be used to induce regeneration in the human heart.

Link: http://www.newswise.com/articles/stem-cells-aid-heart-regeneration-in-salamanders

Cells accumulate all sorts of mutations and other damage, and the damage load rises over the years despite the best efforts of our evolved repair systems. This is the basis of aging: degeneration and disease is driven by damage and reactions to damage.

The research community has cataloged this damage, and can make strong arguments as to what is fundamental and what is a secondary effect. Our biology is enormously complex, however, and so many specific forms of damage and their progression are far from fully understood. The research community doesn't have a solid case for what exactly it is that some forms of amyloid - clumps of misfolded proteins that accumulate with age - are actually doing to cause harm, for example. Many other examples can be found in the specifics of nuclear DNA damage, the innumerably stochastic mutations scattered about the cells of the body. What are all of these different mutations really actually doing, individually and in aggregate? To answer that question comprehensively would involve generations of study with today's technology.

So it shouldn't be terribly surprising to find that comparatively little is known about the consequences of the loss of the Y chromosome in a small proportion of male cells that occurs with aging. Chromosome loss is a form of DNA damage that occurs in both genders, but for the purposes of this post we'll restrict ourselves to considering just the Y chromosome. If you go digging around for articles and papers you'll find that most work on this topic is coming from the cancer research community, and thus don't have a great deal to say on what this might mean outside of the context of cancer tissue and cancer patients, who are not a representative sample of the population at large.

The paper below, however, goes further and shows an association between Y chromosome loss and all-cause mortality in men. This is a starting point, though it doesn't say anything about why this might be the case. The cancer link is evident, as DNA damage is firmly established as a cause of cancer, but the rest is an open question. As for all associations with age-related damage, it is always possible that this is just a case of aging being a global phenomenon in the body. If there is more of any one measured type of damage, then mortality rates will tend to be higher in that population because there is also more of all the other unmeasured forms of damage.

Mosaic loss of chromosome Y in peripheral blood is associated with shorter survival and higher risk of cancer

Incidence and mortality for sex-unspecific cancers are higher among men, a fact that is largely unexplained. Furthermore, age-related loss of chromosome Y (LOY) is frequent in normal hematopoietic cells, but the phenotypic consequences of LOY have been elusive.

From analysis of 1,153 elderly men, we report that LOY in peripheral blood was associated with risks of all-cause mortality (hazards ratio (HR) = 1.91) and non-hematological cancer mortality (HR = 3.62). LOY affected at least 8.2% of the subjects in this cohort, and median survival times among men with LOY were 5.5 years shorter.

Association of LOY with risk of all-cause mortality was validated in an independent cohort (HR = 3.66) in which 20.5% of subjects showed LOY. These results illustrate the impact of post-zygotic mosaicism on disease risk, could explain why males are more frequently affected by cancer and suggest that chromosome Y is important in processes beyond sex determination. LOY in blood could become a predictive biomarker of male carcinogenesis.

Cellular senescence is an important topic in aging: the number of senescent cells increases with age, and they cause harm to surrounding tissues. The research community is on the verge of being able to effectively remove these cells, however, using the tools under development by the cancer research community to target and destroy cancer cells with minimal side effects.

There may also be other ways to deal with senescent cells. The research result below was published earlier this year and makes for an interesting companion piece to a more recently published paper in which researchers showed that a method of growing large numbers of liver cells called hepatocytes via serial transplantation in mice was reversing cellular senescence along the way. Here cancer researchers find that cell transplants into rats have a similar effect, at least for cellular senescence that is artificially induced via introduction of a mild toxin that causes DNA damage and other cellular dysfunction leading to cancer. I would have to see a similar result in old animals with natural levels of cellular senescence before becoming too enthusiastic about this:

Increasing evidence indicates that carcinogenesis is dependent on the tissue context in which it occurs, implying that the latter can be a target for preventive or therapeutic strategies. We tested the possibility that re-normalizing a senescent, neoplastic-prone tissue microenvironment would exert a modulatory effect on the emergence of neoplastic disease.

Rats were exposed to a protocol for the induction of hepatocellular carcinoma (HCC). Using an orthotopic and syngeneic system for cell transplantation, one group of animals was then delivered 8 million normal hepatocytes, via the portal circulation. Hepatocytes transplantation resulted in a prominent decrease in the incidence of both pre-neoplastic and neoplastic lesions.

At the end of 1 year 50% of control animals presented with HCC, while no HCC were observed in the transplanted group. Extensive hepatocyte senescence was induced by the carcinogenic protocol in the host liver; however, senescent cells were largely cleared following infusion of normal hepatocytes. Furthermore, levels of Il-6 increased in rats exposed to the carcinogenic protocol, while they returned to near control values in the group receiving hepatocyte transplantation. These results support the concept that strategies aimed at normalizing a neoplastic-prone tissue landscape can modulate progression of neoplastic disease.

Link: http://www.impactaging.com/papers/v6/n1/full/100631.html

Naked mole rats live up to nine times longer than other similarly sized rodents and are to all appearances immune to cancer. These facts make the species of considerable interest to researchers who study aging: what exactly are the biological mechanisms by which this longevity is achieved? So far it seems that naked mole rats are very resistant to the consequences of high levels of oxidative damage to molecular machinery within cells, and they have exceptionally good maintenance of proteostasis, the ability to keep protein levels stable over time and avoid the buildup of amyloids made up of misfolded proteins. But there is still much to be determined of the mechanisms by which these attributes are managed.

Here is a recent report from researchers involved in these investigations, focusing on cellular quality control mechanisms:

A new study links the naked mole rat's remarkable lifespan to a molecular chaperone protein known as heat shock protein 25 (HSP25). HSP25 and other chaperone proteins act like a tiny quality-control team within an animal's cells, quickly eliminating incorrectly manufactured or damaged proteins before they can cause a problem. Researchers say understanding changes in the actions of HSP25 during aging could shed light on age-related diseases like Alzheimer's and Parkinson's.

The researchers compared HSP25 levels in naked mole rats to levels of the protein found in rodents with different maximum lifespans, from mice (four years) to guinea pigs (12 years) to Damaraland mole rats (20 years) and others in between.

"Using a variety of rodents, we found that the amount of HSP25 present in their tissues positively correlated with the animal's maximum lifespan. If we can understand how HSP25 levels are regulated, what its function is and how it contributes to cell health, we might find ways to use this protein to combat devastating age-related diseases. In animals with higher levels of HSP25, having more of these quality-control proteins means they are primed to react when there is a problem, so they can quickly transport the faulty protein to cellular garbage dumps and maintain the health of the cell."

Link: http://www.newswise.com/articles/naked-mole-rats-and-the-secret-to-longevity

Registration is open for Rejuvenation Biotechnology 2014, which will be held later this year in Santa Clara, California on August 21st. This is hopefully the first of many events to be organized by the SENS Research Foundation in the gap years between the main SENS conferences in the UK, to encourage work on - and enthusiasm for - developing the means to treat and ultimately cure degenerative aging. SENS, the Strategies for Engineered Negligible Senescence, provides a clear research and development plan to build the first versions of treatments capable of repairing the known root causes of aging: various forms of cellular and molecular damage that accumulate with age.

A critical part of the process of establishing any new technology or paradigm - medical or otherwise - is broadening the base of developers as soon as possible. Work must spread beyond the academic research community and into the business research and development community, becoming more attractive to large companies and entrepreneurs alike. Some portions of SENS are presently within striking distance of early commercial products for groups with a long-term view, willing to bet on up to five year development plans to reach a large payoff. Those products would likely not be actual therapies, but rather stepping stone proof of concept technologies that facilitate further development at a lower cost and faster pace.

For example, the SENS Research Foundation currently funds the development of the necessary fundamental technologies for working with glucosepane, the dominant advanced glycation end-product (AGE) in human tissues that causes harm as it accumulates with age. For various historical reasons the biochemistry community has neglected the development of means to work effectively with compounds like glucosepane, and so formalizing and licensing the results of such research forms a product in and of itself, something that will make other developers more able to make progress towards treatments that can break down and remove glucosepane, thus reversing its contribution to age-related degeneration.

The SENS vision and research programs have made more than enough progress within the scientific community for advocates to now also be working on bringing in allies and interested partners from the medical development and pharmaceutical industry. These things progress one step at a time. As is always the case for SENS Research Foundation events, a stellar lineup of leading researchers are scheduled to attend and present at the forthcoming conference:

Rejuvenation Biotechnology Conference 2014

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

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

Confirmed speakers include:

Richard Barker (CASMI)
Maria Blasco (Spanish National Cancer Research Centre)
Judith Campisi (Buck Institute for Research on Aging)
George Church (Harvard and MIT)
Laura Esserman (University of California, San Francisco)
Caleb Finch (USC Davis School of Gerontology)
W. Gray Jerome (Vanderbilt University Medical Center)
Jeffrey Karp (Harvard Medical School)
Jeanne Loring (Scripps Research Institute)
Stephen Minger (GE Healthcare Life Sciences, UK)
Brock Reeve (Harvard Stem Cell Institute)
David Schaffer (Berkeley Stem Cell Center)
Evan Snyder (Sanford/Burnham Medical Research Institute)
Matthias Steger (Hoffmann-La Roche)
Michael West (Biotime, Inc.)

An ambitious form of 3-D printing is envisaged by these researchers: they want to develop the means to print out replacement cartilage tissue in place inside the body by use of minimally invasive techniques such as the introduction of a catheter threaded with the print head machinery that deposits cells and matrix materials:

Osteoarthritis is marked by a gradual disintegration of cartilage, a flexible tissue that provides padding where bones come together in a joint. Artificial cartilage built using a patient's own stem cells could offer enormous therapeutic potential. "Ideally we would like to be able to regenerate this tissue so people can avoid having to get a joint replacement, which is a pretty drastic procedure and is unfortunately something that some patients have to go through multiple times."

Creating artificial cartilage requires three main elements: stem cells, biological factors to make the cells grow into cartilage, and a scaffold to give the tissue its shape. [The] 3-D printing approach achieves all three by extruding thin layers of stem cells embedded in a solution that retains its shape and provides growth factors. The ultimate vision is to give doctors a tool they can thread through a catheter to print new cartilage right where it's needed in the patient's body.

In another significant step, [researchers have] successfully used the 3-D printing method to produce the first "tissue-on-a-chip" replica of the bone-cartilage interface. Housing 96 blocks of living human tissue 4 millimeters across by 8 millimeters deep, the chip could serve as a test-bed for researchers to learn about how osteoarthritis develops and develop new drugs. "With more testing, I think we'll be able to use our platform to simulate osteoarthritis, which would be extremely useful since scientists really know very little about how the disease develops. Osteoarthritis has a severe impact on quality of life, and there is an urgent need to understand the origin of the disease and develop effective treatments. We hope that the methods we're developing will really make a difference, both in the study of the disease and, ultimately, in treatments for people with cartilage degeneration or joint injuries."

Link: http://www.newswise.com/articles/cartilage-made-to-order

Various forms of amyloid build up in tissues with age, forming fibrils and clumps. These are precipitates of misfolded proteins, and while the harm caused by amyloids is not fully understood in all cases they are associated with numerous specific diseases of aging. The amyloid plaques that accompany Alzheimer's disease are perhaps the best known, for example.

It is thought that the oldest people, those who live longer than 110 years of age, are largely felled in end by senile systemic amyloidosis which involves amyloids formed of misfolded transthyretin. There is also a rare genetic disease in which this occurs early in life, called transthyretin-related hereditary amyloidosis or familial amyloidotic polyneuropathy - and as is often the case in such matters research into the rare genetic disease has more funding than research into the common age-related condition. Fortunately any potential treatment involving removal of amyloid is directly applicable to both types of condition.

Transthyretin (TTR) amyloidoses comprise a wide spectrum of acquired and hereditary diseases triggered by extracellular deposition of toxic TTR aggregates in various organs. Despite recent advances regarding the elucidation of the molecular mechanisms underlying TTR misfolding and pathogenic self-assembly, there is still no effective therapy for treatment of these fatal disorders.

Recently, the "molecular tweezers", CLR01, has been reported to inhibit self-assembly and toxicity of different amyloidogenic proteins in vitro, including TTR, by interfering with hydrophobic and electrostatic interactions known to play an important role in the aggregation process. In addition, CLR01 showed therapeutic effects in animal models of Alzheimer's disease and Parkinson's disease. Here, we assessed the ability of CLR01 to modulate TTR misfolding and aggregation in cell culture and in an animal model.

In cell culture assays we found that CLR01 inhibited TTR oligomerization [and] alleviated TTR-induced neurotoxicity by redirecting TTR aggregation into the formation of innocuous assemblies. To determine whether CLR01 was effective in vivo, we tested the compound in mice expressing TTR V30M, a model of familial amyloidotic polyneuropathy, which recapitulates the main pathological features of the human disease. Immunohistochemical and Western blot analyses showed a significant decrease in TTR burden in the gastrointestinal tract and the peripheral nervous system in mice treated with CLR01, with a concomitant reduction in aggregate-induced endoplasmic reticulum stress response, protein oxidation, and apoptosis. Taken together, our preclinical data suggest that CLR01 is a promising lead compound for development of innovative, disease-modifying therapy for TTR amyloidosis.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3996111/

Most of your tissues are in a constant state of flux, the cells within a mix of those destroying themselves after dividing too many times, those dividing to create new cells to make up the numbers, and a smaller flow of fresh cells with many divisions remaining that are created by a small population of stem cells. Some tissues turn over their cell populations very rapidly, such as blood or the lining of the gut. Others consist largely of cells that will last as long as you live, such as much of the central nervous system. In all these cases, however, an embedded population of stem cells supports continued maintenance and function. If stripped of stem cells you would crumble into premature death in perhaps a decade or so.

That said, aging is effectively a process of being stripped of stem cells in addition to all of its other detrimental consequences. The maintenance of tissues diminishes degree by degree with the years until organs and systems fail, eventually fatally. Modern research suggests that, for those tissues where there is good data, the stem cells are still largely present, however. They have simply relinquished their jobs, lapsing into lasting quiescence or senescence in response to rising levels of damage. This set of affairs most likely evolved as a cancer suppression mechanism, our natural life span a balance between risk of death by tissue failure versus risk of death by over-active damaged cells spawning a cancer.

Experiments in moving stem cells between young and old tissue environments suggest that most types of old stem cells examined to date are quite ready to get back to work - and even do their jobs effectively despite their age - if only the signals present in their environment instructed them to do so. It is expected that if one could wave a wand in old humans and restore stem cells in all tissues to youthful activity, the result would be a lot of cancer in addition to improved tissue maintenance, however. Still, temporarily altering specific signals to boost stem cell activity has great potential as a therapy for the near future, with raised risk of cancer compensated for by an increasing effectiveness in cancer detection and treatment. First generation stem cell transplants are in effect a way of making native cells do more than they would otherwise have done by adjusting the balance of signals in the affected tissues. In years ahead more sophisticated methods will be used to achieve better and more controlled results in the same vein.

Ultimately the goal of rejuvenation by repair of cellular and molecular damage will hopefully automatically lead to restoration of stem cell activities. If the damage goes away, so too should the signaling environment that is a response to that damage.

Here is a readable review paper on stem cells present in adult tissues and their relationship to aging. There is a lot of detail packed in there, so take a look at the whole thing:

Adult Stem Cells and Diseases of Aging

Adult stem cells serve to replenish and direct repair at sites of tissue injury throughout the body, and exhaustion of dysfunction of an adult stem cell population in vivo with age results in degenerative disease. Several finely tuned and contextually regulated pathways coordinate the activities of tissue-resident adult stem cell pools over time in response to a host of cellular stressors in an effort to maintain the balance between growth-promoting function and oncogenic resistance. Manipulation of one or more of these pathways has the potential to prevent or reverse the impact of advancing age on adult stem cell function, but is fraught with the difficulty of tipping the balance toward metabolic derangement, or more likely toward cancer formation. Harvest and manipulation of adult stem cells ex vivo for use in regenerative medicine is a piecemeal approach to addressing systemic age-related chronic illnesses, but for now may prove to be a safer approach. In this regard, it is noteworthy that the clinical safety of hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs) has been well documented, not in the least on the basis of decades of successful clinical outcomes of heterologous bone marrow transplantation.

Given the growing evidence that many diseases of aging may reflect adult stem cell exhaustion, it is not surprising there is great interest in restoring adult stem cell function to ameliorate these conditions and regenerate aged tissues. Adoptive transfer of fetal MSCs into adult mice has been shown to extend median lifespan of the animals. Adult stem cell mobilization and transplant are two obvious strategies that have achieved moderate success for certain types of injury and disease in humans, and many types of adult stem cells have been utilized for this purpose. MSC cellular therapy has proven to be safe for a number of vascular disorders and is an attractive option for patients who are poor surgical candidates.

Despite these successes, the problem remains that adult stem cells from elderly donors, the very people who most frequently require enhanced peripheral stem cell function for tissue repair, undergo changes in their functional capacity as a result of aging. This decline in functional capacity, therefore therapeutic utility, has been combatted using some surprisingly simple interventions: Conditioning with hypoxia prior to transplant, for example, has been extensively documented as effective for reducing reactive oxygen species production by adult stem cells and improving their therapeutic efficacy in many in vivo ischemia and other disease models. This has proven sufficient to counteract the impaired oxidative stress resistance of MSCs from elderly donors.

Further development of therapeutic approaches to maintain these cells in vivo requires that the mechanistic basis of their age-related degeneration or renewal be understood. This is an area continually being informed by studies of early-onset aging syndromes and of families exhibiting extreme longevity. Transcriptional reprogramming, which effectively wipes away all signs of age from most cell types, is also yielding valuable insights into what makes a cell young or old. Rejuvenating stem cells to stave off aging safely will require highly innovative approaches, but the results of this research will have far-reaching implications for regenerative medicine.

Researchers here demonstrate that neural stem cells transplanted into aged rats following stroke are an effective enough treatment to be considered, and thus an old tissue environment is not a barrier to deriving benefit from such stem cell transplants:

Neural stem cells (NSCs) show therapeutic potential for ischemia in young-adult animals. However, the effect of aging on NSC therapy is largely unknown. In this work, NSCs were transplanted into aged (24-month-old) and young-adult (3-month-old) rats at 1 day after stroke. Infarct volume and neurobehavioral outcomes were examined. The number of differentiated NSCs was compared in aged and young-adult ischemic rats and angiogenesis and neurogenesis were also determined.

We found that aged rats developed larger infarcts than young-adult rats after ischemia. The neurobehavioral outcome was also worse for aged rats comparing with young-adult rats. Brain infarction and neurologic deficits were attenuated after NSC transplantation in both aged and young-adult rats. The number of survived NSCs in aged rats was similar to that of the young-adult rats and most of them were differentiated into glial fibrillary acidic protein+ (GFAP+) cells. More importantly, angiogenesis and neurogenesis were greatly enhanced in both aged and young-adult rats after transplantation compared with phosphate-buffered saline (PBS) control, accompanied by increased expression of vascular endothelial growth factor (VEGF).

Our results showed that NSC therapy reduced ischemic brain injury, along with increased angiogenesis and neurogenesis in aged rats, suggesting that aging-related microenvironment does not preclude a beneficial response to NSCs transplantation during cerebral ischemia.

Link: http://dx.doi.org/10.1038/jcbfm.2014.61

As researchers continue to work on cellular reprogramming, we will see an increasing number of new research results like this one. A compelling reason for this type of work is to secure low-cost and reliable sources of large numbers patient-matched cells, grown from easily obtained tissue samples such as skin and blood:

[Scientists] have reprogrammed mature blood cells from mice into blood-forming hematopoietic stem cells (HSCs), using a cocktail of eight genetic switches called transcription factors. The reprogrammed cells, which the researchers have dubbed induced HSCs (iHSCs), have the functional hallmarks of HSCs, are able to self-renew like HSCs, and can give rise to all of the cellular components of the blood like HSCs. The findings mark a significant step toward one of the most sought-after goals of regenerative medicine: the ability to produce HSCs suitable for hematopoietic stem cell transplantation (HSCT) from other cell types, in particular more mature or differentiated cells.

The success of any individual patient's HSCT is tied to the number of HSCs available for transplant: the more cells, the more likely the transplant will take hold. However, HSCs are quite rare. "HSCs only comprise about one in every 20,000 cells in the bone marrow. If we could generate autologous HSCs from a patient's other cells, it could be transformative for transplant medicine and for our ability to model diseases of blood development."

In a series of mouse transplantation experiments, [the team found that] Hlf, Runx1t1, Pbx1, Lmo2, Zfp37 and Prdm5, Mycn, and Meis1 were sufficient to robustly reprogram two kinds of blood progenitor cells (pro/pre B cells and common myeloid progenitor cells) into iHSCs. [The] team reprogrammed their source cells by exposing them to viruses containing the genes for all eight factors and a molecular switch that turned the factor genes on in the presence of doxycycline. They then transplanted the exposed cells into recipient mice and activated the genes by giving the mice doxycycline.

The resulting iHSCs were capable of generating the entire blood cell repertoire in the transplanted mice, showing that they had gained the ability to differentiate into all blood lineages. Stem cells collected from those recipients were themselves capable of reconstituting the blood of secondary transplant recipients, proving that the eight-factor cocktail could instill the capacity for self-renewal - a hallmark property of HSCs.

Link: http://www.eurekalert.org/pub_releases/2014-04/bch-srb042214.php

Sepsis is a disastrous runaway failure state of the immune system and metabolism that can occur in the wake of a severe infection. It leads to organ failure and can rapidly kill you even if the infection that caused it is dealt with. Sepsis is more of a looming threat for the old than the young, those with age-damaged immune systems and other frailties. For all this, it isn't something that receives all that much attention in comparison to other common fatal age-related conditions such as heart failure and cancer. With that in mind, here is an open access paper that provides an overview of the present state of knowledge of sepsis, while introducing us to the gloomy situation that exists with regards to treatment options for sepsis in the old:

Sepsis in Old Age: Review of Human and Animal Studies

Sepsis is a serious problem among the geriatric population as its incidence and mortality rates dramatically increase with advanced age. Despite a large number of ongoing clinical and basic research studies, there is currently no effective therapeutic strategy that rescues elderly patients with severe sepsis. Recognition of this problem is relatively low as compared to other age-associated diseases.

Sepsis has been the tenth leading cause of death in patients over the age of 65 in the US since 2001. Older people make up a greater proportion (58-65%) of sepsis patients, and both incidence and mortality rates are significantly greater in the aged. Importantly, in addition to increased mortality rates for the elderly, older sepsis patients die earlier during hospitalization, and those that do survive often require additional care in long-term nursing facilities to regain functional status.

A recent study evaluated long-term mortality in elderly severe sepsis patients (only those surviving at three months post sepsis were included) and found an overall mortality rate of 55% with a 30.6% one-year morality rate and a 43% two-year mortality rate. This means that more than half of the elderly patients who survive sepsis through hospital discharge will be dead within two years.

The authors here suggest that many of the present issues in the sepsis research community - lack of progress towards more effective treatments foremost among them - stem from a poor choice of animal models used in studies.

The incidence of sepsis increases exponentially from childhood to geriatric age with a magnitude of approximately 100-times. Mortality from sepsis also increases progressively with age. The incidence of sepsis is steadily increasing as our population ages. Despite these problems, little is known about the pathophysiology of sepsis which is specific to older patients.

Sepsis patients, in addition to being a heterogeneous population, have large variations in disease course factors including severity, source of infection, comorbidities, and timing of hospital admission. While caution has to be paid for biological differences between men and rodents, the use of laboratory animals is essential for understanding the detailed pathophysiology of sepsis.

Despite the fact that there is clearly an increased precedence of elderly patients suffering from sepsis, the majority of basic research on sepsis has been conducted using young animals. This mismatch introduces a serious disconnect in interpretation of sepsis studies using mice or men because most humans with sepsis are over 50 years old, and most mice used in sepsis research are less than 3 months old, comparable to a person under 20 years of age.

For example, immune responses to infection are clearly altered by aging, thus, the use of aged animals in sepsis research would provide important information that would greatly differ from data obtained using young animals. The number of studies on sepsis using aged animals (i.e. rodents) is surprisingly small. By utilizing the PubMed journal search engine, we estimate that among all published studies using animal models of sepsis, less than 1% used appropriately aged animals.

The paper goes into greater detail as to noteworthy differences in the progression and character of sepsis between young and old individuals, and explains why these differences matter in practice. It's worth reading the whole thing.

Researchers may gain some insight into the aging of stem cells and the relevance (or irrelevance) of nuclear DNA damage to aging from the analysis of blood and tissue donated by a supercentenarian:

Our blood is continually replenished by hematopoietic stem cells that reside in the bone marrow and divide to generate different types of blood cells, including white blood cells. Cell division, however, is error-prone, and more frequently dividing cells, including the blood, are more likely to accumulate genetic mutations. Hundreds of mutations have been found in patients with blood cancers such as acute myeloid leukemia (AML), but it is unclear whether healthy white blood cells also harbor mutations.

In this new study, the authors used whole genome sequencing of white blood cells from a supercentenarian woman to determine if, over a long lifetime, mutations accumulate in healthy white blood cells. The scientists identified over 400 mutations in the white blood cells that were not found in her brain, which rarely undergoes cell division after birth. These mutations, known as somatic mutations because they are not passed on to offspring, appear to be tolerated by the body and do not lead to disease. The mutations reside primarily in non-coding regions of the genome not previously associated with disease, and include sites that are especially mutation-prone such as methylated cytosine DNA bases and solvent-accessible stretches of DNA.

By examining the fraction of the white blood cells containing the mutations, the authors made a major discovery that may hint at the limits of human longevity. "To our great surprise we found that, at the time of her death, the peripheral blood was derived from only two active hematopoietic stem cells (in contrast to an estimated 1,300 simultaneously active stem cells), which were related to each other. Because these blood cells had extremely short telomeres, we speculate that most hematopoietic stem cells may have died from 'stem cell exhaustion,' reaching the upper limit of stem cell divisions." Whether stem cell exhaustion is likely to be a cause of death at extreme ages needs to be determined in future studies.

Link: http://www.eurekalert.org/pub_releases/2014-04/cshl-hog041814.php

This is an intriguing result, though it is worth noting that - per the published paper - it was carried out in animals genetically altered to rapidly develop atherosclerosis. This is a common approach in exploratory studies: use a model in which the disease process runs more rapidly than normal, so as to bring down costs and time, but it opens the possibility for a potential treatment to only undo some of the effects of the model rather than actually working against the normal, much slower disease mechanisms. So the next step in this case is to run the experiment in unmodified laboratory animals and see what happens:

Working with mice and rabbits, [scientists] have found a way to block abnormal cholesterol production, transport and breakdown, successfully preventing the development of atherosclerosis, the main cause of heart attacks and strokes and the number-one cause of death among humans. The condition develops when fat builds inside blood vessels over time and renders them stiff, narrowed and hardened, greatly reducing their ability to feed oxygen-rich blood to the heart muscle and the brain.

[Researchers] identified and halted the action of a single molecular culprit responsible for a range of biological glitches that affect the body's ability to properly use, transport and purge itself of cholesterol - the fatty substance that accumulates inside vessels and fuels heart disease. The offender, the researchers say, is a fat-and-sugar molecule called glycosphingolipid, or GSL, which resides in the membranes of all cells, and is mostly known for regulating cell growth. Results of the experiments, the scientists say, reveal that this very same molecule also regulates the way the body handles cholesterol.

The [team] used an existing man-made compound called D-PDMP to block the synthesis of the GSL molecule, and by doing so, prevented the development of heart disease in mice and rabbits fed a high-fat, cholesterol-laden diet. The findings reveal that D-PDMP appears to work by interfering with a constellation of genetic pathways that regulate fat metabolism on multiple fronts - from the way cells derive and absorb cholesterol from food, to the way cholesterol is transported to tissues and organs and is then broken down by the liver and excreted from the body.

Link: http://www.hopkinsmedicine.org/news/media/releases/johns_hopkins_scientists_alter_fat_metabolism_in_animals_to_prevent_most_common_type_of_heart_disease

Alzheimer's disease is one of the few areas of research into age-related conditions that needs comparatively little assistance at this time: public awareness of the issue of dementia is growing and so is support for greater funding. The research community is already large and energetic, and at least some well-funded groups are working on technologies - such as immune therapies aimed at removal of amyloid deposits - that will probably be of use to other efforts to reverse the causes of aging. This avalanche is well underway.

All that said, it is still a very complex problem as yet comparatively poorly understood, for all that tangible progress is taking place year after year. Much like cancer research, I expect to see Alzheimer's research - already large in comparison to much of the rest of the field of aging research - grow further to consume a great deal of funding, spur the accelerating development of biotechnology, and generate much new knowledge of the intricate relationship between metabolism and aging, as well as the fine details of the operation of the human brain. Below you'll find two fairly representative samples of recent research from the Alzheimer's research community.

Loss of Memory in Alzheimer's Mice Models Reversed through Gene Therapy

[Researchers] have discovered the cellular mechanism involved in memory consolidation and were able to develop a gene therapy which reverses the loss of memory in mice models with initial stages of Alzheimer's disease. The therapy consists in injecting into the hippocampus - a region of the brain essential to memory processing - a gene which causes the production of a protein blocked in patients with Alzheimer's, the "Crtc1" (CREB regulated transcription coactivator-1). The protein restored through gene therapy gives way to the signals needed to activate the genes involved in long-term memory consolidation.

In persons with the disease, the formation of amyloid plaque aggregates, a process known to cause the onset of Alzheimer's disease, prevents the Crtc1 protein from functioning correctly. "When the Crtc1 protein is altered, the genes responsible for the synapses or connections between neurons in the hippocampus cannot be activated and the individual cannot perform memory tasks correctly this study opens up new perspectives on therapeutic prevention and treatment of Alzheimer's disease, given that we have demonstrated that a gene therapy which activates the Crtc1 protein is effective in preventing the loss of memory in lab mice".

A new approach to treating Alzheimer's disease

Cellular processes are not perfect. They, like us, make mistakes. Sometimes, the by-products of those mistakes are harmless. Other times, they can lead to disease or even death. With Alzheimer's disease, the mistake occurs when a protein called neuron's membrane is cut in the wrong place, leading to a buildup of abnormal fragments called amyloid-beta. These fragments clump together to form a plaque around neurons, eventually interfering with brain function.

But the cell has systems to deal with mistakes. A protein complex called retromer acts like a cellular garbage truck, collecting faulty gene products and trafficking them to be destroyed or recycled. For years, Alzheimer's research has focused on preventing the formation of amyloid-beta with little success. But instead of trying to stop mistakes, what if researchers improved the system for dealing with them? A team of researchers [did] just that. They have devised a novel approach to the treatment of Alzheimer's disease that significantly increases retromer levels while decreasing amyloid-beta levels in neurons, without harming the cell.

Pharmacological chaperones stabilize retromer to limit APP processing

Retromer is a multiprotein complex that trafficks cargo out of endosomes. The neuronal retromer traffics the amyloid-precursor protein (APP) away from endosomes, a site where APP is cleaved into pathogenic fragments in Alzheimer's disease. Here we determined whether pharmacological chaperones can enhance retromer stability and function.

First, we relied on the crystal structures of retromer proteins to help identify the 'weak link' of the complex and to complete an in silico screen of small molecules predicted to enhance retromer stability. Among the hits, an in vitro assay identified one molecule that stabilized retromer against thermal denaturation. Second, we turned to cultured hippocampal neurons, showing that this small molecule increases the levels of retromer proteins, shifts APP away from the endosome, and decreases the pathogenic processing of APP.

These findings show that pharmacological chaperones can enhance the function of a multiprotein complex and may have potential therapeutic implications for neurodegenerative diseases.

Autophagy consists of a collection of cellular housecleaning processes responsible for recycling damaged cellular components. It is known to relate to longevity, as demonstrated in numerous animals studies in which aging is slowed via genetic or metabolic manipulation, and in which autophagy is seen to take place more energetically. This all seems logical, as aging is nothing more than an accumulation of unrepaired damage and the reactions to that damage, while autophagy seeks to minimize present damage before it causes more harm.

Since we've already touched on of autophagy and its relationship to longevity today, as well as the prospects for developing therapies based on increased levels of autophagy, I thought I'd point out this popular science article on the topic:

To keep themselves neat, tidy and above all healthy, cells rely on a variety of recycling and trash removal systems. If it weren't for these systems, cells could look like microscopic junkyards - and worse, they might not function properly.

One of the cell's trash processors is called the proteasome. It breaks down proteins, the building blocks and mini-machines that make up many cell parts. The barrel-shaped proteasome disassembles damaged or unwanted proteins, breaking them into bits that the cell can re-use to make new proteins. In this way, the proteasome is just as much a recycling plant as it is a garbage disposal.

Proteins aren't the only type of cellular waste. Cells also have to recycle compartments called organelles when they become old and worn out. For this task, they rely on an organelle called the lysosome, which works like a cellular stomach. Containing acid and several types of digestive enzymes, lysosomes digest unwanted organelles in a process termed autophagy.

While cells mainly use proteasomes and lysosomes, they have a couple of other options for trash disposal. Sometimes they simply hang onto their trash, performing the cellular equivalent of sweeping it under the rug. Scientists propose that the cell may pile all the unwanted proteins together in a glob called an aggregate to keep them from gumming up normal cellular machinery. If the garbage can't be digested by lysosomes, the cell can sometimes spit it out in a process called exocytosis. Once outside the cell, the trash may encounter enzymes that can take it apart, or it may simply form a garbage heap called a plaque. Unfortunately, these plaques outside the cell may be harmful, too.

Further study of the many ways cells take out the trash could lead to new approaches for keeping them healthy and preventing or treating disease.

Link: http://www.newswise.com/articles/how-cells-take-out-the-trash

Autophagy is the name given to a collection of processes that recycle damaged cellular components and unwanted or harmful molecules. Materials flagged for recycling are engulfed by one of the cell's lysosomes and then dismantled inside it. Greater levels of autophagy are observed in a majority of the means of extending life in laboratory animals through genetic or metabolic manipulation to slow aging, including calorie restriction, in which the body reacts to low levels of nutrients, raw materials for protein manufacture in cells, by stepping up its efforts to reclaim the needed raw materials from existing structures that are past their prime.

The association of enhanced longevity and enhanced autophagy shouldn't be a surprise: aging is the accumulation of unrepaired damage, and autophagy is a process that attempts to minimize the present level of cellular damage before it can cause more harm. At some point the research community will make inroads towards creating therapies based on boosted autophagy - though this doesn't appear to be happening anywhere near as rapidly as I expected it to. Here is an example of research into the regulation of autophagy, similar to many other papers published in past years, but the expected use of this sort of knowledge to build a treatment has yet to happen:

The discovery of a gene network regulating lysosomal biogenesis and its transcriptional regulator transcription factor EB (TFEB) revealed that cells monitor lysosomal function and respond to degradation requirements and environmental cues. We report the identification of transcription factor E3 (TFE3) as another regulator of lysosomal homeostasis that induced expression of genes encoding proteins involved in autophagy and lysosomal biogenesis [in] response to starvation and lysosomal stress.

We found that in nutrient-replete cells, TFE3 was recruited to lysosomes through interaction with active Rag guanosine triphosphatases (GTPases) and exhibited mammalian (or mechanistic) target of rapamycin complex 1 (mTORC1)-dependent phosphorylation. Phosphorylated TFE3 was retained in the cytosol through its interaction with the cytosolic chaperone 14-3-3. After starvation, TFE3 rapidly translocated to the nucleus and bound to the CLEAR (Coordinated Lysosomal Expression and Regulation) elements present in the promoter region of many lysosomal genes, thereby inducing lysosomal biogenesis.

Depletion of endogenous TFE3 entirely abolished the response [of] cells to starvation, suggesting that TFE3 plays a critical role in nutrient sensing and regulation of energy metabolism. Furthermore, overexpression of TFE3 triggered lysosomal exocytosis and resulted in efficient cellular clearance in a cellular model of a lysosomal storage disorder, Pompe disease, thus identifying TFE3 as a potential therapeutic target for the treatment of lysosomal disorders.

Link: http://dx.doi.org/10.1126/scisignal.2004754

With advancing age ever more cells in your body enter a state of senescence. They stop dividing and emit signals that both degrade surrounding tissue structures and raise the odds of nearby cells also becoming senescent. This is an adaptation of a mechanism involved in embryonic development that lowers the odds of suffering cancer: senescent cells appear in response to cellular damage in a range of circumstances, and the types of damage that provoke cellular senescence either raise the risk of cancerous cells emerging or accompany a rising risk of cancer in normal aging. So cellular senescence is a part of the balance that evolution has come to in humans between declining ability to function on the one hand and fatal cancer on the other.

The research community, however, is going to become very good at dealing with cancer in the decades ahead. Cellular senescence isn't a great partner for a technologically sophisticated humanity, as the downside in aging very much outweighs whatever good is being done. For my money I think that the first generation of effective treatments that reverse the contribution of cellular senescence to degenerative aging will be blunt efforts that involve the targeted destruction of near-all senescent cells. This targeted destruction in fact goes on all the time in younger years, as one of the jobs of the immune system is to seek out and remove problem cells. Unfortunately like all biological systems it becomes damaged and disarrayed in later life, and alongside the damage that provokes a greater incidence of cellular senescence this is one of the reasons why the body accumulates ever more senescent cells as the years pass. We don't need these senescent cells, they can be removed, and we will benefit from their removal. The technologies used will be very similar to those already in trials for the targeted destruction of cancer cells: immune therapies, nanoparticles, engineered viruses, and so forth.

Later forms of treatment may be more sophisticated, however. Why destroy senescent cells if they can be reprogrammed into a non-senescent state? The field of cellular programming is still in its infancy at this point, and even the most impressive results are half happenstance and incompletely understood in the context of the bigger picture. Researchers throw compounds at cells to see what happens, and out of this assemble theories that inform the next set of efforts to throw compounds at cells to see what happens. Cells are enormously complex mechanisms, but from these efforts will eventually emerge a field in which any cell can be instructed to act as we want it to - even while within the body.

Stem cell treatments are leading to a greater knowledge of the mechanisms by which senescent cells might be coerced back into a more useful and functional state. Just as the delivery of stem cells causes regeneration by changing the local tissue environment and releasing signals that convince native cells to get back to work, it seems that this may also beneficially influence the balance of signals that leads to greater or lesser levels of cellular senescence. This possibility is illustrated in the following research using cell cultures. When researchers cultured and stressed their cell lines in the presence of signals emitted by stem cells, there was measurably less cellular senescence than was the case without those signals:

Rat Induced Pluripotent Stem Cells Protect H9C2 Cells from Cellular Senescence via a Paracrine Mechanism

Cellular senescence may play an important role in the pathology of heart aging. We aimed to explore whether induced pluripotent stem cells (iPSCs) could inhibit cardiac cellular senescence via a paracrine mechanism.

We collected iPSC culture supernatant as conditioned medium (CM) for the rat cardiomyocyte-derived cell line H9C2. Then we treated H9C2 cells, cultured with or without CM, with hypoxia/reoxygenation to induce cellular senescence and measured senescence-associated β-galactosidase (SA-β-gal) activity, G1 cell proportion and expressionM of the cell cycle regulators p16INK4a, p21Waf1/Cip1 and p53 at mRNA and protein levels in H9C2 cells. In addition, we [measured] concentrations of trophic factors in iPSC-derived CM.

We found that iPSC-derived CM reduced SA-β-gal activity, attenuated G1 cell cycle arrest and reduced the expression of p16INK4a, p21Waf1/Cip1 and p53 in H9C2 cells. Furthermore, the CM contained more trophic factors, e.g. tissue inhibitor of metalloproteinase-1 and vascular endothelial growth factor, than H9C2-derived CM.

[We conclude that] paracrine factors released from iPSCs prevent stress-induced senescence of H9C2 cells by inhibiting p53-p21 and p16-pRb pathways. This is the first report demonstrating that antisenescence effects of stem cell therapy may be a novel therapeutic strategy for age-related cardiovascular disease.

Here is a Russian-language interview with Mikhail Batin of the Science for Life Extension Foundation, following on from the recent 3rd International Conference on the Genetics of Aging and Longevity in Sochi, Russia. The state of automated translation for Russian is still very rough around the edges, so the quoted material below is tidied up somewhat from the original:

Q: But with diseases such as cancer, cardiovascular disease, and diabetes, they occur not only in the old, but also in young people. What are your arguments that old age is a disease?

A: Well, the frequency of cancer in a person of age 70 is 200 times higher than at 20 years. All age-dependent disease incidence increases with age, and grows exponentially. Aging underlies these diseases. We just tend to think that it is normal when a person goes bad, developing poor vision, poor hearing, poor thinking - and this is not normal. Aging is an illness and people die because of it.

Q: Actually, people do not want to grow old, especially women. And those who have enough willpower to lead a healthy lifestyle, eat right, play sports. And experience shows that it is, in general, it helps them to get sick less and live longer. So, maybe that's enough? Need there any special measures to combat aging?

A: It helps, but not so much. Even the person leading a healthy lifestyle does not rule out the use of antibiotics, early diagnosis of diseases, etc. Yes, you need to eat less and move more, but that does not mean you cannot also do something significant, for example, to develop the means of reversing some processes of aging not affected by exercise and diet. The idea of ​​sufficiency is bad, let's instead go ahead and set big goals.

Q: And if people don't want to live long? There was a survey of Americans in which they were asked how much they want to live. Most chose a limit of 80-90 years. And to live to 120 years old is only desired by a few. So what to do - "an iron fist pounding mankind to happiness" or work to educate the public in order to change this position?

A: You know, people often want what other people want. This is common. They do not want to stand out from the masses. So people protect the present state of their world, it's such a conquering conservatism. Yet as soon as the radical possibilities to extend life emerge and become common, people will immediately want to use them. People do not refuse technology, they just do not want to think about making it.

Link: http://translate.google.com/translate?sl=ru&u=http://www.gazeta.ru/science/2014/04/03_a_5970617.shtml

One branch of investigation into the mechanisms and progression of aging uses comparisons between species of differing longevity as a way to identify where to work. The ultimate aim is to narrow down the exact biological differences between short-lived and long-lived species, a process that can probably be simplified by focusing first on the exceptional cases.

Surveys and theorizing of the sort quoted below are a part of the process of deciding which of the thousands of readily available species to study are most likely to yield useful information:

Maximum lifespan in birds and mammals varies strongly with body mass such that large species tend to live longer than smaller species. However, many species live far longer than expected given their body mass. This may reflect interspecific variation in extrinsic mortality, as life-history theory predicts investment in long-term survival is under positive selection when extrinsic mortality is reduced. Here, we investigate how multiple ecological and mode-of-life traits that should reduce extrinsic mortality (including volancy (flight capability), activity period, foraging environment and fossoriality), simultaneously influence lifespan across endotherms.

Using novel phylogenetic comparative analyses and to our knowledge, the most species analysed to date (n = 1368), we show that, over and above the effect of body mass, the most important factor enabling longer lifespan is the ability to fly. Within volant species, lifespan depended upon when (day, night, dusk or dawn), but not where (in the air, in trees or on the ground), species are active. However, the opposite was true for non-volant species, where lifespan correlated positively with both arboreality and fossoriality. Our results highlight that when studying the molecular basis behind cellular processes such as those underlying lifespan, it is important to consider the ecological selection pressures that shaped them over evolutionary time.

Those of you following along over the past decade or so as researchers picked out exceptional species in order to investigate the details of their biochemistry will not be too surprised to see flight linked with longevity. Bats and birds feature prominently in the lists of species with unusual longevity for their size, and there are a range of theories as to how the metabolic demands of flight might lead to the evolution of a longer-lived species.

Link: http://dx.doi.org/10.1098/rspb.2014.0298

Every cell in your body is a busy factory, constantly engaged in turning raw materials into complex proteins via the processes of gene expression, following the blueprints in your DNA. The source of much of the necessary supply of raw materials is the cell itself: a great deal of recycling takes place as damaged proteins and larger structures such as organelles are broken down into constituent molecules that are promptly fed back into the factory process.

This recycling isn't just a matter of obtaining parts: it is quality control for cellular machinery vital to life. Autophagy is the name given to the collection of processes by which unwanted and damaged cellular components are identified and then fed into the furnaces known as lysosomes. A lysosome is a specialized organelle packed with enzymes capable of dismantling near everything it is likely to receive in the course of its duties. It engulfs the refuse and destroys it, producing useful raw materials in the process.

With time, however, our lysosomes do in fact ingest a range of items that they cannot deal with. In our long-lived cells, many of which must last a lifetime, lysosomes become bloated and malfunctioning, packed to the gills with harmful materials collectively known as lipofusin. The ability of cells to keep themselves damage-free and functional deteriorates as a consequence, and this is one of the contributing causes of degenerative aging as a whole. It is particularly important in conditions such as macular degeneration, but a long laundry list of other age-related conditions - many of them ultimately fatal - have lysosomal dysfunction and lipofuscin accumulation noted as contributed causes.

We know that this happens, and we know that it causes great harm, but what can be done to prevent it and reverse it? To answer that question, here is the latest in a series of posts on rejuvenation research by philanthropist Jason Hope.

SENS Research Foundation Targets Lysosomal Aggregates

Cells create waste products and, left unaddressed, these byproducts disable body cells to cause serious illnesses. Scientists at SENS Research Foundation Research Center are currently developing ways to remove these waste products, known as lysosomal aggregates, from cells, in order to restore the cells to health and thereby treat these illnesses or prevent their onset. To understand the nature of the scientists' work, it helpful to create a working analogy that makes understanding lysosomal aggregates easier.

Lysosomal aggregates are like non-biodegradable plastic bags and other garbage rising over the tops of landfills to pollute nearby land. Left unaddressed, unhealthy substances from the garbage disrupt the lives of plants and animals surrounding the landfill to the point of causing disease and death to those organisms. The nature of the illness and disease depends largely on the type of waste polluting the landscape. Plastic bags might entangle a bird, for example, or antifreeze may poison a passing coyote. Each toxin causes a specific effect on a particular organism.

Each particular lysosomal aggregate tends to form in a specific type of body cell. When the amount of aggregate is large enough to interfere with normal cell function, the cell can no longer carry out its function, and as more and more cells of a given type become dysfunctional it leads to illness. Age-related macular degeneration, or AMD, is an excellent example of this action. Special cells in the retina of the eye, known as retinal pigment epithelium or RPE cells, produce the waste material A2E. Many scientists think the accumulation of A2E disables RPE cells to cause the vision loss associated with AMD.

The Lysosomal Aggregates team at SENS Research Foundation Research Center is working to identify optimal A2E-degrading enzymes, and to deliver them directly into the lysosomes in the eye. In their previous work, the team had been able to identify many enzymes capable of stopping A2E in a petri dish but was unable to deliver these enzymes into an actual lysosome in an eye. They are working to develop methods to deliver these enzymes to the lysosomes. One procedure in particular, known as SENS20, works both in vitro and in actual RPE cells, but others may work even better.

Lysosomal aggregates [are also] associated with atherosclerosis, commonly known as hardening of the arteries. Oxidation can cause breakdown of the "bad cholesterol" LDL in the bloodstream. This breakdown increases the levels of 7-ketocholesterol, or 7KC, known to cause the narrowed arteries and poor cardiac function associated with atherosclerosis. Researchers from Rice University are working to develop enzymes that reduce 7KC in hopes of reversing the processes that cause atherosclerosis.

SENS Research Foundation is making great strides in reducing the devastating health effects caused by lysosomal aggregates. With continued research, the scientists hope to someday treat or prevent widespread debilitating illnesses like age-related macular degeneration and atherosclerosis.

A web of correlations links health, longevity, wealth, education, and intelligence. More intelligent and educated people tend to be wealthier. They also tend to live longer. All sorts of sensible causes can be proposed, such as those involving better access to medical services and a better ability to make use of that access, or the education, willpower, and peer pressure to make improved lifestyle choices. Don't get fat, keep exercising, and so forth: over the long term calorie restriction and regular exercise produce benefits to health and life expectancy in the average individual that are large in comparison to that provided by any presently available medical technology. There are less usual suggestions as well, such as the possibility of a biological connection between better health and greater intelligence.

Biology and health is very complex, and there is plenty of room to argue cause versus effect and relative impact even in deceptively simple associations such as these. The data showing these associations is robust, however, and here is another example:

[Economists] crunched the numbers and found that the richer you are, the longer you'll live. [They] parsed this data from the University of Michigan's Health and Retirement Study, a survey that tracks the health and work-life of 26,000 Americans as they age and retire. The data is especially valuable as it tracks the same individuals every two years in what's known as a longitudinal study, to see how their lives unfold.

The good news is that men of all incomes are living longer. Yet the data shows that the life expectancy of the wealthy is growing much faster than the life expectancy of the poor. Here's the sort of detail this remarkable data set can show. You can look at a man born in 1940 and see that during the 1980s, the mid-point of his career, his income was in the top 10% for his age group. If that man lives to age 55 he can expect to live an additional 34.9 years, or to the age of 89.9. That's six years longer than a man whose career followed the same arc, but who was born in 1920. For men who were in the poorest 10%, they can expect to live another 24 years, only a year and a half longer than his 1920s counterpart.

The story is rather different for women. At every income level, for both those born in 1920 and 1940, women live longer than men. But for women, the longevity and income trends are even more striking. While the wealthiest women from the 1940s are living longer, the poorest 40% are seeing life expectancy decline from the previous generation. "At the bottom of the distribution, life is not improving rapidly for women anymore. Smoking stands out as a possibility. It's much more common among women at lower income levels."

Link: http://blogs.wsj.com/economics/2014/04/18/the-richer-you-are-the-older-youll-get/

Researchers have developed an improvement upon sutures that has a range of potential applications beyond merely sealing injuries:

The principle is simple: nanoparticles contained in a solution spread out on surfaces to be glued bind to the gel's (or tissue's) molecular network. This phenomenon is called adsorption. At the same time the gel (or tissue) binds the particles together. Accordingly, myriad connections form between the two surfaces. This adhesion process, which involves no chemical reaction, only takes a few seconds. In their latest, newly published study, the researchers used experiments performed on rats to show that this method, applied in vivo, has the potential to revolutionize clinical practice.

In a first experiment, the researchers compared two methods for skin closure in a deep wound: traditional sutures, and the application of the aqueous nanoparticle solution with a brush. The latter is easy to use and closes skin rapidly until it heals completely, without inflammation or necrosis. The resulting scar is almost invisible.

In a second experiment, still on rats, the researchers applied this solution to soft-tissue organs such as the liver, lungs or spleen that are difficult to suture because they tear when the needle passes through them. At present, no glue is sufficiently strong as well as harmless for the organism. Confronted with a deep gash in the liver with severe bleeding, the researchers closed the wound by spreading the aqueous nanoparticle solution and pressing the two edges of the wound together. The bleeding stopped. To repair a sectioned liver lobe, the researchers also used nanoparticles: they glued a film coated with nanoparticles onto the wound, and stopped the bleeding. In both situations, organ function was unaffected and the animals survived.

"Gluing a film to stop leakage" is only one example of the possibilities opened up by adhesion brought by nanoparticles. In an entirely different field, the researchers have succeeded in using nanoparticles to attach a biodegradable membrane used for cardiac cell therapy, and to achieve this despite the substantial mechanical constraints due to its beating. They thus showed that it would be possible to attach various medical devices to organs and tissues for therapeutic, repair or mechanical strengthening purposes.

Link: http://presse-inserm.fr/en/innovative-strategy-to-facilitate-organ-repair/12253/

The future of cell therapies includes regenerative treatments and tissue engineering, as well as many other possibilities, but it all depends on the development of highly efficient, low-cost ways to generate a ready supply of cells of any given type from a patient's own cells, such as a skin sample. The lower the cost the faster that research progresses today, and the establishment of low-cost methods of generating patient-specific cells is very much required to enable widespread use of affordable therapies tomorrow.

A little more than a decade ago it looked like the best way to create these cell supplies was to work on a technique called somatic cell nuclear transfer (SCNT), in which the nucleus from a patient's cell is introduced into an egg cell that has had its nucleus removed. The result recapitulates some of the early development of a blastocyst from which pluripotent cells can be harvested and developed into any type of human cell. Unfortunately this turned out to be more challenging than expected from a technical point of view, and as you may recall there was in addition a great deal of foolish political intervention that made it even harder to move forward. Then not so long afterwards the techniques for generating induced pluripotent stem (IPs) cells by direct reprogramming were discovered and the majority of the research community jumped ship for that much easier methodology.

Some researchers kept working on the roadblocks preventing implementation of SCNT in human cells, however, and have now finally achieved an initial success with adult human cells. This is the sort of result that can lead to the infrastructure necessary to generate patient-specific cells, but in this case it has more of the feel of the closing of a chapter. The leading edge of the research community now works with induced pluripotency and related forms of direct cell reprogramming, and is making rapid progress with those techniques. Success with SCNT is to be praised, but I think unlikely that it will gather much support in the present environment.

First Embryonic Stem Cells Cloned From A Man's Skin

Last year, scientists in Oregon said they'd finally done it, using DNA taken from infants. Robert Lanza, chief scientific officer at Advanced Cell Technology, says that was an important step, but not ideal for medical purposes. "There are many diseases, whether it's diabetes, Alzheimer's or Parkinson's disease, that usually increase with age," Lanza says. So ideally scientists would like to be able to extract DNA from the cells of older people - not just cells from infants - to create therapies for adult diseases.

"What we show for the first time is that you can actually take skin cells, from a middle-aged 35-year-old male, but also from an elderly, 75-year-old male" and use the DNA from those cells in this cloning process, Lanza says. They injected it into 77 human egg cells, and from all those attempts, managed to create two viable cells that contained DNA from one or the other man. Each of those two cells is able to divide indefinitely, "so from a small vial of those cells we could grow up as many cells as we would ever want."

Scientists use cloning to make stem cells matched to two adults

Lanza and his colleagues said their experiments revealed that some eggs were better at it than others. Researchers used 49 eggs from three women, though eggs from only two of them produced results. "The magic is in the egg," Lanza said.

Lanza said that most stem cell scientists have "jumped on the iPS bandwagon," but he argued that stem cells created by SCNT could still play a vital role in regenerative medicine. He envisions a day when multiple lines of stem cells are kept in banks and made available to patients based on their biological similarity, much the way blood and donor organs are now handled. "If we had these banks, we would have the raw material to do tissue engineering and grow up organs, or to grow up vessels, tendons or whatever you want."

Human Somatic Cell Nuclear Transfer Using Adult Cells

Derivation of patient-specific human pluripotent stem cells via somatic cell nuclear transfer (SCNT) has the potential for applications in a range of therapeutic contexts. However, successful SCNT with human cells has proved challenging to achieve, and thus far has only been reported with fetal or infant somatic cells. In this study, we describe the application of a recently developed methodology for the generation of human embryonic stem cells via SCNT using dermal fibroblasts from 35- and 75-year-old males. Our study therefore demonstrates the applicability of SCNT for adult human cells and supports further investigation of SCNT as a strategy for regenerative medicine.

This is an interesting view on the later stages Parkinson's disease that seems fairly orthogonal to the present mainstream focus on α-synuclein and its removal:

The cause of neuronal death in Parkinson's disease is still unknown, but a new study proposes that neurons may be mistaken for foreign invaders and killed by the person's own immune system. "This is a new, and likely controversial, idea in Parkinson's disease; but if true, it could lead to new ways to prevent neuronal death in Parkinson's that resemble treatments for autoimmune diseases."

For decades, neurobiologists have thought that neurons are protected from attacks from the immune system, in part, because they do not display antigens on their cell surfaces. "That idea made sense because, except in rare circumstances, our brains cannot make new neurons to replenish ones killed by the immune system. But, unexpectedly, we found that some types of neurons can display antigens."

Cells display antigens with special proteins called MHCs. Using postmortem brain tissue donated to the Columbia Brain Bank by healthy donors [researchers] first noticed - to their surprise - that MHC-1 proteins were present in two types of neurons. These two types of neurons - one of which is dopamine neurons in a brain region called the substantia nigra - degenerate during Parkinson's disease.

[The researchers] conducted in vitro experiments with mouse neurons and human neurons created from embryonic stem cells. The studies showed that under certain circumstances - including conditions known to occur in Parkinson's - the neurons use MHC-1 to display antigens. Among the different types of neurons tested, the two types affected in Parkinson's were far more responsive than other neurons to signals that triggered antigen display. The researchers then confirmed that T cells recognized and attacked neurons displaying specific antigens.

"Right now, we've showed that certain neurons display antigens and that T cells can recognize these antigens and kill neurons, but we still need to determine whether this is actually happening in people. We need to show that there are certain T cells in Parkinson's patients that can attack their neurons. This idea may explain the final step. We don't know if preventing the death of neurons at this point will leave people with sick cells and no change in their symptoms, or not."

Link: http://newsroom.cumc.columbia.edu/blog/2014/04/17/parkinsons-autoimmune-disease/

Targeted delivery of drugs and proteins to modify metabolism and cell behavior may in the future be accomplished by engineered cells. Cells already do a great many useful things, so why reinvent the wheel when there is existing machinery that can be adapted to new purposes? This is a line of research with the potential to radically change the face of medicine and our own biology, leading to a future in which most of us have large numbers of enhanced and altered cells in every organ, monitoring and reacting to local conditions in order to help maintain the body against the processes of aging and disease far more effectively than our present evolved mechanisms can manage.

A synthetic biology team has created a new technology for modifying human cells to create programmable therapeutics that could travel the body and selectively target cancer and other sites of disease. "The project addressed a key gap in the synthetic biology toolbox. There was no way to engineer cells in a manner that allowed them to sense key pieces of information about their environment, which could indicate whether the engineered cell is in healthy tissue or sitting next to a tumor."

The end result is a protein biosensor that sits on the surface of a cell and can be programmed to sense specific external factors. For example, the engineered cell could detect big, soluble protein molecules that indicate that it's next to a tumor. When the biosensor detects such a factor, it sends a signal into the engineered cell's nucleus to activate a gene expression program, such as the production of tumor-killing proteins or chemicals. Since this toxic program would be activated only near tumor cells, such an approach could minimize side effects as well as improve therapeutic benefits.

Called a Modular Extracellular Sensor Architecture (MESA), the biosensor platform is completely self-contained so that several different biosensors can be present in a single cell without interfering with one another, allowing bioengineers to build increasingly sophisticated functional programs. The platform is also highly modular, enabling the biosensors to be customized to recognize factors of relevance to various patients' needs. "By linking the output of these biosensors to genetic programs, one can build in a certain logical command, such as 'turn the output gene on when you sense this factor but not that factor.' In that way, you could program a cell-based therapy to specify which cells it should kill."

Link: http://www.mccormick.northwestern.edu/news/articles/2014/04/building-smart-cell-based-therapies.html

In these years we stand at the crossroads for human longevity. A long, slow, and largely unintentional upward trend in health and life expectancy has been running for near two hundred years now, caused by increases in wealth and technological progress, each driving the other. Increased longevity in turn helps to increase wealth and speed progress: all of these benefits are individually but facets of the whole gem.

The medical science of the past has blossomed into full-bored biotechnology, and change and growth in this field has become exceptionally rapid over the past twenty years, mirroring progress in computing hardware and software development. Scientists can now individually carry out tasks in a few months that would have required an entire laboratory staff and years of labor in the early 1990s, if it even possible at all back then. Many researchers advocate that now is the time to approach aging as the medical condition it is, to stop treating it with religious awe, as though it were some mystical thing that stands outside of the rest of medicine, and use the tools we have to make it go away.

Some of these researchers are engaged in a form of networked disruptive innovation within aging research that they hope will eventually displace the present mainstream. This is how progress happens in human organizations: the heretics agitate and prove themselves correct via research and development until such time as the old mainstream gives in and agrees that they were right all along.

That is the high road ahead from the crossroads. Upon this road the research community abandons its reluctance to treat aging, the public comes to think of aging in the same way as they presently think of cancer, research funding flows, and great progress is made towards means of halting and reversing the underlying causes of aging. Age-related diseases start to become things of the past, like widespread cholera and tuberculosis, just a few decades past this turning point.

But there are other roads ahead. Disruptive movements don't always win in their first spin around the block. The old guard can last for decades past their time, poisoning the well and ensuring that progress remains slow. Regulation can also suppress new paradigms, and indeed entire fields of human endeavor, for decades at a time - and medical development certain does not lack for obstructive bureaucracy. The treatment of aging is actually forbidden in the US by regulatory fiat, and there is no effective path towards gaining approval for the commercial application of potential therapy to intervene in the causes of aging. This is well known and the chilling effect percolates all the way back up the chain of research and development to create difficulties in fundraising for such goals.

So there are low roads to either side away from the crossroads. These are largely the ruts of status quo and slow progress in which billions of dollars continue to go towards research that increases our knowledge of the details of the molecular dance that is aging, but which can offer no plausible hope or promise of significantly extending life soon enough to matter to us. Life spans continue to edge upward, but we all die just a little older than our parents, and suffer all of the same age-related conditions, just a little less painfully. It is the road on which the study of aging for the sake of knowledge rather than action continues to dominate, and in which the public continues to be largely disinterested in extended healthy life or avoidance of the diseases of aging: marching towards death in their tens of millions, but never raising a hand to do anything about it.

This possibility is why advocacy for the better options in longevity science and human rejuvenation must exist. Without disruptive change in the public perception of aging and medicine for aging, without disruptive change in the attitudes of the scientific community, then the status quo is what we will get - and it will let us die by failing to take full advantage of all that can be done in this age of biotechnology.

The paper quoted below is a joint effort by Jan Vijg and Aubrey de Grey, both scientists who see the potential for big changes to the field in the years ahead and would like to see those changes come about. It isn't open access, unfortunately, but the abstract is a good encapsulation of the crossroads we presently find ourselves at.

Innovating Aging: Promises and Pitfalls on the Road to Life Extension

One of the main benefits of the dramatic technological progress over the last two centuries is the enormous increase in human life expectancy, which has now reached record highs. After conquering most childhood diseases and a fair fraction of the diseases that plague adulthood, medical technology is now mainly preoccupied by age-related disorders. Further progress is dependent on circumventing the traditional medical focus on individual diseases and instead targeting aging as a whole as the ultimate cause of the health problems that affect humankind at old age.

In principle, a major effort to control the gradual accumulation of molecular and cellular damage - considered by many as the ultimate cause of intrinsic aging - may rapidly lead to interventions for regenerating aged and worn-out tissues and organs. While considered impossible by many, there really is no reason to reject this as scientifically implausible. However, as we posit, it is not only scientific progress that is currently a limiting factor, but societal factors that hinder and may ultimately prevent further progress in testing and adopting the many possible interventions to cure aging.

Here is an open access paper that covers some of the challenges that have faced the interpretation of just how and why it is that mitochondria have an important role in the aging process. The mitochondrial free radical theory of aging has been broadly considered, in several forms, but as for just about every theory of aging early models turned out to be too simple and straightforward. The reality on the ground is more complex, which is why you'll find a mass of data that supports this theory and another mass of data that contradicts it:

Since its inception more than four decades ago, the Mitochondrial Free Radical Theory of Aging (MFRTA) has served as a touchstone for research into the biology of aging. The MFRTA suggests that oxidative damage to cellular macromolecules caused by reactive oxygen species (ROS) originating from mitochondria accumulates in cells over an animal's lifespan and eventually leads to the dysfunction and failure that characterizes aging.

A central prediction of the theory is that the ability to ameliorate or slow this process should be associated with a slowed rate of aging and thus increased lifespan. A vast pool of data bearing on this idea has now been published. ROS production, ROS neutralization and macromolecule repair have all been extensively studied in the context of longevity. We review experimental evidence from comparisons between naturally long- or short-lived animal species, from calorie restricted animals, and from genetically modified animals and weigh the strength of results supporting the MFRTA.

Viewed as a whole, the data accumulated from these studies have too often failed to support the theory. Excellent, well controlled studies from the past decade in particular have isolated ROS as an experimental variable and have shown no relationship between its production or neutralization and aging or longevity. Instead, a role for mitochondrial ROS as intracellular messengers involved in the regulation of some basic cellular processes, such as proliferation, differentiation and death, has emerged. If mitochondrial ROS are involved in the aging process, it seems very likely it will be via highly specific and regulated cellular processes and not through indiscriminate oxidative damage to macromolecules.

Link: http://dx.doi.org/10.1186/2046-2395-3-4

A few things are of interest in this survey, with one being that a majority of people don't like specific instances of societal change resulting from technological advances if asked about them, which isn't much of a surprise given human nature. Another is that extended human longevity shows up as a desired goal for a larger minority than has been the case in the past - I would expect to see growth in this number when measured, given the events of the past few years. This being a survey there is little distinction made between the fantastical drawn from science fiction and the plausible drawn from science, which is unfortunate, but it is still worth a look.

The American public anticipates that the coming half-century will be a period of profound scientific change, as inventions that were once confined to the realm of science fiction come into common usage. This is among the main findings of a new national survey by The Pew Research Center, which asked Americans about a wide range of potential scientific developments - from near-term advances like robotics and bioengineering, to more "futuristic" possibilities like teleportation or space colonization.

Asked to describe in their own words the futuristic inventions they themselves would like to own, the public offered three common themes: 1) travel improvements like flying cars and bikes, or even personal space crafts; 2) time travel; and 3) health improvements that extend human longevity or cure major diseases. One in ten Americans (9%) list the ability to travel through time as the futuristic invention they would like to have, and an identical 9% would want something that improved their health, increased their lifespan, or cured major diseases.

At the same time, many Americans seem to feel happy with the technological inventions available to them in the here and now - 11% answered this question by saying that there are no futuristic inventions that they would like to own, or that they are "not interested in futuristic inventions." And 28% weren't sure what sort of futuristic invention they might like to own.

A substantial majority of Americans (81%) believe that within the next 50 years people needing an organ transplant will have new organs custom made for them in a lab. Belief that this development will occur is especially high among men, those under age 50, those who have attended college, and those with relatively high household incomes. But although expectations for this development are especially high within these groups, three-quarters or more of every major demographic group feels that custom organs are likely to become a reality in the next half-century.

Link: http://www.pewinternet.org/2014/04/17/us-views-of-technology-and-the-future/

The research community is very interested in a reliable method of measuring biological age: not how old you are in years, but how far along you are in the aging process, how much damage has accumulated in cells and macromolecules and how well or poorly your organs and other systems are reacting to that damage. Such a measurement of age is known as a biomarker of aging, and while there are all sorts of measures that correlate fairly well with biological age - good enough for large statistical studies to use in order to mine data for meaning - there is not yet a good, accurate, standardized way to run some numbers and use them as a measure of how aged you are.

Why is this important? Principally because it costs an enormous amount of money to assess the ability of any treatment to slow or reverse aspects of aging and thereby extend healthy life. The only way to know at present is to wait and see, and even in mice that means years and millions of dollars. But what if we could be fairly sure that by taking some measurements after a single treatment, researchers could predict with a high degree of accuracy whether or not aging is reversed or slowed and future life span thus extended? If achieved, that would mean ten times as much work on assessment of possible therapies in mice could take place for a given amount of funding. That's a big deal, even without considering that the only practical way to determine whether a putative life-extending treatment actually works or not in humans is to establish an accurate biomarker of aging based on short term, immediate measures. It simply isn't practical to take the wait and see approach for decades.

Personally I rather hope that the arrival of an accepted biomarker of aging will do much to damp down the level of fraud and misinformation that spills forth from the "anti-aging" marketplace. There's always someone trying to sell a lie to the masses, and it is unfortunate that their voices are so very much louder than those of the scientific community. Given that pretty much nothing sold on the market today will move the needle at all on human life span, and nothing is yet shown to even match the benefits of calorie restriction or exercise, I look forward to a way to demonstrate this unequivocally.

In any case, in recent years the measurement of patterns of DNA methylation has shown promise as a potential biomarker of aging. DNA methylation is a part of the process of epigenetic changes that take place in response to circumstances, altering levels of proteins produced by cells. Our biology is essentially an assembly of fluid machines in which the controlling switches and levers are the levels of various proteins in circulation. Everything reacts to everything else, in a complex never resting dance of overlapping feedback loops at every level. From this, however, patterns emerge. Aging takes a broadly similar path for all of us, and thus there are some broadly similar reactions to its damage in our cells. The trick is having enough computational power and the right tools of biotechnology to be able to pull out those patterns from the thousands of unrelated variations in DNA methylation that exist in all our tissues.

This is a popular science piece, but still has some interesting information on how things are going with the DNA methylation approach to generating a biomarker of aging that might prove useful as a measure of the effectiveness of future treatments for aging:

Biomarkers and ageing: The clock-watcher

Horvath's clock emerges from epigenetics, the study of chemical and structural modifications made to the genome that do not alter the DNA sequence but that are passed along as cells divide and can influence how genes are expressed. As cells age, the pattern of epigenetic alterations shifts, and some of the changes seem to mark time. To determine a person's age, Horvath explores data for hundreds of far-flung positions on DNA from a sample of cells and notes how often those positions are methylated - that is, have a methyl group attached.

He has discovered an algorithm, based on the methylation status of a set of these genomic positions, that provides a remarkably accurate age estimate - not of the cells, but of the person the cells inhabit. White blood cells, for example, which may be just a few days or weeks old, will carry the signature of the 50-year-old donor they came from, plus or minus a few years. The same is true for DNA extracted from a cheek swab, the brain, the colon and numerous other organs. This sets the method apart from tests that rely on biomarkers of age that work in only one or two tissues, including the gold-standard dating procedure, aspartic acid racemization, which analyses proteins that are locked away for a lifetime in tooth or bone.

Others began downloading the epigenetic-clock program from Horvath's website to test it on their own data. Marco Boks at the University Medical Centre Utrecht in the Netherlands applied it to blood samples collected from 96 Dutch veterans of the war in Afghanistan aged between 18 and 53. The correlation between predicted and actual ages was 99.7%, with a median error measured in months. At Zymo Research, a biotechnology company in Irvine, California, Wei Guo and Kevin Bryant wondered whether the program would work on a set of urine samples Zymo had collected from 11 men and women aged between 28 and 72. The correlation was 98%, with a standard error of just 2.7 years.

[Researchers] expect that the most interesting use of the clock will be to detect 'age acceleration': discrepancies between a person's epigenetic and chronological ages, either overall or in one particular part of their body. Horvath says that recent work has found that people with HIV who have detectable viral loads appear older, epigenetically, than healthy people or those with HIV who have suppressed the virus. Another study, not yet published, observes that some tissues show significant age acceleration in morbidly obese people.

As noted below researchers are making an effort to establish the basis for a comprehensive study of aging in longer-lived species. Most present work on aging in mammals takes place in mice and rats, and while there are many similarities between mice and humans there are also sometimes unexpected differences in the biochemistry of aging between short-lived and long-lived species. For example that the important types of advanced glycation end-product (AGE), which produce cross-links that accumulate in tissues over a life span to cause damage and dysfunction, turned out to be very different in rodents and humans sabotaged some of the first serious efforts to produce AGE-breaker drugs to slow or reverse this contribution to the aging process.

Scientists aim to bridge the gap between lab research and aging's complexities in real life using the power of dogs. [They] are joining interdisciplinary collaborators from across the country to form the Canine Longevity Consortium - the first research network to study canine aging. It will lay the groundwork for a nationwide Canine Longitudinal Aging Study (CLAS), using dogs as a powerful new model system that researchers can study to find how genetic and environmental factors influence aging and what interventions might mitigate age-related diseases.

"Dogs offer tremendous potential as a model system for human aging. They share many genetic characteristics with humans that let us combine traditional demographic and epidemiological approaches with new techniques like comparative genomics. Unlike any other model system for aging, dogs share our environment and, increasingly, our health care options. Once developed, a canine model holds enormous promise, and we expect it to have a significant impact on aging research."

[Researchers] aim to craft the CLAS to see how an individual dog's aging trajectory is shaped by genes and the environment, gain detailed understanding of when and why dogs die, and find treatments to combat age-related illness. The researchers will start with pilot projects to choose the best breeds for the study and to determine how best to collect, analyze and share the large-scale data it will produce. The team will conduct an epidemiological analysis of genetic and environmental factors influencing canine lifespan, high-resolution mapping of canine longevity, and a yearlong epidemiological analysis of age and cause of death in all dogs seen within a select group of three private veterinary clinics.

Link: http://www.news.cornell.edu/stories/2014/04/aging-research-goes-dogs

Researchers here make use of the process of decellularization to match a donor organ to the recipient. In the ideal procedure, donor cells are removed and the remaining extracellular matrix of the organ is repopulated with the recipient's cells, thereby eliminating most issues of transplant rejection. The use of a donor matrix bypasses the present inability to construct a sufficiently complex scaffold for most tissues, complete with cues and guides for blood vessel formation and other structures within tissue:

A tissue-engineered oesophageal scaffold could be very useful for the treatment of pediatric and adult patients with benign or malignant diseases such as carcinomas, trauma or congenital malformations. Here we decellularize rat oesophagi inside a perfusion bioreactor to create biocompatible biological rat scaffolds that mimic native architecture, resist mechanical stress and induce angiogenesis.

Seeded allogeneic mesenchymal stromal cells spontaneously differentiate (proven by gene-, protein and functional evaluations) into epithelial- and muscle-like cells. The reseeded scaffolds are used to orthotopically replace the entire cervical oesophagus in immunocompetent rats.

All animals survive the 14-day study period, with patent and functional grafts, and gain significantly more weight than sham-operated animals. Explanted grafts show regeneration of all the major cell and tissue components of the oesophagus including functional epithelium, muscle fibres, nerves and vasculature. We consider the presented tissue-engineered oesophageal scaffolds a significant step towards the clinical application of bioengineered oesophagi.

Link: http://dx.doi.org/10.1038/ncomms4562

SENS, the Strategies for Engineered Negligible Senescence is a detailed research plan for developing the means to prevent and reverse degenerative aging by repairing its causes. SENS assembles the list of causes from the present scientific consensus on fundamental differences between old and young tissues, differences that are not known to be caused by any lower-level process. The potential repair therapies are also assembled from the best and latest of research strategies in a range of fields: stem cell therapies, targeted cell destruction, engineered enzymes to break down unwanted biomolecules, immune therapies, and so forth. SENS as a program is shepherded by the SENS Research Foundation but has growing support in the broader scientific community, and far from every last relevant research program is actually initiated by, funded by, or even known to the Foundation.

Robust mouse rejuvenation (RMR) has been the first long term milestone for SENS since its proposal and initial development by Aubrey de Grey. No new technology arrives fully formed, and it is understood that the first versions will be flaky, expensive, and generally much less effective than the later refinements. But in the case of rejuvenation treatments, this may not matter all that much, as even a somewhat effective form of rejuvenation provides the patient more time in which to wait on those refinements - or perhaps even assist in their development. So robust mouse rejuvenation as originally outlined means a full enough implementation of SENS to be capable of doubling the remaining life expectancy of an elderly mouse, demonstrated and then replicated in rigorous laboratory studies. It doesn't mean an absolutely complete implementation, and it doesn't mean full and absolute rejuvenation: it is a first pass to demonstrate greater benefits than any other approach to date.

It is important to note that when I talk about implementation of SENS in the laboratory, I am almost always talking about robust mouse rejuvenation. I do not mean clinical translation of this result, and neither do I mean a complete and fully effective suite of rejuvenation treatments. The path from robust mouse rejuvenation to the clinic might be decades long in the highly regulated US and Europe, but first generation SENS treatments will hopefully jump into clinics in other parts of the world just as rapidly as did first generation stem cell therapies. Medical tourism is a wonderful thing, and will probably one day save your life.

SENS is presently divided into seven general categories of damage that cause aging, each of which seems largely independent from one another and requires a very different approach to repair: a whole different line of research, no doubt running in different labs and organized by different research groups. We may see the seven categories split further in the years ahead if any of the subcategories prove to be either much harder or more important to aging than is presently assumed. For example, if I were writing SENS from scratch I might put immune system aging in its own bucket rather than lumping it under the general category of death-resistant cells. But that's just my view.

It is presently thought that each category of age-related damage in SENS is enough to kill you in roughly a human life span or a little longer even if all of the others are defeated. This may or many not turn out to be the case, but the evidence for this viewpoint is compelling, as each of the SENS categories of damage has at least one fatal age-related condition associated with it, and for which it is the primary known driver. This is in fact how these forms of damage were first categorized and investigated by the research community, as researchers work backwards from the visible and deadly consequences of aging in search of the mechanisms by which they unfold. The assumption that all aspects of SENS must be at least partially addressed in order to prevent aging and extend healthy life is why robust mouse rejuvenation is marked as a goal: get every category of repair treatment in the SENS portfolio working to at least the level of a proof of concept.

How long remains between now and the implementation of robust mouse rejuvenation? Ah well, there's the rub. How long is a piece of string? It is very hard to predict timelines for research when funding is at a low ebb, even research like SENS wherein it is fairly clear as to what the researchers should be working on, which lines of work are most promising, and where the end goals lie. If there was a good level of funding for SENS, say at the level of $100 million a year, then we could fall back to planning estimates of a decade or so to get to robust mouse regeneration. We could do that because with that much money there can be many irons in the fire, and the law of averages begins to smooth out random chance: some projects fail, some do very well and come in early, surprise advances sometimes happen, and some projects take far longer than they were expected to. When there is comparatively little funding then progress in research is uncertain, and I would be surprised to learn that there was more than about $10 million devoted to directly SENS-related work outside the stem cell and cancer research communities this year given that the SENS Research Foundation's yearly budget is around $5 million at the moment.

The glass half full way of looking at this is to see that people like you and I can make a large difference to the level of funding just through ordinary fundraisers, like those that raised $20,000 and $60,000 for SENS research projects last year.

But I think it is worth bearing in mind that robust mouse rejuvenation is not a coordinated single point in time at which all parts of SENS will suddenly become available at once. Different areas of SENS research stand at very different stages of readiness and progress, and some will clearly be done first, and perhaps considerably in advance of the others. The best candidates at this point for early success are, I think, breaking of glucosepane cross-links and mitochondrial repair of some form. If a method of breaking down the predominant form of cross-links in human tissues is demonstrated to produce benefits, will the world sit around waiting for robust mouse rejuvenation in order to develop it? Of course not. In fact, I'd wager that robust mouse rejuvenation will probably be contemporary with medical tourism for first generation treatments based on the more easily developed parts of the SENS rejuvenation toolkit.

You may still get nailed by one of the other forms of age-related damage on roughly the same time scale as a normal human life span, but it is hard to argue that you will not find improvements to health and function through repair of only one or two forms of age-related damage. If you can undergo a treatment to remove glucosepane cross-links to improve function of skin and blood vessels, then I'd argue that your life is better as a result even though all of the other forms of damage are gnawing away at your health in their own ways. Robust mouse rejuvenation is an aspirational goal, but it isn't a dividing line. Results will be more piecemeal and staggered, and any result with significant merit will probably be rapidly developed as a treatment in less regulated parts of the world. Until research funding for SENS and SENS-like research grows greatly, the pace of progress towards rejuvenation will remain variable and uncertain.

It is perhaps unexpected that incidence of dementia and incidence of cancer seem to have a robust inverse relationship, one that has shown up in multiple different study populations. In general we think of aging as a global phenomenon in the body keyed to rising levels of damage in all tissues: if you are farther down the road than your peers for whatever reason then you would expect a higher risk of all of the potential failure modes in the complex systems of your body.

In one sense, yes, this is true. But in some people risk of cancer rises significantly more rapidly than risk of dementia, and in others vice versa. As this study shows the differentiation in risk starts early in the progression of age-related cognitive decline:

Older people who are starting to have memory and thinking problems, but do not yet have dementia may have a lower risk of dying from cancer than people who have no memory and thinking problems. "Studies have shown that people with Alzheimer's disease are less likely to develop cancer, but we don't know the reason for that link. One possibility is that cancer is underdiagnosed in people with dementia, possibly because they are less likely to mention their symptoms or caregivers and doctors are focused on the problems caused by dementia. The current study helps us discount that theory."

The study involved 2,627 people age 65 and older in Spain who did not have dementia at the start of the study. They took tests of memory and thinking skills at the start of the study and again three years later, and were followed for an average of almost 13 years. The participants were divided into three groups: those whose scores on the thinking tests were declining the fastest, those whose scores improved on the tests, and those in the middle.

During the study, 1,003 of the participants died, including 339 deaths, or 34 percent, among those with the fastest decline in thinking skills and 664 deaths, or 66 percent, among those in the other two groups. A total of 21 percent of those in the group with the fastest decline died of cancer, according to their death certificates, compared to 29 percent of those in the other two groups. People in the fastest declining group were still 30 percent less likely to die of cancer when the results were adjusted to control for factors such as smoking, diabetes and heart disease, among others.

Link: http://www.eurekalert.org/pub_releases/2014-04/aaon-opw040314.php

Here is an open access review that looks at what is known of the proximate mechanisms that cause increasing fragility of bone with advancing age. These are not the root causes, but it remains to be determined how exactly the laundry list of primary differences between old tissues and young tissues produces the results discussed below. Arguably it is faster and more efficient to investigate by doing; work to reverse these primary changes in tissue samples and animals and see what happens. That is a lot easier than trying to understand the full scope of the complexity of aging, and has a much greater chance of producing meaningful therapies to halt the advance of aging in the near term:

Every hip fracture begins with a microscopic crack, which enlarges explosively over microseconds. Most hip fractures in the elderly occur on falling from standing height, usually sideways or backwards. The typically moderate level of trauma very rarely causes fracture in younger people. Here, this paradox is traced to the decline of multiple protective mechanisms at many length scales from nanometres to that of the whole femur.

With normal ageing, the femoral neck asymmetrically and progressively loses bone tissue precisely where the cortex is already thinnest and is also compressed in a sideways fall. At the microscopic scale of the basic remodelling unit (BMU) that renews bone tissue, increased numbers of actively remodelling BMUs associated with the reduced mechanical loading in a typically inactive old age augments the numbers of mechanical flaws in the structure potentially capable of initiating cracking.

Menopause and over-deep osteoclastic resorption are associated with incomplete BMU refilling leading to excessive porosity, cortical thinning and disconnection of trabeculae. In the femoral cortex, replacement of damaged bone or bone containing dead osteocytes is inefficient, impeding the homeostatic mechanisms that match strength to habitual mechanical usage. In consequence the participation of healthy osteocytes in crack-impeding mechanisms is impaired.

Observational studies demonstrate that protective crack deflection in the elderly is reduced. At the most microscopic levels attention now centres on the role of tissue ageing, which may alter the relationship between mineral and matrix that optimises the inhibition of crack progression and on the role of osteocyte ageing and death that impedes tissue maintenance and repair.

Link: http://www.thebonejournal.com/article/S8756-3282(14)00002-7/fulltext

A number of competing lines of research aim at producing large volumes of blood to order, with an eye to eventually eliminating the need for blood donors and all of the shortcomings inherent in donated blood - the need for screening and other expenses in the donation process, the short shelf-life of blood outside the body, and so forth. Firstly there is the approach of creating synthetic blood substitutes, which will be most likely restricted to short-term use in trauma cases for the near future as the intent is to provide the critical function of oxygen transport and little else. Then there are the varied efforts to grow blood from stem cells, some of which are coming closer to clinical trials, an initial step on the way to commercialization. A decade from now blood factories will be established in much the same way as skin factories are a going concern at present: there will likely be some mix of generic blood types produced in bulk from known lineages alongside the ability to create blood to order from a specific patient's cells.

A few years back the researchers involved in the work quoted below estimated that blood derived from stem cells would be in trials by now. They are presently looking at starting small trials in 2016 at the earliest, which perhaps illustrates why scientists are usually cautious about putting timelines on the table, especially in an environment of heavy government regulation, where new delays and new expenses are ever on the menu.

First volunteers to receive blood cultured from stem cells in 2016

The consortium will be using pluripotent stem cells, which are able to form any other cell in the body. The team will guide these cells in the lab to multiply and become fresh red blood cells for use in humans, with the hope of making the process scalable for manufacture on a commercial scale. The team hopes to start the first-in-man trial by late 2016.

Blood transfusions play a critical role in current clinical practice, with over 90m red blood cell transfusions taking place each year worldwide. Transfusions are currently made possible by blood donation programmes, but supplies are insufficient in many countries globally. Blood donations also bring a range of challenges with them, including the risk of transmitting infections, the potential for incompatibility with the recipient's immune system and the possibility of iron overload. The use of cultured red blood cells in transfusions could avoid these risks and provide fresh, younger cells that may have a clinical advantage by surviving longer and performing better.

Professor Marc Turner, Principal Investigator, said: "Producing a cellular therapy which is of the scale, quality and safety required for human clinical trials is a very significant challenge, but if we can achieve success with this first-in-man clinical study it will be an important step forward to enable populations all over the world to benefit from blood transfusions. These developments will also provide information of value to other researchers working on the development of cellular therapies."

Artificial blood 'will be manufactured in factories'

Prof Turner has devised a technique to culture red blood cells from induced pluripotent stem (iPS) cells - cells that have been taken from humans and 'rewound' into stem cells. Biochemical conditions similar to those in the human body are then recreated to induce the iPS cells to mature into red blood cells - of the rare universal blood type O.

There are plans in place for the trial to be concluded by late 2016 or early 2017, he said. It will most likely involve the treatment of three patients with Thalassaemia, a blood disorder requiring regular transfusions. The behaviour of the manufactured blood cells will then be monitored.

This sort of pace of development will likely be beaten to the end goal of commercial blood manufacture by less constrained and more ambitious commercial development in East Asia, I'd imagine. That has been the pattern so far in the development of applied stem cell technologies, at least.

Adults are old, but children are young: at some point in the early development of an embryo, a collection of presently poorly cataloged processes erase the changes of aging present in the adult cells that created it. It is probably the case that there is little in this that can be applied directly to making us live longer, as the sort of radical restructuring of cells that takes place in the developing embryo would be fatal to the much more complex adult organism. We couldn't apply this to ourselves for all the same reasons that we can't constantly renew ourselves like the tiny creatures called hydra. Our nervous system, mind, and other complex and finely balanced processes depend on the present detailed structure of our long-lived cells, and that structure would be erased.

However, as the authors of this paper point out, there is potentially much to be learned from the embryo that could be of benefit for stem cell treatments. In this case the research community absolutely wants to be able to reverse the damage of aging in induced pluripotent stem cells (IPSCs) generated from an old patient. To a certain extent this already happens, but greater control and effectiveness is desired:

Stem cells are defined not only by their differentiation potential but also by their capacity for unlimited self-replication. The need for prolonged self-replication requires adequate telomere length and telomere maintenance, which can limit the powerful new methods available for generating induced pluripotent cells. IPSCs lacking sufficient telomere length fail to [pass] the most stringent tests of pluripotency, and cannot be maintained in culture over long periods. This might have contributed, in part, to the variable quality of iPSCs during early efforts [and] may ultimately limit the future application of iPSCs in regenerative medicine. To correct this, present efforts in the field of iPSCs have strived to improve the quality of iPSC generated by focusing on telomere dynamics during the process of reprogramming.

Telomeres protect and cap linear chromosome ends, yet these genomic buffers erode over an organism's lifespan. Short telomeres have been associated with many age-related conditions in humans, and genetic mutations resulting in short telomeres in humans manifest as syndromes of precocious aging. In women, telomere length limits a fertilized egg's capacity to develop into a healthy embryo. Thus, telomere length must be reset with each subsequent generation. Although telomerase is purportedly responsible for restoring telomere DNA, recent studies have elucidated the role of alternative telomeres lengthening (ALT) mechanisms in the reprogramming of early embryos and stem cells.

Telomere length in the oocyte is markedly shorter than somatic cells. In contrast, sperm are of the few cell types documented to elongate telomeres over the human lifespan, presumably due to the effects of telomerase activity in spermatogonia throughout the life of the male. Following fertilization and activation of the egg, embryonic cells undergo dramatic telomere lengthening. Notably, telomerase activity remains undetectable in these cells. This effect remains robust in telomerase knock-out mice, suggesting an ALT-dependent mechanism at play in preimplantation mammalian development. Moreover, the lengthening takes place in parthenogenetically activated eggs, which lack sperm input during activation, suggesting that the capacity for telomere length reprogramming resides in the oocyte.

Link: http://dx.doi.org/10.1155/2014/925121

The accumulation of senescent cells with age is one of the causes of degenerative aging, as senescent cells behave badly, emitting proteins that harm surrounding tissues. Finding a way to clearly identify senescent cells is a necessary step on the path to a targeted treatment that can destroy them, using engineered immune cells, nanoparticles, viruses, or any of the other approaches to selective cell destruction that are presently under development. Much of the work towards this end is focused on p16, which seems promising but may or may not in the end prove to be discriminating enough. Here researchers are exploring a different marker of senescence:

While TRF2 is found at telomeres, where it plays an essential role in maintaining telomere integrity, little is known about the cellular localization of methylated TRF2. In this report, we have shown that methylated TRF2 is associated with the nuclear matrix and that this localization is largely free of human telomeres. We show that methylated TRF2 drastically alters its nuclear staining as normal human primary fibroblast cells approach and enter replicative senescence. This altered nuclear staining, which is found to be overwhelmingly associated with misshapen nuclei and abnormal nuclear matrix folds, can be suppressed by hTERT and it is barely detectable in transformed and cancer cell lines.

We find that dysfunctional telomeres and DNA damage, both of which are potent inducers of cellular senescence, promote the altered nuclear staining of methylated TRF2, which is dependent upon the ATM-mediated DNA damage response. Collectively, these results suggest that the altered nuclear staining of methylated TRF2 may represent ATM-mediated nuclear structural alteration associated with cellular senescence. Our data further imply that methylated TRF2 can serve as a potential biomarker for cellular senescence.

Link: http://www.impactaging.com/papers/v6/n4/full/100650.html

The SENS Research Foundation is one of the few scientific organizations energetically working on realistic approaches to human rejuvenation treatments, based on repair of the known cellular and molecular damage that causes aging. This is very much a departure from the current mainstream of medicine where researchers largely ignore aging as a cause of disease in favor of trying to patch over age-related conditions in their late stages. As a strategy this is doomed to be an expensive and poor path forward, which is precisely why we need disruptive initiatives like the SENS Research Foundation to shake things up and illustrate the better path ahead. The Foundation funds research where there are roadblocks or a lack of progress, but is as much involved in advocacy, both within the scientific community to convince more researchers to work in this important field, and outside the community in order to sway funding sources and the public at large.

The latest SENS Research Foundation newsletter arrived in my in-box today, along with an announcement that registration is open for a new rejuvenation biotechnology conference that will be held in California later this year.

Registration Now Open For Rejuvenation Biotechnology 2014

Where: Hyatt Regency Santa Clara, Santa Clara, CA
When: August 21 - 23, 2014
To Register: http://sens.org/rb2014

SENS Research Foundation is pleased to announce that registration is now open for the Rejuvenation Biotechnology 2014 Conference. The conference theme is Emerging Regenerative Medicine Solutions for the Diseases of Aging. The Rejuvenation Biotechnology Conference builds upon novel strategies being pioneered by the Alzheimer's and cancer communities. By convening the foremost leaders from academia, industry, investment, policy, and disease advocacy, SRF seeks to inspire consideration of the wider potential of these strategies and evaluate the feasibility of preventative and combinatorial medicine applications to treat all aging-related diseases.

Confirmed speakers include:

* Richard Barker, CASMI
* Maria Blasco, Spanish National Cancer Research Centre
* George Church, Harvard Medical School
* Aubrey de Grey, SENS Research Foundation
* Caleb Finch, USC Davis School of Gerontology
* Jeanne Loring, Scripps Research Institute
* Stephen Minger, GE Healthcare Life Sciences, UK
* Brock Reeve, Harvard Stem Cell Institute
* Matthias Steger, Hoffmann-La Roche
* Michael West, Biotime, Inc.

Students and researchers are invited to submit poster abstracts for the Rejuvenation Biotechnology Conference Poster Session. Poster submissions will be evaluated by members of the SENS Research Foundation Team. The deadline for poster submissions is July 15, 2014.

We invite everyone in our community to register and participate in this new conference, our first in the US in over 6 years.

As is usually the case, the scientific section of the newsletter is also well worth reading. This time it is an examination of mitochondria and their role in aging:

Question Of The Month #2: Aging and the Limits of Mitochondrial Restoration

Q: Why can't fixing mitochondrial mutations and restoring peak ATP levels in the majority of cells in older people fix everything? I understand there are several classes of accumulated age-related damage like plaque build-up and glycation, which is why it seems like we'd need more than one approach to reverse aging, but if we give cells enough energy, could it be possible that all of it will just take care of itself? In other words, if cells once again have enough energy to perform their jobs to full capacity, couldn't they then carry out functions/mechanisms crucial to getting rid of all the age-related damage? I mean it sounds odd if you think of it using the car analogy: if you give an old car a new battery it's not going to fix other things like rust accumulation or leaky pipes... but because cells all work as a system, I think it's more likely that they'd be able to help control age-related accumulations.

A: While mitochondrial DNA mutations are indeed important to address in the context of a comprehensive rejuvenation strategy like SENS, there are several reasons to think this alone would not be enough to deal with most other forms of aging damage.

First, it's actually not all that clear that the mitochondria in the great majority of an aging person's cells actually suffer much decline in capacity to produce ATP. Certainly many older cells do suffer energy deficits, related to insulin resistance and/or secondary to other age-related metabolic (mal)adaptations - but those are causes unrelated to mitochondrial mutations.

True, the cells whose mitochondria we're most concerned about suffer a pretty drastic reduction in energy production: those are cells that have been taken over by mitochondria harboring large deletions. But remember that such cells constitute a tiny percentage of the cells in the body. If the goal is simply to restore the capacity of the mitochondria in the majority of aging people's cells to produce ATP to levels similar to young people, we're already there.

Also, while individual cells overtaken by mutant mitochondria certainly lack energy, such energy deficits don't do anything to hold back the great majority of the body's cells (since individual cells have their own mitochondrial power supply). Yet they still suffer aging damage. Furthermore, much aging damage accumulates because we lack the means to deal with it, meaning no amount of energy alone can prevent its accumulation.

Third, a lot of aging damage is extracellular, and such damage can't really be addressed in most cases by cells. This is especially true in the case of damage to extracellular matrix (glycation crosslinks and mechanical fatigue of arterial and other elastin lamellae, for instance), where typically there isn't even any ATP available, irrespective of a person's age.

Fourth: remember, we were all young once. At that point, few or none of our cells had been taken over by mutant mitochondrial DNA, and yet even at that point in our lives we were aging. Indeed, this is true of the two examples you cite in your question: we are all born with at least some aging damage, such as fraying of arterial elastin and early atherosclerotic lesions. If youthful mitochondrial energetics were enough to abrogate the accumulation of aging damage, the degenerative process wouldn't get going until a substantial number of our cells were occupied by mutant mitochondria (which, again, arguably doesn't even happen when people reach what are today rather advanced ages).

Most importantly: while it may one day be possible to begin administering rejuvenation therapies to people who are still in their youthful prime, at present we do not have the luxury to do this. Early recipients of rejuvenation biotechnologies will, by and large, be people whose bodies are already riddled with multiple kinds of cellular and molecular aging damage. Even if mitochondria capable of churning out ATP with the alacrity of Usain Bolt in his prime were enough to prevent other forms of aging damage from getting started (and again, the normal course of aging argues strongly otherwise), it seems far less plausible that it would be able to reverse the accumulation of aging lesions in people who have already been suffering such damage for six decades or more of life.

In short: if we are to save the greatest possible number of people from the age-related slide into disease, disability, dependence, dementia, and eventual death, we are going to have to tackle the full spectrum of aging damage that has already riddled their bodies, and obviating mitochondrial mutations seems highly unlikely to achieve this key goal on its own.

Cartilage is a surprisingly complex tissue. While researchers are making progress in growing cartilage from a patient's own cells, they have yet to reliably and fully reproduce all of the mechanical properties of the real thing. Fortunately this is less of an issue in the nose than, say, in the knee, as you aren't resting the weight of your body on your nose:

A research team [has] reported that nasal reconstruction using engineered cartilage is possible. They used a method called tissue engineering where cartilage is grown from patients' own cells. This new technique was applied on five patients, aged 76 to 88 years, with severe defects on their nose after skin cancer surgery. One year after the reconstruction, all five patients were satisfied with their ability to breathe as well as with the cosmetic appearance of their nose. None of them reported any side effects.

The type of non-melanoma skin cancer investigated in this study is most common on the nose [because] of its cumulative exposure to sunlight. To remove the tumor completely, surgeons often have to cut away parts of cartilage as well. Usually, grafts for reconstruction are taken from the nasal septum, the ear or the ribs and used to functionally reconstruct the nose. However, this procedure is very invasive, painful and can, due to the additional surgery, lead to complications at the site of the excision.

[Researchers have] now developed an alternative approach using engineered cartilage tissue grown from cells of the patients' nasal septum. They extracted a small biopsy, isolated the cartilage cells (chondrocytes) and multiplied them. The expanded cells were seeded onto a collagen membrane and cultured for two additional weeks, generating cartilage 40 times the size of the original biopsy. The engineered grafts were then shaped according to the defect on the nostril and implanted.

Link: http://www.eurekalert.org/pub_releases/2014-04/uob-sgc041014.php

In terms of complexity, this seems on a par with generating a new trachea or esophagus, both goals that were achieved in recent years:

Four young women born with abnormal or missing vaginas were implanted with lab-grown versions made from their own cells, the latest success in creating replacement organs that have so far included tracheas, bladders and urethras. Follow-up tests show the new vaginas are indistinguishable from the women's own tissue and have grown in size as the young women, who got the implants as teens, matured. All four of the women are now sexually active and report normal vaginal function. Two of the four, who were born with a working uterus but no vagina, now menstruate normally.

The pilot study is the first to show that vaginal organs custom-built in the lab using patients' own cells can be successfully used in humans, offering a new option for women who need reconstructive surgeries. All four of the women in the study were born with Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome, a rare genetic condition in which the vagina and uterus are underdeveloped or absent. Conventional treatment generally involves the use of grafts made from intestinal tissue or from skin, but both tissues have drawbacks.

The researchers started off by collecting a small amount of cells from genital tissue and grew two types of cells in the lab: muscle cells and epithelial cells, a type of cell that lines body cavities. About four weeks later, the team started applying layers of the cells onto a scaffold made of collagen, a material that can be absorbed by the body. They then shaped the organ to fit each patient's anatomy, and placed it in an incubator. A week later, the team created a cavity in the body and surgically attached the vaginal implants to existing reproductive organs. Once implanted, nerves and blood vessels formed to feed the new organ, and new cells eventually replaced the scaffolding as it was absorbed by the body.

Link: http://in.reuters.com/article/2014/04/10/health-organs-vaginas-idINL2N0N21WE20140410

To a first approximation no-one cares about research funding. No-one cares until it is too late, until their life depends upon a cure or at least a treatment that doesn't yet exist. The vast majority of people are focused on circuses and distractions among the possibilities that presently exist, not on the creation of new possibilities. Just look at the ocean of funding for sports, politics, and war in comparison to the small drops of funding for medical research.

Among the comparatively small class of people who do care about research funding, most of these individuals care because they are in business and the existence of competitors forces them onto the rat wheel of progress. They don't care because they want to produce specific end results, they care because they have to organize research in order to keep up and defend their business. That feels like a rat wheel when you are on the inside, since all of your competitors have wheels of their own and are rarely far behind, tomorrow's board meeting will be much the same as today's regardless of how fast you run, and success on the wheel just means the chance to run again later. From the outside these are the true engines of progress, however, racing ahead to give us ever better products and services - including ever-better medicine.

But this is why we have patient advocacy, in which the small number of people with greater foresight, those who do care about medical research funding because they have looked ahead and understand enough of a field to know what is plausible, try to convince those with lesser foresight of the need for action.

At present research into aging and longevity receives a pittance in funding, private or public, in comparison to any sensible yardstick. People simply don't care to do anything about degenerative aging, and this prevalent attitude is reflected at the large scale in funding levels for various activities. Where there is a will to act and work on ways to treat aging, it is driven by iconoclasts, heretics, and visionaries: the sensible few, not the comfortably conformist many.

Yet it isn't just longevity research in which researchers can bemoan the fact that their field is unjustly the poor cousin in the broader field of medicine, receiving next to nothing in comparison to its great importance. While more than 90% of the Western world suffers and dies due to aging, only a fraction of existing medical research funding goes towards doing anything about this, and even then all existing medical research funding is but a fraction of the funds spent on either (a) idle pastimes, or (b) cleaning up after the consequences of aging. This is the common condition for anyone involved in medical research of any sort, and even the most mainstream of institutions working on diseases of aging can point out that they too are neglected in comparison to their importance:

Alzheimer's Is Expensive, Deadly and Growing. So Where's the Research Money?

"The epidemic is upon us," says Dr. John Trojanowski, co-director of the Center for Neurodegenerative Disease Research and director of the Institute on Aging, both at the University of Pennsylvania School of Medicine. "It's a very difficult thing to say to a patient that there's nothing we have for you, but that is the honest response. There are no disease-modifying therapies for Alzheimer's."

Alzheimer's is one of the costliest chronic diseases to the country. Total costs of caring for Americans with Alzheimer's and other dementias is expected to reach $214 billion this year, with Medicare and Medicaid covering $150 billion and out-of-pocket expenses reaching $36 billion.

Historically, Alzheimer's research has been grossly underfunded. The National Institutes of Health (NIH) dedicated $5.3 billion to cancer research in 2013, nearly $3 billion to HIV/AIDS, $1.2 billion to heart disease and $1 billion to diabetes. Alzheimer's research received just over $500 million.

"I believe that this disease will be the defining medical condition of our generation--hopefully not the next generation," says Dr. Ronald Petersen, director of the Mayo Clinic Alzheimer's Disease Research Center and chair of the Advisory Council for NAPA. "If we don't get on top of it, it will bankrupt the health-care system."

As is the style of the press these days the article above focuses on public funding and its grandstanding political theater rather than the larger and arguably more important body of private research funding. The public funding numbers might seem large, but they are only a fraction of the valuation of the bubblegum industry or any single large sports franchise, of which there are many. But as I said above, to a first approximation no-one cares about research funding. If they did a great many problems would perhaps already be solved.

Researchers here theorize that alterations to neurons are an important part of the metabolic improvements and enhanced longevity produced by calorie restriction, at least in nematode worms:

Progressive neuronal deterioration accompanied by sensory functions decline is typically observed during aging. On the other hand, structural or functional alterations of specific sensory neurons extend lifespan in the nematode C. elegans. Hormesis is a phenomenon by which the body benefits from moderate stress of various kinds which at high doses are harmful. Several studies indicate that different stressors can hormetically extend lifespan in C. elegans and suggest that hormetic effects could be exploited as a strategy to slow down aging and the development of age-associated (neuronal) diseases in humans. Mitochondria play a central role in the aging process and hormetic-like bimodal dose-response effects on C. elegans lifespan have been observed following different levels of mitochondrial stress.

Here we tested the hypothesis that mitochondrial stress may hormetically extend C. elegans lifespan through subtle neuronal alterations. In support of our hypothesis we find that life-lengthening dose of mitochondrial stress reduces the functionality of a subset of ciliated sensory neurons in young animals. Notably, the same pro-longevity mitochondrial treatments rescue the sensory deficits in old animals. We also show that mitochondrial stress extends C. elegans lifespan acting in part through genes required for the functionality of those neurons. To our knowledge this is the first study describing a direct causal connection between sensory neuron dysfunction and extended longevity following mitochondrial stress. Our work supports the potential anti-aging effect of neuronal hormesis and open interesting possibility for the development of therapeutic strategy for age-associated neurodegenerative disorders.

Link: http://dx.doi.org/10.1016/j.exger.2014.03.026

The research community continues to validate the benefits resulting from comparatively simple first generation stem cell transplants, of the sort that have been available via medical tourism for a decade:

In an analysis of published research, [researchers] identified 46 studies that examined the use of mesenchymal stromal cells - a type of multipotent adult stem cells mostly processed from bone marrow - in animal models of stroke. They found MSCs to be significantly better than control therapy in 44 of the studies. Importantly, the effects of these cells on functional recovery were robust regardless of the dosage, the time the MSCs were administered relative to stroke onset or the method of administration. (The cells helped even if given a month after the event and whether introduced directly into the brain or injected via a blood vessel.)

MSCs do not differentiate into neural cells. Normally, they transform into a variety of cell types, such as bone, cartilage and fat cells. The cells are attracted to injury sites and, in response to signals released by these damaged areas, begin releasing a wide range of molecules. In this way, MSCs orchestrate numerous activities: blood vessel creation to enhance circulation, protection of cells starting to die, growth of brain cells, etc. At the same time, when MSCs are able to reach the bloodstream, they settle in parts of the body that control the immune system and foster an environment more conducive to brain repair.

"Stroke remains a major cause of disability, and we are encouraged that the preclinical evidence shows [MSCs'] efficacy with ischemic stroke. MSCs are of particular interest because they come from bone marrow, which is readily available, and are relatively easy to culture. In addition, they already have demonstrated value when used to treat other human diseases."

Link: http://news.uci.edu/press-releases/bone-marrow-stem-cells-show-promise-in-stroke-treatment-uci-team-finds/

Researchers are doing far too many things with cells for any one person to know about every single study, or even every category of study. In the past twenty years the doors have opened and the costs dropped to the point at which any laboratory can support numerous separate and adventurous voyages of discovery into cell behavior and biology. Cells are stretched, sliced, grown, transplanted this way and that, genetically engineered, exposed to substances, and so on and so forth, and thousands of these studies are ongoing at any given time.

In among all of this exploration, we should not be surprised to find that some researchers uncover ways to reverse aspects of cellular aging. It is important to remember that cell aging is a different thing altogether from the aging of an organism made up of cells. One affects the other, but it isn't a direct relationship by any means. Cells respond to their circumstances and there is plenty of evidence to suggest that if given the right stimulus some types of cell can remake themselves to a large degree, stripping out damage and unwanted waste to become pristine. We know that this happens somewhere in the sequence of events that leads to embryonic development: parents are old, children are young. We also know that bacteria, hydra, and similar entities can perform much the same operation under some circumstances. This is certainly not something you'd want taking place in your nervous system, however, and the fact that we have complex brains and nervous systems may be a consequence of the fact that our cells don't habitually carry out this sort of dramatic cleansing process, unlike those of some species of lower organism.

There are other less drastic examples, however, such as those associated with the state of cellular senescence in which a cell ceases to divide but doesn't destroy itself. Cells in old tissues become senescent in greater numbers, due to some combination of greater levels of cellular damage and a response to signaling proteins present in the cellular environment. This is most likely an adaptation of an embryonic development process to the suppression of cancer risk in later life. However, it is of decidedly mixed results: less cancer, yes, but senescent cells are generally badly behaved in ways that harm tissue integrity and organ function. We would like to get rid of them as the accumulation of senescent cells is in fact one of the causes of degenerative aging. Removal of these cells by means of targeted destruction seems to be beneficial in those studies attempted to date.

What if we could reverse cellular senescence, however? It is a little early to claim that this is a plausible goal, or that it would cause fewer problems than it solved, but there is some research taking place along these lines. In connection with all of this, the paper linked below outlines the discovery of cells acting to reverse their senescent status in response to circumstances as they are manipulated in a system for growing liver cells known as hepatocytes. This involves the use of genetically engineered immune deficient mice as hosts for transplanted human hepatocyte cells, and one characteristic of this system is that as the human cells grow in number they can be serially transplanted between mice to increase the rate of growth so as to obtain a usefully large amount of cells in a usefully short period of time. It is worth remembering that the research community is not yet at the point of being able to arbitrarily grow every type of cell at the drop of the hat: many lines of research still require complex systems involving laboratory animals in order to investigate cells in a life-like environment. This will change in the years ahead, but it is what it is for now.

Using this system of serial transplants of human hepatocytes between mice, these researchers noticed that the cells responded to transplantation by reversing their senescent status:

Reversal of hepatocyte senescence after continuous in vivo cell proliferation

A better understanding of hepatocyte senescence could be used to treat age-dependent disease processes of the liver. Whether the continuously proliferating hepatocytes could avoid or reverse senescence has not been fully not elucidated yet. We confirmed that the livers of aged mice accumulated senescent and polyploid hepatocytes, which is associated with accumulation of DNA damage and activation of p53-p21 and p16ink4a-pRB pathways.

Induction of multiple rounds continuous cell division is hard to apply in any animal model. Taking advantage of serial hepatocyte transplantation assays in the fumarylacetoacetate hydrolase deficient (Fah-/-) mouse, we studied the senescence of hepatocytes that had undergone continuous cell proliferation over a long time period, up to 12 rounds of serial transplantations.

We demonstrated that the continuously proliferating hepatocytes avoided senescence and always maintained a youthful state. The re-activation of telomerase in hepatocytes after serial transplantation correlated with reversal of senescence. Moreover, senescent hepatocytes harvested from aged mice became rejuvenated upon serial transplantation, with full restoration of proliferative capacity. The same findings were also true for human hepatocytes. After serial transplantation, the high initial proportion of octoploid hepatocytes decreased to match the low level of youthful liver, suggesting that the hepatocyte "ploidy conveyer" is regulated differently during aging and regeneration. The findings of reversal of hepatocyte senescence could enable future studies on liver aging and cell therapy.

You might consider this result in the context of other studies that have shown renewal of stem cell activity when stem cells are moved from old individuals to young individuals, or simply have the protein levels present in an old environment replaced by those of a younger environment. It is a data point and a starting position for further research into whether or not it is useful to attempt to reprogram cells in the body by altering levels of signaling proteins. The initial signs are promising, but there is ever the concern that waking these cells will raise the risk of cancer, or cause other disruptions that may outweigh the benefits.

Cryonics is the low-temperature preservation of at least the brain immediately following death, in order to preserve the structures that encode the data of the mind. For those who will age to death prior to the advent of rejuvenation treatments in the decades ahead this is the only shot at a longer life in the future. A society with the technologies necessary to restore a cryopreserved individual to life is a society that should have no issues with regenerating a new body and repairing the damage of aging.

Cryonics remains a small industry, not all that much larger than it was in the 1970s when early amateur efforts transitioned into more professional non-profit organizations. We live in a world in which it has long been technologically feasible to prevent the absolute loss to oblivion of a majority of the people who die in any given year, yet only a vanishingly small fraction of the population seem to have any interest in this goal. The rest march in lock-step to die without making any meaningful attempts to do something about it.

Here is a short interview with the president of the Cryonics Society of Canada:

The Alcor Life Extension Foundation, and the Cryonics Institute are the two main organizations in North America that offer cryopreservation and long-term storage. They have different business structures and very different prices. KrioRus in Russia is a third option. It is the first, and currently only, cryonics company in Europe or Asia.

Each organization has a process for membership that includes the requisite paperwork. Most people that sign up opt to have their services funded through a life insurance policy. The organizations can best advise you on which insurance companies are most ideal for this purpose. You will likely pay a small amount in membership dues, and then upon pronouncement, your insurance policy (or alternate means of funding) will be applied to your immediate needs.

Cryonics is not illegal in Canada. It is regarded as an end-of-life choice, and there are no legal barriers to performing this service. The only exception is in British Columbia, which passed a law several years ago forbidding the marketing of cryonics services. Members in B.C. have been successfully cryopreserved, though, within full observation of the law.

Cryonics patients are legally dead, so although there are no specific laws which deal with cryopreservation, cryonics organizations handle patients while observing the laws governing anatomical donations of a body to science and the laws that govern the funeral service. Transportation of patients is done in collaboration with a licensed funeral director, after a person has been legally pronounced and certified as deceased by the appropriate medical provider. By keeping the wishes of the patient known, and the process transparent, legal authorities generally do not take issue with the practice.

Mainstream science has historically been skeptical of cryonics, as it is a process that cannot yet be reversed by modern technology. There has been a shift, though, in recent years, in the mainstream, where cryonics has been viewed less and less like science fiction and more like a plausible near-future advancement. How cryonicists respond is quite varied. The Cryonics Society of Canada exists to try to educate the public about cryonics and to advocate for its members. Some members are very vocal and positive about their involvement. Others prefer to keep the matter private.

Link: http://www.themanitoban.com/2014/04/one-short-sleep-past-wake-eternally/19972/

Here researchers theorize on connections between some measurable aspects of aging, those being mitochondrial damage and the role of iron in metabolic processes. As is always the case this sort of search for connections is bedeviled by the fact that aging is a global process: all sorts of changes happen in parallel, and establishing cause and effect, or even just linkage rather than mere association, is ever a challenge.

Free (labile or chelatable) iron is extremely redox-active and only represents a small fraction of the total mitochondrial iron population. Several studies have shown that the proportion of free iron increases with age, leading to increased Fenton chemistry in later life. It is not clear why free iron accumulates in mitochondria, but it does so in parallel with an inability to degrade and recycle damaged proteins that causes loss of mitochondrial protein homeostasis (proteostasis). The increase in oxidative damage that has been shown to occur with age might be explained by these two processes.

While this accumulation of oxidative damage has often been cited as causative to ageing there are examples of model organisms that possess high levels of oxidative damage throughout their lives with no effect on lifespan. Interestingly, these same animals are characterised by an outstanding ability to maintain correct proteostasis during their entire life. Reactive oxygen species can damage critical components of the iron homeostasis machinery, while the efficacy of mitochondrial quality control mechanisms will determine how detrimental that damage is.

Here we review the interplay between iron and organellar quality control in mitochondrial dysfunction and we suggest that a decline in mitochondrial proteostasis with age leaves iron homeostasis (where several key stages are thought to be dependent on proteostasis machinery) vulnerable to oxidative damage and other age-related stress factors. This will have severe consequences for the electron transport chain and TCA cycle (among other processes) where several components are acutely dependent on correct assembly, insertion and maintenance of iron-sulphur clusters, leading to energetic crisis and death.

Link: http://dx.doi.org/10.1016/j.exger.2013.12.015

While destined to be a deserted sideline of longevity science at some point in the years ahead, research into calorie restriction mimetic drugs is presently in its heyday. Calorie restriction with optimal nutrition slows aging and extends life in near every species tested to date, though the shorter the natural life span of the species the greater the effect. A calorie restricted mouse can live 40% longer in excellent health, but that certainly isn't the case for humans - we'd have noticed an effect that large long ago. This is interesting, because the short-term effects on metabolism and markers of health are similarly large and beneficial in both species. Nonetheless, the consensus in the research community expects the effects of calorie restriction on human life span to be at the most in the ballpark of a 5% increase. The effects on health are much more impressive, however: if calorie restriction were a drug, it would dwarf the sales of any other pharmaceutical created to date, and deservedly so.

So if this is so great, why is it going to be a backwater? Because the objective of a calorie restriction mimetic drug is, as the name suggests, to mimic the metabolic response to calorie restriction - to produce at least some of the same health benefits. A perfect mimetic would result in the same outcome as practicing calorie restriction. But that means a mere boost to health and life that is large in comparison to doing nothing, but is tiny on the scale of what is possible through future medical science. We are entering the era of rejuvenation biotechnology, in which researchers are even today working on the foundations of ways to reverse the cellular and molecular damage that causes degenerative aging. That is the road to indefinite health, completely prevention of age-related disease, and a youth that lasts for as long as you want it to. It won't take much of that for the current fad of drug development aimed at slightly slowing down aging to wither away in favor of the obviously better line of business.

Nonetheless, much - arguably most - of the members of the comparatively small research community interested in treating aging are working away on this backwater to be. It is the mainstream flavor of today, just as the (probably only marginally better) mainstream flavor of tomorrow will involve genetic studies of aging and longevity. The disruption of treating aging as damage and working to repair it is under way with the advent of organizations like the SENS Research Foundation, but has a fair way to go yet before it takes over the mainstream.

The open access paper linked below gives a very good feel for the present state of calorie restriction mimetic research. There are a lot of compounds that seem promising, and researchers are engaged in tying their effects back to the growing knowledge of the puzzle of interrelated proteins and genes that make up the highly flexible operation of metabolism. For most this is the primary goal: not the generation of therapies, but the use of calorie restriction and ways to imperfectly recreate its effects as tools to understand the way in which metabolism determines the pace of aging, all the way down to the most fundamental interactions between proteins in cells. This is a very long-term project. The research community will have effectively cured aging long before the whole intricate dance of its progression is completely understood down to the lowest levels, or at least this will happen if all goes well in the repair strategy field.

All that said, the research into metabolism and aging is interesting and worth reading. It just isn't the road to human longevity in any practical, useful to those of us reading this today sense.

D-Glucosamine supplementation extends life span of nematodes and of ageing mice

D-Glucosamine (GlcN) is being widely used to prevent and treat osteoarthritis in humans and, according to a number of clinical studies, may be effective in this regard. However, mounting evidence suggests that GlcN may be ineffective in ameliorating symptoms and parameters of osteoarthritis. Nevertheless, GlcN has been in long-term use in humans for several decades and induces no relevant side effects aside from occasional allergic reactions.

Short-term administration of high-dose GlcN to model systems or humans acutely impairs glucose metabolism that resembles some of the metabolic features of diabetes mellitus. By contrast, chronic GlcN intake has no detectable influence, or even blood glucose-lowering effects in humans.

Long-term inhibition of glycolysis, by either applying RNA interference (RNAi) to impair expression of glycolytic enzymes, with the application of 2-deoxy-D-glucose (DOG), or by impeding insulin/IGF1 receptor signalling uniformly extends the life span of C. elegans, whereas increased glucose availability reduces nematodal life span. As none of these aforementioned interventions are readily available for use in humans to extend life span, and particularly owing to the fact that DOG unexpectedly shortens life span of rodents, we have now tested whether GlcN could promote healthspan in C. elegans and rodents.

We here find that GlcN inhibits glycolysis to cause an energy deficit that induces mitochondrial biogenesis and alternate fuel use, namely amino-acid oxidation. This is paralleled by an extension of life span in both C. elegans and ageing mice, the latter also showing improved glucose metabolism. These findings implicate that GlcN supplementation may be a versatile approach to delay ageing in humans.

If you dig into the paper, you'll find that life extension in mice is modest, around 10% or so, but pretty consistent judging from the charts. This is for supplementation starting at the two year mark and continuing for another year, by which time only a few mice remained from either group.

For my money an increased knowledge of metabolism and aging is really the only reason to pursue something with such a modest outcome at the dawn of the age of rejuvenation research. The quest for knowledge is a noble thing in and of itself, but don't fool yourself into thinking that this and similar work forms any sort of a road to radical life extension in humans. It does not and cannot. That goal can only come about in the next few decades, soon enough to matter, through growth and development of repair strategies that focus on identifying and repairing the fundamental differences between old tissues and young tissues - a form of research and development that is far, far removed from the paper quoted above.

Researchers have demonstrated that they can produce a functionally youthful thymus in old mice by increasing levels of a single protein. There have been suggestions that such an approach might be made to work - tweak signal protein levels such that they are similar to those that existed during the early development of the thymus - but I have to admit that I wasn't expecting anything so impressive at this stage. It is an important advance if verified in other labs, as regeneration of the thymus is one of the methods by which the failing immune system in older people could be restored to greater function, at least partially ameliorating this one aspect of frailty in the aged.

One of the issues that contributes to the age-related decline of the immune system is a comparative lack of a supply of fresh immune cells, those capable of tackling new threats. The thymus, where these cells mature, has evolved to pump out a large supply of immune cells in childhood but it then atrophies soon afterwards - a process known as thymic involution. The adult thymus is a shadow of its former self and delivers only a trickle of new immune cells.

The SENS Research Foundation has been funding work on tissue engineering of the thymus, as a part of a portfolio of work on the foundations of human rejuvenation, and I'm sure that this will be a welcome addition to the list of potential strategies for thymic regeneration:

British scientists have for the first time used regenerative medicine to fully restore an organ in a living animal, a discovery they say may pave the way for similar techniques to be used in humans in future. The [team] rebuilt the thymus - an organ central to the immune system and found in front of the heart - of very old mice by reactivating a natural mechanism that gets shut down with age. The regenerated thymus was not only similar in structure and genetic detail to one in a young mouse, the scientists said, but was also able to function again, with the treated mice beginning to make more T-cells - a type of white blood cell key to fighting infections.

[The researchers] targeted a part of the process by which the thymus degenerates - a protein called FOXN1 that helps control how key genes in the thymus are switched on. They used genetically modified mice to enable them to increase levels of this protein using chemical signals. By doing so, they managed to instruct immature cells in the thymus - similar to stem cells - to rebuild the organ in the older mice.

Link: http://dev.biologists.org/content/141/8/1627.full

Here is a very brief high level overview of some of what is known about the relationship between body temperature and longevity in mammals. As for many aspects of our biology, researchers have pulled out associations from the data but questions of cause, effect, and mechanisms involved are all very much up for debate.

Some studies show a correlation between lower body temperatures and greater longevity, though there is no proof of a cause-and-effect relationship in humans. The first such major study in warmblooded animals was a 2006 experiment involving mice at the Scripps Research Institute. Genetically engineered mice with extra-sensitive temperature control switches in the hypothalamus were raised with core body temperatures just a fraction of a degree cooler than those of their litter mates; caloric intake was the same. The researchers found the median life span was 12 percent greater in the cooler males, 20 percent greater in the females.

As for humans, a large study published in 2011 compared the ages and body temperatures of 18,630 people from 20 to 98 years old who had oral temperature readings as part of a standardized health appraisal at a health maintenance organization. Mean temperature decreased with age, with a difference of 0.3 degrees Fahrenheit between the oldest and youngest groups, even after controlling for sex, body mass index and white-blood-cell count.

"The results are consistent with low body temperature as a biomarker for longevity," the researchers concluded. As for possible reasons for such results, they suggested identifying genetic influences on body temperature and examining the effect of body temperature on multiple cellular processes.

Link: http://www.nytimes.com/2014/04/08/science/colder-can-mean-older.html

I like to see advocates setting forth to create small scale initiatives like the children's book Death is Wrong and the associated fundraiser to distribute copies. At the large scale a broad advocacy movement for a cause in medical research isn't a monolithic thing; it is made up thousands of such efforts, a tapestry of individual who each thought enough of the cause to stand up and do something about it. More of this is always a good thing, and working towards a cure for degenerative aging is the most worthy of causes that I know of.

Donating to the right sort of cutting edge research is one approach, and the one I favor, but equally we have to get out there and persuade more people to do the same. Money has to come from somewhere. There is always a balance between raising research funding to get the job done versus funding the cost of gathering more supporters and thus making it more likely that greater amounts of research funding can be obtained. Research results help to convince more people to fund more research, but there is never enough support in the early crucial stages - the really large amounts of research funding arrive after the most important work is done, as is the case for every trend.

The starting point for large amounts of future funding and rapid progress towards actual, real, working rejuvenation treatments is some mix of research funding and advocacy initiatives today, however. All such efforts should be encouraged, as it is through them that the longevity science community finds its way to a louder voice in the public sphere, a taller soapbox from which to persuade and educate. Aging is a horror, the greatest cause of pain and suffering in this world of ours, and we stand at the verge of being able to do something about it - but only if many more people come to think that this cause has merit and make their own contributions to help out.

Praise for Death is Wrong, a delicious transhumanist book for children

Death is a disease, and hopefully future scientists, perhaps including the young readers of the book, will find a cure. Previous generations thought that death is inevitable, and invented delusional fake philosophies to make death easier to accept. This reaction is understandable - if you can't avoid something, you look for ways to accept it - and explains all usual rhetorical babbling in praise of death: "overpopulation, make room for the young, death is a tool of evolution, boredom after a long life," and the utterly idiotic "death gives meaning to life." The book deconstructs all these fake "arguments" and calls them what they are: understandable but pathetic attempts to rationalize the inevitable.

Provocative strong messages get heard, and teaching children that death will be cured is very provocative in today's dull, defeatist, politically correct cultural climate. I think writing for children forces to keep things clean end simple, without big words and endless caveats, cutting through the noise and getting to the point. Clear, clean, and simple communication focused on the core message, with qualifications and caveats (if they are really needed) in footnotes, is something that transhumanists should practice more, and writing for children is a good way to learn.

Spreading the Word That Death is Wrong

Who could have thought a month ago that an illustrated children's book on indefinite life extension would become a fiercely, passionately discussed phenomenon not just in transhumanist and futurist circles, but on mainstream publications and forums? And yet that is exactly what has happened to Death is Wrong - certainly the most influential and provocative of all of my endeavors to date. I am thrilled that it is precisely my pursuit of this most fundamental and precious goal - preservation of the life of every innocent individual - that has achieved greater public exposure, controversy included, than anything else I have ever done.

Review of "Death is Wrong" by Adam Alonzi

Death can be cured. Let this sink into your brain, not because it is comforting, but because it is true. Even obvious truths will not gain acceptance unless we vigorously campaign against the falsehoods. Death is not something to embrace, and it is not something to ignore. To turn it into a matter of metaphysics or "bioethics" is insulting to those who, by no fault of their own, are burdened by the ailments of old age. There are many extraordinary men and women who could go on working for hundreds of years if their stars were not designed to dim so soon.

The future of cancer treatments involves the targeted delivery of cell-killing mechanisms to cancer cells. As a strategy this offers the potential to minimize side-effects to far below the levels of present day established treatments such as chemotherapy and radiotherapy. There are many ways to kill cells while causing minimal effects to surrounding tissues, assuming a selective means of delivery to specific cells, and here researchers improve upon the use of nanoparticles as the mechanism of destruction:

Using magnetically controlled nanoparticles to force tumour cells to 'self-destruct' sounds like science fiction, but could be a future part of cancer treatment. In brief, the technique involves getting the nanoparticles into a tumour cell, where they bind to lysosomes, the units in the cell that perform 'cleaning patrols'. The lysosomes have the ability to break down foreign substances that have entered a cell. They can also break down the entire cell through a process known as 'controlled cell death', a type of destruction where damaged cells dissolve themselves.

The researchers have used nanoparticles of iron oxide that have been treated with a special form of magnetism. Once the particles are inside the cancer cells, the cells are exposed to a magnetic field, and the nanoparticles begin to rotate in a way that causes the lysosomes to start destroying the cells.

The research group [is] not the first to try and treat cancer using supermagnetic nanoparticles. However, previous attempts have focused on using the magnetic field to create heat that kills the cancer cells. The problem with this is that the heat can cause inflammation that risks harming surrounding, healthy tissue. The new method, on the other hand, in which the rotation of the magnetic nanoparticles can be controlled, only affects the tumour cells that the nanoparticles have entered.

Link: http://www.lunduniversity.lu.se/o.o.i.s?id=24890&news_item=6140

In recent years researchers have gained some understanding of how aging diminishes the vital activity of stem cell populations by linking the blood flows of old and young mice, a process called heterochronic parabiosis. It has opened the door to identifying and altering environmental factors that lead to stem cell decline, an approach that doesn't address the underlying damage of aging that causes changes in the levels of chemical signals in tissue, but which may still prove beneficial.

This open access paper argues that parabiosis has a rich history in research and is presently underused as a tool for further investigation:

Modern medicine wields the power to treat large numbers of diseases and injuries most of us would have died from just a hundred years ago, yet many of the most devastating diseases of our time are still untreatable. Chronic conditions of age such as cardiovascular disease, diabetes, osteoarthritis or Alzheimer's disease turn out to be of a complexity that may require transformative ideas and paradigms to understand and treat them. Parabiosis, which is characterised by a shared blood supply between two surgically connected animals, may just provide such a transformative experimental paradigm. Although forgotten and shunned now in many countries, it has contributed to major breakthroughs in tumour biology, endocrinology and transplantation research in the past century.

Interestingly, recent studies from the United States and Britain are reporting stunning advances in stem cell biology and tissue regeneration using parabiosis between young and old mice, indicating a possible revival of this paradigm. We review here briefly the history of parabiosis and discuss its utility to study physiological and pathophysiological processes. We argue that parabiosis is a technique that should enjoy wider acceptance and application, and that policies should be revisited to allow its use in biomedical research.

Link: http://www.smw.ch/content/smw-2014-13914/

As I'm sure you all know by now, we'd be languishing a lot further away from the goal of human rejuvenation if not for Aubrey de Grey and the network of people within and without the research community who have joined in to help push longevity science towards respectability and plausibility. Today a great deal more funding is going towards lines of work that contribute materially to halting and reversing degenerative aging than was the case a decade ago. For that we can thank the efforts of de Grey, the Methuselah Foundation staff, the SENS Research Foundation staff, numerous allied researchers, and thousands of volunteers and donors. This work and support has helped create a great change in the research and funding environment, and made radical life extension something that is discussed seriously in far more communities.

Yet there is still a great deal of work to be done. The great change in society and attitudes towards aging has only just started; most people still accept aging and death as set in stone, and even oppose efforts to treat aging as the medical condition it is. The next stage ahead is one in which the average fellow in the street has the same perception of aging as he does of cancer, and supports efforts to do something about it just as strongly. Only then will truly massive funding for the defeat of aging arrive from the traditional sources. Until then, we continue to bootstrap support and funding, year by year.

Aubrey de Grey is a prolific speaker, and gives many presentations in any given year. I'm pointing out this recently uploaded video of a presentation given by de Grey last year because one of the slides caught my eye. It provides the following information on yearly budgets for research institutions:

Even though 90% of US deaths and at least 80% of US medical costs are caused by aging:

National Institutes of Health budget ($M): ~30,000
National Institute of Aging budget: ~1,000
Division of Aging Biology budget: ~150
Spent on translational research (max): ~10
SENS Research Foundation budget: ~5

There is something to think about. On the one hand this is a reminder of just how far removed funding priorities are from the sensible goal of dealing with aging. On the other hand, you can see that this is a field of research in which small foundations funded by philanthropy can make a large difference to the current rate of progress, given that very little funding goes to the most promising programs. When looking at these numbers it is also worth noting that public funds, for which it is comparatively easy to obtain good data, are thought to make up a little over a third of overall medical research. It is very unclear as to the breakdown of private medical research funding when it comes to work relevant to aging, however. Perhaps it is similar, perhaps not.

A true maverick, Aubrey de Grey challenges the most basic assumption underlying the human condition - that aging is inevitable. He argues instead that aging is a disease - one that can be cured if it's approached as "an engineering problem." His plan calls for identifying all the components that cause human tissue to age, and designing remedies for each of them - forestalling disease and eventually pushing back death.

He has developed a possibly comprehensive plan for such repair, termed Strategies for Engineered Negligible Senescence (SENS), which breaks the aging problem down into seven major classes of damage and identifies detailed approaches to addressing each one. A key aspect of SENS is that it can potentially extend healthy lifespan without limit, even though these repair only needs to approach perfection rapidly enough to keep the overall level of damage below pathogenic levels. With his astonishingly long beard, wiry frame and penchant for bold and cutting proclamations, de Grey is a magnet for controversy. A computer scientist, self-taught biogerontologist and researcher, he has co-authored journal articles with some of the most respected scientists in the field.

Finding genetic correlations with longevity in humans is challenging. All results found to date produce only small statistical effects, and very few indeed can be replicated between different study populations. This suggests that genetic contributions to longevity are diffuse and highly variable. Any single difference contributes very little, and that contribution is contingent on many other differences, such that any given regional population will have a very different map of genetic variations to longevity differences.

Here is a rare example of a more robust association between a genetic locus and longevity, and you'll note that as for other results the statistical effect on mortality is small. The paper is open access, but the full text is PDF only.

The genetic contribution to the variation in human lifespan is approximately 25%. Despite the large number of identified disease-susceptibility loci, it is not known which loci influence population mortality. We performed a genome-wide association meta-analysis of 7729 long-lived individuals of European descent (older than 85 years) and 16121 younger controls (younger than 65 years) followed by replication in an additional set of 13060 long-lived individuals and 61156 controls. In addition, we performed a subset analysis in cases older than 90 years.

We observed genome-wide significant association with longevity, as reflected by survival to ages beyond 90 years, at a novel locus, rs2149954, on chromosome 5q33.3. We also confirmed association of rs4420638 on chromosome 19q13.32, representing the TOMM40/APOE/APOC1 locus. In a prospective meta-analysis the minor allele of rs2149954 (T) on chromosome 5q33.3 associates with increased survival with a hazard ratio of 0.95. This allele has previously been reported to associate with low blood pressure in middle age. Interestingly, the minor allele (T) associates with decreased cardiovascular mortality risk, independent of blood pressure.

We report on the first GWAS-identified longevity locus on chromosome 5q33.3 influencing survival in the general European population. The minor allele of this locus associates with low blood pressure in middle age, although the contribution of this allele to survival may be less dependent on blood pressure. Hence, the pleiotropic mechanisms by which this intragenic variation contributes to lifespan regulation have to be elucidated.

Link: http://dx.doi.org/10.1093/hmg/ddu139

Researchers uncover proteins necessary to the benefits of calorie restriction by the use of genetic engineering to create lineages of laboratory animals that each lack a specific protein of interest, and then observing the results of calorie restriction for each lineage. Unlike most such efforts, in this case some of the mechanisms thought important to calorie restriction still function even without neuropeptide Y, the protein in question, but nonetheless life is not extended.

Since calorie restriction changes near everything in metabolism along the way to extending life, it has been difficult to identify which of these myriad changes are required or which contribute the greatest benefit. This work may prove useful to winnow the list of responses to calorie restriction in order to find those most important to health and longevity.

Knowledge of genes essential for the life-extending effect of dietary restriction (DR) in mammals is incomplete. In this study, we found that neuropeptide Y (Npy), which mediates physiological adaptations to energy deficits, is an essential link between DR and longevity in mice. The lifespan-prolonging effect of lifelong 30% DR was attenuated in Npy-null mice, as was the effect on the occurrence of spontaneous tumors and oxidative stress responses in comparison to wild-type mice.

In contrast, the physiological processes activated during adaptation to DR, including inhibition of anabolic signaling molecules (insulin and insulin-like growth factor-1), modulation of adipokine and corticosterone levels, and preferential fatty acid oxidation, were unaffected by the absence of Npy. This study clearly showed that Npy is a neuropeptide that links DR to longevity in mammals. However, Npy is not required for many of the physiological adaptations to DR.

Among the neuroendocrine changes induced by DR, inhibition of anabolic signaling molecules, including insulin, GH/IGF-1, and mTOR, and upregulation of adiponectin were found to extend lifespan in rodents without restricted food intake. Thus, the effects of DR were attributed to these molecules or related signaling pathways based on the observed physiological adaptations. However, in the present study, the salutary effects of DR were significantly reduced in Npy−/− mice, even though they showed normal physiological adaptions to DR. Therefore, these neuroendocrine adaptations to DR may not be essential for longevity or cancer and stress resistance.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3970128/

Rheumatoid arthritis is characteristically a disease of young women, as I was once told by an old man in the medical profession. That is a little of an exaggeration, but autoimmune diseases are not age-related by and large. Can they teach us anything about aging, however?

With this question in mind, you might think of accelerated aging conditions such as progeria, conditions that are not in fact accelerated aging, despite appearances, but rather a single form of damage run amok due to genetic mutation. In the case of progeria, this damage involves malformed lamin proteins, something that does seem to occur in a very minor way in normal aging. Researchers are still digging in to what might be learned there - it remains elusive as to whether this is in any way important, or a cause or a consequence, in normal aging.

Another example is the study of type 2 diabetes. This is a condition often used as a proxy for aging in animal studies, as the effect on some measures of health is to speed up the normal decline. But that doesn't mean it is accelerated aging any more than is progeria. Aging is cellular and molecular damage and the consequences of that damage. There are lots of ways to induce damage in an organism, but that doesn't mean that the type of damage you are looking at has any great relevance to aging. Some do, some don't, and some have only a very narrow relevance in some cases. It all depends on the details.

Back to rheumatoid arthritis, as there are researchers who argue that some of its effects can be categorized as an accelerated aging of the immune system. A fair fraction of the frailty of age stems from vulnerability to infections and a growing inability of the immune system to clear out senescent and potentially cancerous cells. As long-term readers will know by now, the immune system malfunctions with age for reasons that are at least partially structural, falling into a state of chronic inflammation coupled with increasing ineffectiveness. The question for today is whether the forms of damage and malfunction exhibited in rheumatoid arthritis are at all relevant to the normal progression of immune aging: the result looks like accelerated aging at the high level, in terms of reduced function and changes in various measures, but is there actually any overlap in the type of causative damage involved?

Some opinions on the subject follow in an open access paper, but it's worth remembering that rheumatoid arthritis might be one of the least understood of the common autoimmune conditions. Despite a great deal of work, researchers haven't yet resolved its causes or more than a fraction of the mechanisms involved in driving the condition. It may even be several quite distinct conditions lumped under this one heading, all with a similar outcome but deriving from different origins. It's a complex field, one with plenty of room for debate in the absence of a full picture that joins all of the puzzle pieces together.

Targets of Immune Regeneration in Rheumatoid Arthritis

Many of the aging-related morbidities, including cancer, cardiovascular disease, neurodegenerative disease, and infectious susceptibility, are linked to a decline in immune competence with a concomitant rise in proinflammatory immunity, placing the process of immune aging at the center of aging biology. Immune aging affects individuals older than 50 years and is accelerated in patients with the autoimmune disease rheumatoid arthritis.

Immune aging results in a marked decline in protective immune responses and a parallel increase in tissue inflammatory responses. By studying immune cells in patients with rheumatoid arthritis, several of the molecular underpinnings of the immune aging process have been delineated, such as the loss of telomeres and inefficiencies in the repair of damaged DNA. Aging T cells display a series of abnormalities, including the unopposed up-regulation of cytoplasmic phosphatases and the loss of glycolytic competence, that alter their response to stimulating signals and undermine their longevity.

Understanding the connection between accelerated immune aging and autoimmunity remains an area of active research. With increasing knowledge of the molecular pathways that cause immunosenescence, therapeutic interventions can be designed to slow or halt the seemingly inevitable deterioration of protective immunity with aging.

Research into the effects of HIV infection and AIDS on the immune system is another area with a similar relationship to normal immune aging, I should mention. There are those who think that at least some shared mechanisms are at work in both cases.

The publicity materials for this study discuss cardiac risks such as high blood pressure and blood glucose in youth without mentioning how they usually come about. The most common path towards suffering these danger signs in earlier life is to let yourself become fat and sedentary. Both of these line items are independently associated with greater ill-health and medical expenditure in later life:

Young adults with such cardiac risk factors as high blood pressure and elevated glucose levels have significantly worse cognitive function in middle age, according to a new study by dementia researchers. The findings bolster the view that diseases like Alzheimer's develop over an individual's lifespan and may be set in motion early in life. And they offer hope that young adults may be able to lower their risk of developing dementia through diet and exercise, or even by taking medications.

"These cardiovascular risk factors are all quite modifiable. We already know that reducing these risk factors in midlife can decrease the risk of dementia in old age. If it turns out that the damage begins before middle age, we may need to expand our focus and work on reducing heart disease risks in earlier stages of life."

The study examines data from more than 3,300 18- to 30-year-olds in the Coronary Artery Risk Development in Young Adults (CARDIA) study, which began enrolling thousands of participants nationwide in 1985 to understand how heart disease develops in black and white adults. Cardiac risk factors were measured every two to five years for 25 years, at which point those in the study underwent tests to measure their executive function, cognitive processing speed and verbal memory. Those whose blood pressure and glucose exceeded recommended levels during the 25-year study performed worse on all three tests, while high cholesterol was associated only with poor verbal memory.

The authors cited a number of mechanisms by which elevated blood pressure and glucose could diminish cognition in middle age, such as by reducing blood supply to the brain, causing changes in brain structure and increasing inflammation and oxidative stress, which can damage neurons. Another possibility is that these risk factors may interfere with the clearance of amyloid proteins associated with Alzheimer's disease.

Link: http://www.eurekalert.org/pub_releases/2014-03/uoc--ecr033114.php

A popular science article on the current state of progress towards therapies for cancer based on mobilizing the immune system to attack cancer cells:

More than a century ago, American bone surgeon William Coley came across the case of Fred Stein, whose aggressive cheek sarcoma had disappeared after he suffered a Streptococcus pyogenes infection following surgery to remove part of the large tumor. Seven years later, Coley tracked Stein down and found him alive, with no evidence of cancer. Amazed, Coley speculated that the immune response to the bacterial infection had played an integral role in fighting the disease, and the doctor went on to inoculate more than 10 other patients suffering from inoperable tumors with Streptococcus bacteria. Sure enough, several of those who survived the infection - and one who did not - experienced tumor reduction.

Coley subsequently developed and tested the effect of injecting dead bacteria into tumors, hoping to stimulate an immune response without risking fatal infection, and found that he was able to cause complete regression of cancer in some patients with sarcoma, a type of malignant tumor often arising from bone, muscle, or fat. Unfortunately, with the increasing use of radiation treatments and the advent of systemic chemotherapy, much of Coley's work was abandoned by the time he died in 1936.

Today, however, the use of immune modulation to treat cancer is finally receiving its due. Unlike chemotherapy and radiation treatments, which directly attack cancer cells, immunotherapy agents augment the body's normal immune machinery, increasing its ability to fight tumors. This strategy involves either introducing compounds that directly stimulate the immune cells to work harder, or introducing synthetic proteins that mimic the components of the normal immune response, thereby increasing the body's entire immune reaction. With a handful of therapies already on the market, and dozens more showing promise in all stages of clinical development, these treatments are poised to forever change the way that we approach cancer management.

Link: http://www.the-scientist.com/?articles.view/articleNo/39511/title/Deploying-the-Body-s-Army/

The Rejuvenation Research journal is completely open access as of when I looked it over today. I believe that to be a fairly recent change, so those of you without subscriptions might want to wander through the archives in search of interesting reading. In particular you might find the editorials by Aubrey de Grey to be well worth reading, and looking over those articles should provide great deal of insight into the state of aging research and the related noteworthy tensions and debates within the scientific community. Below is quoted the most recent editorial (in PDF format only, I'm afraid to say), followed by a couple of others that you may also find worthwhile:

The Real End of Ageism (PDF)

The "isms" are not so easily consigned to history, as anyone who belongs to any of the respective groups knows all too well. But ageism has a particular distinction: the group most guilty of it is precisely those affected by it, i.e. the elderly themselves.

Really? How can I make such a claim? Surely the elderly are vocal in defence of their rights to be treated as equals with the young? In many ways they certainly are. But bizarrely, when it comes to their health everything is different. They tend to the view that medical care should be prioritized for those who have not yet enjoyed a good innings. If you haven't encountered this yourself and don't believe me, try it: talk about it to a few retirees and you're in for a shock.

Let's look under the hood a bit. Why would the elderly take this view? It turns out to be very easy to explain. In a world in which aging is truly inevitable, forever, there is a pretty solid ethical basis for the idea that equitable distribution of aggregate quality of life among all people translates into working harder to maintain or restore the health of the young than the old, simply because they have more to gain before the inevitable final curtain falls. And that's exactly the premise that the elderly are non-randomly more likely than the young to adopt, since they've had that much longer having it drilled into them by the rest of humanity. They've lost the ability to aim high.

So I come to my call to action. Throughout history, humanity has only acted energetically against discrimination when those who are suffering it led the way. Therefore, we need to change this attitude on the part of the elderly, and fast, if we are to maximize humanity's cognizance of the horror of aging and its urge to defeat it as soon as science allows. We need to make the aged less ageist. And the only way we can do it is by educating them that aging is within striking distance of being brought under comprehensive medical control: the same sort of control that they are familiar with - but their parents, or at least their grandparents, were not - in respect of the diseases, such as tuberculosis and diphtheria, that back then claimed over one third of all babies before the age of one.

Selling Anti-Aging Research: The Perils of Mixed Messages

In practice, researchers do make estimates of probabilities of success all the time - in choosing what projects to work on, in evaluating each other's work during peer review, etc. So the issue here is actually not the assessment itself, but the publicizing of the assessment. Researchers in aging are acutely aware of the intense hope with which their work is followed by the wider world, and are paralyzed by fear of over-selling and under-delivering, which (they presume) would result in their being painted as no better than the purveyors of miracle anti-aging cures of time immemorial.

To me, it is that attitude which is reprehensible. Whether or not it is true [that] the loss of reputation arising from such over-selling (if it turned out so to be) would be so awful as to outweigh the funding considerations, that dilemma is between two purely selfish motives - money now and notoriety-driven shortage of money later, or less money now but reputation untarnished. What my colleagues should, in fact, be asking themselves is how they can best repay society for its decision to give them their chosen life of freedom from the private-sector rat race. (I will not digress into whether the academic rat race is any better.) I submit that the answer is clear: Researchers should say what they actually think. At present, it is customary for researchers to dangle the carrot of success in our research without mentioning time frames, thus conveniently protecting themselves from any chance of being seen as overoptimistic, but also failing to engender the public enthusiasm so vital for allowing the necessary research to actually happen. This cannot be allowed to continue.

Late-Onset, Preventative, Combination Treatments: The Triple Challenge Facing the Most Promising Anti-Aging Research Paradigm

There is no doubt whatsoever that therapies that significantly delayed the onset of age-related ill-health would be by far the most cost-effective category of medicine in history, whether that cost is measured in dollars or in human suffering. It is thus a paradox that so little effort is expended by governments or the private sector in the quest to develop such therapies, as compared to the vast amount spent on the very modestly effective treatments for age-related diseases and disability that we have today or on the equally modest prospective improvements on those treatments that disease-specific researchers aim to develop. I do not claim originality for this observation.

I believe that the main reason for this ostensibly misguided caution is that biogerontologists simply do not have good evidence that such a quest would even modestly succeed, even with a dramatic rise in the funds allocated to it. Though they are quite good at convincing themselves and each other of the promise of hypothetical "magic bullet" interventions - the most popular within the field being drugs that would mimic calorie restriction (CR) - they essentially never convince anyone with purse strings to hand. In my view, this is not because they lack marketing eloquence or motivation, but because the hard facts do not inspire objective confidence that successes seen thus far in the laboratory will ever, even in principle, translate to the clinic. The recent negative results in primate calorie restriction have surely rendered this problem even more intractable.

Calorie restriction has a such a large impact on health that you almost have to disregard any study of health and longevity in laboratory animals that fails to control for it. Even mild differences in levels of calorie intake can swamp out the effects actually being studied. In humans calorie restriction doesn't have the same dramatic effect on longevity as it does in mice - we'd have noticed by now - but it does produce a dramatic improvement in measures of health. So it is probably past time that we look with suspicion on any study that fails to account for levels of calorie intake.

This work seems like a good example of the type, as the researchers examined dietary habits that most likely correlate strongly with overall calorie intake, but did not control for calorie intake in the analysis:

Study participants were adults aged 35 years or over within the Health Survey for England (HSE). Since 2001, HSE participants have been asked about fruit and vegetable consumption on the previous day. Cox regression was used to estimate hazard ratios for an association between fruit and vegetable consumption and all-cause, cancer and cardiovascular mortality, adjusting for age, sex, social class, education, body mass index, alcohol consumption and physical activity.

We found a strong inverse relationship between fruit and vegetable consumption and all-cause mortality which was stronger when deaths within a year of baseline were excluded and when fully adjusting for physical activity. Seriously ill individuals may eat less due to illness-induced anorexia, or perhaps those with chronic illness receive more health advice and may therefore consume more fruit and vegetables. By excluding deaths within a year of baseline, we attempted to address reverse causality.

Fruit and vegetable consumption was significantly associated with reductions in cancer and cardiovascular disease mortality, with increasing benefits being seen with up to more than seven portions of fruit and vegetables daily for the latter. Consumption of vegetables appeared to be significantly better than similar quantities of fruit. When different types of fruit and vegetable were examined separately, increased consumption of portions of vegetables, salad, fresh and dried fruit showed significant associations with lower mortality. However, frozen/canned fruit consumption was apparently associated with a higher risk of mortality.

Link: http://jech.bmj.com/content/early/2014/03/03/jech-2013-203500.full

Researchers are making inroads into understanding and manipulating mechanisms of nerve regrowth so as to improve the outcome following injury:

The researchers were interested in understanding how axons in the peripheral nervous system (PNS) make a vigorous effort to grow back when they are damaged, whereas central nervous system (CNS) axons mount little or no effort. If damage occurs in the peripheral nervous system, which controls areas outside of the brain and spinal cord, about 30% of the nerves grow back and there is often recovery of movement and function. The researchers wanted to explore whether it was possible to generate a similar response in the CNS.

To investigate the differences between how the two systems respond to damage, the researchers looked at mouse models and cells in culture. They compared the responses to PNS damage and CNS damage in a type of neuron called a dorsal root ganglion, which connects to both the CNS and the PNS.

When nerves are damaged in the PNS, the damaged nerves send 'retrograde' signals back to the cell body to switch on an epigenetic program to initiate nerve growth. Very little was previously known about the mechanism which allows this 'switching on' to occur. The researchers identified the sequence of chemical events that lead to the 'switching on' of the program to initiate nerve regrowth and pinpointed the protein PCAF as being central to the process. Furthermore when they injected PCAF into mice with damage to their central nervous system, there was a significant increase in the number of nerve fibres that grew back.

Link: http://www3.imperial.ac.uk/newsandeventspggrp/imperialcollege/newssummary/news_1-4-2014-10-18-5

Calorie restriction improves health and extends life in nearly all shorter-lived species examined to date. In mice life span can be extended by 40% or more this way, but theorists don't expect an outcome of the same magnitude to take place in human calorie restriction practitioners. Firstly, our ancestors would certainly have noticed such a large effect at some point in the past few thousand years, and at the very least in the past few hundred. Secondly, longevity resulting from calorie restriction is thought to have evolved to enable greater resistance to seasonal shortages of food. A season is a short time for a human, but a long time for a mouse - and thus only the mouse has the evolutionary pressure to develop a very plastic life span in response to food availability.

Nonetheless, the calorie restriction response evolved very early on in the tree of life, and the short term effects in mice and humans are surprisingly similar. In human studies from recent years the practice of calorie restriction is shown to produce very favorable changes to metabolism and health, far greater and better than can be achieved with any present drug or medical technology. It's the same situation as exists for exercise: if either were a drug it would outsell every pharmaceutical created to date. But trying telling people they should exercise more and eat less and see how far you get.

Short-term studies are one thing, but studying calorie restriction over the long term in long-lived species is a big investment. A pair of primate studies that record the effects of calorie restriction on health and life span started decades ago and are still underway. One runs under the auspices of the NIA, the other at the University of Wisconsin-Madison. You may recall that the NIA researchers published results back in 2012 that suggested calorie restriction does not in fact have any significant effect on primate longevity. Some of the research community have in turn pointed out that the NIA study has potential issues, but I won't rehash all of that here as it is covered in the article quoted below. You might look back at these posts for background:

• Considering a Negative Result for Primate Calorie Restriction
• No Extension of Average Lifespan in Primate Study of Calorie Restriction

The latest results from the Wisconsin-Madison study have now been published, and they are more positive and more in line with what we'd expect based on short term response to calorie restriction in primates, humans included.

Monkey Caloric Restriction Study Shows Big Benefit; Contradicts Earlier Study

The latest results from a 25-year study of diet and aging in monkeys shows a significant reduction in mortality and in age-associated diseases among those with calorie-restricted diets. The study of 76 rhesus monkeys was performed at the Wisconsin National Primate Research Center in Madison. When they were 7 to 14 years of age, the monkeys began eating a diet reduced in calories by 30 percent. The comparison monkeys, which ate as much as they wanted, had an increased risk of disease 2.9 times that of the calorie-restricted group, and a threefold increased risk of death.

Still, the effects of caloric restriction on primates have been debated. An influential 2012 report on 120 monkeys being studied at the National Institute of Aging (NIA) reported no differences in survival for caloric restriction animals and a trend toward improved health that did not reach statistical significance.

The discrepancy may be a result of how the feeding was implemented in control animals in the NIA study. "In Wisconsin, we started with adults. We knew how much food they wanted to eat, and we based our experimental diet on a 30 percent reduction in calories from that point." In contrast, the NIA monkeys were fed according to a standardized food intake chart designed by the National Academy of Science. The Wisconsin researchers concluded that the NIA controls were actually on caloric restriction as well. "At all the time points that have been published by NIA, their control monkeys weigh less than ours, and in most cases, significantly so."

Twenty monkeys entered the NIA study as mature adults, 10 in the test group and 10 in the control group, and five of these (four test monkeys and one control monkey) lived at least 40 years. "Heretofore, there was never a monkey that we are aware of that was reported to live beyond 40 years. Hence, the conclusion that caloric restriction is ineffective in their study does not make sense to me and my colleagues."

This should all be filed away under basic good health practices. Yet calorie restriction, including attempts to recreate its effects on metabolism through drugs and targeted manipulation of gene expression, is the not the path to greatly extended longevity. It is among the best of presently available paths to raising your odds of having a better old age, which is good in and of itself, but you can't calorie restrict yourself to a decent chance of living to see 100. A good 99% of the people with the best diets and lifestyles die without seeing a century of life. The only thing that will make a significant difference to your prospects of great and healthy longevity is faster progress towards rejuvenation treatments - ways to prevent and reverse the course of aging. They don't exist yet, but they could in the decades ahead. Here and now that means fundraising and advocacy: pushing SENS and similar repair-based approaches to treating aging into the research mainstream.

Researchers here show an association between blood vessel stiffening and the deposition of β-amyloid in people who have not yet developed Alzheimer's disease. In general we should not be surprised to see associations between different measurable aspects of aging, as aging is a global phenomenon resulting from a small number of root causes. Thus many of the outcomes proceed in parallel to one another.

Here, however, the causes of stiffness and rising levels of amyloid formation are - so far as we know at present - two somewhat independent groups of processes. So the fact that they associate suggests that vascular dysfunction contributes to Alzheimer's disease, a relationship already suspected from a range of other evidence. Certainly the degeneration of blood vessels with aging is the cause of other forms of dementia.

Deposition of Aβ was determined in a longitudinal observational study of aging by positron emission tomography twice 2 years apart in 81 nondemented individuals 83 years and older. Arterial stiffness was measured with a noninvasive and automated waveform analyzer. Pulse wave velocity (PWV) was measured. The change in Aβ deposition over 2 years was calculated with repeat Aβ-positron emission tomography.

The proportion of Aβ-positive individuals increased from 48% at baseline to 75% at follow-up. Brachial-ankle PWV was significantly higher among Aβ-positive participants at baseline and follow-up. Femoral-ankle PWV was only higher among Aβ-positive participants at follow-up. Measures of central stiffness and blood pressure were not associated with Aβ status at baseline or follow-up, but central stiffness was associated with a change in Aβ deposition over time.

This study showed that Aβ deposition increases with age in nondemented individuals and that arterial stiffness is strongly associated with the progressive deposition of Aβ in the brain, especially in this age group. The association between Aβ deposition changes over time and generalized arterial stiffness indicated a relationship between the severity of subclinical vascular disease and progressive cerebral Aβ deposition.

Link: http://dx.doi.org/10.1001/jamaneurol.2014.186

The existence of very small embryonic-like cells (VSELs) is debated, as while several groups have claimed to isolate them from adult tissues over the past few years, others have failed to replicate this work. There have been some suggestions that these cells might be created in response to specific stresses - which may or may not be present in a researcher's approach to isolating them - rather than lying dormant in all adult tissues. This is important because if VSELs can be reliably obtained from tissues such as skin they will provide a ready, low-cost source of pluripotent cells for research and therapeutic use.

Here is an open access paper published by another group of researchers who are investigating VSELs and their potential utility for future therapies:

The purpose of this study was to determine the lineage progression of human and murine very small embryonic-like (HuVSEL or MuVSEL) cells in vitro and in vivo. VSEL cells represent a rare population in the bone marrow (less than 0.02% of nucleated cells). VSEL cells have been identified in most tissues that have been examined, including blood and other solid organs. VSEL cells have scant cytoplasm and, as the name suggests, have morphologic characteristics indicative of an immature state of differentiation, including dispersed chromatin. In addition, VSEL cells express genes that are expressed by embryonic stem cells, including Oct4, nanog, and stage-specific embryonic antigen SSEA-1. Thus, VSEL cells may give rise to derivatives of all three germ layers. VSEL cells may therefore be prime candidates for cells with the capacity to regenerate many different structures.

In vitro, HuVSEL and MuVSEL cells differentiated into cells of all three embryonic germ layers. HuVSEL cells produced robust mineralized tissue of human origin. Immunohistochemistry demonstrated that the HuVSEL cells gave rise to neurons, adipocytes, chondrocytes, and osteoblasts. MuVSEL cells were also able to differentiate into similar lineages. First round serial transplants of MuVSEL cells demonstrated that 60% of the cells maintained their VSEL cell phenotype while other cells differentiated into multiple tissues at 3 months. Secondary transplants did not identify donor VSEL cells, suggesting limited self renewal but did demonstrate VSEL cell derivatives in situ for up to 1 year. At no point were teratomas identified.

These studies show that VSEL cells produce multiple cellular structures in vivo and in vitro and lay the foundation for future cell-based regenerative therapies for bone, neural, and connective tissue disorders.

Link: http://online.liebertpub.com/doi/full/10.1089/scd.2013.0362