Fight Aging!

The extracellular matrix (ECM) is the complex structure of proteins surrounding and supporting cells. The varied mechanical properties of different tissues derive from the particular arrangement and types of molecules making up this structure: the elasticity of skin and blood vessels, the load bearing resilience of bone and cartilage, and so forth. Some of the fundamental forms of cellular and molecular damage that cause aging produce degenerative effects through changes to the extracellular matrix that degrade its properties. For example, cross-links formed by sugary metabolic waste glue together structural proteins. The most persistent types of cross-link accumulate over the years and their presence contributes to the loss of elasticity in skin and blood vessel walls, as well as to the growing fragility of bones in the elderly.

A different type of problem is caused by senescent cells, which have removed themselves from the cell cycle in response to damage or a potentially damaging local tissue environment. Senescent cells adopt what is known as a senescent-associated secretory phenotype, releasing a mix of compounds that encourage other nearby cells to become senescent, but which also degrade or restructure the surrounding extracellular matrix. Cellular senescence may be a repurposed tool of embryonic development, a mechanism that helps shape growing organs, and its activities in attacking the extracellular matrix are a holdover from that role. Whether or not this is the case, senescent cells are destructive and degrade the structural properties of the extracellular matrix where they gather in numbers.

Both senescent cells and cross-links could be dealt with in the very near future, removing and reversing their contributions to degenerative aging, given sufficient funding for research. Selective destruction of senescent cells has been demonstrated in principle, and a few research groups are working on different approaches to making a therapy of this approach. On the cross-link side of the house, the single most important type of cross-link in humans is formed of a single compound, glucosepane. Thus drug development has a single target to hit: all it takes is for the tools to be produced and for one laboratory to find a good drug candidate. This work is also underway in the early stages, carried out by a few small research groups. Neither of these lines of research is anywhere near well enough funded, or appropriately funded for the size of the potential benefits, however. A sizable chunk of the presently ongoing work is funded by one organization, the SENS Research Foundation, and supported entirely by philanthropic donations. This is the story for much of the potential rejuvenation toolkit that could be built in the years ahead - but which will take much longer to realize than it might, because funding and interest are the limiting factors. This is exactly why advocacy and education for this cause are so very important.

Structural properties of tissue determined by the extracellular matrix go beyond elasticity and strength. There is also the matter of electrical properties, important in the heart and nervous system. Degradation of the extracellular matrix in heart tissues and its impact on the heart's electrical conduction system is probably a contributing factor the increased prevalence of arrhythmias and similar issues with advancing age.

The role of extracellular matrix in age-related conduction disorders: a forgotten player?

Prevalence of cardiac arrhythmias increases over time during aging, carrying significantly higher morbidity and mortality in the elderly. Defective impulse generation and conduction and ECM disarray with augmented intramyocardial fibrosis during aging are considered the main biological processes responsible of these disturbances.

In this context, in spite of the interest addressed by the literature to the "aged cardiomyocyte" as the main pathological responsible of age-related conduction disturbances, there are several lines of evidence pointing at changes in the structure and function of the extracellular matrix (ECM) as an important actor. At the biophysical level, cardiac ECM exhibits a peculiar degree of anisotropy, which is responsible for the elastic and compliant properties of the ventricle and for the structural properties of heart valves. However, ECM components and their arrangement are also the main determinants of the conductive properties of the specialized electrical conduction system. Moreover, cardiac ECM is actively sending biological signals regulating cellular function and tissue homeostasis. Alterations of ECM function in the elderly might additionally exert a detrimental effect on the normal function of the conduction system and on overall ventricular function and cardiac performance. Age-associated alterations of cardiac ECM are therefore able to profoundly affect the function of the conduction system with striking impact on the patient clinical conditions.

The function of the sinoatrial node (SAN) deteriorates with age with an increase in the nodal conduction time and a decrease in the intrinsic heart rate. Collectively, those alterations translate at the clinical side in the so-called sick sinus syndrome, whose manifestations include bradycardia, sinus arrest, and sinus exit block. Additionally, considering the hemodynamic changes occurring with aging, which are basically constituted by a reduction of ventricular compliance and an increased contribution of atrial contraction to ventricular filling, dual chamber pacemakers maintaining synchrony between atria and ventricles are advantageous in older adults. During the aging process, the described structural and functional changes occurring in the left ventricle are interlaced with malfunction of the conduction system, which in turn results in non-efficient and non-synchronous activation of both ventricles, fostering a vicious circle eventually worsening the detrimental effects on cardiac performance.

Conduction disturbances are frequent among the elderly and carry significant morbidity and mortality representing a clinical and economical burden. Complex cellular interplay and paracrine biological signaling underlie this phenomenon and targeting fibrosis generation and its pathological characteristics might be a promising therapeutical approach for age-related arrhythmic disease. Deepening knowledge on ECM age-associated alterations might be important in the development of novel therapeutical approaches in the widespread panorama of age-related disease.

Here is an interesting look at the progression and prevalence of DNA damage leading to leukemia, cancers of bone marrow and white blood cells. Cancer is an age-related disease because its proximate cause is DNA damage and we accumulate ever more of this damage as time goes on. DNA repair systems in our cells and destruction of precancerous cells by the immune system are highly efficient but not perfect, and falter with age due to other forms of accumulating damage. The development of a robust suite of effective cancer treatments is an essential part of progress towards effective treatments for degenerative aging, and perhaps so is a means of DNA repair as well:

It is almost inevitable that we will develop genetic mutations associated with leukaemia as we age. Based on a study of 4,219 people without any evidence of blood cancer, scientists estimate that up to 20 per cent of people aged 50-60 and more than 70 per cent of people over 90 have blood cells with the same gene changes as found in leukaemia. Scientists investigating the earliest stages of cancer development used an exquisitely sensitive sequencing method capable of detecting DNA mutations present in as few as 1.6 per cent of blood cells, to analyse 15 locations in the genome, which are known to be altered in leukaemia. By comparing their findings with other research conducted with a lower degree of sensitivity over whole exomes, the scientists were able to conclude that the incidence of pre-leukaemic cells in the general population is much higher than previously thought and increases dramatically with age.

The pre-leukaemic mutations studied appear to give a growth advantage to the cells carrying them and this starts a process in which cells with these mutations dominate blood making. As they increase in number, the likelihood that one or more of them will acquire more mutations becomes greater, something that could eventually lead to leukaemia and leukaemia-like disorders. Interestingly, the study found that mutations affecting two particular genes, SF3B1 and SRSF2, appeared exclusively in people aged 70, suggesting that these mutations only give a growth benefit later in life, when there is less competition. This finding explains why myelodysplastic syndromes, a group of leukaemia-like conditions associated with these genes, appear almost exclusively in the elderly.

None of the 4219 people studied were found to have a mutation in NPM1, the most common acute leukaemia gene mutated in up to 40 per cent of cases. This unexpected result suggests that mutations in NPM1 behave as gatekeepers for this cancer; once a mutation in this gene occurs in a cell with particular previously accumulated pre-leukaemic mutations, the disease progresses rapidly to become leukaemia. "The significance of mutations in this gene is astonishingly clear from these results: it simply doesn't exist where there is no leukaemia. When it is mutated in the appropriate cell, the floodgates open and leukemia is then very likely to develop. This fits with studies we've conducted in the past in which we found that the gene primes blood stem cells for leukaemic transformation."

Link: http://www.eurekalert.org/pub_releases/2015-02/wtsi-lma022415.php

Researchers are working on a method of delivering cells for cartilage regrowth in aged joints that doesn't use a porous scaffold in order to guide cell growth, but rather relies on the engineering of specific cell characteristics. In theory this should produce a better end result:

In many cases, the cause of age-related joint pain is a loss of hyaline cartilage, which does not have the capacity to regenerate, meaning once gone it is gone forever. Hyaline cartilage is constituted of chondrocytes and its secretions, extracellular matrix (ECM) proteins, which includes collagens II and XI. They do not include collagen I, which is the primary collagen in fibrocartilage, or scar tissue. The key to a successful recovery then is to introduce into the deteriorated cartilage chondrocytes that secrete only hyaline cartilage ECM proteins.

One of the most common strategies for treating hyaline cartilage damage is autologous chondrocyte transplantation. This technique involves acquiring hyaline cartilage from a biopsy and then transplanting it to the injured site. Because the biopsy is smaller than the area that needs repair, the chondrocytes must be expanded, a task that requires enzymatic digestion of the ECM proteins. Unfortunately, the expansion causes the chondrocytes to secrete collagen I, which is why the presence of fibrous tissue is inevitable after such operations.

To solve this problem, researchers report a new protocol that expands not chondrocytes, but induced pluripotent stem (iPS) cells. When a sufficient number of iPS cells are expanded, the protocol then calls for the researchers to differentiate the cells into chondrocytes. Because these chondrocytes are differentiated directly from iPS cells, there is no need to digest ECM proteins, which avoids the problem of fibrous tissue and allows for only hyaline cartilage to be synthesized. Another advantage to this method is that it avoids the use of artificial scaffolds. In other studies artificial scaffolds are included into the transplant to provide support until the chondrocytes begin secreting their own ECM proteins. However, it is unclear if artificial materials prevent optimal integration into the cartilage. Because the chondrocytes have already begun secreting ECM proteins, they can be transplanted without scaffolds.

The team transplanted their particles into three animal models: mouse, rat and mini-pig, finding positive signs for integration and maintenance. "These findings are only preliminary, but they show good indications of safety. The next step is to find the best conditions for transplantation in larger animals before we can consider patient treatment."

Link: http://www.eurekalert.org/pub_releases/2015-02/cfic-sic022315.php

Seeking to recreate the benefits of calorie restriction - greater health and longer life - without the part of the process wherein you must eat less is a grail for modern medical research. The calorie restriction response is of greater benefit to basically healthy people than that produced by any currently available medical technology. Putting forward the idea that people should eat fewer calories is not a popular position in this modern age of comparatively wealth and comfort, however. It is entirely reasonable to expect that any new medicine that safely produced even a sizable fraction of the long term health improvements and slowing of aging triggered by the practice of calorie restriction would make a great deal of money. Thus there is a willingness in the research and development community to invest large amounts in scientific programs that have a chance of making this happen. Based on the pace of progress over the past two decades we shouldn't expect this grail to materialize any time soon, however. Calorie restriction changes near everything that can be measured in the operation of metabolism, and picking apart the complexity of this response costs billions and years even for a tiny slice of progress in understanding. Look at the history of sirtuin research, for example: a lot of hype at the outset, and nothing to show for it today but very expensive knowledge, a tiny addition to a vast catalog yet to be written.

Nonetheless the grail continues to attract attention. To the extent that this draws new funding into human life science research, this is all to the good: there's no such thing as too much life science research. Recreating calorie restriction isn't, however, an effective path to rejuvenation. It's just another way to tinker with the operation of metabolism to gently slow down the damage of aging. This is not particularly helpful to the old, who are already heavily damaged, and if takes decades for the research community to get anywhere, as seems most likely, it is not all that helpful to today's middle aged folk either. Research will always move forward, and tomorrow will be better than today, but it is very important that rejuvenation research aimed at dramatically cutting the rate of death and disease caused by aging moves as rapidly as possible to as beneficial an outcome as possible. Hundreds of millions of lives are the cost of a few years of delay. Calorie restriction mimetic development is a poor, expensive path. We should be focused on repair based strategies like SENS instead, those capable of producing rejuvenation and greatly extended healthy life spans as an outcome.

All things considered practicing calorie restriction now is a great plan. You can do it for next to nothing, and it has an expected beneficial effect considerably larger than any tinkering you can do with supplements and available medical technologies, assuming you're a basically healthy individual. Investing billions and decades and waiting for a drug that can do less for you than eating less? Not such a great plan. Decades and billions should be delivering far better results than that in terms of treatments for degenerative aging.

Here is news of work on a more recent approach to mimicking the effects of calorie restriction: it has become apparent that sensory neurons have a large effect on the calorie restriction response in lower animals, independent of actual calorie intake. This raises the possibility of some form of top-down manipulation in which at least some of the metabolic changes associated with calorie restriction are induced by altering the biochemistry of these sensory neurons. I should note that this is still all very early stage research, however. The grail is really no closer because of it.

Perception of food consumption overrides reality

The study focused on a molecule called AMP-activated protein kinase, or AMPK, which acts as a molecular fuel gauge to detect energy levels. It's been known that AMPK plays important roles in all cell types, but researchers didn't understand which of these activities were most critical to regulating longevity. The researchers found that AMPK inhibited the activity of a protein called CRTC-1 in mitochondria - the primary energy-producing organelles in cells - throughout the organism, by altering production of a neurotransmitter.

The researchers were struck by the fact that altering the AMPK pathway in just a limited set of neurons was sufficient to override its effects on metabolism and longevity in other tissues. Aging was influenced more by what the animals perceived they were eating than what they actually ate. The study suggests that manipulating this energy-sensing pathway can cause organisms to perceive their cells to be in a low-energy state, even if they are eating normally and energy levels are high. Drugs targeting the cells' energy-sensors in this way could potentially address age-related diseases, including cancer and neurodegeneration, and may offer an alternative to calorie restriction.

Neuronal CRTC-1 Governs Systemic Mitochondrial Metabolism and Lifespan via a Catecholamine Signal

Low energy states delay aging in multiple species, yet mechanisms coordinating energetics and longevity across tissues remain poorly defined. The conserved energy sensor AMP-activated protein kinase (AMPK) and its corresponding phosphatase calcineurin modulate longevity via the CREB regulated transcriptional coactivator (CRTC)-1 in C. elegans. We show that CRTC-1 specifically uncouples AMPK/calcineurin-mediated effects on lifespan from pleiotropic side effects by reprogramming mitochondrial and metabolic function. This pro-longevity metabolic state is regulated cell nonautonomously by CRTC-1 in the nervous system. Targeting central perception of energetic state is therefore a potential strategy to promote healthy aging.

When it comes to the mechanisms by which the operation of metabolism determines natural variations in longevity, few areas are as well studied as the role of insulin and insulin-like growth factor (IGF-1). This is no doubt in part due to the size and influence of the type 2 diabetes research community, but it is also the case that most of the methods so far demonstrated to slow aging and extend life in mice, such as calorie restriction, appear to act at least partially through alterations to insulin metabolism and related systems. Here is a review on this topic, with a focus on the brain:

Insulin is the most powerful anabolic hormone discovered to date. Besides the well-established action of insulin in peripheral organs, such as liver, muscle, and adipose tissue, it is becoming increasingly clear that insulin affects important features of glucose metabolism via central mechanisms. Insulin signaling has been linked to longevity in organisms ranging from nematodes to mammals.

There is an impressive body of literature implicating insulin/IGF-1 like ligands and insulin/IGF-1 signaling in the regulation of metabolism, development, and longevity in the roundworm C. elegans. In response to food or the perception of food, multiple insulin-like ligands are secreted from neurosecretory cells in the brain of C. elegans and D. melanogaster, indicating that in these invertebrates, the central nervous system (CNS) plays a key role in insulin signaling mediated regulation of physiology and lifespan in response to environmental cues. In mammals, the insulin/insulin-like growth factor-1 signaling cascade exhibits some striking differences compared to the insulin/insulin-like growth factor-1 signaling cascade in invertebrates. These differences include the acquisition of growth hormone as a main regulator of IGF-1 production by the liver, and the acquisition of separate receptors for insulin and IGF-1. Again, several of the existing long-lived mammalian mutants with defects in insulin/IGF-1 signaling point to a role of the CNS in the regulation of mammalian longevity.

Also in humans, preserved insulin sensitivity has been associated with longevity. Insulin resistance has been shown to predict the development of age-related diseases, including hypertension, coronary heart disease, stroke, cancer, and type 2 diabetes. In the general population, the association between aging and decline in insulin sensitivity has been demonstrated in several studies. Mechanisms suggested to contribute to decreased insulin sensitivity in the elderly include (i) age-related receptor and post-receptor defects in insulin action, (ii) an age-related decrease in insulin stimulated whole body glucose oxidation, (iii) an age-related reduction in beta cell response to glucose, and (iv) impaired insulin-mediated glucose uptake, and inability to suppress hepatic glucose output. In contrast, centenarians, which exhibit exceptional longevity, seem protected against the age-related decline in insulin sensitivity when compared to a group of advanced middle-aged individuals.

We speculate that healthy longevity is associated with preserved brain insulin action. Enhanced insulin efficacy might occur through measures aimed at minimizing inflammation; and enhanced delivery might be promoted to the brain areas that are crucial for healthy longevity. Inflammation, including that occurring in the hypothalamus, has been linked to age-related decline in insulin sensitivity. Physical exercise is known to be protective against numerous diseases and reduction of inflammation has been implicated in the health benefits conferred by exercise. Notably, a lower intake of calories and food that is rich in saturated fat and carbohydrates has been shown to reduce inflammaging. Future research may focus on hypothalamic microglia as relevant targets for prevention and treatment of metabolic disorders.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4319489/

There are a score or so of different forms of amyloid that accumulate in the aging body and brain. These are misfolded proteins that precipitate out of tissue fluids to form clumps, and the biochemistry surrounding this process can cause harm in numerous ways. Alzheimer's disease is associated with amyloid-beta, and long years of research in that field illustrate that the mechanisms by which amyloid formation can damage tissue function are potentially very complex. A few other forms of amyloid are directly linked to age-related disease, but many are not, or ambiguity remains regarding how they are harmful. Still, the presence of amyloid is a clear difference between young tissue and old tissue. Any potential rejuvenation toolkit should include a way to safely clear these misfolded protein aggregates, such as via immunotherapies of the sort under development as potential Alzheimer's treatments.

Here is a speculative paper on the role of microbes in amyloid accumulation in the body. While reading note that amyloid levels, at least for amyloid-beta, are very dynamic. The body can clear it, but those clearance processes either diminish with the damage of aging or are slowly overwhelmed by increased generation:

Atypical amyloid generation, folding, aggregation and impaired clearance are characteristic pathological features of human neurodegenerative disorders including Alzheimer's disease (AD). What is generally not appreciated is that a major secretory product of microbes is amyloid, and that the contribution of microbial amyloid to the pathophysiology of the human central nervous system (CNS) is potentially substantial. While earlier findings suggested that these amyloids may serve some immune-evasive strategy, it has recently become evident that humans have a tremendously heavy systemic burden of amyloid which may contribute to the pathology of progressive neurological diseases with an amyloidogenic component.

Diverse microbes of the human microbiome generate functional amyloids. The large amount of microbial-generated GI amyloid implicates high potential systemic exposure to bacterial amyloid, and the bioavailability of amyloid to the CNS increases as humans age. Microbial and CNS amyloids are biologically similar in their structure and immunogenicity and complex mechanistic interrelationships between these amyloids are beginning to emerge.

Microbes or their secretory or degradation products including their amyloids and lipopolysaccharides are powerful inflammatory activators and inducers of cytokines and complement proteins, affecting vascular permeability and generating free-radicals that further support amyloidogenesis. These pathogenic signaling features are also highly characteristic of AD neuropathology. A more detailed understanding of human microbial ecosystems and their amyloids should give insight into amyloid-misfolding and their contribution to inflammatory-signaling in health, aging and disease. It will certainly be interesting to see: (i) if any microbial-generated amyloids co-localize with the amyloid-dense senile plaque deposits of AD; (ii) if GI tract microbiome-derived amyloids become more available systemically as humans age; and (iii) what the evolution and nature of amyloid-related communication between the gastrointestinal tract and the CNS has on the development or propagation of amyloids in pro-inflammatory degenerative disease.

Link: http://dx.doi.org/10.3389/fnagi.2015.00009

Ours is an era on the verge of developing means to treat the root causes of degenerative aging and thereby extend healthy life, eliminate age-related disease, and rejuvenate the old. The decades ahead are a critical time, in which the best and most promising approaches to research and development either take off or falter. There are all too many examples from the past in which promising new technologies languished long past the point at which they could have been created and made widely available. We don't want that to happen here, as it means the difference between health or frailty, life or death for all of us.

The first in a series of Rejuvenation Biotechnology conferences organized by the SENS Research Foundation was held late last year, and by all accounts went very well. You should certainly take a look at the BioWatch News special issue devoted to the conference and its goals if you have not already done so. It is a thoughtful look at some of the issues facing research and development in those parts of the field of aging research focused on intervention and cures.

The aim of the Rejuvenation Biotechnology conference series is to lay the groundwork for closer collaboration between industry and research establishments in the development of near future therapies to treat degenerative aging. The scientific foundations needed for rejuvenation therapies are progressing at a pace that is far slower than we'd all like, but it is nonetheless time to prepare the way for clinical translation of research results. That process takes time, and to pick one example, initial attempts at clearance of senescent cells might be only a few years away from initial clinical trials at this point: a for-profit startup company was recently founded to work on one approach. While it is easy to imagine that any practical treatment for aging would be mobbed by developers seeking to bring it to market as soon as it makes it out of early stage research, in truth that sort of outcome only happens when sufficient preparation has taken place. That means at the very minimum building a network of relationships and knowledge.

Videos of presentations given at the Rejuvenation Biotechnology conference were recently posted by the SENS Research Foundation staff. I think you'll find them interesting. Many more than are shown here can be found at the SENS Research Foundation YouTube channel.

The Rejuvenation of Aged Skeletal Muscle by Systematic Factors

The primary research focus of the Jang laboratory is to understand the molecular and biochemical mechanisms of age-related muscle loss and function. The Jang laboratory applies bioengineering approaches and stem cell-based therapies to study skeletal muscle dysfunction during aging and in age-associated muscle diseases. The laboratory develops and applies novel tools using a combination of animal and stem cell models.

A Twist of Fate - Generating New Neocortical Neurons

The line of investigation aims to establish ways of regenerating the principle neurons of the adult cerebral cortex when these neurons are lost due to trauma or degeneration, including degeneration due to aging. Since endogenous precursors do not replace cortical neurons when they are lost, two strategies are being developed: manipulating these precursors with molecular genetic techniques to start generating neurons and transplanting engineered precursors that are programmed to disperse in the cortex and differentiate into cortical projection neurons.

Building a Rejuvenation Biotechnology Industry - Panel Discussion

This panel synthesized the discussions from all of the conference sessions and panels. A cross-section of academics, pharmaceutical reps, policy makers, and other presenters revisited the merits of a damage repair paradigm to address the diseases of aging considered at this conference. Panelists considered the changes that would be required to lay the groundwork for a new industry perspective focused on addressing damage indications for the diseases of aging either through preventing or repairing such damage.

Via the Buck Institute Science of Aging blog, here is a look at the work of a scientist who specializes in the intersection of the stem cell and aging fields, an area that includes cancer and regenerative research:

Hematopoietic stem cells regenerate over a person's lifetime and can differentiate into all the different blood cell types found in humans, such as T-cells and B-cells. In principal, the hematopoietic stem cell population can regenerate from a single cell. So in theory a single transplanted cell can repopulate the pool. We have tried to do this in the hematopoietic system of old mice by taking hematopoietic stem cells from young mice and transplanting them into old mice, and the result was disappointing. The new stem cells did not integrate well and the aged in vivo environment did not allow for the newly introduced stem cells to function properly. In terms of using induced pluripotent stem cells (IPS cell) there are additional risks involved. IPS cells can transform and become cancerous, and they need to be generated and differentiated in culture, which is both time consuming and costly. I think trying to better understand why endogenous stem cells stop functioning and then adjusting the environment in vivo to keep them active, is a promising alternative avenue of treatment.

Studies have shown that stem cells are often the origin of many cancers. Due to their long lives and high replication rate, when compared to somatic cells, stem cells have an increased risk of acquiring DNA mutations that can cause cancer and other diseases. When studying hematopoietic stem cells, it is possible to isolate them from a simple blood sample. These cells can then have their DNA sequenced for possible mutations that might lead to cancer. With a better understanding of these mutations, new cancer treatments that are genetically designed and targeted for those mutations can be created, and then used in a patient specific manner. The problem is that although you may be able to test for these predictive mutations in other tissues, it is very difficult to obtain tissue samples from various organs. One must also keep in mind that a mutation detected in blood cells is not always present in other organs. The mutations that we are detecting are not always those that one is born with but also those that occur over a person's lifetime due to continual DNA damage and repair. So different cells and organs will have different mutations that occur over time. People are now developing nanotechnologies to take measurements from different cells.

Link: http://sage.buckinstitute.org/interview-with-dr-karl-lenhard-rudolph-mechanisms-of-aging-and-transformation-of-stem-cells/

Tissue engineering of muscle continues to move forward, with a new approach here demonstrated in mice:

Tissue engineering of skeletal muscle is a significant challenge but has considerable potential for the treatment of the various types of irreversible damage to muscle that occur in diseases like Duchenne muscular dystrophy. So far, attempts to re-create a functional muscle either outside or directly inside the body have been unsuccessful. In vitro-generated artificial muscles normally do not survive the transfer in vivo because the host does not create the necessary nerves and blood vessels that would support the muscle's considerable requirements for oxygen. Now, however, researchers have succeeded in generating mature, functional skeletal muscles in mice using a new approach for tissue engineering. The scientists grew a leg muscle starting from engineered cells cultured in a dish to produce a graft. The subsequent graft was implanted close to a normal, contracting skeletal muscle where the new muscle was nurtured and grown.

The scientists used muscle precursor cells - mesoangioblasts - grown in the presence of a hydrogel (support matrix) in a tissue culture dish. The cells were also genetically modified to produce a growth factor that stimulates blood vessel and nerve growth from the host. Cells engineered in this way express a protein growth factor that attracts other essential cells that give rise to the blood vessels and nerves of the host, contributing to the survival and maturation of newly formed muscle fibres. After the graft was implanted onto the surface of the skeletal muscle underneath the skin of the mouse, mature muscle fibres formed a complete and functional muscle within several weeks. Replacing a damaged muscle with the graft also resulted in a functional artificial muscle very similar to a normal tibialis anterior.

Link: http://www.alphagalileo.org/ViewItem.aspx?ItemId=150064&CultureCode=en

There are now many lineages of genetically engineered mice that exhibit longer healthy, median, and maximum life spans, though none have yet come close to the 60-70% record set by growth hormone loss of function mutants. It is no longer newsworthy for a new variety of long-lived mouse to be discovered, and indeed many now pass by without comment. Extending life in mice by 10-30% through a single genetic alteration is a commonplace occurrence. Many of these interventions work through an overlapping set of related mechanisms that can be manipulated at many points, such as increased cellular housekeeping, and many are related to the calorie restriction response, the increase in health and life span that occurs due to a lower calorie intake.

Slowing aging by altering the operation of metabolism is ultimately not the real path to extending human life spans. Firstly where we can make direct comparisons between results in short-lived animals and results in humans, the effects on human life span are minimal even when the short term health benefits are similar. Calorie restriction certainly doesn't extend life by 40% in humans as it can in mice. Growth hormone loss of function mutations in humans such as Laron syndrome do not produce people who live vastly longer than the rest of us. Secondly a way slow aging will not help old people: what good is it to slow down the rate of damage accumulation for someone already so damaged as to be close to death? We want damage repair, means of rejuvenation, not mere slowing of the decline. Thirdly it is proving to be enormously expensive to make any real progress on this front: billions of dollars over two decades has produced only knowledge, and no practical treatment that comes anywhere near the proven benefits provided by regular moderate exercise or calorie restriction.

Slowing aging is a great way to investigate the vast unknown areas of cellular metabolism if the end goal is only knowledge, producing the catalog of human metabolism down to the tiniest detail, and not a matter of extending human life span. If we want longer lives, then the research community should be focused on rejuvenation through damage repair, which is a completely different research strategy in comparison to slowing aging. The aim is not to alter the operation of metabolism at all, but instead to periodically sweep away the damage that occurs as a side-effect of its normal operation.

This is not to say that research into slow-aging mutants is uninteresting. On the contrary, it is exciting stuff if you like to follow progress in the life sciences. A great deal is being learned and scarcely a day goes by without something newsworthy turning up. For example there is this open access paper, in which a calorie-restriction-like method of extending life is shown to improve wound healing in old age. Note that this lineage of long-lived mice (exhibiting a 20% increase in life span or thereabouts) was not created for that purpose, and has existed for more than 20 years. The canonical review paper on their longevity is from 1999. It is entirely possible that there are as yet a range of mouse lineages in labs that exhibit modest life extension and yet no-one has noticed because life span studies haven't been carried out:

Wound healing and longevity: Lessons from long-lived αMUPA mice

Although there is no clear consensus on whether aging affects the quality of skin wound healing (SWH), the rate of SWH is often used as one of the biomarkers for biological age and could be indicative of a longevity phenotype. However, a clear-cut answer as to whether the longevity phenotype is associated with accelerated SWH remains obscure. Even in case of calorie restriction (CR), one of the most successful longevity-promoting interventions in mammals, the few studies conducted thus far did not bring about decisive results.

To address this issue, we investigated SWH in the long-lived transgenic αMUPA mice, a unique genetic model of extended lifespan. The αMUPA mice carry a transgene specifically expressed in the ocular lens. Being initially generated in 1987 to investigate eye pathologies, these transgenic mice were unexpectedly found to display a longevity phenotype. Compared to their wild type (WT) counterparts, the αMUPA mice spontaneously eat less when fed ad libitum, and live longer. The αMUPA mice also maintain an overall young look and physical activity at advanced ages and show a significantly reduced rate of spontaneous and induced tumorigenesis. Thus, the αMUPA mice share many common features with CR, yet are not hindered by several major drawbacks of CR such as hunger-induced stress and a need for individual housing (social stress). In view of using αMUPA mice as a CR-mimicking model to study the impact of CR on SWH, it is important to stress that the αMUPA mice strongly express the transgene in the ocular lens and ectopically in the brain but not in the skin, thus excluding the gene-specific effects on SWH.

We found that αMUPA mice showed a much slower age-related decline in the rate of WH than their wild-type counterparts. After full closure of the wound, gene expression in the skin of old αMUPA mice returned close to basal levels. In contrast, old wild-type mice still exhibited significant upregulation of genes associated with growth-promoting pathways, apoptosis and cell-cell/cell-extra cellular matrix interaction, indicating an ongoing tissue remodeling or an inability to properly shut down the repair process. It appears that the CR-like longevity phenotype is associated with more balanced and efficient WH mechanisms in old age, which could ensure a long-term survival advantage.

This open access paper reviews what is known of the biochemistry of Parkinson's disease. The underlying issue is usually presented as the loss of a small population of dopamine generating neurons. This happens to some degree to everyone over the course of aging; lose enough of these neurons and you will manifest the condition. As to why some people do and some people don't, it's all a question of whether you are inherently more susceptible to the underlying cell death mechanisms, as is the case in a small fraction of the population, or simply through happenstance reach a threshold of loss sufficient to cause symptoms. The question proposed here is whether loss of neurons is all that is going on, or whether the many other changes that occur with aging are also necessary for the development of Parkinson's as a disease:

It is generally considered that Parkinson's disease (PD) is induced by specific agents that degenerate a clearly defined population of dopaminergic neurons. Data commented in this review suggest that this assumption is not as clear as is often thought and that aging may be critical for PD. Neurons degenerating in PD also degenerate in normal aging, and the different agents involved in the etiology of this illness are also involved in aging. Senescence is a wider phenomenon affecting cells all over the body, whereas Parkinson's disease seems to be restricted to certain brain centers and cell populations.

However, reviewed data suggest that PD may be a local expression of aging on cell populations which, by their characteristics (high number of synaptic terminals and mitochondria, unmyelinated axons, etc.), are highly vulnerable to the agents promoting aging. PD is the result of the slow neurodegenerative action of aging, an effect that can be accelerated by repeated damage to dopaminergic neurons accumulated over a person's lifespan. When the dopaminergic neurons degeneration reaches a critical level and the compensatory mechanisms are insufficient to maintain the basic functions of dopamine, the first motor disturbances appear and the diagnosis of PD can be made. Thus, the etiologic agents involved in PD could be the same as those involved in aging.

The action of these agents could be particularly important in dopaminergic neurons because of their high vulnerability to age-related agents and because these cells are highly susceptible to a number of silent toxics. This could explain why 50 years after first finding of dopaminergic neuron degeneration in sporadic PD, no specific causes for this illness have yet been found. In our opinion, more direct attention to the aging processes could accelerate the acquisition of new knowledge on the biological basis of PD, and actions aimed at delaying aging or promoting rejuvenation could also be useful to control the onset and progression of PD.

Link: http://onlinelibrary.wiley.com/enhanced/doi/10.1111/acel.12312/

Here is little more press for the Palo Alto Longevity Prize, which will make awards for the extension of healthy life in mammals based on heart rate variability as a measure of physiological aging. Aside from all the normal networking and influence effects produced by research prizes, and this one will certainly boost the growing Bay Area community of longevity advocates and researchers, the initiative should go some way towards validating or invalidating the use of measures such as heart rate variability as a biomarker of aging. Independently of progress towards ways to intervene in the aging process, the development of good biomarkers to measure physiological age is very important. How else to evaluate any proposed rejuvenation therapy in a reasonable amount of time? Without biomarkers, the only things you can do are guess or wait: running full life span studies is very expensive even in mice, and never mind in longer-lived species. Anything that makes rigorous research more expensive slows down progress, and should be targeted for improvement.

As the sponsor of the million-dollar Palo Alto Longevity Prize, Joon Yun, M.D., knows that with each passing week, a million additional people will die around the globe, and the majority of them will die because of aging-related diseases. Dr. Yun, who thinks about aging research as a race against time, is a medical doctor and president of Palo Alto Investors, an investment management firm with more than $1 billion invested in healthcare. What he saw led him to wonder if aging wasn't just an accumulation of diseases, but rather, a process. He wondered if instead of trying to treat individual diseases in a whack-a-mole type approach, could we instead look for upstream switches that could prevent or resolve aging?

The questions was, how could he contribute? Calling on his undergraduate background in biology at Harvard, Dr. Yun decided to use the same model that evolution does. Evolution operates through the production of variation and from many possibilities, selects winners. He learned about the power of incentive prizes to nurture innovations and decided to apply it as a tool for aging research. In Dr. Yun's view, the current healthcare system, which treats the symptoms of aging, but not its underlying cause, helps individuals live longer. But there are two flaws with this approach. The first is, the longer individuals live, the more healthcare they consume, leading to feed-forward increases in costs. The second flaw is that aging remains a terminal disease.

Dr. Yun and the scientific advisors of the Palo Alto Longevity Prize are looking at aging from a more fundamental perspective. They realized that aging, if you go deep enough, is an unraveling of homeostatic capacity. A young man, who in his 20s had both healthy blood pressure and healthy blood sugar, may find that in his 50s, his eroding homeostatic capacity no longer effectively regulates these functions and now has hypertension and diabetes. Therefore, Dr. Yun and his team elected to focus on improving homeostatic capacity as a way to improve health, and improving health as a way to improve longevity.

Link: http://www.genengnews.com/insight-and-intelligence/palo-alto-longevity-prize-asks-if-the-aging-code-can-be-cracked/77900392/

Good advocacy can consist of a few bold actions that attract attention and make waves: if done well those waves can take on a life of their own. Making large wagers for this purpose has a long history, as money has a certain gravity when it comes to gathering interest from people on the sidelines. Indeed, the benefits provided by research prizes - which is to say an acceleration of progress while attraction new attention to a field of scientific endeavor - accrue for many of the same reasons. If you can engineer a way to legitimately talk about a large amount of money in connection with a cause you support, then you should do so. People will talk, and that is very much the point of the exercise.

Below you'll find a report of a recent act of advocacy for the cause of longevity science. To the degree that it succeeds it of course also benefits the folk involved and their business ventures, but deservedly so I think. There is more than enough biotechnology investment money floating around in this world to fully fund numerous approaches to human rejuvenation a dozen times over without blinking, were there the interest and the will to do so. The archetype of ending aging, the SENS research programs, could run to completion for a billion dollars or so, for example, to produce working demonstrations of all necessary repair therapies in laboratory mice. That much is spent on advancing a single convincing drug candidate these days. Success in bringing an end to degenerative aging is thus really more a matter of convincing people to pay attention than anything else. The science is ready to roll on at a rapid pace, but the funding and the public support for these initiatives lags far behind:

Anti-Aging Experts Made a Million-Dollar Bet on Who Dies Last

Dmitry Kaminskiy, senior partner of Hong Kong-based technology venture fund, Deep Knowledge Ventures, and Dr. Alex Zhavoronkov, PhD, CEO of bioinformatics company Insilico Medicine Inc. which specializes in drug discovery and drug repurposing for aging and age-related diseases, signed a wager to indicate exactly how sure they are that science is turning the tide against the eternal problem of human aging: If one of the parties passes away before the other, $1 million dollars in Insilico Medicine stock will be passed to the surviving party. The agreement will vest once both parties reach 100 years.

"Longevity competitions may be a great way to combat both psychological and biological aging," Dr. Zhavoronkov emailed me. "I hope that we will start a trend." He sees longevity bets catching on around the world, and thinks if people will embrace competition to live longer, they may leave behind a global culture that largely accepts aging and human death as a given. Kaminskiy agrees. "I would really like to make similar bets with Bill Gates, Elon Musk or Mark Zuckerberg so they could live longer lives and create great products, but I don't think they will be worthy competitors on longevity," he wrote me in an email. "But I would like to challenge Sergey Brin and Larry Page to a similar competition due to their seemingly high interest in the sphere and Calico project."

The last two years have seen the creation of major anti-aging companies, such as Google's Calico and J. Craig Venture's new San Diego-based genome sequencing start-up Human Longevity Inc., (co-founded with Peter Diamandis of the X-Prize Foundation and stem cell pioneer Robert Hariri) which already has 70 million dollars in financing. Billionaires like Larry Ellison and Peter Thiel are also funding research into longevity science.

If the bet between Kaminsky and Zharvorokov seems a like a way to generate publicity hype for longevity science, that's because it is. But like many other longevity leaders, they are not in this to for money or fame. They are doing this for a singular and extremely human reason: They don't want to die. And they want others to know that - in the 21st Century, an age spilling over with new radical science, medicine, and technology - they might not have to either. "Technology is evolving so fast," Kaminskiy said, "that I have no doubt that we will be able to live centuries instead of decades."

At some point, as I've been saying for far too long now, a meaningful number of people with a lot of money will come to realize that they can spend that money to obtain many more years of healthy, vigorous life. Rejuvenation research will begin to look like a very sane investment to people with a great deal of wealth to invest. Things will become interesting in the years following that awakening, to say the least.

Of late researchers have started to investigate a variety of biological systems that decline with aging to determine the degree to which they are degraded by signals in the tissue environment, as a reaction to the presence of damage in tissues, versus degraded by intrinsic damage within the system itself. There will be attempts to force reactivation and better function by altering levels of signaling molecules rather than by repairing underlying damage, an approach that may well provide significant benefits but which is probably not the best way forward.

Natural killer (NK) cells are an important part of the immune system, with responsibilities that include destroying errant cells and viruses. In this open access paper researchers find that NK cells are degraded in function by the aged tissue environment and restored to youthful function in a young tissue environment. The next step is to identify the specific signals responsible for this effect:

Natural killer (NK) cells are critical in eliminating tumors and viral infections, both of which occur at a high incidence in the elderly. Previous studies showed that aged NK cells are less cytotoxic and exhibit impaired maturation compared to young NK cells. We evaluated whether extrinsic or intrinsic factors were responsible for the impaired maturation and function of NK cells in aging and whether impaired maturation correlated with functional hyporesponsiveness. We confirmed that aged mice have a significant decrease in the frequency of mature NK cells in all lymphoid organs. Impaired NK cell maturation in aged mice correlated with a reduced capacity to eliminate allogeneic and B16 tumor targets in vivo. This could be explained by impaired degranulation, particularly by mature NK cells of aged mice.

Consistent with impaired aged NK cell maturation, expression of T-bet and Eomes, which regulate NK cell functional maturation, was significantly decreased in aged bone marrow (BM) NK cells. Mixed BM chimeras revealed that the nonhematopoietic environment was a key determinant of NK cell maturation and T-bet and Eomes expression. In mixed BM chimeras, NK cells derived from both young or aged BM cells adopted an 'aged' phenotype in an aged host, that is, were hyporesponsive to stimuli in vitro, while adopting a 'young' phenotype following transfer in young hosts. Overall, our data suggest that the aged nonhematopoietic environment is responsible for the impaired maturation and function of NK cells. Defining these nonhematopoietic factors could have important implications for improving NK cell function in the elderly.

Link: http://onlinelibrary.wiley.com/enhanced/doi/10.1111/acel.12303/

If aging is defined as an increase in mortality rate over time, then old flies eventually stop aging - their mortality rate reaches a high level but increases no further after that point. As a phenomenon this is much harder to explain than a continued rise in mortality rate, both from a mechanistic and evolutionary point of view. There was some suggestion that the sparse human data for extremely old individuals showed signs of this late life mortality plateau, but that has since been fairly comprehensively refuted:

The growing number of individuals living beyond age 80 underscores the need for accurate measurement of mortality at advanced ages. Accurate estimates of mortality at advanced ages are essential for improving forecasts of mortality and predicting the population size of the oldest-old age group. At the same time, estimating hazard rates at very old ages is difficult because of the very small fraction of survivors at these ages in most countries. Data for extremely long-lived individuals are scarce and subject to age exaggeration. To minimize statistical noise in estimates of mortality at advanced ages, researches have to pool data for several calendar periods.

Single-year life tables for many countries have very small numbers of survivors to age 100, which makes estimates of mortality at advanced ages unreliable. On the other hand, aggregation of deaths for several calendar periods creates a heterogeneous mixture of cases from different birth cohorts. In addition to the heterogeneity problem, there is the issue of using proper empirical estimates of hazard rate at extreme ages when mortality is high and grows with age very rapidly. This problem is sometimes overlooked by researchers who believe that mortality estimates, which work well at young adult ages (like one-year probability of death) can work equally well at very old ages.

Our earlier published study challenged the common view that the exponential growth of mortality with age (Gompertz law) is followed by a period of deceleration, with slower rates of mortality increase. Taking into account the significance of this finding for actuarial theory and practice, we tested these earlier observations using additional independent datasets and alternative statistical approaches. An alternative approach for studying mortality patterns at advanced ages is based on calculating the age-specific rate of mortality change (life table aging rate, or LAR) after age 80. This approach was applied to age-specific death rates for Canada, France, Sweden and the United States. It was found that for all 24 studied single-year birth cohorts, LAR does not change significantly with age in the age interval 80-100, suggesting no mortality deceleration in this interval. Simulation study of LAR demonstrated that the apparent decline of LAR after age 80 found in earlier studies may be related to biased estimates of mortality rates measured in a wide five-year age interval.

Taking into account that there exists several empirical estimates of hazard rate, a simulation study was conducted to find out which one is the most accurate and unbiased estimate of hazard rate at advanced ages. Computer simulations demonstrated that some estimates of mortality as well as kernel smoothing of hazard rates may produce spurious mortality deceleration at extreme ages.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4318539/

All societies have a complex relationship with aging and the old, but in the English-language Western cultures that I'm most familiar with it seems especially convoluted and strange. Individualism and a high value placed on future potential and raw talent do not have to go hand in hand with a lack of respect for older folk who have found their way to positions of authority on their own merits, but it certainly seems that way at times. Any number of fields in which older people can do well, such as hands-on software engineering, shut their doors to anyone with more than three decades of active experience. Media outlets relentlessly display youth and only youth: the state of being old is hidden away. The comparatively small number of young entrepreneurs are idolized, while the vast majority of successful captains of industry, largely older folk, fade into the backdrop.

There is simultaneously a fear of being old, an unwillingness to talk about the realities of being old, and a knee-jerk rejection of serious attempts to extend healthy life through medical science. Yet at the same time, the marketing of obviously fake "anti-aging" potions is a multi-billion dollar industry. The drawn-out details of the late stages of aging to death are hidden away to be rediscovered by every family, one small group at a time, and never to be shared in public or polite society. Everyone looks away.

Conflicted doesn't even begin to describe this morass. I think it is ancient at root, and what we have today is the modern iteration of fears and apprehensions that are as old as human society. No-one wants to look their own mortality in the face. Consider the old fable of The Three Living and the Three Dead, often presented in the form of three nobles meeting with three corpses while out riding in the woods, who tell them: "What you are, we were. And what we are, you will be." Ageism has an impact on medicine because it has an impact on every aspect of life:

Ageism and its clinical impact in oncogeriatry: state of knowledge and therapeutic leads

Cancer is a major health problem that is widespread in elderly people. Paradoxically, older people suffering from cancer are often excluded from clinical trials and are undertreated when compared to younger patients. One explanation for these observations is age stigma (ie, stereotypes linked to age, and thus ageism). These stigmas can result in deleterious consequences for elderly people's mental and physical health in "normal" aging. This discrimination against elderly patients is not limited to research; it is observed in the clinic too. Older patients are undertreated when compared to younger patients. Yet it should be remembered that "advanced" age alone should not be a contraindication for treatments that can increase a patient's quality of life or significantly extend a patient's survival.

A recent paper, quoted below, marshals evidence to suggest that ageism in its present form is not in fact an ancient thing at all, but rather a modern phenomenon. The authors argue that correlations between the rise of modern medicine, lengthening life expectancy, and ageism suggest that there is something in the growing ability of medical science to treat the consequences of aging that encourages ageist views. Ironic if so, as ageism is one of the hurdles we face when trying to direct more resources to help eliminate suffering and pain in aging. Most people would rather devote resources to any of the presently popular charitable causes instead, and you often hear arguments along the lines of "the old have had their fair innings at life." But are the old not people too?

Increasing Negativity of Age Stereotypes across 200 Years: Evidence from a Database of 400 Million Words

Scholars argue about whether age stereotypes (beliefs about old people) are becoming more negative or positive over time. No previous study has systematically tested the trend of age stereotypes over more than 20 years, due to lack of suitable data. Our aim was to fill this gap by investigating whether age stereotypes have changed over the last two centuries and, if so, what may be associated with this change. We hypothesized that age stereotypes have increased in negativity due, in part, to the increasing medicalization of aging.

This study applied computational linguistics to the recently compiled Corpus of Historical American English (COHA), a database of 400 million words that includes a range of printed sources from 1810 to 2009. After generating a comprehensive list of synonyms for the term elderly for these years from two historical thesauri, we identified 100 collocates (words that co-occurred most frequently with these synonyms) for each of the 20 decades. Inclusion criteria for the collocates were: (1) appeared within four words of the elderly synonym, (2) referred to an old person, and (3) had a stronger association with the elderly synonym than other words appearing in the database for that decade. This yielded 13,100 collocates that were rated for negativity and medicalization.

We found that age stereotypes have become more negative in a linear way over 200 years. In 1880, age stereotypes switched from being positive to being negative. In addition, support was found for two potential explanations. Medicalization of aging and the growing proportion of the population over the age of 65 were both significantly associated with the increase in negative age stereotypes.

One approach to targeting cancer cells for destruction is to employ viruses as the kill mechanism, coupled with antibodies that can discern the type of cell to kill. The ideal outcome is that viruses infect only cancer cells, multiply inside them, destroy the cells and burst out to seek more victims, and then die out when there are no more cancer cells to target. There are, as always, challenges along the way to attaining this result, however:

Antibodies are proteins of the immune system that travel through the bloodstream and recognize potential threats to the body, whether bacteria, viruses or abnormal cells. Most antibodies have a characteristic Y shape. The tips of the Y form a "lock" that binds to a specific "key" carried by foreign bodies that the immune system should destroy. For decades, investigators have been putting human or mouse antibodies on viruses, and they haven't worked - the antibodies would lose their targeting ability. It was a technical problem. During replication, the virus is made in one part of the cell, and the antibody is made in another. To incorporate the two, the antibody is dragged through the internal fluid of the cell. This is a harsh environment for the antibodies, so they unfold and lose their targeting ability.

Now, scientists showed that unlike human antibodies or those of most other animals, the antibodies of camels and alpacas survive the harsh environment inside cells and retain the ability to seek out targets, potentially solving a longstanding problem in the field of gene therapy. The "lock" of camelid antibodies consists of the stem of the Y only, so it can't unfold in the harsh internal environment of the cell. The researchers used human cells grown in the lab for the study. They say it demonstrates the possibility of directly delivering genetically engineered viruses to specific cells. The goal is to infect only cancer cells and then trigger the virus to replicate until the cells burst, killing them and releasing more of the targeted viruses.

"We found that when we incorporated the camelid antibodies into the virus, they retained their binding specificity. This opens the door to targeting these antibodies to specific tumor markers. We want this new level of targeting specificity because it would allow us to inject the virus into the bloodstream, where it would exclusively infect and replicate in tumor cells, even if they are disseminated throughout the body. These viruses are already engineered to replicate only in tumors. These camelid antibodies would enable them to become even more tumor-specific and open the door for use in metastatic cancer."

Link: http://www.futurity.org/camel-antibodies-tumors-859932/

Epigenetics is the study of dynamic alterations to DNA that affect the rate at which specific proteins are generated from its blueprint, but do not change the blueprint itself. One example is DNA methylation, the decoration of DNA with methyl groups. Patterns of DNA methylation change with advancing age, and some of those changes are similar enough between individuals to be used as a measure of age.

Why do epigenetic patterns change with aging? The obvious suggestion, though at this point it remains a challenge to drawn direct lines from cause to effect, is that it is a reaction to rising levels of the cellular and molecular damage that causes degenerative aging. The same forms of damage occur in everyone, so reactions to that damage should be similar in everyone. Epigenetic changes occur in reaction to other environmental circumstances, so it shouldn't be surprising to find them happening in response to the damage of aging.

Two well-known features of aging are the gradual decline of the body's ability to regenerate tissues, as well as an increased incidence of diseases like cancer and Alzheimers. One of the most recent exciting findings which may underlie the aging process is a gradual modification of DNA, called epigenetic drift, which is effected by the covalent addition and removal of methyl groups, which in turn can deregulate the activity of nearby genes. However, this study presents the most convincing evidence to date that epigenetic drift acts to stabilize the activity levels of nearby genes.

This study shows that instead, epigenetic drift may act primarly to disrupt DNA binding patterns of proteins which regulate the activity of many genes, and moreover identifies specific regulatory proteins with key roles in cancer and Alzheimers. The study also performs the most comprehensive analysis of epigenetic drift at different spatial scales, demonstrating that epigenetic drift on the largest length scales is highly reminiscent of those seen in cancer. In summary, this work substantially supports the view that epigenetic drift may contribute to the age-associated increased risk of diseases like cancer and Alzheimers, by disrupting master regulators of genomewide gene activity.

Link: http://dx.doi.org/10.1371/journal.pgen.1004996

The long upward trend in human life expectancy derives from progress in medicine in its broadest definition. The varied technologies and techniques involved have very different contributions to the shape of life expectancy, however. To pick the obvious examples: control of infectious disease improves the proportion of the population who can expect to reach adulthood, while better treatments for age-related disease improve the quality and remaining length of life of the old. In a number of past studies, researchers have worked through data sets on human life span to quantify the effects of various facets of medical progress. One such work estimates the upward trend in life expectancy is produced by an equal contribution from (a) reduction in premature deaths, such as via infectious disease, and (b) reduction in late life mortality rates, such as through better treatments for age-related disease.

If there was a more equal mortality rate at all ages, then life spans would vary more widely. In the past there was a high mortality rate at all ages due to infectious disease. In the future there will be a very low mortality rate at all ages, thanks to medical technologies capable of maintaining youth through periodic repair of the causes of aging, the various forms of cellular and molecular damage that accumulate over the years. In both cases the outcome would be a larger variation in life spans than is presently the case. Today, however, the state of medicine has created a distribution of mortality rates that runs from low in youth to high in old age, and this acts to decrease the variability of life span. Many more people make it to old age than was the case, and old age is where they die. The point to bear in mind is that this is both unusual considered in the broader scope of history and also a transient state of affairs: it wasn't the case in the past, and it won't be the case in the future.

Is it fair that some people will live much longer than others? Is life fair at all? Can it be made to be fair? No to all three counts. In a world in which aging is treatable and life is only limited by fatal accidents, some people will live for thousands of years longer than others. That is simply the way it will be, even if everyone sets out to keep accident rates as low as possible. Unfairness is looked upon with grave displeasure these days; ours is a culture that drinks deeply of the shallow waters of egalitarianism. The prospect of unfairness is often put forward in opposition to forms of development that might improve matters for everyone. It is shameful that some people would choose to ensure a continuation of present death and suffering because they feel uncomfortable about the inherently unfair nature of accident statistics. Yet this is not an unusual position.

If you are among the population of demographers who like to dig more deeply into the data, then there are numerous epicycles to be found beyond the high-level picture noted above, some counter-intuitive:

Why do lifespan variability trends for the young and old diverge? A perturbation analysis

For much of human history, mortality rates at all ages were relatively high and the length of human life was highly variable. During the course of the demographic transition, mortality rates declined, life expectancy rose, and the variability of the distribution of lifespans, or ages at death, changed in response. Two stages in the history of lifespan variability have been identified. In the first stage, spanning the late nineteenth and early twentieth century "the level of mortality fell ... resulting in a very large reduction in the disparities of life spans." The second stage, starting in the 1950s, was one in which "the increase in life expectancy is no longer associated with a reduction in the dispersion of life spans - or with only a very small reduction." A closer examination of variability trends suggests another key, yet overlooked, aspect of this story. In high-longevity populations, survival improvements have taken place at all ages, including the oldest, but trends in the variability of the distribution of ages at death have not exhibited a uniform pattern. Variation in the length of life has declined as life expectancy at birth has risen, but the variation in lifespan among survivors to older ages (e.g. 65 and above) has increased.

Previous research has shown that lives saved at younger ages reduce lifespan disparity, while lives saved at older ages increase it, with the threshold demarcating early and late ages changing in response to changes in the mortality schedule and the historical contingencies that shape it. Our results likewise indicate that early and late deaths have different implications for the variability of lifespan conditional on survival to successive ages. Perturbation analysis enabled us to quantify this relationship, showing the differential responses of variability measure conditional on survival to younger and older ages to the parameters defining the course of child, adult, and background mortality levels. In particular, we showed that lifespan variability decreases for younger ages because of its sensitivity to the childhood mortality parameters, and that lifespan variability at older ages has increased because its sensitivity to the decline in adult mortality is in fact negative.

Notably, the expansion of lifespan variability at older ages takes place despite the fact that deaths are being concentrated into older ages. While the classic description of mortality compression predicts that lifespan variability will decline as life expectancy rises, this decline in variability doesn't materialize at older ages because, as we show, the relationship between mortality rates and lifespan variability is negative at those ages. While the data leave no doubt that deaths are indeed being delayed into increasingly older ages, our analysis shows that the implications of such changes for lifespan variability patterns are not pre-determined, but rather depend in intricate ways on the specific pattern of mortality change by age and over time.

The longitudinal nature of our analysis further highlights the impact of the temporal pattern of mortality change (i.e. an initial decline in childhood mortality followed by a decline in adult mortality some decades later) on the differential trends in lifespan variability at younger and older ages. Mortality has declined at all ages, but not at the same time or to the same extent. For the successive cohorts aging through the dramatic population changes of the twentieth century, survival has improved at all ages, but more so in early life than in adulthood. At the same time, each successive cohort is reaching older ages with added benefits of lower mortality (and likely better health) throughout the life course, suggesting that the period trends we describe here may also be explained by cohort effects and changing distributions of health and vulnerability to mortality within cohorts.

Scientists continue to make progress in this first phase of tissue engineering, in which real and mock tissues of various types grown from cells will largely be used to expand and speed up further research rather than in treatment:

Researchers have reported development of the first three-dimensional tissue system that reproduces the complex structure and physiology of human bone marrow and successfully generates functional human platelets. Using a biomaterial matrix of porous silk, the new system is capable of producing platelets for future clinical use and also provides a laboratory tissue system to advance study of blood platelet diseases. "There are many diseases where platelet production or function is impaired. New insight into the formation of platelets would have a major impact on patients and healthcare. In this tissue system, we can culture patient-derived megakaryocytes - the bone marrow cells that make platelets - and also endothelial cells, which are found in bone marrow and promote platelet production, to design patient-specific drug administration regimes."

The new system can also provide an in vitro laboratory tissue system with which to study mechanisms of blood disease and to predict efficacy of new drugs - providing a more precise and less costly alternative to in vivo animal models. The new system combined microtubes spun of silk, collagen and fibronectin surrounded by a porous silk sponge. Megakaryocytes - some of which were derived from patients - were seeded into the engineered microvasculature. The researchers were able to increase platelet production in the bioreactor by embedding the silk with active endothelial cells and endothelial-related molecular proteins that support platelet formation.

Laboratory tests showed that the platelets being generated and recovered from the tissue system were able to aggregate and clot. While the number of platelets produced per megakaryocyte was lower than normally made in the body, the researchers note that the system represents a significant advance over previous models. The scalable nature of the bioreactor system provides engineering options to increase yields of platelets in ongoing studies. In addition to providing a platform for studying the processes that regulate platelet production and related diseases, the researchers hope the platelets produced can be used as a source of growth factors for wound healing in regenerative medicine, including healing of ulcers and burns.

Link: http://www.eurekalert.org/pub_releases/2015-02/tu-3eb021815.php

Engineering a patient's own T-cells to express chimeric antigen receptors (CARs) has shown considerable promise as a cancer treatment. This alteration steers the immune cells to attack tumor cells, and has for example been used to drive leukemia into remission in trials. Here researchers are preparing a trial to test the use of CARs in targeting the brain cancer glioblastoma:

Immune cells engineered to seek out and attack a type of deadly brain cancer were found to be both safe and effective at controlling tumor growth in mice that were treated with these modified cells. The results paved the way for a newly opened clinical trial for glioblastoma patients. The new preclinical study details the design and use of T cells engineered to express a chimeric antigen receptor (CAR) that targets a mutation in the epidermal growth factor receptor protein called EGFRvIII, which is found on about 30 percent of glioblastoma patients' tumor cells.

First, the team developed and tested multiple antibodies, or what immunologists call single-chain variable fragments (scFv), which bind to cells expressing EGFRvIII on their surface. The scFvs recognizing the mutated EGFRvIII protein must be rigorously tested to confirm that they do not also bind to normal, non-mutated EGFR proteins, which are widely expressed on cells in the human body. Out of the panel of humanized scFvs that were tested, the researchers selected one scFv to explore further based on its binding selectivity for EGFRvIII over normal non-mutated EGFR.

The lead scFv was then tested for its anti-cancer efficacy. Using human tumor cells, the scientific team determined that the EGFRvIII CAR T cells could multiply and secrete cytokines in response to tumor cells bearing the EGFRvIII protein. Importantly, the researchers found that the EGFRvIII CAR T cells controlled tumor growth in several mouse models of glioblastoma. On the basis of these preclinical results, the investigators designed a phase 1 clinical study of CAR T cells transduced with humanized scFv directed to EGFRvIII for both newly diagnosed and recurrent glioblastoma patients carrying the EGFRvIII mutation.

The investigational approach begins when some of each patient's T cells are removed via an apheresis process similar to dialysis, the cells are engineered using a viral vector that programs them to find cancer cells that express EGFRvIII. Then, the patient's own engineered cells are infused back into their body, where a signaling domain built into the CAR promotes proliferation of these "hunter" T-cells. In contrast to certain T cell therapies that also target some healthy cells, EGFRvIII is believed to be found only on tumor tissue, which the study's leaders hope will minimize side effects.

Link: http://www.uphs.upenn.edu/news/News_Releases/2015/02/maus/

Precision targeting makes all medicine better: delivering smaller total doses to precise locations in the body opens many doors. Types of therapeutic compound that would otherwise be impractical to use become practical. Localized dosage levels that would otherwise be impossible can be obtained. Many examples of targeted medicine under development in recently involve the delivery entirely new types of drug or therapy, but there is also a strong incentive to generalize that delivery platform and walk back through the existing library of potential therapeutics to find those that can now be made much more useful.

Most of the targeting mechanisms reported in the media are associated with cancer research: a matter of finding ways to kill specific cells with certain characteristics with minimal collateral damage. Killing cells is easy. The hard part is doing it while leaving their neighbors - and the patient - alive and healthy. So it is the targeting mechanism that is the important part of this line of development, not the method for cell destruction, of which there are many. The next generation of cancer treatments aims to leave behind the fine line between harming the cancer and harming the patient that shapes chemotherapy and radiation therapy, building a basis for treatments that cause no discomfort while seeking out and destroying tumor cells wherever they may be. This is an important line of research, as it turns out that there are numerous types of cell in the aged body that we'd like to be able to safely and effectively destroy: senescent cells, fat cells, cells with damaged mitochondria, dysregulated immune cells, and so forth.

There are also other uses for targeting beyond cell destruction. Let us say, for example, that you can target therapeutics to the precise areas in blood vessel walls in which the characteristic fatty lesions of atherosclerosis are in a late stge of development, and either slow down or reverse that process. The type of approach demonstrated below may also be useful in the early stages of the condition, long before any noteworthy damage develops, but of course that is never going to be the goal in initial proof of concept studies. In the present regulatory environment researchers must work towards a therapy for the late stages of age-related disease if they want their work to progress towards clinical application:

Keeping Atherosclerosis in-check with Novel Targeted Inflammation-Resolving Nanomedicines

Targeted biodegradable nano 'drones' that delivered a special type of drug that promotes healing ('resolution') successfully restructured atherosclerotic plaques in mice to make them more stable. This remodeling of the plaque environment would be predicted in humans to block plaque rupture and thrombosis and thereby prevent heart attacks and strokes. Targeted nanomedicines made from polymeric building blocks that are utilized in numerous FDA approved products to date were nanoengineered to carry an anti-inflammatory drug payload in the form of a biomimetic peptide. Furthermore, this peptide was derived from one of the body's own natural inflammatory-resolving proteins called Annexin A1. The way the nanomedicines were designed enabled this biological therapeutic to be released at the target site, the atherosclerotic plaque, in a controlled manner.

In mouse models with advanced atherosclerosis, researchers administered nanomedicines and relevant controls. Following five weeks of treatment with the nanomedicines, damage to the arteries was significantly repaired and plaque was stabilized. Specifically, researchers observed a reduction of reactive oxygen species; increase in collagen, which strengthens the fibrous cap; and reduction of the plaque necrotic core, and these changes were not observed in comparison with the free peptide or empty nanoparticles.

Researchers caution that although plaques in mice look a lot like human plaques, mice do not have heart attacks, so the real test of the nanoparticles will not come until they are tested in humans. "In this study, we've shown, for the first time, that a drug that promotes resolution of inflammation and repair is a viable option, when the drug is delivered directly to plaques via nanoparticles." To be ready for testing in humans, the team plans to fine-tune the nanoparticles to optimize drug delivery and to package them with more potent resolution-inducing drugs. "We think that we can obtain even better delivery to plaques and improve healing more than with the current peptides."

Targeted nanoparticles containing the proresolving peptide Ac2-26 protect against advanced atherosclerosis in hypercholesterolemic mice

Chronic, nonresolving inflammation is a critical factor in the clinical progression of advanced atherosclerotic lesions. In the normal inflammatory response, resolution is mediated by several agonists, among which is the glucocorticoid-regulated protein called annexin A1.

The proresolving actions of annexin A1 can be mimicked by an amino-terminal peptide encompassing amino acids 2-26 (Ac2-26). Collagen IV (Col IV)-targeted nanoparticles (NPs) containing Ac2-26 were evaluated for their therapeutic effect on chronic, advanced atherosclerosis in fat-fed Ldlr−/− mice. When administered to mice with preexisting lesions, Col IV-Ac2-26 NPs were targeted to lesions and led to a marked improvement in key advanced plaque properties, including an increase in the protective collagen layer overlying lesions, suppression of oxidative stress, and a decrease in plaque necrosis. These findings support the concept that defective inflammation resolution plays a role in advanced atherosclerosis, and suggest a new form of therapy.

This open access paper presents an interesting view on age-related hearing loss, a contrast to more frequently reported efforts to regenerate hair cells in the ear known to be lost in old age:

Hearing loss constitutes a major health problem affecting 16% of the adult population worldwide. Aging is the main risk factor associated with hearing impairment. Age-related sensorineural hearing loss (SNHL) is the third most common disability of the elderly affecting about half of the population over 75 years old. SNHL is a pathology of the cochlea that is generally regarded as mechanical or chemical damage-induced hair cell death triggering spiral ganglion neuron (SGN) death and subsequent dysfunction of auditory nerve. Recent researches in SNHL field have lead to a more complex vision of the relationship between inner ear damage and SNHL. Indeed, SGN loss without hair cell damage or death was observed.

Interestingly, cholesterol homeostasis and metabolism are central to numerous pathologies including neurodegenerative diseases, and regulate the many of the processes involved in neuron survival and functionality. Consequently, interfering with cholesterol homeostasis should afford innovative therapeutic strategies to improve the care of SNHL. Even if studies related to cholesterol homeostasis in inner ear are scarce, some reports support a relationship between cholesterol homeostasis deregulation and SNHL. Indeed, atherosclerosis, high plasma total cholesterol, and low HDL levels are positively correlated with SNHL. The most plausible explanation is that hypercholesterolemia triggers the stenosis of spiral modiolar artery leading to cochlear ischemia and subsequent SNHL. Consequently, therapies that limit high plasma cholesterol level could be useful to prevent SNHL caused by cochlear ischemia.

Link: http://journal.frontiersin.org/article/10.3389/fnagi.2015.00003/full

Like skin, the walls of blood vessels lose their elasticity over the course of aging. Mechanisms involved in this loss include rising levels of long-lived cross-links in the extracellular matrix, wherein metabolic byproducts such as glucosepane glue together proteins and so alter the structural properties of important tissues. Our biochemistry struggles to break these cross links and so they accumulate as a consequence of the natural operation of metabolism. In blood vessels the consequences of loss of elasticity become increasingly serious over time, as this is a part of a feedback loop of dysfunction in the cardiovascular system that causes hypertension, heart abnormalities, and damage to blood vessels and surrounding tissues throughout the body. All of this could be dialed back just by maintaining elasticity in blood vessels, which would involve the development of treatments to clear cross-links, among other items, a field of research that sadly sees little funding and interest given its potential:

Isolated systolic hypertension is a major health burden that is expanding with the aging of our population. There is evidence that central arterial stiffness contributes to the rise in systolic blood pressure (SBP); at the same time, central arterial stiffening is accelerated in patients with increased SBP. This bidirectional relationship created a controversy in the field on whether arterial stiffness leads to hypertension or vice versa. Given the profound interdependency of arterial stiffness and blood pressure, this question seems intrinsically challenging, or probably naïve.

The aorta's function of dampening the pulsatile flow generated by the left ventricle is optimal within a physiological range of distending pressure that secures the required distal flow, keeps the aorta in an optimal mechanical conformation, and minimizes cardiac work. This homeostasis is disturbed by age-associated, minute alterations in aortic hemodynamic and mechanical properties that induce short- and long-term alterations in each other. Hence, it is impossible to detect an "initial insult" at an epidemiological level.

Earlier manifestations of these alterations are observed in young adulthood with a sharp decline in aortic strain and distensibility accompanied by an increase in diastolic blood pressure. Subsequently, aortic mechanical reserve is exhausted, and aortic remodeling with wall stiffening and dilatation ensue. These two phenomena affect pulse pressure in opposite directions and different magnitudes. With early remodeling, there is an increase in pulse pressure, due to the dominance of arterial wall stiffness, which in turn accelerates aortic wall stiffness and dilation. With advanced remodeling, which appears to be greater in men, the effect of diameter becomes more pronounced and partially offsets the effect of wall stiffness leading to plateauing in pulse pressure in men and slower increase in pulse pressure (PP) than that of wall stiffness in women. The complex nature of the hemodynamic changes with aging makes the "one-size-fits-all" approach suboptimal and urges for therapies that address the vascular profile that underlies a given blood pressure, rather than the blood pressure values themselves.

Link: http://dx.doi.org/10.1007/s11906-014-0523-z

The molecular biology of Alzheimer's disease is enormously complex, and efforts to better understand it have spurred a great deal of the broader work that has taken place to decipher and catalog the biology of the brain over the past twenty years. Even given the rapid improvements in biotechnology taking place over that time and the large-scale funding pouring into Alzheimer's research, the present state of knowledge is still incomplete, a work in progress.

Alzheimer's is a disease of protein aggregation, its progression and severity associated with the formation of deposits of misfolded proteins known as amyloid and neurofibillary tangles (NFTs). It isn't just this, however, that is the crux of the condition, but rather the fine details of how amyloid and NFTs form and interact with their surroundings. In those fine details lie mechanisms that cause cellular dysfunction and death, and that is still a very active area of research. These mechanisms, in play once there are significant amounts of misfolded protein in the brain, are completely separate from the question of how an older individual gets to that point, however. Levels of misfolded proteins are dynamic over short time frames, and Alzheimer's has the look of a condition that develops due to a slow failure of the mechanisms that clear metabolic waste from brain fluids. There is as much debate in the research community over those root causes as there is over the precise details of the mechanisms that disrupt brain function in the later stages of the condition. Is it damage to the choroid plexus that filters cerebrospinal fluid, is it declining function in small vessels that drain that fluid, or something entirely different? These details are all open for further evidence, discussion, and argument.

The main thrust of Alzheimer's research when it comes to building prospective treatments remains the clearance of amyloid, such as via immunotherapies. It has been a long haul since this strategy was first proposed, however, and still there is no practical treatment to show for all the effort expended. This is despite a number of attempts that made it all the way to clinical trials. As is often the case, protracted delay in reaching treatment milestones has led to a certain degree of discontent and rebellion against the amyloid clearance consensus, and a healthy diversity of alternative approaches are in the works. This I think is for the better whether or not clearance of amyloid falters in the end, or simply turns out - like everything in biology - to be much harder and more complex than anticipated.

The research reported below is, I think, I good illustration of some of the complexity involved in the biochemistry of Alzheimer's disease. On the one hand this complexity makes everything harder, and on the other hand it offers a plethora of points at which well designed drugs might interfere with the disease process. Still, I would prefer to see work on repair of clearance mechanisms rather than work on sabotaging the disease process that becomes important once there is a lot of amyloid present. It should always be better - more efficient, more comprehensive - to strike at the root causes rather than even very effectively neutering later stages of the cascade of consequences.

Molecular inhibitor breaks cycle that leads to Alzheimer's

Alzheimer's disease is one of a number of conditions caused by naturally occurring protein molecules folding into the wrong shape and then sticking together - or nucleating - with other proteins to create thin filamentous structures called amyloid fibrils. Proteins perform important functions in the body by folding into a particular shape, but sometimes they can misfold, potentially kick-starting this deadly process. Recent research has however suggested a second critical step in the disease's development. After amyloid fibrils first form from misfolded proteins, they help other proteins which come into contact with them to misfold and form small clusters, called oligomers. These oligomers are highly toxic to nerve cells and are now thought to be responsible for the devastating effects of Alzheimer's disease.

This second stage, known as secondary nucleation, sets off a chain reaction which creates many more toxic oligomers, and ultimately amyloid fibrils, generating the toxic effects that eventually manifest themselves as Alzheimer's. Without the secondary nucleation process, single molecules would have to misfold and form toxic clusters unaided, which is a much slower and far less devastating process. By studying the molecular processes by which each of these steps takes effect, the research team assembled a wealth of data that enabled them to model not only what happens during the progression of Alzheimer's disease, but also what might happen if one stage in the process was somehow switched off. Researchers were able to identify a molecular chaperone, Brichos, that effectively inhibits secondary nucleation.

The research team then carried out further tests in which living mouse brain tissue was exposed to amyloid-beta, the specific protein that forms the amyloid fibrils in Alzheimer's disease. Allowing the amyloid-beta to misfold and form amyloids increased toxicity in the tissue significantly. When this happened in the presence of the molecular chaperone, however, amyloid fibrils still formed but the toxicity did not develop in the brain tissue, confirming that the molecule had suppressed the chain reaction from secondary nucleation that feeds the catastrophic production of oligomers leading to Alzheimer's disease.

A molecular chaperone breaks the catalytic cycle that generates toxic Aβ oligomers

Alzheimer's disease is an increasingly prevalent neurodegenerative disorder whose pathogenesis has been associated with aggregation of the ​amyloid-β peptide (​Aβ42). Recent studies have revealed that once ​Aβ42 fibrils are generated, their surfaces effectively catalyze the formation of neurotoxic oligomers. Here we show that a molecular chaperone, a human Brichos domain, can specifically inhibit this catalytic cycle and limit human ​Aβ42 toxicity.

We demonstrate in vitro that Brichos achieves this inhibition by binding to the surfaces of fibrils, thereby redirecting the aggregation reaction to a pathway that involves minimal formation of toxic oligomeric intermediates. We verify that this mechanism occurs in living mouse brain tissue. These results reveal that molecular chaperones can help maintain protein homeostasis by selectively suppressing critical microscopic steps within the complex reaction pathways responsible for the toxic effects of protein misfolding and aggregation.

At the small scale, bone structure is constantly remodeled throughout life. We lose bone mass and strength as we age, a condition known as osteoporosis, in part due to a systemic shift of the balance of activities between osteoclasts that remove bone structure and osteoblasts that create it. In older people there is too much absorption of bone and not enough bone deposition. Here researchers demonstrate a way to tilt that balance back towards a more youthful measure:

We recently reported that in vitro, engineered 50 nm spherical silica nanoparticles promote the differentiation and activity of bone building osteoblasts but suppress that of bone-resorbing osteoclasts. Furthermore, these nanoparticles promote bone accretion in young mice in vivo.

In the present study the capacity of these nanoparticles to reverse bone loss in aged mice, a model of human senile osteoporosis, was investigated. Aged mice received nanoparticles weekly and bone mineral density (BMD), bone structure, and bone turnover were quantified. Our data revealed a significant increase in BMD, bone volume, and biochemical markers of bone formation. Biochemical and histological examinations failed to identify any abnormalities caused by nanoparticle administration. Our studies demonstrate that silica nanoparticles effectively blunt and reverse age-associated bone loss in mice by a mechanism involving promotion of bone formation. The data suggest that osteogenic silica nanoparticles may be a safe and effective therapeutic for counteracting age-associated bone loss.

Link: http://dx.doi.org/10.1016/j.nano.2015.01.013

One of the detrimental consequences of the high cost of medical regulation is that researchers spend a lot of time looking for marginal new uses for the existing catalog of approved drugs rather than building better technologies. Thus most of the current crop of possible calorie restriction mimetic drugs, none of which you should be particularly excited about, are compounds known for years and used for other means, such as rapamycin. Here is news of another possible candidate mined from the present drug library, determined by testing in yeast cultures:

Calorie restriction (CR) promotes longevity among distinct organisms from yeast to mammals. Although CR-prolonged lifespan is believed to associate with enhanced respiratory activity, it is apparently controversial for accelerated energy consumption regardless of insufficient nutrient intake. In reconciling the contradiction of less food supply versus much metabolite dispense, we revealed a CR-based mode of dual-phase responses that encompass a phase of mitochondrial enhancement (ME) and a phase of post-mitochondrial enhancement (PME), which can be distinguished by the expression patterns and activity dynamics of mitochondrial signatures. ME is characterized by global antioxidative activation, and PME is denoted by systemic metabolic modulation.

CR-mediated aging-delaying effects are replicated by artesunate, a semi-synthetic derivative of the antimalarial artemisinin that can alkylate heme-containing proteins, suggesting artesunate-heme conjugation functionally resembles nitric oxide-heme interaction. A correlation of artesunate-heme conjugation with cytochrome c oxidase activation has been established from adduct formation and activity alteration. Exogenous hydrogen peroxide also mimics CR to trigger antioxidant responses, affect signaling cascades, and alter respiratory rhythms, implying hydrogen peroxide is engaged in lifespan extension. Conclusively, artesunate mimics CR-triggered nitric oxide and hydrogen peroxide to induce antioxidative networks for scavenging reactive oxygen species and mitigating oxidative stress, thereby directing metabolic conversion from anabolism to catabolism, maintaining essential metabolic functionality, and extending life expectancy in yeast.

Link: http://dx.doi.org/10.1007/s11427-014-4736-9

Raised levels of chronic inflammation play an important role in degenerative aging, as well as in many medical conditions. Much of this inflammation in aging is driven by systemic changes, as it is very similar in every individual: it is partly a consequence of the evolved limits of the immune system when operating over a long period of time and faced with the presence of persistent pathogens like cytomegalovirus that cannot be permanently cleared from tissues. There are of course numerous other mechanisms at work, and the big picture is still being filled in by ongoing research - a lot of the immune system remains poorly understood. One way of looking at the evolution of biological systems is that they tend to be optimized for survival during youth at the expense survival at later ages. Reproductive success is the primary measure of selection, and this seems to product outcomes such as an adaptive immune system that is highly effective at birth, yet runs off the rails after being exposed to too many diverse threats, or even a single persistent viral threat it cannot deal with, such as herpesviruses, HIV, or similar.

In recent years the characteristic age-related malfunctioning of the immune system has come to be called inflammaging as researchers explore its details. The immune system even considered portion by portion is immensely complex, and so is the character of the inflammatory response, especially when it becomes harmful. Inflammatory contributions to various medical conditions, aging included, can be spurred by many different mechanisms. Immune activity is regulated and influenced by numerous genes and proteins, and so naturally many research groups are attempting to catalog this space in order to find the basis for potential treatments to suppress inflammation, or better, ways to exert more sophisticated control over inflammation.

One gene of particular interest of late is NLRP3, a part of the inflammasome of the innate immune system. Here are a couple of recently published research results relating to this narrow slice of the broader field, one of which identifies a mechanism triggered by activities that reduce inflammation while the other is news of a possible new drug aimed at roughly the same area.

Anti-inflammatory mechanism of dieting and fasting revealed

The compound β-hydroxybutyrate (BHB) directly inhibits NLRP3, which is part of a complex set of proteins called the inflammasome. The inflammasome drives the inflammatory response in several disorders including autoimmune diseases, type 2 diabetes, Alzheimer's disease, atherosclerosis, and autoinflammatory disorders. "These findings are important because endogenous metabolites like BHB that block the NLRP3 inflammasome could be relevant against many inflammatory diseases, including those where there are mutations in the NLRP3 genes."

BHB is a metabolite produced by the body in response to fasting, high-intensity exercise, caloric restriction, or consumption of the low-carbohydrate ketogenic diet. It is well known that fasting and calorie restriction reduces inflammation in the body, but it was unclear how immune cells adapt to reduced availability of glucose and if they can respond to metabolites produced from fat oxidation. Working with mice and human immune cells, researchers focused on how macrophages -- specialized immune cells that produce inflammation -- respond when exposed to ketone bodies and whether that impacts the inflammasone complex. The team introduced BHB to mouse models of inflammatory diseases caused by NLP3. They found that this reduced inflammation, and that inflammation was also reduced when the mice were given a ketogenic diet, which elevates the levels of BHB in the bloodstream.

Scientists uncover marvel molecule that could lead to treatments for inflammatory diseases

Researchers showed how the molecule MCC950 can suppress the 'NLRP3 inflammasome', which is an activator of the key process in inflammatory diseases. Inflammasomes have been identified as promising therapeutic targets by researchers over the last decade. And now the discovery of MCC950's abilities represents a hugely significant development in the effort to find treatments for inflammatory diseases, for which current therapies are either highly ineffective or have major limitations. "MCC950 is blocking what was suspected to be a key process in inflammation. There is huge interest in NLRP3 both among medical researchers and pharmaceutical companies and we feel our work makes a significant contribution to the efforts to find new medicines to limit it."

So far, the results have shown great promise for blocking multiple sclerosis in a model of that disease, as well as in sepsis, where in response to bacteria, potentially fatal blood poisoning occurs. However, the target for MCC950 is strongly implicated in diseases such as Alzheimer's disease, atherosclerosis, gout, Parkinson's disease and rheumatoid arthritis, which means it has the potential to treat all of these conditions.

Reading between the hype there, it sounds like the next generation of anti-inflammatory treatments for various conditions will probably be an incremental improvement over the present state of the art, which is much as one would expect. At some point the methods of tinkering with the controlling signals may become useful enough to apply to the common processes of inflammaging that occur in every older individual, though this is a very top-down, messing-with-metabolism approach. If not addressing the underlying causes for increased chronic inflammation, even sophisticated means of suppression are just papering over the real issue. Lowering the rate at which some tertiary damage occurs by suppressing some secondary damage doesn't tackle the primary damage, which remains to grow as the root causes of all degeneration and dysfunction - so benefits from this approach to therapy will by necessity be limited.

This unfortunately describes the majority of modern medicine when it comes to age-related disease, and is why it is very important for the research and development community to unite behind the new approach of treating the mechanisms of aging as the cause of age-related disease. No more patching, and much more going after root causes should be the name of the game. Ultimately medicine for aging should consist of forms of repair for the damage that lies at the base of the pyramid of consequences: that is the place where the lion's share of the effort should be directed if we want to see real progress.

Advanced glycation end-products (AGEs) of various types are both generated in the body and arrive via the diet. Some are short-lived and easily broken down, but still a problem in people with abnormal metabolisms, such as diabetics, as well as through promotion of chronic inflammation for the rest of us via their interaction with RAGE, the receptor for AGEs. Some forms of AGE, most notably glucosepane in humans, are hard or impossible for our biochemistry to deal with, however, and they linger to form cross-links that glue together important proteins in tissues. These unwanted additions progressively degrade structural properties such as elasticity of blood vessels and strength of bone, and are a contributing factor in many of the aspects of degenerative aging.

When it comes to the contribution of AGEs to the progression of neurodegenerative conditions such as Alzheimer's disease the focus is on inflammation and RAGE. Here the most studied AGE is N(6)-Carboxymethyllysine (CML), as the relevant mechanisms are very different from those involving glucosepane and cross-linking. This open access paper provides a tour of the biochemistry, but note that the full thing is only available in PDF format (link above the title):

Protein glycation occurs through a complex series of very slow reactions in the body, including the Amadori reaction, Schiff base formation, and the Maillard reaction. These give rise to the formation of advanced glycation end products (AGEs). Since these glycation reactions were slow, it was believed that this process predominantly affected long-lived proteins. However, it was later found that even short-lived compounds such as lipids, nucleic acids, and intracellular growth factors are glycated. N(6)-carboxymethyllysine (CML) is thus far the most important AGE that occurs in vivo. It has been extensively studied and implicated in neurodegenerative disorders.

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases. A recent report suggests that glycation plays a key role in the formation of amyloid protein. AGEs are also formed from the reaction of reactive carbonyl or dicarbonyl compounds with lysine or arginine groups on proteins, and are present in beta-amyloid plaques and neurofibillary tangles (NFTs). The plaque fractions of AD brains contain higher levels of AGEs than samples from age-matched controls. Furthermore, immunohistochemical methods have convincingly demonstrated that AGEs are present in NFTs and senile plaques. Although some authors suggested that AGEs are very late markers of the disease, it is now widely accepted that they are active participants in the progression of the disease.

A link between diabetes mellitus and AD was recently postulated because humans with diabetes show a greater deposition of brain AGEs and RAGE, which may mediate a common pro-inflammatory pathway in neurodegenerative disorders. Immunohistochemical studies of human postmortem samples showed that patients with the combination of AD and diabetes had higher AGE levels, increased numbers of beta-amyloid dense plaques, higher RAGE- and tau-positive cells, and major microglial activation in their brains when compared to the brains of patients with AD alone.

The AGE-RAGE damaging axis is now considered to be a promising drug target. The main molecular approaches used to inhibit RAGE activation are inactivation of the ligand, inactivation of RAGE and downregulation of RAGE expression. Additionally, there are defense enzymes and protein present in the body that protect the neuronal cell from glycation and carbonyl stress. The formation of toxic oligomeric species could be controlled by using novel inhibitors. Using combination therapies, novel drugs could be designed that simultaneously target multiple pathways and may obviously be more efficient than those drugs that modify a single pathway and thereby decrease the risk of side effects.

Link: http://dx.doi.org/10.2478/s11658-014-0205-5

As a result of parabiosis research there is presently some interest in exploring transfer of blood from young donors and direct alteration of levels of circulating proteins to try to impact the progression of aging in the old. Making old blood more like young blood appears to reactivate dormant stem cell populations to some degree, and thus produce benefits due to increased tissue maintenance. At this stage it remains to be seen what else is happening under the hood, as well as what the cancer risk profile of doing this might be. Stem cell activity falters with age because it reduces cancer incidence, a part of the evolutionary trade off that enables we humans to live much longer than other primates.

In any case, here is an example of slowing aging via transfer of blood plasma, but the researchers are doing this in a breed of senescence-accelerated mice. So what is happening here might have some similarities to the case of young blood for old animals at the detail level - and here the researchers are looking at cellular senescence in particular - but it is really a situation in which researchers cause a specific narrow form of damage and then prevent some of the consequences of that damage by delivering functional biological parts. In all such studies the relevance to normal biology and normal aging is strained at best, and often there turns out to be no relevance. It is worth bearing in mind that a team did in fact recently conduct a blood transfusion study for young blood to old individuals in normal mice, and saw no benefit.

Aging is related to loss of functional stem cells accompanying loss of tissue and organ regeneration potentials. Previously, we demonstrated that the life span of ovariectomy-senescence accelerated mice (OVX-SAMP8) was significantly prolonged and similar to that of the congenic senescence-resistant strain of mice after platelet rich plasma (PRP)/embryonic fibroblast transplantation. The aim of this study is to investigate the potential of PRP for recovering cellular potential from senescence and then delaying animal aging.

We first examined whether stem cells would be senescent in aged mice compared to young mice. Primary adipose derived stem cells (ADSCs) and bone marrow derived stem cells (BMSCs) were harvested from young and aged mice, and found that cell senescence was strongly correlated to animal aging. Subsequently, we demonstrated that PRP could recover cell potential from senescence, such as promote cell growth (cell proliferation and colony formation), increase osteogenesis, decrease adipogenesis, restore cell senescence related markers and resist the oxidative stress in stem cells from aged mice.

The results also showed that PRP treatment in aged mice could delay mice aging as indicated by survival, body weight and aging phenotypes (behavior and gross morphology) in term of recovering the cellular potential of their stem cells compared to the results on aged control mice. In conclusion these findings showed that PRP has potential to delay aging through the recovery of stem cell senescence and could be used as an alternative medicine for tissue regeneration and future rejuvenation.

Link: http://dx.doi.org/10.1016/j.biomaterials.2014.08.034

The SENS Research Foundation coordinates fundamental research into the technologies needed for future rejuvenation treatments. There is in fact a very clear roadmap leading from where we are today to the means to repair the cellular and molecular damage that causes aging. Outside of stem cell research and cancer research, most of that roadmap is lagging far behind, however. There is little interest and little funding despite the fact that other causes of aging as just as important to the development of age-related disease as faltering stem cell activity and the conditions that give rise to ever higher risk of cancer with passing years. Thus the SENS Research Foundation staff aim to push past roadblocks and spur further progress where that progress is very much needed: in ways to repair mitochondrial damage or clear persistent cross-links from aged tissues, for example. These efforts are funded by philanthropic donations, so we get the progress we are willing to support. Certainly there is no other organization out there yet doing anywhere near as much to advance repair-based approaches to treating and reversing degenerative aging.

This month's newsletter from the SENS Research Foundation turned up in my inbox today. If that wasn't the case for you, you might consider subscribing or making a donation to help fund the important work carried out by the Foundation. The newsletter pointed out a short interview from late last year that I'd missed:

Q & A with SENS Research Foundation President, CEO and Co-Founder Michael Kope

SRF is a public charity, and we intend to transform the way the world researches and treats age-related disease, by promoting truly comprehensive regenerative medicine. The unique aspect of our work is our focus on a damage-repair paradigm, and we advance that with our own scientific research and with collaborative projects, conferences, events and education programs.

SRF supports three research projects at its Mountain View Research Center, and an additional fifteen projects at universities and institutes around the world. The list includes Oxford, Harvard, Yale, the Buck Institute and the Wake Forest Institute for Regenerative Medicine. The goals are as ambitious as removing the underlying causes of age-related diseases such as macular degeneration, atherosclerosis, Alzheimer's and cancer.

And we're not just research programs: educating the public, building a community of support, and training researchers to support a growing rejuvenation biotechnology field are also major endeavors of the organization. Our internship program is growing, our research advisory board is expanding, and rarely a week goes by without a speaking engagement or event on our calendars.

As is often the case the most interesting part of the newsletter is the Question of the Month section, which this time around looks what we know about cellular and molecular damage accumulation in very early life. While reading, it is worth bearing in mind that the application of reliability theory to aging best fits the observed data in models where individuals are born already possessing a modest but non-zero amount of damage.

Question of the Month #8: Aging Damage and Early Early Detection

Q: Because the cellular and molecular damage of aging is a by-product of metabolism, I have always assumed that it accumulates throughout our entire lives - from when we are a baby until we die. Is this true? Is there any research showing that very young children have low levels of tissue-stiffening crosslinks, extracellular aggregates like beta-amyloid, or intracellular aggregates (like lipofuscin or the ones driving atherosclerosis) in their tissues?

A: Scientists don't have any single, comprehensive answer to this broad question, in part because there hasn't been a systematic investigation into it, and in part because the answer likely depends on the specific kind of aging damage under consideration. To really answer it, one would need to begin an investigation for each aging-damage precursor by taking tissue samples from newborns, and then performing ongoing testing periodically throughout life. As a second-best, you'd do a cross-sectional study comparing neonates, five-year-olds, pubescent children, very young adults, and then adults, including ages spread fairly evenly across the remaining lifespan. It would be difficult to perform such studies both institutionally and technically, as they would be quite expensive and would involve sourcing tissue samples from individuals of all of these ages, acquiring consent to use them for studies, and securing funding to do all this.

From a technical standpoint, it is already difficult to quantify many kinds of aging damage even in older people. The extreme case here is the key tissue-stiffening crosslink glucosepane, which is very fragile when subjected to most laboratory tissue treatments and has heretofore needed to be painstakingly extracted from tissues using a laborious series of sequential enzymatic extractions. Happily, this is likely to change soon, thanks to excellent progress being made in research that SENS Research Foundation has been funding in the Spiegel Research Group at Yale for several years now, developing enabling technologies for the development of glucosepane crosslink breakers. And it is inherently even more difficult to probe tissue samples for aging damage in very young people, for the obvious reason that the damage is by definition present at much lower levels in very young people's tissues than it is in older people's.

What little data we do have on aging damage precursors in the very young comes, for instance, from autopsy studies of stillborn infants. All such infants have at least some lipid deposition in their arteries, with as many as 25% of them having the "fatty streaks" that are the first visible sign of accumulating foam cells. These early lesions are particularly common in infants born to mothers with high serum cholesterol. Children are also born with some mechanical fatigue and fraying of the complex, lamellar structures of the stretchy protein elastin that provide arterial tissue with its elasticity, and this damage progressively increases with age. And there is already crosslink damage in the trachea and the bronchi of the lungs of newborn rats.

It's important to remember, however, that from the perspective of developing the therapies we need to delay and prevent degenerative aging, it doesn't matter whether or how much of these various aging lesions are present in very young people. Whatever their level may be, and whatever their rate and mechanisms of accumulation, the aging damage that is already present in the bodies of young adults is clearly harmless at the low levels at which it's present, as evidenced by the (by definition) youthful good health that college students and thirtysomethings enjoy. It's only decades later, as the level of cellular and molecular damage in different tissues accumulates to a characteristic "threshold of pathology," that enough of a given tissue's functional units are disabled to overcome its evolutionarily-inbuilt redundance and meaningfully impair tissue function.

In order to restore and maintain youthful health and functionality, then, we don't need to eradicate aging damage from the tissues of aging people; nor do we need to begin treating healthy young adults to push their burden of aging damage down to levels typical of children. Rather, we only need to develop rejuvenation biotechnologies capable of periodically removing, repairing, replacing, or rendering harmless enough of a tissue's molecular and cellular damage as to restore its structural integrity to what it is in young adults - complete with its original, lower but nonzero level of damage. At that point, the rejuvenated body will be structurally and functionally young, and its metabolic derangements will be restored to health as a downstream consequence of the intrinsic order of the youthful body. With this return to normal functionality at every level will come restored health, vigor, and vitality that ongoing periodic treatment can maintain - for many years longer at first, and ultimately indefinitely.

The immune system incorporates a large number of very sophisticated mechanisms for clearing debris, killing errant cells and pathogens, and removing unwanted metabolic waste. Therefore many research groups aim to harness and steer immune cells to achieve specific goals, such as the clearance of amyloid beta deposits associated with Alzheimer's disease. There are many different approaches to developing immune therapies of this nature, some more sophisticated than others. Here is one of the less complex possible approaches:

New research shows that the body's immune system may be able to clear the brain of toxic plaque build-up that is the hallmark of Alzheimer's disease, reversing memory loss and brain cell damage. Alzheimer's disease is an irreversible, progressive brain disease that causes problems with memory, thinking and behavior. Brains with Alzheimer's disease show build-up of a sticky plaque -- made of a protein called beta-amyloid -- that induces memory loss. When afflicted with Alzheimer's, the immune system, which typically rids the body of toxic substances, becomes imbalanced and inefficient at clearing those plaques.

Researchers used genetically modified mice to show that blocking a substance called interleukin-10 activates an immune response to clear the brain of the beta-amyloid plaques to restore memory loss and brain cell damage. Alzheimer's-afflicted mice in which the immune cells were activated behaved more like mice without the disease in various learning and memory tests. Future studies will test the effectiveness of drugs that target interleukin-10 in rats that the scientists have genetically modified to develop Alzheimer's disease. "Our study shows that 'rebalancing' the immune response to wipe away toxic plaques from the brain may bring new hope for a safe and effective treatment for this devastating illness of the mind."

Link: http://www.keckmedicine.org/usc-neurogeneticists-harness-immune-cells-to-clear-alzheimers-associated-plaques-from-rodent-brains/

Much of the damage done following an ischemic stroke occurs when blood flow returns: there is a sudden and overwhelming production of reactive molecules and cells die as a result. Given sufficiently potent and safe antioxidants, this harmful process could be suppressed provided a treatment is delivered rapidly:

Injectable nanoparticles that could protect an injured person from further damage due to oxidative stress have proven to be astoundingly effective in tests to study their mechanism. Combined polyethylene glycol-hydrophilic carbon clusters - known as PEG-HCCs - could quickly stem the process of overoxidation that can cause damage in the minutes and hours after an injury. The tests revealed a single nanoparticle can quickly catalyze the neutralization of thousands of damaging reactive oxygen species molecules that are overexpressed by the body's cells in response to an injury and turn the molecules into oxygen. These reactive species can damage cells and cause mutations, but PEG-HCCs appear to have an enormous capacity to turn them into less-reactive substances.

The research targeted traumatic brain injuries, after which cells release an excessive amount of the reactive oxygen species known as a superoxide into the blood. These toxic free radicals are molecules with one unpaired electron that the immune system uses to kill invading microorganisms. In small concentrations, they contribute to a cell's normal energy regulation. Generally, they are kept in check by superoxide dismutase, an enzyme that neutralizes superoxides. But even mild traumas can release enough superoxides to overwhelm the brain's natural defenses. In turn, superoxides can form such other reactive oxygen species as peroxynitrite that cause further damage.

The researchers hope an injection of PEG-HCCs as soon as possible after an injury, such as traumatic brain injury or stroke, can mitigate further brain damage by restoring normal oxygen levels to the brain's sensitive circulatory system. "This could be a useful tool for emergency responders who need to quickly stabilize an accident or heart attack victim." The study also determined PEG-HCCs remain stable, as batches up to 3 months old performed as good as new.

Link: http://news.rice.edu/2015/02/09/nano-antioxidants-prove-their-potential-2/

There are many trade-offs to be made in aging research, and most of them involve the balance between expended resources and time on the one hand and the expectation value of knowledge gained on the other. The challenge inherent in the present study of aging is that in terms of quality and usefulness of data there is still little that beats waiting and watching - sitting back and following the entire life span of your subjects, taking measurements as you go. This is wildly impractical for human aging, enormously expensive and unlikely to happen again any time soon for other longer-lived primates, given the debates over the structure and results of two presently running calorie restriction life span studies in rhesus macaques, and merely painfully expensive to arrange for mice. Things start to look up once you head on past mice to very short-lived species such as flies and nematode worms: the cost falls and studies of aging that produce quality data for that species become affordable, as well as being something that can be carried over the course of a few months.

What is the value of good quality data for nematode aging, under the influence of a variety of genetic alterations, environmental circumstances, and other treatments, however? Far less than if we magically had access to similar data for humans, that is certain, but to a surprising degree many aspects of the cellular biochemistry of aging are shared between very diverse species, even those as distant as humans and nematodes. The insights that can be obtained, while rarely if ever directly applicable across such a large gulf, are well worth the cost. They serve to steer much more expensive research in mammals, guiding the larger expenditures to the lines of work more likely to produce results. In turn work in mice serves to steer the again much more expensive process of producing applications of research for human use.

So short-lived animals whose biochemistry is well understood serve an important role in exploratory research. Starting there, even though far removed from human biology, ultimately reduces costs and rules out dead ends in the process of medical development and aging research considered as a whole. Further, a diversity of short-lived species to study is a good thing: comparisons between them can help to more efficiently identify initially promising findings that turn out to be peculiar to one species, which is a lot better than figuring that out only later, after five years of further mouse studies. Here is an example of scientists working to develop the infrastructure and understanding needed for a comparatively new addition to the species employed in the laboratory for aging research:

Tiny fish makes big splash in aging research at Stanford

"Live fast, die old" maybe isn't the catchiest motto. But, for the African turquoise killifish, it's apt. The killifish is one of the world's shortest-lived vertebrates, with some varieties living only four months. Old killifish display many characteristics of aging humans: declining fertility and cognitive function, a loss of muscle mass and an increasing likelihood to develop cancerous tumors. The fact that the fish shares many biological characteristics with humans makes it a promising candidate for the study of aging and longevity. But until now, scientists didn't have the necessary tools and information with which to conduct genetic studies.

Now, researchers have mapped the location of specific genes involved in aging and age-related diseases along the killifish's chromosomes. They've studied patterns of gene expression in its various tissues, and used genome-editing technology to mutate 13 genes thought to be associated with the aging process. This new biological tool kit, which the researchers have made publicly available, will make it possible to trace the effect of specific genetic changes on aging and the diseases that accompany it.

A short life span allows researchers to quickly assess the effect of genetic variations among different strains of fish. It also allows them to breed and raise hundreds of progeny for study within the span of months, rather than the many years required to conduct similar experiments in other vertebrates. "The life span of a mouse can be as long as three to four years. This is close to the average length of a postdoctoral or graduate student position. This means that it would be very difficult for a researcher to conduct a meaningful analysis of aging in the mouse within a reasonable time period."

The killifish's rapid life cycle meant that researchers were able to generate fish carrying the mutations within 30-40 days, and stable lines - that is, fish with the mutation stably integrated into all their cells, which they will then pass on to all their progeny - within about two to three months. In contrast to laboratory mice, the length of killifish telomeres, which average around 6,000-8,000 nucleotides, is similar to that of humans. As a result, researchers were able to quickly see the effect of a telomerase-disabling mutation in the fish. Interestingly, fish in which telomerase activity was disabled displayed a variety of traits that are similar to those seen in humans with a disorder called dyskeratosis congenita, which is also due to a mutation in telomerase. The researchers conclude that the killifish is currently the fastest way to study diseases of telomere shortening in vertebrates. They are hopeful that the other mutant strains will be equally useful in their lab and in other labs worldwide.

Parabiosis research in which the circulatory systems of a young and old mouse are connected has led to a cataloging of differences in circulating factors in old versus young blood. Researchers have demonstrated that resetting the levels of GDF-11 in old mice produces beneficial effects, probably through reactivation of stem cell populations and thus increased repair and maintenance of tissues. Other important signaling molecules will no doubt be discovered and manipulated in the years ahead.

Outside of the ability to energize native stem cell populations, there may not be too much more here, however. Even that has to be cautiously approached because of the risk of spurring cancer - the consensus is that the fading of stem cell activity reduces cancer risk, but at the cost of a slow decline in tissue and organ function. Much of the rest of the aging process is driven by things like accumulation of metabolic waste products that the body breaks down only slowly, if at all, however, things that are not much affected by stem cell activity. So it may well be that parabiosis research and the resulting manipulation of factors in the blood is one of the first stepping stones to a future of stem cell therapies that discards transplantation in favor of controlling a patient's own stem cells, but nothing more.

The proposal quoted below is one logical next step following on from present research indicating factors in old blood can be manipulated for benefit. The author suggests a sophisticated form of periodic blood filtration and augmentation, in which the level of some factors is reduced and others raised. Whether this particular technology comes to pass or not depends strongly on the details of the ongoing cataloging and manipulation of important signaling molecules in animal studies, of course.

This hypothesis proposes a new prospective approach to slow the aging process in older humans. The hypothesis could lead to developing new treatments for age-related illnesses and help humans to live longer. Scientists have presented evidence that systemic aging is influenced by peculiar molecules in the blood. Researchers discovered elevated titer of aging-related molecules (ARMs) in blood, which trigger cascade of aging process in mice; they also indicated that the process can be reduced or even reversed. By inhibiting the production of ARMs, they could reduce age-related cognitive and physical declines and lead to slower rates of aging.

A prospective "antiaging blood filtration column" (AABFC) is a nanotechnological device that would fulfill the central role in this approach. An AABFC would set a near-youth homeostatic titer of ARMs in the blood. In this regard, the AABFC immobilizes ARMs from the blood while blood passes through the column. The AABFC harbors antibodies against ARMs. ARM antibodies would be conjugated irreversibly to ARMs on contact surfaces of the reaction platforms inside the AABFC till near-youth homeostasis is attained. The treatment is performed with the aid of a blood-circulating pump. Similar to a renal dialysis machine, blood would circulate from the body to the AABFC and from there back to the body in a closed circuit until ARMs were sufficiently depleted from the blood.

The optimal application criteria, such as human age for implementation, frequency of treatments, dosage, ideal homeostasis, and similar concerns, should be revealed by appropriate investigations. If AABFC technology undergoes practical evaluations and gains approval, it would hold future promises such as: 1) prolonged lifespans; 2) slowed age-related illnesses in the elderly; 3) reduced health expenses; 4) reduced cosmetic surgeries performed on the elderly; 5) healthier astronauts in extended outer space journeys; 6) reduced financial burden of advanced care for the elderly imposed upon both government and society; and 7) rejuvenating effects in healthy, non-aged individuals.

Link: http://dx.doi.org/10.2147/DDDT.S71216

Oxidative stress refers to higher levels of oxidizing molecules present in and around cells, causing more damage by reacting with protein machinery that must then be repaired. Work over the past two decades has show that raising or lowering levels of reactive oxygen species (ROS) produced by the mitochondria within a cell can extend or shorten life in lower animals such as nematode worms: the outcome obtained depends on the details of the process. Cells react to the presence of ROS with increased housekeeping activities, so a modest increase can lead to a net reduction in damage while a large increase overwhelms repair systems and causes greater harm.

Since ROS do have a variety of roles in cellular metabolism, and are not just agents of harm, it matters greatly where in the cell ROS levels are altered. In this paper researchers explore localized increases in ROS levels in nematode cells by selectively deleting genes that encode varieties of superoxide dismutase antioxidant proteins. These antioxidants reside in various different compartments of the cell, and so reduced levels lead to increased ROS, but only in the areas of the cell where the antioxidant is normally present:

Reactive oxygen species (ROS) are highly reactive, oxygen-containing molecules that can cause molecular damage within the cell. While the accumulation of ROS-mediated damage is widely believed to be one of the main causes of aging, ROS also act in signaling pathways. Recent work indicates that low levels of ROS can be beneficial and promote longevity. In this paper, we use a long-lived mitochondrial mutant C. elegans strain clk-1 to further examine the relationship between ROS and lifespan. While it was originally believed that clk-1 mutants had increased lifespan as a result of decreased ROS production, ROS levels have been shown to be increased in clk-1 worms.

Increasing levels of superoxide, one form of ROS, through treatment with paraquat, results in increased lifespan. Interestingly, treatment with paraquat robustly increases the already long lifespan of the clk-1 mitochondrial mutant, but not other long-lived mitochondrial mutants such as isp-1 or nuo-6. To genetically dissect the subcellular compartment in which elevated ROS act to increase lifespan, we deleted individual superoxide dismutase (sod) genes in clk-1 mutants, which are sensitized to ROS. We find that only deletion of the primary mitochondrial sod gene, sod-2 results in increased lifespan in clk-1 worms. In contrast, deletion of either of the two cytoplasmic sod genes, sod-1 or sod-5, significantly decreases the lifespan of clk-1 worms.

Further, we show that increasing mitochondrial superoxide levels through deletion of sod-2 or treatment with paraquat can still increase lifespan in clk-1;sod-1 double mutants, which live shorter than clk-1 worms. The fact that mitochondrial superoxide can increase lifespan in worms with a detrimental level of cytoplasmic superoxide demonstrates that ROS have a compartment specific effect on lifespan - elevated ROS in the mitochondria acts to increase lifespan, while elevated ROS in the cytoplasm decreases lifespan. This work also suggests that both ROS-dependent and ROS-independent mechanisms contribute to the longevity of clk-1 worms.

Link: http://dx.doi.org/10.1371/journal.pgen.1004972

Chronic kidney disease (CKD) is a particular unpleasant condition, not least because it accelerates many of the other manifestations of aging, but also because there is comparatively little that can be done to treat it at this time. There are lines of work based around suppressing fibrosis characteristic of aged, damaged kidneys, and also the potential use of stem cell therapies to regenerate healthy kidney tissue, but practical implementations are yet to emerge. Since a little less than 10-20% of the adult population in developed nations suffers from chronic kidney disease, depending on where you want to drawn the line, progress on the path to treatments has the potential to help a large number of patients.

One of the signs of failing kidney function is uremia, the increased presence of metabolic products such as urea in the bloodstream. It shows that the kidneys are not filtering as well as they should, and as levels of these unwanted products grow they are accompanied by a very broad range of damaging and increasingly serious consequences. Many of these consequences look a lot like the general progression of aging from the outside: increased frailty on many counts, and increased risk of suffering other age-related conditions.

In this open access review paper the authors seek to draw comparisons between the biochemistry of aged people without chronic kidney disease and younger people suffering the condition. There are numerous similarities, but is this a case in which those similarities are a learning opportunity? This is a question perhaps worth thinking about in the context of type 2 diabetes, a condition that can also be thought of as accelerating certain aspects of aging, and has for some time been used in animal studies as a model substitute for aging.

Aging and uremia: Is there cellular and molecular crossover?

Observation alone suggests that patients with end stage kidney disease (ESKD) are biologically older than their unaffected peers. As a group, ESKD patients have a morbidity and mortality profile similar to that of the geriatric population, and the pathophysiology of the uremic syndrome has interesting parallels with the aging process. Based on these thoughts it has been posited that kidney failure results in accelerated, pathological aging. Indeed there are striking analogies between the effects of aging and uremia on the structure and function of the heart and vasculature, with similar arterial stiffening-related changes seen in pulse contour, pulse wave velocity, and impedance, and similar structural abnormalities with wall thickening, decreased elastin, and increased collagen content.

Whilst much has already been written about the intriguing similarities that appear to exist between the aging process and CKD, comparatively little work has been undertaken looking at the cellular and molecular hallmarks of aging in the context of the known evidence concerning uremia-induced cellular and molecular pathways.

1) The principle cell death and survival molecular pathways consisting of apoptosis, necroptosis and autophagy are strongly interrelated and crossover at many points. Whilst our current knowledge on how these interacting pathways are controlled and regulated is far from complete there is a growing appreciation of how similar many of the molecular signalling induced by uremia and aging appear to be.

2) Aging and uremia share many important cellular characteristics such as increases in cell senescence, telomere shortening and exhaustion of stem cells. This provides further evidence that supports the contention that uremia can be considered as a form of accelerated aging.

3) The klotho gene was originally identified as being involved in the suppression of aging in transgenic mouse studies. Defective klotho expression resulted in mice having a premature aging phenotype, which had striking similarities to that of CKD patients. The deficiency in klotho seen in uremia and aging might underpin the enhanced cell senescence, apoptosis and stem cell depletion common to both states. Given that tissue klotho expression is greatest in the kidneys a common mechanism is perhaps to be expected.

4) Spontaneous post-translational protein modifications result from the non-enzymatic attachment of reactive molecules to protein functional groups. This process occurs in healthy individuals with aging, but is increased in certain disease states. Alterations to protein structure may result in functional changes, which can be pathogenetic. One of the most widely studied and publicised forms of post-translational protein modification is the formation of advanced glycation end products (AGEs) by the non-enzymatic modification of tissue proteins by physiologic sugars. AGEs accumulate in tissues as a function of increased production (e.g., in diabetes mellitus), decreased renal removal of AGE precursors (e.g., in advanced CKD) and time (as occurs in physiological aging). Increased oxidative stress and AGE generation are known to play a role in the pathophysiology of aging, and both of these events are present in patients with CKD and therefore represent two further potential crossovers between uremia and the aging process.

Based on this evidence it could be posited that the physical resemblance between advanced age and uremia is underpinned by shared cellular and molecular "abnormalities". These observations also reinforce the idea of the "uremic syndrome", in which dysfunctions in multiple body systems arise due to a pervasive defect at a cellular level. Information gathered by research into aging pathways and "anti-aging therapies" might inform interventions to avoid, slow the progression of or even reverse some of the pathological changes seen in uremia. Given that these pathways are seen throughout most tissues and cell types it is also possible that a single intervention might treat several pathologies. However, the aging process remains incompletely understood in healthy individuals, and those pathways that are known are complex and heavily interconnected. Disentangling these in the uremic syndrome, in which multiple co-existing and interdependent metabolic abnormalities arise, will be a challenge.

The point to take away here, I think, is that damage is damage. We suffer age-related degeneration and loss of function because our biology accumulates unrepaired damage of a variety of forms to cells and tissue structure. Clearly some of the detrimental outcomes resulting from damage accumulation reinforce one another to speed up the production of further damage. The whole of aging is an accelerating downward spiral: it isn't a linear process of advancing dysfunction. Frailty and mortality take hold much more rapidly in the later stages.

The progression of degenerative aging is presently the greatest cause of pain and suffering in the world, so why are we not all greatly in favor of working towards medical technologies capable of preventing the detrimental results of aging? Beyond removing frailty and disease, a side-effect of therapies capable of halting all age-related dysfunction through the repair of accumulated damage to cells and tissues is we'll all live very much longer in good health and youthful vigor.

The yearning for eternal life and youth has been a preoccupation of humans for millennia. Yet quite a few people remain unconvinced that cheating death is a good idea. For every promising advance in cancer treatment or hip replacement, a chorus chimes in with a warning about being careful what we wish for: Sure, we're curing diseases and easing pain, but perhaps the cost - in health and in dollars - is too high. This approach isn't just wrong; it's almost criminally obtuse. These objections conflate the physical process of aging with the mere passage of years. Our quest must be - as it has been for all of recorded history - not merely to live a long time, but to slow and stop the process of aging. Eternal youth, not just long life.

The current medical paradigm is to go after each individual disease as it emerges in a perpetual game of therapeutic whac-a-mole. The result is that individuals begin to accumulate infirmities. About 50 percent of Medicare beneficiaries are being treated for five different chronic conditions. This is ultimately a losing proposition, because aging bodies accrue more and more lethal and disabling conditions that compete to kill them. Patients routinely survive health crises that would have done them in even a generation earlier, but to what end? If an older patient doesn't die of a heart attack, prostate cancer could do him in. If a stroke doesn't get her, the Alzheimer's will. Ultimately, more than 25 percent of Medicare spending goes toward the 5 percent of beneficiaries who die each year.

There is a better way. We must look beyond individual pathologies to their root, aging itself. If anti-aging treatments can maintain people in the state of health of the average 30-year-old, the onset of chronic illnesses will be forestalled and health care and pension expenditures will be much lower. And it increasingly looks like we may actually be able to slow or even stop the aging process, to the tremendous benefit of humanity.

If bodies can be kept young, they will be less vulnerable to diseases at any chronological age. If 55 really were physiologically the new 45, the incidence of cardiovascular disease would go down by about 50 percent and the prevalence of cancer would be cut by nearly 80 percent. Bodies age in much the same way that automobiles do. In the course of roaming around the world, they accumulate damage, which, if not repaired, leads to a breakdown. Unlike automobiles, human bodies do have some capacity for fending off hurts and for self-repair, but those mechanisms eventually wear out. Fortunately, researchers are making considerable progress in figuring out credible ways to repair the damage and thus slow down the aging process.

Link: http://reason.com/archives/2015/02/06/eternal-youth-for-all/print

Aging and cancer have evolved hand in hand, and numerous aspects of our biology play an important role in both. At the simplest, highest level we have things like the decline in stem cell activity and tissue maintenance with age as a part of the evolution of human life span as a balance between death by cancer and death by functional failure of organs. There is also the role of senescent cells in both suppressing and promoting cancer, and their accumulation as a cause of degenerative aging. There are many other more complex and less well understood relationships between aging and cancer, but this review focuses largely on cellular senescence as a comparatively new area for building interventions:

A growing body of evidence supports the view that the complex relationship between mechanisms underlying aging and cancer evolves with organismal chronological age. Significant progress has been made in defining cell-autonomous and cell-nonautonomous mechanisms that in young and adult organisms simultaneously delays aging and suppress tumor formation. Furthermore, it is now well established that the intricate interplay between mechanisms underlying aging and cancer reflects the proliferative history of cells and is impacted by the progression of a cellular senescence program. Recent findings imply that the advancement of the multistep cellular senescence program imposes antagonistically pleiotropic effects on aging and cancer.

Despite an important conceptual advance in our understanding of the complex interplay between mechanisms underlying aging and cancer, we are still lacking answers to the following fundamentally important questions. Which of the numerous morphological and functional changes observed in various types of senescent cells in culture and in vivo are universal hallmarks of a state of cellular senescence - and, thus, which of these changes can be used as diagnostic biomarkers of cells entered such a state in any tissue? Given that the progression of the cellular senescence program imposes antagonistically pleiotropic effects on aging and cancer what therapeutic interventions have a potential to be used not only for enhancing those effects that are anti-aging and/or anti-cancer but also for attenuating those effects that are pro-aging and/or pro-cancer?

Recent findings in mice engineered for a reversal of the cellular senescence state by a drug-inducible telomerase reactivation or for a late-life immune clearance of senescent cells by their drug-inducible elimination suggest that small chemicals can be used for: (1) a protein target-specific pharmacological enhancement of the beneficial for organismal healthspan effects imposed by the cellular senescence program; and/or (2) a protein target-specific pharmacological attenuation of the deleterious for organismal healthspan effects inflicted by this program.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4306474/

In a recent Reddit discussion, philanthropist Bill Gates had this to say about the present growth in research aimed at extending healthy life spans:

It seems pretty egocentric while we still have malaria and TB for rich people to fund things so they can live longer. It would be nice to live longer though I admit.

The comments were of course replicated far and wide in the echo chamber of the press: Gates has a soapbox of an enviable size, even among billionaires. The context here is the Silicon Valley network of wealth that, in quite different ways, funds both Google Venture's new California Life Company investment and the less flashy but so far much more important rejuvenation research and advocacy organized by the SENS Research Foundation. It is also worth recalling that Microsoft cofounder Paul Allen continues to pour a large amount of wealth into cutting edge biotechnology research. The philanthropy of the Bill and Melinda Gates Foundation by comparison is focused on improving the lot of the poor directly, as a matter of delivering and implementing existing technological capabilities rather than building completely new things. Though of course they do fund malaria and other infectious disease research in a big way, which is definitely cutting edge biotechnology.

Both advancing the cutting edge and delivering existing capabilities to the poor are viable approaches to making the world a better place. There must be progress at the cutting edge to produce new medicine and other important technologies. Much of the early stage novel, risky, ground-breaking research only happens because it is funded by philanthropy. Large funding sources in government and business are risk averse and much more interested in supporting incremental but certain progress - yet the only reason that progress even exists in the first place is that someone was willing to put money on the very early stage work that made it possible. Similarly once a new technology is shown to be possible it is a good thing to aid deployment and continued improvements in implementation that help ease the hurdles to bring the results to less fortunate regions of the world. That part of the development process has many of the same problems as early stage research: a lot of people willing to fund a sure thing, and far too few willing to sink money into solutions for what look like roadblocks and dead ends. The sure things never do much; it is the radical new approaches that enable real progress.

Everyone gets to chose where they put their money and how they think about the world. It is nonetheless always disappointing to see influential people completely misunderstand the point of longevity science. Comments like those made by Gates could just as well have been applied to heart disease fifty years ago. Why are all those rich people funding heart treatments and better drugs for an age-related condition? Isn't that just selfish? Yet the distinct character of our era is that access to technology is comparatively flat: the progression of availability from expensive and inaccessible to accessible to the vast majority of people occurs very rapidly. Look at the spread of mobile phones and internet access over the past two decades as an example of what happens in a market where governments interfere far less than is done in medicine. Even in medicine, many of the medical technologies funded by rich people in past decades, and initially only available to the wealthy and connected in their earliest forms, are now available in places that include rural India and reaches of Africa. Such as those drugs for heart conditions.

Improving medicine is not about making things happen for the wealthy. It is about whether we all win together or we all lose together. Mocking or shunning improvements aimed at preventing the suffering and frailty of aging because some wealthy person might get the treatments first is lunacy: all technologies are available to the wealthy first and far in advance of the rest of us. That is what being wealthy gets you, pretty much by definition, and if it serves as an incentive to get them involved then all the better. They fund the first wave, and the rest of us obtain access in the later stages of development, when the new technology moves beyond prototypes and first generation implementations to become better, cheaper, and more robust.

Here is another way of looking at this: what causes the greatest harm to poor people? It isn't malaria. It is aging, and by a long, long way. Malaria killed in the vicinity of 650,000 people in 2012. In that same year somewhere north of 40 million people aged to death. More than three quarters of the world's population are exceptionally poor compared to the people we call poor in the US: so perhaps 30 million or more of those deaths fall into that demographic, fifty times as many as caused by malaria. I think it fair to say that degenerative aging places a far worse burden upon those individuals than on you and I. It is terrible for all of us, and kills all of us if we're lucky enough to evade the rest of the life's slings and arrows, but there's a big difference between being old and frail in agrarian poverty versus a first world city. If you are a rational, compassionate, utilitarian individual - and few are, sadly - then it should be clear that the best thing that can be done with limited resources is to work as rapidly as possible to produce effective treatments for aging that prevent and reverse age-related disease. Just getting a first generation of these treatments into the development pipeline at all, and not even taking any further steps beyond that to help speed things along, guarantees that the poor of the near future will have far better lives as a result. We would hope to do more than just that of course.

The greatest positive change we can create in the world is to eliminate the pain and suffering of aging through medical science. The outcome in terms of future lives saved and lives improved is so large in comparison to the treatment of any specific disease, even endemic diseases such as malaria, that it compels attention. That said, overall medical research funding is tiny in comparison to the wealth that flows through the entertainment industry, that goes towards killing people in ever more inventive ways, that is used to make candy, that changes the color of a US president's vest from red to blue, and so on. We like our wars and our circuses, and the scraps left over after that is done are all that goes towards making the world better by building new medical technologies. There is more than enough funding out there to cure every disease, to grow the life science research community by a factor of a hundred, and achieve countless other important goals besides. People just choose to spend it on other things, all ultimately pointless, forgotten, and irrelevant in the long term. The only thing that really matters is progress in technology, and especially in medicine, but persuading the world of that fact is still a hard sell.

As regular readers well know I think that fears of overpopulation following healthy life extension are essentially ridiculous, on a par with raising the prospect of boredom as a reason to reject longevity science and thus force billions to suffer and age to death unnecessarily. Led by the hairshirt teachings of environmentalism perhaps a majority of people believe the world to be overpopulated today, but the regions usually pointed out as examples are characterized by terrible governance, poverty created by war and kleptocracy in the midst of a wealth of resources, human and otherwise, that go unused.

The common Malthusian vision of overpopulation - that we will run out of oil, or food, or land, or any other resource because there are more people - is driven at root by the failure to appreciate economics, how the world works and what drives human action. The world changes and people react to potential shortages and rising prices by developing new technologies and new resources. Those who cannot look beyond what exists today will always cry that the sky is falling, as they think in terms of dividing a fixed set of resources that never changes. Those arguments were made in every past era: the Roman age had its authors who thought that doom lay ahead if there were too many more people. In reality these views are always wrong, time and again. Even land is effectively unlimited given access to the rest of the solar system and sufficiently advanced construction technologies.

Many worry that radical life extension or the elimination of death will lead to overpopulation and ecological destruction. In other words, while it may be best for individuals to live forever, it might be collectively disastrous. However, I don't believe that overpopulation and its attendant problems should give researchers in this area pause. So I argue that we should try to eliminate death, dealing with overpopulation - assuming we even have to - when the time comes. My suggestions may be considered reckless, but remember there is no risk-free way to proceed into the future. Whatever we do, or don't do, has risks. If we cease developing technology we will not be able to prevent the inevitable asteroid strike that will decimate our planet; if we continue to die young we may not develop the intelligence necessary to design better technology. Given these considerations, we shouldn't let hypotheticals about the future deter our research into defeating death. The tragedy of 150,000 people dying every single day - 100,000 of them from age-related causes - is a huge price to pay for speculative hypotheses about the future.

Note too that this objection to life-extending research could have been leveled at work on the germ theory of disease, or other life-extending research and technology in the past. Don't cure diseases because that will lead to overpopulation! Don't treat sick children because they might survive and have more children! I think most of us are glad we have a germ theory of disease, and treat sick children. Our responsibility is to help people live long, healthy lives, not worry that by doing so other negative consequence might ensue. We are glad that some of our ancestors decided that a twenty-five year life span was insufficient, instead of worrying that curing diseases and extending life might have negative consequences. Most importantly, I believe it is immoral for us to reject anti-aging research and the technologies it will produce, thereby forcing future generations to die involuntarily. After anti-aging technologies are developed, the living should be free to choose to live longer, live forever, or even die young if they want to. But it would be immoral for us not to try to make death optional for them.

Link: http://reasonandmeaning.com/2015/02/10/answering-the-overpopulation-objection-to-living-forever/

Naked mole-rats (NMRs) live nine times longer than other similarly sized rodent species and show comparatively few signs of degeneration in functional health along the way. There is considerable interest in understanding exactly why this is the case: what are the important differences in the biochemistry of this species? Progress on this front is probably not going to directly result in ways to extend healthy life in humans, but it will help to prioritize efforts to treat the causes of aging by understanding which of the possible contributions are most important.

Genome maintenance (GM) is an essential defense system against aging and cancer, as both are characterized by increased genome instability. Our study is the first step in a comparative genomics approach to study GM in relation to aging and cancer. Focusing on human, mouse, and NMR because of their contrasting aging phenotypes and the availability of high-quality genome sequences, we investigated copy number differences of GM genes and discovered that very few GM genes have been lost among these three species during evolution.

Interestingly, we found NMR to have a higher copy number of CEBPG, a regulator of DNA repair, and TINF2, a protector of telomere integrity. NMR, as well as human, was also found to have a lower rate of germline nucleotide substitution than the mouse. While we can only speculate whether the two genes with additional copies in the NMR, CEBPG and TINF2, confer a significant advantage, for example, through an increase in gene dosage, it is possible for a subtle difference at the genomic level to have a large phenotypic effect, such as increased lifespan.

The finding that the NMR has a slower nucleotide substitution rate is interesting, particularly in the context of their longevity, and suggests that GM in NMR is superior to GM in the mouse. As more genomes become sequenced and annotated to higher quality, these findings can be validated further, elucidating the role of genome maintenance in modulating lifespan. Our findings in this comparative analysis of GM in human, mouse, and NMR suggest that NMR has more robust GM than mouse, which could play a role in the former's extreme longevity.

Link: http://onlinelibrary.wiley.com/enhanced/doi/10.1111/acel.12314/

The SENS Research Foundation remains the only easy way for ordinary folk such as you and I to donate funds in certainty that we are helping to advance the state of rejuvenation biotechnology. It is also the only easy way for someone with a few million to spend to do the same, for that matter. The organization funds research programs and advocacy aimed at pushing past zones of slow progress and neglect in relevant fields of medical research, so as to speed the arrival of treatments for degenerative aging. There is a clear plan, but a lot to be done.

Thus while the well-funded stem cell and cancer research communities need little help beyond a few nudges to keep them on the right road, these are only two of seven areas of research in which significant advances are required in order to eliminate age-related disease and extend healthy lifespans by decades or more. There is far too little work taking place on clearance of senescent cells, or removing cross-links in old tissues, or mitochondrial repair, or breaking down the numerous forms of amyloid and other metabolic wastes that clog up important cellular processes. In all these areas the SENS Research Foundation is one of the few organizations persistently finding ways to move the needle, to speed things up, to bring more attention to the field. The scope of success here is at present only limited by funding: there are any number of scientists in the aging research community who would drop their present work in favor of SENS biotechnology to treat aging given the budget.

With that in mind, here is a little news for those who might have a few bitcoins left over after all the excitement of the past eighteen months or so:

Donate to SENS Research Initiatives via Bitcoin

SENS Research Foundation is now able to accept Bitcoin donations: go to https://www.coinbase.com/srf and make the donation. Coinbase keeps your information confidential, so we don't see the donor. If you would like a tax receipt for your donation please send us your name and the amount of your donation via email.

Bitcoin remains an interesting endeavor, not for what most people think of as bitcoin itself, a payment system and currency, but rather for the underlying combination of cryptography and profit incentives that enables the maintenance of a reliable distributed ledger without the need for a centralized ledger-keeper. Any such ledger-keeper can be easily compromised by a determined attacker, whether criminal or representative of the state, and there is considerable value in a system that is inherently resistant to that sort of attack. The greater the participation in this system, the more secure it becomes: attackers would need immense resources to overwhelm the ledger, and they couldn't do so invisibly.

Rapid transfer of value between two parties anywhere in the world with no intermediary via bitcoins is really the least of what can be achieved with this sort of a system. The real value here isn't a currency, it is trust. You should think of the distributed ledger as a trust engine: the many computing mills churning away around the world on simple cryptographic algorithms are less engaged in mining bitcoins than they are in generating and ensuring trust. Thus programmable contracts are potentially much more valuable than bitcoin transfer, even considering only the simplest possibilities such as timed release of property or escrow without the need for a trusted third party to hold funds. Future iterations of the distributed ledger implementation will no doubt improve upon the options available, but the basic concept is here for the long term I think.

Amyloid-β is a species of misfolded protein that forms solid clumps in the brain. Its accumulation and related processes are associated with the progression of Alzheimer's disease. This isn't a slow progress of gathering waste, however, as levels of amyloid-β are quite dynamic. It is more the slow deterioration in mechanisms associated with ongoing clearance. So in addition to the great level of interest in developing treatments to clear amyloid-β from brain tissues, there is also much ongoing research relating to understanding why amyloid presence increases with age. One contribution is possibly a decline in the function of various drainage paths that occurs for much the same reasons as the general decline in blood vessel function throughout the body:

In the brain, protein waste removal is partly performed by paravascular pathways that facilitate convective exchange of water and soluble contents between cerebrospinal fluid (CSF) and interstitial fluid (ISF). Several lines of evidence suggest that bulk flow drainage via the glymphatic system is driven by cerebrovascular pulsation, and is dependent on astroglial water channels that line paravascular CSF pathways. The objective of this study was to evaluate whether the efficiency of CSF-ISF exchange and interstitial solute clearance is impaired in the aging brain.

CSF-ISF exchange and interstitial solute clearance was evaluated in young (2-3 months), middle-aged (10-12 months), and old (18-20 months) wild-type mice. The relationship between age-related changes in the expression of the astrocytic water channel aquaporin-4 (AQP4) and changes in glymphatic pathway function was also evaluated. Advancing age was associated with a dramatic decline in the efficiency of exchange between the subarachnoid CSF and the brain parenchyma. Relative to the young, clearance of intraparenchymally injected amyloid-β was impaired by 40% in the old mice. A 27% reduction in the vessel wall pulsatility of intracortical arterioles and widespread loss of perivascular AQP4 polarization along the penetrating arteries accompanied the decline in CSF-ISF exchange. We propose that impaired glymphatic clearance contributes to cognitive decline among the elderly and may represent a novel therapeutic target for the treatment of neurodegenerative diseases associated with accumulation of misfolded protein aggregates.

Link: http://www.ncbi.nlm.nih.gov/pubmed/25204284

With advancing age ever more cells in any given tissue in the body are found to be in a senescent state. These cells have permanently exited the cell cycle in response to damage or stress, most likely in order to suppress cancer risk, but their accumulation causes progressive harm to tissue structure. One promising approach to removing this contribution to degenerative aging is the use of targeted cell destruction therapies, such as those under development in the cancer research community. Periodic clearance of senescent cells would prevent the dysfunction they cause, and while this research is poorly funded in comparison to its potential, a few groups are working on it.

Cellular senescence is a process in which cells at risk of becoming cancerous adopt a state of permanent growth arrest. While this process prevents tumor formation (a cell that does not divide cannot become a tumor), senescent cells may also cause or contribute to aging and age-related conditions. The senescent phenotype is complex, and consists of many changes to the nature of the cell: permanent arrest of cell division; morphological changes; beta galactosidase expression and other epigenetic changes including the senescence-associated secretory phenotype in which senescent cells secrete a myriad of factors with potent biological activities. This senescence-associated secretory phenotype, or SASP, is the most potentially damaging effect of senescent cells. While senescent cells account for less than 10% of total cells in aged tissues, the SASP allows these cells to play a much larger role than their relatively small numbers would otherwise suggest. It is hypothesized that this aspect of senescent cells is what drives aging or age-related conditions.

Senescence as a therapeutic target for aging. If senescent cells are so bad, why not get rid of the genes that cause the formation of senescent cells in the first place? Evidence from humans and animals indicates this is not an effective strategy. For example, mutations in the retinoblastoma or P53 genes, the two most essential pathways for senescence, result in strong predisposition to cancer. Therefore, the loss of the cells' ability to undergo senescence would cause a person to die of cancer long before they would grow old enough to worry about the effects of senescent cells.

What about killing the senescent cells that have already formed in the body? This could allow cells to senesce and prevent cancer, but could then eliminate them from the body before they produce harmful effects. In 2011, a group of researchers decided to test this idea using a mouse engineered to kill senescent cells when the mice were given a drug. The results were astonishing: the mice were prevented from developing a host of issues including cataracts and loss of fat, hair, and muscle. They proved to be healthier in most ways than untreated mice. This new therapeutic option, termed "senolysis" (lysis or breaking down of senescent cells), is currently being tested by several aging researchers for its effectiveness in treating the conditions of old age.

Now that senescent cells have been demonstrated to cause many of the conditions of old age, the field of senescence research is primed for a renaissance that could result in a host of new strategies for the therapeutic treatment of aging.

Link: http://sage.buckinstitute.org/aging-fundamentals-cellular-senescence/

The output of the actuarial community often demonstrates its members to be ahead of the curve when it comes to the near future of medicine and great uncertainty over coming trends in life expectancy. This is a time of very rapid progress in the underlying biotechnologies applicable to medical research, and also a time in which both the aging research community and broader medical community are beginning a sweep change in their approach to age-related disease. There is every reason to expect that the near future of human adult life expectancy will look nothing like the past fifty years of slow and fairly steady growth: once the research community begins to actually try to address the causes of aging through medicine, then all bets are off. A likely outcome, indeed the outcome I'd expect if repair-based strategies like the SENS research projects gain large-scale funding and support, is a large upward leap in life span with comparatively little advance warning.

Actuaries are, in theory at least, aware of all of this: it is their job to take account of uncertainty in their projections. Enormous sums of money flow through life insurance companies, pension funds, and other areas of business related to life span. There is thus an equally enormous incentive for these organizations and their allies to understand the state of progress in medicine. Having a solid grasp of the uncertainty of the future is necessary to these businesses, and for many years the actuarial community has been sounding the alarm on rising uncertainty in their projections. This is a direct result of the uncertainty inherent in medical development during a time of rapid progress and strategic upheaval in the research community. Comparatively small differences in funding or happenstance collaboration today could dramatically shift the timing of the future advent of practical rejuvenation treatments.

We all know that the average person in the street is surprisingly disinterested in living longer in good health, and perhaps even hostile to the concept. This is one of the challenges we face as advocates seeking greater support for research to bring an end to the suffering and frailty that presently accompanies old age. Are actuaries any more bold than the rest of the public when it comes to radical life extension through progress in medicine? Possibly not:

Longevity expectations in the pension fund, insurance, and employee benefits industries

Considerable progress has been made in many areas of biomedical science since the 1960s, suggesting likely increases in life expectancy and decreases in morbidity and mortality in the adult population. These changes may pose substantial risks to the pensions and benefits industries. While there is no significant statistical evidence demonstrating rapid decreases in mortality rates, there are conflicting opinions among demographers and biogerontologists on the biological limits of the human lifespan and trends in life expectancy.

We administered a survey of the International Employee Benefits Association (IEBA), a large, international industry group. Industry professionals employed by consulting (35%), insurance (24%), pension (14%), and other (27%) companies responded to 32 questions. Respondents showed reasonably conservative views on the future of longevity and retirement, including that for women. The respondents formed their personal longevity expectations based on their family history and, to a lesser degree, on the actuarial life tables. Most of the sample expressed no desire to life past age 100 years, even if the enabling technologies required to maintain a healthy youthful state were available, and only a few respondents in the sample expressed a desire to live for the maximum period (at least) offered by the survey question. The majority of the respondents would not undergo any invasive procedures, and only 56% of the respondents would opt for noninvasive therapies to extend their healthy lifespans to 150 years of age if these were available.

The results of this study strengthen the argument that the captains of these industries may not use the recent advances in biomedical sciences when forming their personal longevity expectations and engaging in corporate financial planning. Moreover, most of these decision makers do not even appear to show much interest in significantly extending their own longevity should such technologies become available. Considering the recent advances in all areas of biomedical science, the rapid convergence of information technology with biomedicine, and the propagation of these technologies into mainstream clinical and consumer markets, this appears shortsighted, if only from a business perspective. Quite simply, one could lose a lot of money - to the level of affecting the future of the global financial system - by failing to predict these trends correctly. All stakeholders, including pension fund providers, insurance companies, governments, and individuals, may benefit from accelerating biomedical advances and investing in projects that increase productive longevity, or at least from taking such research and development work into account when projecting mortality rates into the future.

In aging research inadvertent calorie restriction has been the usual confounding factor in life span studies carried out with short-lived animals. If the treatment under study happened to cause animals to eat less then there was indeed an extension of life, but due to reduced calorie intake rather than the treatment. The calorie restriction response is large compared to the results of most interventions under study, and many studies were contaminated because there was no control for calorie intake. There are any number of other ways in which life span studies can be compromised, however. For example solvents extend life in nematodes, which is a problem for all experiments using them, a list that includes a range of genetic studies of longevity carried out prior to the solvent discovery. Here researchers find a similar problem in fly studies, wherein a part of the methodology of genetic engineering is shown to extend life:

Some studies on the genetic roots of aging will need a second look after the discovery that a common lab chemical can extend the life span of female fruit flies by 68 percent. For years, scientists have engineered fruit flies whose genes can be turned on and off by a synthetic hormone, allowing detailed studies of the effects of single genes on life span. Many of the genes have close relatives in humans. Unfortunately, the hormone used to perform the studies turns out to be anything but neutral.

Researchers grew suspicious of the hormone that they and others were using to activate the genes - mifepristone, a synthetic chemical known to terminate pregnancy in humans. Many studies have shown that reproduction shortens lifespan in flies and other organisms. Researchers wondered if the hormone they were using could be affecting reproduction in flies, and in turn their life span. They discovered that flies exposed to the hormone laid only half the usual amount of eggs - and lived 68 percent longer, from a median age of 56 to 94 days. The mifepristone had little or no effect on the life expectancy of female flies that had not mated, which had an even better overall survival rate and maximum lifespan.

"This opens up a new line of inquiry for longevity studies, and identifies candidate genes and mechanisms for regulating the trade-off between reproduction and lifespan that may be shared with humans. It does, however, mean that our earlier longevity studies that relied on mifepristone as a gene switch will need to be reevaluated."

Link: http://www.eurekalert.org/pub_releases/2015-02/uosc-nf020415.php

Advanced glycation end-products (AGEs) are involved in aging, as they can form cross-links that damage tissue structure, and trigger chronic inflammation via the receptor for AGEs. There are are many types of AGE and their influence is not all the same. Some can be broken down rapidly by our biochemistry, and some cannot. They can be manufactured in the body as a form of metabolic waste and also ingested in the diet, so there are two very different characteristics of AGE presence, one class that builds up slowly over time, and another that varies according to intake and ongoing clearance. Further, the types of AGE involved in the pathology of aging in shorter lived animals such as mice are very different to the important types in we longer-lived humans, something that sabotaged early efforts to build treatments that clear the AGEs that damage tissue. More recent initiatives focus on glucosepane as the important source of cross-links in human tissues.

The degree to which dietary AGEs are significant in aging is a topic for debate. On the whole it looks to be the case that the inflammatory consequences of short-lived AGEs are the more important set of mechanisms for that source:

Advanced glycation end products (AGEs) are a group of compounds that are combinations of sugars and proteins and other large molecules. They can be formed in the body, and there is a large body of literature on AGEs and Alzheimer's disease. However, AGEs are also formed when food is cooked at high temperatures or aged for a long time such as in hard cheese. AGEs increase the risk of various chronic diseases through several mechanisms including increased inflammation and oxidative stress. They can also bind to the receptor for AGEs (RAGE). RAGE transports beta-amyloid proteins across the blood-brain barrier and contributes to the development of Alzheimer's disease.

This study looked at the content of AGEs in national diets and clinical studies and compared total AGEs to Alzheimer's disease rates. For this purpose, the values for AGE for many types of food were taken from a study in which researchers cooked 549 foods by different methods and measured the AGE content of the cooked food. They found that the higher the cooking temperature, the higher the AGE content. For example, 100 grams of raw beef had 707 kU of AGEs, but 100 grams of roast beef had 6071 kU. In typical national diets, we found that meat made the highest contribution of AGEs, followed by vegetable oils, cheese, and fish. Foods such as cereals/grains, eggs, fruit, legumes, milk, nuts, starchy roots, and vegetables generally make low contributions to the total amount of AGEs in a diet, either because they are generally prepared at low temperatures or since they comprise smaller portions of diets.

"This epidemiological study supports our previous findings in animals and humans of an important role for dietary AGEs in Alzheimer's disease. We found that mice kept on a diet high in AGEs, similar to Western diet, had high levels of AGEs in their brains together with deposits of amyloid-β, a component of the plaques characteristic of Alzheimer's disease, while at the same time developed declines in cognitive and motor abilities. The mice fed a low AGE diet remained free of these conditions. In addition, clinical studies have shown that subjects with higher blood AGE levels, in turn resulting from high AGE diets, are more likely to develop cognitive decline on follow up."

Link: http://www.eurekalert.org/pub_releases/2015-02/ip-nsp020215.php

A sweeping cultural change in the aging research community has taken place over the past fifteen years. It was a culture in which talking in public about the prospects for the treatment of aging and extension of healthy life was a good way to sabotage your career, and that certainly suppressed progress at a time when new technologies allowed the exploration of extending healthy life spans in laboratory animals. Now, however, many researchers freely raise funding, speak out about treating aging as a disease, and work towards that goal. This sea change didn't happen by accident: it required hard work and advocacy on the part of many groups both within and outside the scientific community to break the old barriers and bring the perception of legitimacy to longevity science. The reward for all of that work is that those formerly opposed now pretend that they agreed all along that it is a great idea to work on helping people to live much longer healthy lives through medical science.

One result of this change in attitudes and speech is that scientific conference series are becoming just as open about the goal of developing therapies for the causes of degenerative aging. A recent addition to the conference circuit was the 2014 International Conference on Aging and Disease, held in Beijing last November. Here are some very readable open access position papers resulting from the event:

Stop Aging Disease! ICAD 2014

The primary stated goal of the International Society on Aging and Disease is "to improve the quality of lives through stimulating research into the association between aging and aged-related disease". The society's concise motto is simply: "Stop Aging Disease!" The conference made yet another step in advancing this goal by "fostering communication among researchers and practitioners working in a wide variety of scientific areas with a common interest in fighting aging and aged-related disease."

The importance of those goals cannot be overestimated, and this importance was further emphasized in the conference resolution and in the position paper issued by the ISOAD following the conference. As the resolution and the position paper state, the degenerative aging processes and related diseases are the gravest challenge to global public health. They cause the largest proportion of disability and mortality worldwide, and should be addressed with the urgency and effort corresponding to the severity of the problem. The weight of the problem of aging-related degeneration and the urgent need for solutions was acknowledged by the conference participants. Yet, beyond the description of the problem, the conference presented a wide array of strategies to tackle it. It emphasized the paramount strategy of connecting the study of aging and aging-related diseases, no longer just exclusively addressing individual diseases and symptoms, but relating them to their unifying determinative factors - the degenerative processes of ageing.

The Critical Need to Promote Research of Aging and Aging-related Diseases to Improve Health and Longevity of the Elderly Population

Over the past decades, the average life expectancy has increased globally. Currently, while the longest life expectancies are still found in the "developed" countries, the fastest and largest increase has been recorded in the "developing" world. Considering the demographics of the world population, between 2000 and 2050 the proportion of people over 60 years will double from about 11% to 22%, which, in absolute terms, means an increase from 605 million to 2 billion people. Although the increasing life expectancy generally reflects positive human development, new challenges are arising. They stem from the fact that growing older is still inherently associated with biological and cognitive degeneration, although the severity and speed of cognitive decline, physical frailty and psychological impairment can vary between individuals.

Nonetheless, degenerative aging processes are the major underlying cause for non-communicable diseases (NCDs), including cancer, ischemic heart disease, stroke, type 2 diabetes, Alzheimer's disease and others. Mental health deterioration due to chronic neurodegenerative diseases represents the largest cause of disability in the world, responsible for over 20% of years lived with disability. Hence, major efforts must be directed toward their alleviation.

New directions in research and development take a more holistic approach for tackling the degenerative processes and negative biological effects of human aging, addressing several major fundamental causes of aging and aging-related diseases at once and in an interrelated manner. For example, at the 2013 US National Institutes of Health (NIH) Geroscience Summit, the following priority research areas have been identified: Adaptation to Stress, Epigenetics, Inflammation, Macromolecular Damage, Metabolism, Proteostasis, and Stem Cells/Regeneration, but there are several other examples of similar approaches, prioritizing research of major sets of aging processes. Instead of targeting single age-related diseases, the mechanisms of the aging process itself are being analyzed with the goal of finding ways for intervention and prevention. Such approaches are very promising, for the following reasons:

1) They are already supported by scientific proofs of concept, involving the evidential increase in healthy lifespan in animal models and the emerging technological capabilities to intervene into fundamental aging processes.

2) They can provide solutions to a number of non-communicable, age-related diseases, insofar as such diseases are strongly determined by degenerative aging processes (such as chronic inflammation, cross-linkage of macromolecules, somatic mutations, loss of stem cell populations, and others). Moreover, they are likely to decrease susceptibility of the elderly also to communicable diseases due to improvements in immunity.

3) The innovative, applied results of such research and development will lead to sustainable solutions for a large array of age-related medical and social challenges that may be globally applicable.

4) Such research and development should be supported on ethical grounds, to provide equal health care chances for the elderly as for the young.

Therefore it is the societal duty, especially of the professionals in biology, medicine, health care, economy and socio-political organizations to strongly recommend greater investments in research and development dealing with the understanding of mechanisms associated with the human biological aging process and translating these insights into safe, affordable and universally available applied technologies and treatments.

Past epidemiological studies have found little or very mixed evidence that more or different types of exercise are better. There is clearly a big difference between no exercise and regular moderate exercise, but adding more exercise on top of that doesn't seem to have any reliably greater association with long-term health and lower mortality rates. On the other hand there are studies to show that elite athletes live significantly longer than the general population, but there it may be the case that a successful career in athletics selects for those who are more robust and more likely to live longer anyway. Here is a study demonstrating an interesting pattern of association between levels of exercise and mortality:

People who are physically active have at least a 30% lower risk of death during follow-up compared with those who are inactive. However, the ideal dose of exercise for improving longevity is uncertain. The aim of this study was to investigate the association between jogging and long-term, all-cause mortality by focusing specifically on the effects of pace, quantity, and frequency of jogging. As part of the Copenhagen City Heart Study, 1,098 healthy joggers and 3,950 healthy nonjoggers have been prospectively followed up since 2001. Cox proportional hazards regression analysis was performed with age as the underlying time scale and delayed entry.

Compared with sedentary nonjoggers, 1 to 2.4 hours of jogging per week was associated with the lowest mortality (multivariable hazard ratio [HR]: 0.29). The optimal frequency of jogging was 2 to 3 times per week (HR: 0.32) or ≤1 time per week (HR: 0.29). The optimal pace was slow (HR: 0.51) or average (HR: 0.38). The joggers were divided into light, moderate, and strenuous joggers. The lowest HR for mortality was found in light joggers (HR: 0.22), followed by moderate joggers (HR: 0.66) and strenuous joggers (HR: 1.97). The findings suggest a U-shaped association between all-cause mortality and dose of jogging as calibrated by pace, quantity, and frequency of jogging. Light and moderate joggers have lower mortality than sedentary nonjoggers, whereas strenuous joggers have a mortality rate not statistically different from that of the sedentary group.

Link: http://dx.doi.org/10.1016/j.jacc.2014.11.023

Some people have exceptional memory function in old age, showing far less deterioration than their peers. Researchers here look for differences in the brains of these individuals. The most actionable of the items discovered so far is the level of metabolic waste in the form of neurofibillary tangles. A range of research groups are presently working on ways to clear these tangles in connection with Alzheimer's disease and other neurodegenerative conditions, but any resulting practical treatment should clearly be applied to everyone on a regular basis:

SuperAgers, aged 80 and above, have distinctly different looking brains than those of normal older people. SuperAgers have memories that are as sharp as those of healthy persons decades younger. An analysis of the SuperAger brains after death show the following brain signature:

1) MRI imaging showed the anterior cingulate cortex of SuperAgers (31 subjects) was not only significantly thicker than the same area in aged individuals with normal cognitive performance (21 subjects), but also larger than the same area in a group of much younger, middle-aged individuals (ages 50 to 60, 18 subjects). This region is indirectly related to memory through its influence on related functions such as cognitive control, executive function, conflict resolution, motivation and perseverance.

2) Analysis of the brains of five SuperAgers showed the anterior cingulate cortex had approximately 87 percent less tangles than age-matched controls and 92 percent less tangles than individuals with mild cognitive impairment. The neurofibrillary brain tangles, twisted fibers consisting of the protein tau, strangle and eventually kill neurons.

3) The number of von Economo neurons was approximately three to five times higher in the anterior cingulate of SuperAgers compared with age-matched controls and individuals with mild cognitive impairment. "It's thought that these von Economo neurons play a critical role in the rapid transmission of behaviorally relevant information related to social interactions, which is how they may relate to better memory capacity."

Link: http://www.northwestern.edu/newscenter/stories/2015/02/superager-brains-yield-new-clues-to-their-remarkable-memories.html

Radical life extension is a term showing its years these days: it sounds so very 90s. It can be applied to any goal of adding decades or centuries to healthy human life spans, though as Aubrey de Grey pointed out more than ten years ago in this environment of progress in biotechnology there is little difference between adding a few decades and adding a few centuries. A very binary divide lies ahead of us: either you live long enough to see medical science start to add additional years of life faster than aging can take it away, or you don't. If you do, then your life span is thereafter only bounded by accidents, which given present mortality rates means you will probably live for a thousand years or so, in excellent health and with a youthful physique periodically repaired by ever more advanced therapies.

At present life expectancy for older adults is increasing at perhaps a year every decade, but this is entirely accidental, a side-effect of growing wealth and improvements in medicine. To a first approximation no-one has been trying all that hard to intervene in the aging process: all of the real effort has gone to trying to clean up the consequences, a task that is ultimately futile if you never deal with the root causes. In the years ahead this state of affairs will change, and since there is usually a big difference in outcomes between trying and not trying, we'll no doubt see a great upward discontinuity in the trend of life expectancy as a result. When researchers are actively trying to treat aging as a medical condition, then there will be an appropriate level progress.

The real question is how soon will the fruits of this labor arrive? Trying to spur more rapid progress, and thus a greater likelihood of effective treatments developed before we age to death ourselves, is why there must be advocacy and fundraising. It is why there must be disruption in aging research in which inefficient lines of research are replaced with better ones. The status quo of the recent past is about to be replaced with a new set of research projects for the decades ahead, and if those of us in middle age now want a shot at rejuvenation treatments, then this next crop of research strategies had better be good ones. We have every motivation to help out and fund the research we think best.

Science must be accompanied by advocacy, as at the large scale the only research to receive significant funding is that with widespread public support. Think of the cancer research community and the attitudes of the average fellow in the street with regard to curing cancer. We still stand a long way removed from that sort of support for eliminating all age-related disease and greatly extending healthy life. The public is somewhere between indifferent, hostile, and confused with regard to life extension. People support research on well-known diseases that are caused by aging, but at the same oppose work on greater longevity or eliminating aging, and yet are fearful and saddened by the costs of growing old and that deaths and suffering of those around them.

Still, the past decade of advocacy has led to great changes in attitudes in the research community and in segments of the public. This continues. There is a steady evaporation of skepticism with regard to radical life extension, accelerating of late with the advent of several large and public initiatives in aging research. Where the writers and the speakers go, so too will others follow in the fullness of time:

Living to 150

The Treasurer of Australia, the Hon Joe Hockey MP, recently received widespread attention with the statement: "It's kind of remarkable that somewhere in the world today, it's highly probable that a child has been born who will live to be 150." Hockey made the claim while discussing some of the problems Australia faces as a result of an ageing population. While his statement was ridiculed by cartoonists and political rivals, he received support from some in the medical community. The Dean of Medicine at the University of New South Wales, Peter Smith, described Mr Hockey's claim as a "reasonable assumption". Professor Smith noted that life expectancy for Australians has been climbing dramatically over the past 100 years.

Scientists have long been able to manipulate ageing in other animals. However it has so far proved much harder to extend the lifespan of our own species. Humans have already evolved to have a long lifespan, due mainly to an unusually long post-reproductive phase of life. The same mechanisms used to increase lifespan in short-lived species have little impact on human lifespan, or that of other primates. Hence the fact that we can extend the lifespan of other animals only partially supports the claim that we will soon be able to manipulate human ageing and extend lifespan to 150 years. Significant research effort will be required to reach this milestone.

The most significant consideration favouring lifespans of 150 in the near future term, then, is the fact that there is now a lot of interest in life extension research, both within academia and from well-funded corporations. In late 2013 one of the world's largest companies, Google, established a subsidiary called Calico, with the sole focus of investigating ways to combat human ageing. Similarly Craig Venter, whose company Celera Genomics was the first to sequence the human genome, recently established Human Longevity Inc, a new company with a focus on enhancing human lifespan. One research direction these companies are likely to explore involves incorporating nanotechnologies into our cells. Many gerontologists believe that ageing consists solely of a small number of cellular changes, which are potentially preventable and reversible. Once we develop technologies capable of preventing and reversing these changes, we can prevent and reverse ageing.

Cancer research is perhaps the field of medical science with the greatest level of funding and public support. The next generation of therapies presently under development are a great leap ahead in comparison to the present staples of chemotherapy and radiation therapy, making use of new tools in cellular biotechnology and promising accurate targeting of cancer cells for destruction with few side-effects. This is just as well, as life spans are lengthening now, and will continue to lengthen at an increasingly rapid pace in the future. That additional time brings with it the standard risk of suffering cancer at some point, which is large at this time since more people are living longer in a period of life that has high cancer risk due to the damage of aging.

Overall we should expect incidence of cancer to increase with the present trend towards longer life spans until better medical technologies become widely available, either rejuvenation treatments that repair cellular damage and restore tissue environments to a much lower, youthful risk of cancer, or which can control cancer sufficiently well so that the higher risk doesn't matter. The latter will probably emerge first. Either way, robust and reliable ways to control the risks of cancer are a very necessary part of any near future toolkit for rejuvenation and healthy life extension:

One in two people will develop cancer at some point in their lives, according to the most accurate forecast to date from Cancer Research UK. Thanks to research, the UK's cancer survival has doubled over the last 40 years and around half of patients now survive the disease for more than 10 years. But, as more people benefit from improved healthcare and longer life expectancy, the number of cancer cases is expected to rise. This new estimate replaces the previous figure, calculated using a different method, which predicted that more than 1 in 3 people would develop cancer at some point in their lives.

Age is the biggest risk factor for most cancers, and the increase in lifetime risk is primarily because more people are surviving into old age, when cancer is more common. "Cancer is primarily a disease of old age, with more than 60 per cent of all cases diagnosed in people aged over 65. If people live long enough then most will get cancer at some point. But there's a lot we can do to make it less likely - like giving up smoking, being more active, drinking less alcohol and maintaining a healthy weight. More than four in ten cancers diagnosed each year in the UK could be prevented by changes in lifestyle - that's something we can all aim for personally so that we can stack the odds in our favour. If we want to reduce the risk of developing the disease we must redouble our efforts and take action now to better prevent the disease for future generations."

Link: http://www.alphagalileo.org/ViewItem.aspx?ItemId=149366&CultureCode=en

In this open access paper, researchers look at some of the interacting effects of aging on the maintenance of cartilage tissues:

Aging and inflammation are major contributing factors to the development and progression of arthritic and musculoskeletal diseases. "Inflammaging" refers to low-grade inflammation that occurs during physiological aging. In this paper we review the published literature on cartilage aging and propose the term "chondrosenescence" to define the age-dependent deterioration of chondrocyte function and how it undermines cartilage function in osteoarthritis. We propose the concept that a small number of senescent chondrocytes may be able to take advantage of the inflammatory tissue microenvironment and the inflammaging and immunosenescence that is concurrently occurring in the arthritic joint, further contributing to the age-related degradation of articular cartilage, subchondral bone, synovium and other tissues.

In this new framework "chondrosenescence" is intimately linked with inflammaging and the disturbed interplay between autophagy and inflammasomes, thus contributing to the age-related increase in the prevalence of osteoarthritis and a decrease in the efficacy of articular cartilage repair. A better understanding of the basic mechanisms underlying chondrosenescence and its modification by drugs, weight loss, improved nutrition and physical exercise could lead to the development of new therapeutic and preventive strategies for osteoarthritis and a range of other age-related inflammatory joint diseases.

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

There is a greater fool at the end of many paths of research and development, the wallet or collection of wallets that indirectly bankrolls the work. Early for-profit investment occurs because investors believe they can sell their stake at a higher price down the line. Other reasons exist, such as the desire to do good in the world, but are entirely secondary. Most investors, and certainly the wealthier ones, have a fiduciary duty to turn away from world-saving in favor of making money. The market for early for-profit investment in turn indirectly steers research interests and the ability to raise funds from other sources: whatever is presently hot is much more likely to receive grants and philanthropic sponsorship. The state of the market at the end of the development process thus reaches back to influence every part of the long chain of research and development. The predicted inclinations of the greater fool are the tail that wags the dog.

The greater fool of interest for this post is the one indirectly funding the ongoing construction of a grand catalog of human metabolism, an exhaustive accounting of the fine details of how our cellular biochemistry operates and ages. This is understood in outline, but beneath that outline lies an enormous unexplored space of protein interactions, causes and consequences, and the relationship of various states in the system to health at every level. The greater fool is told by various parties that the goal is to enhance healthy longevity, but that isn't really happening via these explorations of metabolism, and in truth doesn't have much of a hope of happening via this research strategy. Look at the past fifteen years of sirtuin research in connection with the calorie restriction response, wherein the greater fool was - collectively - the GlaxoSmithKline shareholder community following the Sirtris acquisition. Well-managed hype sputtered out quite quickly after that liquidity event into nothing more than a slightly greater understanding of a few very narrow areas of mammalian biochemistry. This process happens over and again for each new potential calorie restriction mimetic, or other methodology claimed to slow the progress of aging by altering the operation of metabolism. Yet there is always a greater fool willing to buy.

Even if a drug was developed to completely mimic the beneficial effects of calorie restriction, so what? That is a convenience device, no more. Those practicing calorie restriction have somewhat better health and somewhat less age-related disease, and might live as many as five years longer. It's a larger effect than any currently available medical technology can provide. Nonetheless, the large majority of those people do not and will not live to see 90 years of age in the environment of today's medical technology. They still live the last years of their lives in frailty and pain. Why spend billions on striving to create a convenience device to recreate some of this marginal effect, tiny in the grand scheme of things? Because some people can get rich doing it.

The recent history of medical development related to slowing aging is that some folk have found they can do very well thank you by promising the prospect of enhanced longevity, while delivering nothing of value beyond scientific knowledge. In different circumstances I might be inclined to praise this as a great hack on investment community culture: direct more funding into life science research rather than cat pictures on the internet, and take a deserved cut as the individual who manages to make that happen. There are certainly far worse things for the greater fool to be talked into doing with his or her money.

Today, however, this business of making hay while the sun shines, based on ways to slightly slow aging largely emerged from calorie restriction research, is a distraction from the prospect of real progress. Messing with metabolism in this way cannot even in principle produce meaningful rejuvenation: aging is damage, and slowing down the damage does nothing for people who are already old and damaged. Yet there are other research strategies that can achieve this goal: the better approach is to repair the damage that causes aging, following the existing detailed research plans that aim to produce new rejuvenation biotechnologies. These can in principle restore youthful function for the old, extend healthy life indefinitely, and should not be any more expensive to explore and develop than a continued future of whatever the next replacement for sirtuin research might be. If billions are spent, then let it be in the pursuit of technologies that do offer the possibility for everyone to live to 90, and in good health, lacking frailty, pain, and disease.

It's a fight to make this case. It shouldn't be, but it is. Attention continues to be soaked up by marginal, ultimately pointless efforts such as the one noted in the article below. It won't let you live to be 90 in confidence, it won't create rejuvenation in the old, and no foreseeable evolution of this strategy can in fact provide those benefits. It is just more of the same search for the greater fool to retroactively bankroll the continuing mapping of metabolism.

The Anti-Aging Pill

An anti-aging startup hopes to elude the U.S. Food and Drug Administration and death at the same time. The company, Elysium Health, says it will be turning chemicals that lengthen the lives of mice and worms in the laboratory into over-the-counter vitamin pills that people can take to combat aging. The startup is being founded by Leonard Guarente, an MIT biologist who is 62 ("unfortunately," he says) and who's convinced that the process of aging can be slowed by tweaking the body's metabolism.

The problem, Guarente says, is that it's nearly impossible to prove, in any reasonable time frame, that drugs that extend the lifespan of animals can do the same in people; such an experiment could take decades. That's why Guarente says he decided to take the unconventional route of packaging cutting-edge lab research as so-called nutraceuticals, which don't require clinical trials or approval by the FDA.

This means there's no guarantee that Elysium's first product will actually keep you young. The product contains a chemical precursor to nicotinamide adenine dinucleotide, or NAD, a compound that cells use to carry out metabolic reactions like releasing energy from glucose. The compound is believed to cause some effects similar to a diet that is severely short on calories - a proven way to make a mouse live longer.

Elysium's approach to the anti-aging market represents a change of strategy for Guarente. He was previously involved with Sirtris Pharmaceuticals, a high-profile biotechnology startup that studied resveratrol, an anti-aging compound found in red wine that it hoped would help patients with diabetes. That company was bought by drug giant GlaxoSmithKline, but early trials failed to pan out. This time, Guarente says, the idea is to market anti-aging molecules as a dietary supplement and follow up with clients over time with surveys and post-marketing studies.

Researchers here demonstrate that they can use very short bursts of laser light to somewhat reduce levels of extracellular waste deposits known as drusen present in the aged retina. The mechanisms of action remain to be explored in greater depth, however:

Age-related macular degeneration (AMD) is a leading cause of vision loss, characterized by drusen deposits and thickened Bruch's membrane (BM). This study details the capacity of nanosecond laser treatment to reduce drusen and thin BM while maintaining retinal structure. Fifty patients with AMD had a single nanosecond laser treatment session and after 2 years, change in drusen area was compared with an untreated cohort of patients. The retinal effect of the laser was determined in human and mouse eyes using immunohistochemistry and compared with untreated eyes. In a mouse model with thickened BM, the effect of laser treatment was quantified using electron microscopy and quantitative PCR.

In patients with AMD, nanosecond laser treatment reduced drusen load at 2 years. Retinal structure was not compromised in human and mouse retina after laser treatment, with only a discrete retinal pigment epithelium (RPE) injury, and limited mononuclear cell response observed. BM was thinned in the mouse model 3 months after treatment, with the expression of matrix metalloproteinase-2 and -3 increased. Nanosecond laser resolved drusen independent of retinal damage and improved BM structure, suggesting this treatment has the potential to reduce AMD progression.

Link: http://dx.doi.org/10.1096/fj.14-262444

Mitochondria are the power plants of the cell. Each cell has a herd of them that reproduce like bacteria and have their own DNA, separate from that of the nucleus. One of the causes of aging is progressive mitochondrial dysfunction caused by forms of DNA damage that (a) deprive mitochondria of necessary proteins for correct function, but also (b) allow the damaged mitochondria a survival advantage during replication. Thus a fraction of cells become overtaken by damaged mitochondria, and this causes them to export damaging reactive molecules into surrounding tissues. That contributes to, for example, the formation of damaged lipids involved in the progression of atherosclerosis.

This paper looks at the process of clonal expansion whereby damaged mitochondria overtake a cell. The authors focus on point mutations, however. While point mutations will be carried along in damaged DNA that provides a survival advantage, I think that the existence of mitochondrial mutator mice that have a very high load of point mutations but no premature aging as a result shows that point mutations are not all that important in this process. It is probably deletions and other more serious forms of damage that are significant.

Mitochondrial DNA (mtDNA) mutations have been shown to accumulate with age in a number of human stem cell populations and cause mitochondrial dysfunction within individual cells resulting in a cellular energy deficit. The dynamics by which mtDNA mutations occur and accumulate within individual cells (known as clonal expansion) is poorly understood. In particular we do not know when in the life-course these mtDNA mutations occur.

Using human colorectal epithelium as an exemplar tissue with a well-defined stem cell population, we analysed samples from 207 healthy participants aged 17-78 years using a combination of techniques and show that: 1) non-pathogenic mtDNA mutations are present from early embryogenesis or may be transmitted through the germline, whereas pathogenic mtDNA mutations are detected in the somatic cells, providing evidence for purifying selection in humans, 2) pathogenic mtDNA mutations are present from early adulthood (earlier than 20 years of age), at both low levels and as clonal expansions, 3) low level mtDNA mutation frequency does not change significantly with age, suggesting that mtDNA mutation rate does not increase significantly with age, and 4) clonally expanded mtDNA mutations increase dramatically with age.

We show that, by 17 years of age, there is a substantial mtDNA point mutation burden. These data confirm that clonal expansion of mtDNA mutations, some of which are generated very early in life, is the major driving force behind the mitochondrial dysfunction associated with ageing of the human colorectal epithelium.

Link: http://dx.doi.org/10.1371/journal.pgen.1004620

There are three principal problems with the current state of organ transplantation, from which all of the other well-known issues arise. Firstly the existing regulatory systems surrounding organ donation actively discourage donors by both restricting possible compensation and making the process far slower and more baroque than it has to be. This is often the case wherever bureaucrats and politicians become involved in medical matters: a donor really has to work hard as well as suffer surgery in order to give an organ, and there will be nothing but thanks for it. There is little fairness and little incentive to be found. For all that it gets most of the attention, this isn't really the important issue, however: it is a symptom. The medical community only makes an effort to reuse organs because of the second problem, the vital and central problem, which is that we do not yet have the biotechnologies needed to manufacture replacement organs to order, from scratch, reliably and safely, and at a mass-market price.

The third problem is that it requires major surgery with a significant risk of death and serious complications in order to transplant an organ. No-one really wants major surgery if they can possibly avoid it, and the risks escalate considerably in later life, at the time when you are most likely to actually need a replacement organ. Thus the ultimate goal of regenerative medicine and tissue engineering is most likely to regrow and repair existing organs in situ in the body. No surgery, just very sophisticated control over cellular behavior alongside equally sophisticated methods of repairing forms of accumulated cellular and molecular damage that cause degradation of organ function.

That grail of medicine lies a way in the future for most applications, however, so for now let us return to the second problem, the current inability to grow organs for transplantation on demand, ideally from the patient's own cells so as to eliminate the possibility of rejection. I think it uncontroversial to suggest that this challenge will be solved in the near future, this technology developed. Indeed comparatively simple and successful attempts have been taking place in limited trials for most of the past decade: tracheas, bladders, and so forth. A recent article on this topic, quoted below, pays attention to the New Organ initiative and its surrounding ecosystem of companies and non-profits involved in advancing the state of the art in regenerative medicine. More attention of this nature is always good to see. These and related efforts are spurring the research and development community to move more rapidly towards viable organ engineering, and the more support they gather the better:

How We'll Finally Put An End To Organ Donation Shortages

Looking at kidneys alone, about 25,000 people die each year waiting for a donation. And as New Organ founder Dave Gobel told io9, there are approximately two million estimated individuals in Europe, North America, and in the British Commonwealth who need replacement organs but don't show up anywhere on waiting lists because they're "deemed by the medical establishment to be 'not a transplant candidate' due to reasons such as having or having had cancer, being too old, and other triage-based disqualifiers."

At the same time, 95% of Americans support organ donation, but only 40% are registered organ donors. There's also the issue of how organs are procured today. "For someone needing a heart/lung transplant, someone must die for them," says Gobel "Imagine being in a situation where you must hope someone dies so you can live." Compounding the problem is that even for the fortunate few who do receive an organ donation (aside from those who receive a kidney), there are severe constraints on the quality of life after an operation. Many face a lifetime filled with the need to take auto-immune suppression drugs to stave off organ rejection, while the same drugs also lower their overall immune competence. "If all of that works out, they will still be facing the fact that transplant organs will often need to be replaced within 10 years of implant," says Gobel. "A ticking time bomb of life. Better than death for sure, but wow, what a life."

New Organ, a collective initiative hosted by Methuselah Foundation (a biomedical charity) and managed by the Institute of Competition Sciences, is currently raising awareness and facilitating research initiatives to help alleviate the shortages, including the New Organ Liver Prize - a $1,000,000 award to the first team "that creates a regenerative or bioengineered solution that keeps a large animal alive for 90 days without native liver function." The organization is currently working on a number of other related initiatives, including a shared roadmap, a prize portfolio to stimulate key breakthroughs, and a growing network of partners.

Indeed, as the biotechnology revolution takes shape, a number of solutions are emerging, including the ability to regenerate whole organs using stem cells, bioprinting tissue, and developing artificial and assistive organs. What's more, we'll soon be able to reliably preserve these bioengineered organs for when they're needed, such as in an emergency. (This prospect is being catalyzed by the Organ Preservation Alliance, a founding partner of New Organ.) Taken together, these advances will do much to meet the growing demand for replacement organs.

In this analysis of many independent studies, the authors suggest that more social contact, on its own and independent of all of the other items associated with it, is not as meaningfully associated with greater life expectancy as was thought. It isn't hard to speculate on the outcomes that are associated with more gregarious individuals, such as greater wealth, and on how these outcomes impact lifestyle choices and use of medical resources. There is a strong web of correlations between wealth, intelligence, education, and life expectancy. It is interesting, but like all examinations of natural variations in human longevity at the present time, it is a distraction from efforts that aim to make everyone live far longer in good health. Given the means to repair the causes of aging and prevent age-related disease, all of the small things that presently shift life expectancy a little in one direction or the other will no longer matter in the slightest.

Social contact frequency is a well-defined and relatively objective measure of social relationships, which according to many studies is closely associated with health and longevity. However, no previous meta-analysis has isolated this measure; existing reviews instead aggregate social contact with other diverse measures of social support, leaving unexplored the unique contribution of social contact to mortality. Furthermore, no study has sufficiently explored the factors that may moderate the relationship between contact frequency and mortality.

We conducted meta-analyses and meta-regressions to examine 187 all-cause mortality risk estimates from 91 publications, providing data on about 400,000 persons. The mean hazard ratio (HR) for mortality among those with lower levels of social contact frequency was 1.13 among multivariate-adjusted HRs. However, sub-group meta-analyses show that there is no significant relationship between contact and mortality for male individuals and that contact with family members does not have a significant effect. The moderate effect sizes and the lack of association for some subgroups suggest that mere social contact frequency may not be as beneficial to one's health as previously thought.

Link: http://dx.doi.org/10.1016/j.socscimed.2015.01.010

Researchers in the field of tissue engineering are making steady progress towards repair of larger sections of nerve damage caused by injury, here demonstrating a little restoration of function in pigs:

Nerve cells or neurons work by growing axons, long fibrous projections that connect neurons and form the body's signal transmission and communication structure. Although new neurons are born, the long axon cables that connect them do not regenerate effectively over long distances, yet they are necessary for normal function. Researchers have been working for decades to coax damaged axons to regenerate, with little success in getting enough axons to grow to the right places.

There are currently no commercially available nerve grafts capable of consistently facilitating axon regeneration across major nerve lesions, generally considered to be a loss of a nerve segment five centimeters or longer. Researchers have now demonstrated the success of tissue-engineered nerve grafts (TENGs) in driving axon regeneration across five centimeter nerve lesions in the legs of pigs (in 10 out of 10 subjects). TENGs are lab-grown nervous tissue comprised of long axonal tracts spanning neurons. The ability to generate TENGs is based upon a mechanism of axon "stretch growth". These tissues are not only similar in structure to endogenous nerves, but suitable for transplantation upon removal from custom bioreactors.

The living TENGs were surgically attached to bridge a missing segment of nerve and were shown to accelerate the regeneration of axons, allowing a population of axons to cross the graft within five weeks. At three months, the bulk of axons had crossed the graft into the existing nerve structures opposite the lesion. Target muscle reinnervation was confirmed via an evoked hoof twitch as early as seven months following TENG repair, and over nine to eleven months post-repair there were steady increases in muscle electrical activity and muscle force generation. Microscopic examination of the regenerated nerves revealed a high density of regrown axons bridging the lesion zone and progressing the length of the repaired nerve to innervate target muscle.

Link: http://newswise.com/articles/penn-researchers-show-value-of-tissue-engineering-to-repair-major-peripheral-nerve-injuries