Fight Aging!

Two of the many topics of interest found in the study of longevity are (a) the long-lived naked mole rat and (b) the processes by which the mammalian brain generates new neurons and connections to maintain itself. Today I'll point out a paper that sits in the overlap between these two fields of study, in which researchers show that naked mole rats retain a very youthful-looking degree of neural plasticity, as well as other measures associated with younger, developing brains, all the way across their lengthy life spans.

The research community has put a great deal of time and money into the study of naked mole rat biology, and especially in recent years. This is an unusual species: very long-lived for its size, one of the very few eusocial higher animals, exhibiting negligible senescence over its considerable life span, and apparently immune to cancer. Given today's research priorities, with much more of a focus placed upon cancer than upon aging, it is the cancer resistance that really pulls in the funding and interest. Still, investigation of the underlying reasons for the exceptional longevity and healthspan of this species continues to produce a growing river of papers.

The brain changes over time, the connections between neurons altering in response to environment and circumstances. This remodeling occurs much more rapidly in youth than in adulthood, and further diminishes with age for reasons that are much debated: you can look at the state of research for any neurodegenerative condition to see the range of theorizing and discussion, coupled with the sheer amount of work left to be done in order to explore the full complexity of neural biochemistry. It is thought that some of the characteristic changes observed in the brain with age are a sort of compensatory remodeling, attempts to cope with rising levels of damage and dysfunction. It is more widely agreed that artificially increasing adult levels of neural plasticity could form the basis for therapies to partially alleviate at least some of the consequences of age-related neurodegeneration.

Here researchers argue that naked mole rats evolved a resilience to age-related degeneration in the brain by greatly extending the period over which the brain is developing. Processes that have diminished by adulthood in other mammals instead continue apace in naked mole rats. The argument ties in nicely with other aspects of the biochemistry of this species wherein it looks very much as though oxygen-poor underground environments were the evolutionary driver for changes that incidentally also happen to produce extended longevity with little degeneration until close to the end of life.

Protracted brain development in a rodent model of extreme longevity

In this study, we show that brain maturation, as indicated by molecular, morphological, and electrophysiological features, is extremely protracted in naked mole-rats. Embryonic and early postnatal (pre-weaning) neurogenesis apparently provides adequate neuronal populations for life-long brain function in naked mole-rats, since cell proliferation rates as measured by marker 5-ethynyl-2'-deoxyuridine (EdU) incorporation at postnatal dates, are not higher than in mice. This is also supported by the finding that markers of apoptosis are not elevated in the postnatal naked mole rat brain. Instead, we observed a prolonged retention of "immature" neuronal features including expression of PSA-NCAM, providing scaffolding for neurite outgrowth, delayed morphogenic maturation of hippocampal neurons, and incomplete synapse patterning as naked mole rats age. Therefore, we propose that while developmental neurogenesis provides adequate neuronal populations for adult brain functions, postnatal maturation of those neurons is greatly extended to provide much needed cellular dynamics to prevent structural damage and cell senescence in a low oxygen environment.

We found lower amounts of neurogenesis in the adult naked mole rat, as compared to the mouse. This suggests that the bulk of neurons is produced during fetal development, and remains physiologically active until senescence. In common laboratory rodents, particularly mice, neuronal apoptosis peaks during the neonatal period to prune redundancy during brain circuit formation. In our sample cohort, we did not find significant cleaved caspase-3 immunoreactivity during the period ranging from 7 days to 10 years postnatally, fuelling the provocative idea that cell production is tightly tuned by metabolic and/or oxygen restrictions, likely limiting otherwise metabolically demanding processes of cell elimination. Alternatively, some neuronal cohorts might not reach full maturity even during the extended life-span of naked mole rats, thus precluding their incentive to initiate apoptotic programs. Instead, we find elevated cleaved caspase-3 levels in the 21-year-old naked mole rat, reflecting the age-related increase of apoptosis found in common laboratory rodents.

In sum, we show that naked mole rats, a "treasure trove" for translational neurobiology, exhibit a very prolonged period of postnatal brain development consistent with a neotenous evolutionary mechanism. Protracted brain development may allow naked mole rat brain to cope with extremely low levels of O2 in their crowded subterranean burrows. Extended development may be accompanied by enhanced brain plasticity to preclude neurodegenerative processes during their extraordinary life-span. Thus, understanding the molecular basis of these processes warrants future research particularly aimed at expanding our tool kit to fight neurodegeneration and age-associated dementia.

The same question applies to naked mole rats as to salamanders and zebrafish: is it really practical from cost/benefit perspective to mine their biochemistry for the improvements we'd like to see in our own? That question can't be answered without doing most of the work, and the answer may be different in each case. Perhaps a useful therapy can result and is well within present medical capabilities if we only knew more. Equally perhaps integrating what is learned would require such sweeping, difficult changes to human biochemistry that we'd be far better off focusing on other types of therapy. We shall see.

A researcher here runs the numbers to demonstrate an inverse correlation between autoimmune disease incidence and life expectancy. It is interesting to speculate on the mechanisms here, which are probably not going to turn out to be a straightforward matter of (a) declining immune function being important in the progression of aging, and (b) more autoimmunity indicating a greater tendency to subclinical immune dysfunction over the course of aging in a population:

The autoimmune diseases are among the ten leading causes of death for women and the number two cause of chronic illness in America. They are a predisposing factor for cardiovascular diseases and cancer. Patients of some autoimmune diseases have shown a shorter lifespan and are a model of accelerated immunosenescence. Centenarians from the other side, are used as a model of successful aging and have shown better preserved several immune parameters and lower levels of autoantibodies. My study is focused on clarifying the connection between longevity and some autoimmune and allergic diseases in 29 developed OECD countries as the multidisciplinary analyses of the accelerated or delayed aging data could show a distinct relation pattern, help to identify common factors and determine new important ones that contribute to longevity and healthy aging.

I have assessed the relations between the mortality rates data of Multiple Sclerosis MS, Rheumatoid arthritis RA, Asthma, the incidence of Type 1 diabetes T1D from one side and Centenarian Rates (two sets) as well as Life Expectancy data from the other side. The obtained data correspond to an inverse linear correlation with different degrees of linearity. I have been the first to observe a clear tendency of diminishing Centenarian Rates or Life Expectancy in countries having higher death rates of Asthma, MS and RA and a higher incidence of T1D in children. I have therefore concluded that most probably there are common mechanistic pathways and factors, affecting the above diseases and in the same time but in the opposite direction the processes of longevity. Further study, comparing genetic data, mechanistic pathways and other factors connected to autoimmune diseases with those of longevity, could clarify the processes involved, in order to promote the longevity and limit the expanding of those diseases in the younger and older population.

Link: http://dx.doi.org/10.1089/rej.2015.1690

Based on the evidence to date, stem cell transplants could be used to treat chronic, non-healing wounds that occur in older patients, though work to be accomplished in order to achieve this goal. Here is an open access review paper on that topic:

Wound healing is an elaborate process that occurs in three distinct, yet overlapping, phases: inflammation, cell proliferation, and remodeling. Adult cutaneous wound repair is characterized by a highly evolved fibroproliferative response to injury that quickly restores the skin barrier, thereby reducing the risk of infection and further injury. The inflammatory phase is characterized by influx of polymorphonuclear cells followed by monocytes/macrophages. Macrophages secrete the growth factors and cytokines necessary for wound healing. Stimulated by these growth factors, healing proceeds to the proliferative phase, made up of fibroplasia, matrix deposition, angiogenesis, and reepithelialization. Remodeling is a dynamic phase during which various collagens are continuously deposited and degrade.

Chronic wounds occur when there is a failure of injured skin to proceed through an orderly and timely process to produce anatomic and functional integrity. Causative factors include malnutrition and immunosuppression, and chronic wounds are commonly seen as a consequence of diabetes mellitus and vascular compromise. Current techniques to manage chronic wounds typically focus on modification of controllable causative factors. The advent of skin substitutes has increased our armamentarium for treating this difficult condition, but to date no ideal therapy is available to treat troublesome, chronic wounds.

New therapies in this area are required to optimize outcomes for our patients. Stem cells, with their unique properties to self-renew and undergo differentiation, are emerging as a promising candidate for cell-based therapy for the treatment of chronic wounds. Mesenchymal stem cells (MSC), a progenitor cell population of the mesoderm lineage, have been shown to be significant mediators in inflammatory environments. Preclinical studies of MSC in various animal wound healing models point towards a putative therapy. This review examines the body of evidence suggesting that MSC accelerate wound healing in both clinical and preclinical studies and also the possible mechanisms controlling its efficacy.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4461792/

Here I point out a recent review on the topic of INDY gene manipulations and consequent increased longevity via altered metabolic processes. Given just how long ago this gene was discovered, and how similar at a high level the research reviews on this topic are today in comparison to those of a decade ago, this line of work well illustrates that even in the more mainstream reaches of science, with better prospects for funding, early stage research into aging and longevity is really very, very slow.

INDY stands for "I'm not dead yet" and was named after it was discovered that reducing levels of the protein that this gene encodes has the effect of extending life in flies. That discovery was made fifteen years ago, almost a different era in the life sciences relevant to aging, back when longevity genes were a new and amazing thing, it wasn't the case that new ways to tinker with metabolism to modestly extend healthy life were being discovered and published on a near monthly basis, as is the situation today, and researchers were very reluctant to talk in public about the prospects for treating aging in humans because it would likely sabotage their careers. How things have changed.

There is no necessary reason for aging research to very, very slow, as opposed to merely slow, or at least no necessary reason that cannot be corrected. Yes, it is the case that getting things done in life science research is painfully slow in comparison to, say, starting a business selling shoes. A great deal of available funding passes through very bureaucratic channels, there is not enough funding to avoid long delays between phases of a research program in order to seek new grants, and then it takes a few years in the middle to actually get anything meaningful accomplished in the lab. In aging research the situation is made worse if you want to run life span studies in species that live for a few years, such as mice. The need for life span studies as the bottom line of "did it work?" in longevity science is something that everyone in the research community would like to do away with. That seems feasible given progress towards markers for biological age, but there is a way to go yet on that front before researchers can make quick measurements before and after a prospective rejuvenation therapy and feel confident that the data will be useful in place of years of running a life span study.

But as for the rest of it, given more money the aging research community could be just as dynamic and productive as, say, the stem cell research community. Still slower than starting up a shoe business, but moving about as rapidly as you can expect from the life sciences. To speed things up further would require, at the least, radical surgery on the regulatory framework of the FDA, or an enormous influx of funding akin to the Apollo program or similar. At the end of the day it comes down to being a reasonable expectation that you should wait five to ten years to see how any particular program turns out, and absent a lot of funding you might still be waiting around fifteen or twenty years later. Five years is about long enough to get one thing accomplished in a life science program, or to figure out that whatever it was you were trying doesn't really work.

So back to INDY as our illustration of this point. The association with increased longevity was established in 2000, and establishing proximate mechanisms and deciding that the alterations to metabolism from lack of INDY looked a lot like calorie restriction was accomplished within a few more years. After that there was something of a hiatus of meaningful progress as judging by a review from 2013, with intervening years dotted with replication of INDY effects in other species such as mice and nematode worms, and more methodical exploration of the chains of biochemical connections leading into and out of the proximate mechanisms. Just last year researchers had come far enough to decide that intestinal stem cell populations had a lot to do with the longevity effect, but then this seems to be generally important in flies, and so any mechanism that extends life probably does much the same.

This year, the paper linked below finally comes to the point at which it is suggested that perhaps INDY is a drug target that someone should look into vis a vis treating aging and the diseases of aging. That can be taken as the starting point for a pretty long process of thought and work and delay. Perhaps something will come of it in some lab somewhere, perhaps not. You might, by analogy, look at the situation for heat shock proteins or other ways to trigger greater cell maintenance via autophagy as potential drug targets to modestly slow aging. That has been seriously suggested for years now, but I've yet to see any meaningful movement in that direction. Bear in mind that I'm not talking about SENS rejuvenation research here, that is still in the process of becoming a large concern, I'm talking about the core mainstream focus of the research community, which is at present to build drugs that might slightly slow down aging - not something we should expect to produce useful results any time soon, but comparatively well funded and supported. That these and many similar projects move erratically if at all is, I think, one symptom of an underfunded and divided field of research, in which many researchers are not at all interested in treating aging, and there is far too little money for all that should be done or could be done to build a better future.

The role of INDY in metabolism, health and longevity

The Drosophila I'm Not Dead Yet (Indy) gene encodes a plasma membrane transporter of Krebs cycle intermediates with highest affinity for citrate. In flies INDY is predominantly expressed in the midgut, which is important for food absorption; the fat body, which modules glycogen and fat storage, and oenocytes (fly liver), which is the site of lipid mobilization and storage. Thus, reduction in INDY reduces uptake, synthesis and storage of nutrients and affects metabolic activity. Reduction of Indy expression in both flies and worms extends longevity by a mechanism that is reminiscent of calorie restriction (CR), which is an environmental manipulation that extends longevity in a variety of species. Flies with reduced INDY levels experience many of the physiological changes that are commonly observed in CR flies. Such changes include altered lipid metabolism and insulin signaling, as well as enhanced mitochondrial biogenesis and spontaneous activity

Studies investigating the function of mammalian Indy (mIndy) show the highest levels of expression in the liver and brain. Similar to the trend of Indy expression in flies, mRNA levels were found to change during starvation in rat hepatocytes and mice liver. Furthermore, studies in mIndy-/- mice show similar effects in mitochondrial function, as well as lipid and glucose metabolism in the liver as those previously described in less complex organisms and in mice on CR. Together, these data suggest that the level and location of INDY serves to regulate and possibly mediate metabolic responses to nutrient availability during aging.

It is thought that these physiological changes are due to altered levels of cytoplasmic citrate, which directly impacts Krebs cycle energy production as a result of shifts in substrate availability. Citrate cleavage is a key event during lipid and glucose metabolism; thus, reduction of citrate due to Indy reduction alters these processes. With regards to mammals, mice with reduced Indy (mIndy-/-) also exhibit changes in glucose metabolism, mitochondrial biogenesis and are protected from the negative effects of a high calorie diet.

The recent work completed by our lab and others support a role for INDY as a regulator of metabolism whose transcriptional levels change in response to calorie content of the food, as well as in response to energetic requirements of the organism. The similar effects of INDY reduction on metabolism in flies, worms, and mice suggest an evolutionary conserved and universal role of INDY in metabolism. Together, these findings suggest that INDY could be potentially used as a drug target for treatment of obesity and Type II Diabetes in humans. Further investigation on the mechanism of INDY reduction could provide valuable information regarding the means to a healthier and more productive life.

Researchers have recently demonstrated a partial restoration of immune response in aged mice using a combination of existing Toll-like receptor agonists. This might be seen as a first step on the road to ways to reverse those aspects of immune system failure with age that depend more on misconfiguration rather than cellular damage.

The immune system declines with age for a variety of reasons, and this decline accounts for a great deal of the frailty of the elderly, vulnerable to infections that the young shrug off, and less able to eliminate precancerous cells. Some of these reasons involve the rising levels of damage to all tissues and cells that occurs with aging, while others are structural and inevitable due to the way in which the immune system works. Even absent cellular damage it would fail over the course of a lifetime. For example, the slow pace of immune cell replacement in adults means that the population of these cells is effectively limited, and in the adaptive immune system ever more of that population consists of memory T cells devoted to past threats rather than naive T cells needed to meet new threats. Most of those memory T cells are not even particularly helpful, being duplicates of one another that exist because of the recurring presence of viruses that cannot be cleared from the body, such as cytomegalovirus. Some form of targeted cell clearance should be a useful approach here, to free up space for new immune cells, and has in fact been demonstrated to produce benefits in the laboratory for other immune cell types.

At base this sort of thing is a programming and configuration problem. Cells are machines that operate according to their state and the chemical signals they receive. Removing the misconfigured cells is one way to deal with the problem, and only requires the ability to reliably identify and target the cells to be destroyed. Given better understanding of cells and their signals in any given tissue type or system in the body, it should also be possible to change cell behaviors for the better, however. This more complex strategy may be particularly applicable to the immune system, given that so much of its age-related dysfunction is a matter of misconfiguration rather than damage. So in this research, you might see the seeds of more complex and comprehensive reprogramming efforts in the future:

Immunosenescence is characterised by decline in both adaptive and innate immune functions. Innate immune responses are activated, mainly, by stimulation of Toll-like receptors (TLRs), the expression and function of which declines with age. Dendritic cells (DCs) from both young and aged individuals exhibit comparable activation in response to most TLR ligands, and are equally capable of direct and cross-presentation of antigens to T cells in vitro, underscoring the likely importance of TLR-induced DC activation in promoting adaptive immunity. TLR stimulation is therefore a promising strategy to enhance vaccine efficacy in the elderly. Combinations of TLR agonists may be especially effective, as demonstrated in animal models and clinical trials.

We previously showed that triggering of multiple TLRs, using a combined adjuvant for synergistic activation of cellular immunity (CASAC), incorporating polyI:C, interferon (IFN)-γ and MHC-class I and II peptides, results in potent cytotoxic T cell-mediated immunity in young mice. Optimization of the adjuvant formulation and investigation of mechanism of action were also performed. We now report the ability of CASAC to improve vaccination-induced responses in aged mice by promoting induction of antigen-specific cellular immunity to both foreign and self tumour-associated peptide antigens.

We have demonstrated that our combined molecular adjuvant CASAC effectively promotes functional antigen-specific CD8+ T cell responses to vaccination with peptides in aged mice, despite their immunosenescent phenotype. CASAC improved responses in aged mice not only to a highly immunogenic foreign antigen, but also to the tumour-associated self-antigen TRP-2 whose immunogenicity is being evaluated in clinical trials. Restoration of response to vaccination in immunosenescent aged mice by CASAC likely reflects the benefits of multiple TLR triggering on DC function and provision of IFN-γ could substitute for lack of IFN-γ from CD8+ memory cells during the early phase of immune response. Since CASAC comprises a combination of agents that individually are approved for human use, our findings suggest that a CASAC-based vaccination strategy may be amenable to rapid clinical translation, particularly against chronically experienced antigens such as persistent infections or tumour-associated antigens in older people.

Link: http://dx.doi.org/10.1186/s12979-015-0033-0

Prompted by attention given to a recent study claiming to cast doubt on the primary role of damaged mitochondria in aging, here is a lengthy and detailed article from the SENS Research Foundation on what is known of mitochondrial DNA damage and aging. It is worth bearing in mind when reading the scientific literature that any single study, especially if claiming to overthrow the consensus, should always be weighed against the rest of the recent literature in a given field:

The study was of fibroblasts, which are a kind of skin cell. It is interesting and contributes to a long-standing debate in this field about the frequency of specific mitochondrial DNA mutations with age and tissue type, and whether they contribute to specific diseases. It is clear at this point that mitochondrial dysfunction occurs with age and that damage in the form of mutations to mitochondria contributes to the diseases and disabilities of aging. We don't believe that this particular study is actually a challenge to scientists' existing understanding about how changes in mitochondria with age both drive and are driven by cellular and molecular damage, and the diseases and disabilities of aging.

What is actually known about the frequency and impact of specifically age-related mitochondrial mutations? First, in line with the ability of dividing cells to dilute out structural damage, multiple studies in aging rodents and humans report that the mutations in mitochondria that persist in cells and thus accumulate with age are confined almost entirely to cell types that don't divide during adulthood (e.g., brain neurons, heart muscle cells, and skeletal muscle). Second, those mutations are quite surprisingly rare: even in tissues that are actually affected by mitochondrial mutations with age, fewer than 1% - and perhaps as few as 0.1% - of cells are found to be affected.

Still, the evidence suggesting that this damage drives degenerative aging is powerful. The level of oxidative damage to mitochondrial DNA, the rate of accumulation of mitochondrial DNA mutations with age, and the structural vulnerability to such mutations are collectively robustly correlated with species maximum lifespan (the strongest integrative measure of the overall rate of aging in a species). Remarkably, this has recently been demonstrated even in rockfish, whose senescence is nearly negligible: lifespan in rockfish species was found to correlate negatively with the rate of mutation of their mitochondrial, but not nuclear, genomes - a relationship that the investigators' analysis suggested was not likely to be an artifact of tradeoffs with fecundity or the rate of germline DNA replication.

Calorie restriction (the most robust intervention that slows the rate of aging in mammals) lowers the rate of accumulation of mitochondrial deletion mutations with age. And when mice are given a transgene that directs a form of the antioxidant catalase directly to their mitochondria - an enzyme that complements the existing antioxidant machinery in the mitochondria in a way that reduces total mitochondrial DNA oxidative damage, including but not limited to deletion mutations - it extends their mean and maximal lifespan and ameliorates multiple pathologies of aging. Yet no such effects are observed when the same enzyme is directed to sites outside of the mitochondria, or when other antioxidant enzymes are expressed elsewhere in the cell, or even when non-complementary enzymes are sent to the mitochondria.

The apparent paradox in all of this is the strong link between mitochondrial DNA deletions and the rate of degenerative aging in the face of the rarity of such mutations. There are two broad kinds of resolution to this paradox. The first is the tissue-specific one. Although cells overtaken by mitochondria bearing DNA deletions are rare, they can have powerful effects on health in tissues where they are unusually enriched in critical cell types, particularly if relatively few of those cells exist in the first place. Such is the case for the key dopamine-producing neurons in an area of the brain known as the substantia nigra pars compacta (SNc). SNc dopaminergic neurons are much more vulnerable to being overtaken by mitochondria bearing large deletions in their DNA than are other cell types in the brain, and such mutations clearly drive dysfunction, including being tightly liked to Parkinson's disease. The same high regional vulnerability to mitochondrial DNA deletions occurs in people suffering with non-Parkinson movement disorders and even in "normal" aging brains, albeit at a lower rate and yet the finding has no parallel in the smaller and less harmful point mutations.

The other kind of tissue-specific effect relates more to the unique properties of the affected cell type itself, with the cardinal case in this category being skeletal muscle. Unlike most cell types, skeletal muscle "cells" are not isolated from all of their neighbors by a membrane. Instead, the long stretches of skeletal muscle fibers are comprised of multiple segments, each of which contains its own nucleus, which is in turn supported by a local population of mitochondria, with additional mitochondria in the membrane-bound space outside the fiber itself. Mitochondrial DNA deletions not only accumulate with age at a faster pace in skeletal muscle than in many other aging tissues, but because of that structure their effects are much more catastrophic. When a local nucleus' mitochondrial population is overtaken by deletion mutations, the segment first atrophies at that point, and then fails, leading the fiber to split or break locally and ultimately causing the loss of the entire fiber. These processes - loss of energy production and the splitting and loss of fibers - are a key driver of sarcopenia, the age-related loss of skeletal muscle mass and function that occurs even in lifelong master athletes.

Because deletion mutations in mitochondrial DNA are core molecular lesions driving these diseases, repair of these mutations will be central to their prevention, arrest, and reversal. But you can't tell that from a study of skin cells.

Link: http://sens.org/research/research-blog/question-month-11-are-mitochondrial-mutations-really-all-important

In this post you'll find pointers to the profiles of some of the SENS Research Foundation summer scholars for 2015. These talented young scientists are placed in influential labs for the summer to work on research relevant to the goal of treating aging and age-related disease. Cultivating today's young academics is the starting point for building the dedicated, enthusiastic research community of tomorrow, the people who will usher in the rejuvenation therapies of the 2030s and beyond.

At the very best possible pace of development, a pace that would require considerably more funding for the relevant research than is presently the case, it will likely be another twenty years before the first comprehensive package of rejuvenation therapies are in the final stages of development, on the way to the clinic. Unless the funding situation dramatically improves in the next few years, the likely timeline is longer: most of today's research interest in the treatment of aging as a medical condition goes towards research programs that cannot possibly produce actual rejuvenation, and can at best only modestly slow the pace of aging. Yet the cost in time and money for that course will likely be much greater than for attempts to create rejuvenation by repairing the causes of aging. It is frustrating, one of many things that must change if we are to see meaningful progress towards an end to aging.

The people who will lead laboratories and found startups at the time of the first commercial rejuvenation treatments are in the final years of their academic biotechnology studies today. Whether or not tomorrow's leaders choose to enter the aging research field is something that we can influence today. For many decades aging research has been the poor cousin in medicine, thought of as a dead-end, ill-funded area of research. Yet this is far from the case: aging research today is a hotbed of cutting-edge molecular biology, rich with potential, and I think it no great exaggeration to say that medical control over degenerative aging will grow to become the principal pillar of medicine in the later decades of this century. There are names and fortunes to be made in the years ahead, but that all starts with education: showing the students of today that work on aging is a great choice for a life science career, and helping them to make connections in the research community and related industries that will serve them well in the years ahead.

As for any human endeavor, a research community doesn't just spontaneously emerge from nothing. It must be cultivated. This is an important aspect of the work of organizations like the SENS Research Foundation. It's not just a matter of funding and coordinating the right research today, but also ensuring that a community of enthusiastic scientists exists to carry that work through to completion in the decades ahead. Thus the SENS Research Foundation runs a yearly placement of talented young scientists in their Summer Scholars program, sending them out to some of the most noted laboratories in the US. Some of this year's crop are profiled:

2015 Summer Scholar Profile: Amanda Paraluppi Bueno

I am very excited to work for SENS Research Foundation because I will have the chance to learn and contribute to research centered around the diseases of aging at the Wake Forest Institute for Regenerative Medicine (WFIRM), which is an extraordinary place for this field. This summer, my Principal Investigator is Dr. Graça Almeida-Porada and my mentors are Saloomeh Mokhtari and Steven Greenberg. Our goal is to develop novel cell-based therapies that could provide a curative treatment for Inflammatory Bowel Disease (IBD).

The Almeida-Porada lab has already shown that increasing the expression of immunomodulatory molecules on mesenchymal stem cells (MSC) leads to better immunosuppression and improvement of IBD in a murine model. Other cells that could help in the treatment of the gut inflammation are endothelial progenitor cells (EPC). These cells are known to increase the vascularization in ischemic tissues. Therefore, EPC could help normalize vascularization in the intestinal submucosa of IBD patients. Hence, I plan to treat IBD in mice using MSC and EPC as cell therapy to promote the modulation of the immune system and increase the vascularization in the intestine.

2015 Summer Scholar Profile: Blake Johnson

I first became interested in the field of regenerative medicine after viewing Dr. Anthony Atala's TED Talk on his 3-D kidney printing work. The ability of regenerative medicine to be applied to a vast array of cells, tissues, and organs and the possibility of making patients truly well again, as opposed to managing symptoms, is inspiring. WFIRM is an outstanding research institution, and it is an honor to have been selected to spend the summer learning and growing here.

This summer, I am working under the direction of Dr. John Jackson to generate thymus organoids capable of producing functional T-cells. The thymus serves an important function as the site of T-cell development. Interestingly, as we age, the thymus undergoes involution, or decreases in size, leading to a decrease in naïve T-cells. The ability to generate a functional thymus outside the body would have a number of clinical applications, including rejuvenation of an aging thymus to boost the immune response in older individuals and development of tolerance in organ transplantation.

2015 Summer Scholar Profile: Le Zhang

This summer, I will be conducting my research project in Dr. Jeanne Loring's laboratory at the Center for Regenerative Medicine in the Scripps Research Institute. The Loring lab has derived dermal fibroblasts from 10 patients with Parkinson's disease. These fibroblasts have been reprogrammed to induced pluripotent stem cell (iPSCs), which have been differentiated into midbrain-specific neural progenitor cells. These cells will later develop into dopaminergic neurons after transplantation. The Loring lab is the first lab conducting iPSC transplantation on Parkinson's disease patients, so it is essential to ensure genomic stability of the cells being transplanted. An important method to determine genomic integrity of patients' iPSC lines is single nucleotide polymorphism (SNP) genotyping, which can be used to examine millions of single base pair differences at genomic sites specific to humans.

SNP analysis will enable me to determine if the cell populations are suitable for transplantation or whether they have too much genetic change and, hence, potential risk for tumorigenesis. My research this summer will generate and analyze genomic SNP profiles from patient-specific dermal fibroblasts, iPSCs, and neuronal progenitors. SNP patterns from the three cell types will be compared to determine whether genomic instability has occurred from fibroblasts to iPSCs then to neuronal progenitors. Hopefully, with efforts from other scientists and me, the Loring Lab will successfully identify some cell lines that are suitable for transplantation and pass the FDA approval.

2015 Summer Scholar Profile: Zeeshaan Arshad

Under the mentorship of Professor Chas Bountra and Dr. David Brindley, my project will propose a model of open innovation in the translation process to address the problem of developing Alzheimer's disease drugs. To do this, I will use a model to compare open innovation to more conventional drug development strategies by measuring certain metrics to determine the effect open innovation has on each stage of the translation process. These metrics can give us an insight into the rate and effectiveness of the process at each stage and, therefore, an idea about how open innovation can improve the translation process.

We are all familiar with Alzheimer's disease. Not only is it a disease that causes significant morbidity and mortality, it is also one of the most costly. So, why haven't we cured it already? There are numerous reasons why this is a difficult problem to solve. The main problem being the lack of understanding of the disease itself, including potential drug targets. This leads to drug discovery being very risky and inefficient. For example, in the last few decades, extensive research has explored targeting amyloid plaques and neurofibrillary tangles as potential drug targets to treat Alzheimer's disease with little success. Furthermore, in the conventional drug development process, organizations work in isolation, creating an environment in which similar compounds are sometimes studied in parallel. So, how can we fix this problem? The answer lies in making the translation process between research and healthcare implementation more effective.

2015 Summer Scholar Profile: Ryan Louer

This summer, I will be working in Dr. Anthony Atala and Dr. James Yoo's lab under Drs. Myung Jae Jeon and Young Sik Choi studying ovarian cell therapies that will be able to produce natural levels of sex steroids that can be controlled by feedback mechanisms and, hopefully, produce viable oocytes. The importance of this research is providing effective therapies for hormone and egg replacement that do not have the potential harmful side effects, such as increased risk for heart disease and certain cancers, that current replacement methods pose. Cell-based therapies can be used in post-menopausal women, women who have had ovarian cancer, and women who have experienced damage to their ovaries from other sources.

Currently, we are characterizing a 3D collagen matrix and structure that closely mimics the natural environment within the ovary. My specific role in the project will be to test and define the importance of the ratio of granulosa cells to theca cells as well as find the optimum total number of cells in each follicle construct. I will be analyzing each ratio and follicle size for the ability to produce a physiologically normal level of estrogen and progesterone as well as assessing overall cell viability.

2015 Summer Scholar Profile: Jonah Simon

At the SRF Research Center, I am working on the Oncology team with Dr. Haroldo Silva. My project is to develop new high-throughput assays for quantifying activity of the Alternative Lengthening of Telomeres (ALT) pathway in human cells. Cancer cells must be able to proliferate without limit - something that normal cells can't do. Telomeres are repetitive noncoding DNA strands at the ends of eukaryotic (plants, animals, etc.) chromosomes. Every time a cell divides, telomeres shorten, protecting the genetic material from being damaged and limiting the proliferation of the cell. Some cells, such as stem cells and cancer cells, are able to lengthen their telomeres to be able to divide without limit. 85% of cancer cells use the enzyme telomerase to lengthen telomeres. The remainder maintain telomere length with ALT, a pathway based on homologous recombination (a mechanism used for DNA repair).

The current assays for ALT activity rely on characteristics of ALT cells: heterogeneous telomere length, the presence of ALT-associated PML bodies (APBs), and the presence of extrachromosomal circular C-strand telomeric DNA (C-Circles, or CCs). All of the current assays have problems, and none of them are high-throughput. One of the assays I'll be developing is a high-throughput version of the APB assay. Classically, this assay measures colocalization of PML protein with TRF2, a telomere binding protein (drug treatment can lower TRF2 expression, making the APB assay unreliable). I will bypass TRF2 and look for colocalization of PML with telomeric DNA directly. I'll accomplish this by using immunofluorescence to detect PML protein and FISH (fluorescent in situ hybridization) to detect telomeric DNA with a complementary fluorescent DNA probe.

Peter Thiel, who has invested millions into the SENS rejuvenation research programs over the past decade, has of late been talking much more in public on the topic of treating aging. Having wealth gives you a soapbox, and it is good that he is now using it to help the cause of treating aging as a medical condition. One of Thiel's recent public appearances was a discussion on death and religion in this context.

In the struggle to produce meaningful progress in rejuvenation research, the tipping point can come from either a very large amount of money, hundreds of millions of dollars at least, dedicated to something very similar to the SENS research programs, or from a widespread shift in the commonplace view of aging. At the large scale and over the long term medical research priorities reflect the common wisdom, and it is my view that public support is needed to bring in very large contributions to research. The wealthiest philanthropists and largest institutional funding bodies follow the crowd as a rule, they only rarely lead it. They presently give to cancer and stem cell research precisely because the average fellow in the street thinks that both of these are a good idea.

So it is very important that we reach a point at which research into treating degenerative aging is regarded as a sensible course of action, not something to be ridiculed and rejected. Over the past decade or two a great deal of work has gone into this goal on the part of a small community advocates and researchers. It is paying off; the culture of science and the media's output on aging research is a far cry from what it was ten years ago. When ever more authorities and talking heads are soberly discussing the prospects of extended healthy life and research into the medical control of aging, it is to be hoped that the public will follow. Inevitably religion is drawn in as a topic in these discussions once you start moving beyond the scientific community:

The Venn diagram showing the overlap of people who are familiar with both Peter Thiel and N.T. Wright is probably quite small. And I think it is indicative of a broader gap between those doing technology and those doing theology. It is a surprise that a large concert hall in San Francisco would be packed with techies eager to hear a priest and an investor talk about death and Christian faith, even if that investor is Peter Thiel.

Thiel has spoken elsewhere about the source of his optimism about stopping and even reversing aging. The idea is to do what we are doing in every other area of life: apply powerful computers and big data to unlock insights to which, before this era, we've never had access. Almost everyone I talk with about these ideas has the same reaction. First there is skepticism  - that can't really happen, right? Second, there is consideration  - well those Silicon Valley guys are weird, but if anyone has the brains and the money to do it, it's probably them. Finally comes reflection, which often has two parts - 1. I would like to live longer. 2. But I still feel a little uneasy about the whole idea.

The concept of indefinite life extension feels uncomfortable to people, thinks Thiel, because we have become acculturated to the idea that death, like taxes, is inevitable. But, he says, "it's not like one day you'll wake up and be offered a pill that makes you immortal." What will happen instead is a gradual and increasingly fast march of scientific discovery and progress. Scientists will discover a cure for Alzheimer's and will say, "Do you want that?" Of course our answer will be "Yes!" They will find a cure for cancer and say, "Do you want that?" And again, of course, our answer will be "Yes!" What seems foreign and frightening in the abstract will likely seem obvious and wonderful in the specific. "It seems," Thiel said, "that in every particular instance the only moral answer is to be in favor of it."

One of Wright's objections was to articulate a skepticism about whether the project of life extension really is all that good, either for the individual or for the world. "If [I] say, okay I'll live to be 150. I'll still be a sinner. I'll still be conflicted. I'll still have wrong emotions. Do I really want to go on having all that stuff that much longer? Will that be helpful to the world if I do?" This roused Thiel. "I really have to disagree with that last formulation...it strikes me as very Epicurean in a way." For Peter Thiel, Epicureanism is akin to deep pessimism. It means basically giving up. One gets the sense he finds the philosophy not just disagreeable but offensive to his deepest entrepreneurial instincts and life experience. "We are setting our sights low," he argued, "if we say everyone is condemned to a life of death and suffering."

Link: http://www.forbes.com/sites/valleyvoices/2015/06/24/peter-thiel-n-t-wright-on-technology-hope-and-the-end-of-death/

Researchers have found that the MEK inhibitor trametinib, used as a cancer treatment, modestly extends life in flies. This is of interest for researchers involved in mapping the relationships between metabolism and natural variations in longevity, but otherwise not all that significant in the grand scheme of things. The plasticity of life span in response to drug treatments that alter the operation of metabolism is much greater in short-lived creatures, and it should be expected that a small extension of life such as this one would map to next to nothing in humans, even assuming that the underlying mechanism of action is in fact shared. I believe that efforts to develop drug treatments to slow aging in humans based on this sort of result are doomed to lengthy and expensive failure, or at best result in very marginal therapies that will do no more than add a couple of years to life expectancy - something that can already be achieved through exercise or calorie restriction.

Adult fruit flies given a cancer drug live 12% longer than average, according to a study researching healthy ageing. Trametinib is used to treat skin cancer and was chosen for its ability to inhibit Ras signalling as part of the Ras-Erk-ETS cell pathway. The role of Ras has been well characterised in cancer but it is also known to affect the ageing process. Previously, the DNA of yeast was changed to reduce Ras activity, which extended lifespan, so the team wanted to explore inhibitors of this pathway in an animal. "Our aim is to understand the mechanisms of ageing and alter the processes that lead to loss of function and to disease. We studied this molecular pathway in flies because they are reasonably complex and yet age more quickly than mammals. We were able to extend their lifespan both genetically and by using a cancer drug to target the Ras pathway, which provides us with the first evidence for the anti-ageing potential of drugs developed to dampen this pathway."

Female fruit flies were given trametinib as an additive in their food. A small dose of 1.56 µM, which is approximately equivalent to a daily dose of the drug in a human cancer patients, increased the fruit flies' average life expectancy by 8%. With a higher dose of 15.6 µM, the flies lived 12% longer on average. To test the anti-ageing properties of the drug in later life, fruit flies over 30 days old that had almost all stopped laying eggs were given the same moderate dose of 15.6 µM, and still had an increased life expectancy of 4%. Flies exposed continuously to the drug from an earlier stage in life lived longer than those who began dosing later in life, possibly indicating a cumulative effect of the drug. "Identifying the importance of the Ras-Erk-ETS pathway in animal ageing is a significant step on the way to developing treatments that delay the onset of ageing. The pathway is the same in humans as it is in flies and, because the Ras protein plays a key role in cancer, many small molecule drugs already exist, some of which have been approved for clinical use. With support from pharma, we can refine these molecules over the next 10-20 years to develop anti-ageing treatments which don't have the adverse effects of cancer drugs."

Link: https://www.ucl.ac.uk/news/news-articles/0615/250615-fruit-flies-live-longer/

Economic growth is fetishized in modern society, an idol and a yardstick. This shouldn't be surprising given the benefits that accompany the wealth of a society, amply demonstrated within the span of a lifetime for many countries in Asia and Africa, as entire populations moved rapidly from a state of agrarian poverty to build far wealthier industrial societies. It is argued here that rising life expectancy is a principal driver of economic growth, not just a benefit of increased wealth, and given this we should expect to see interesting times ahead of us.

It is arguably the case that the Industrial Revolution happened where it did and when it did in part due to a few generations of small but steady increases in life expectancy. This drove a slowly compounded increase in wealth and technology, which in turn fed back into further increases in life expectancy, and over time this small difference between England and the rest of Europe grew large enough to be the economic basis for a suddenly rapid expansion in technology and prosperity. Progress is the consequence of investment, and investment requires wealth. The growth curve is exponential, a bootstrapped grind from nothing that accelerates and feeds on itself as progress produces wealth that drives progress.

But why does longevity improve economic growth? Firstly because people who expect to be around for longer have more of an incentive to invest in improving the state of their property over the long term, and that happens to coincide with what should be going on if the goal is to create greater wealth for all. Short term thinking is the great destroyer of prosperity. Secondly age-related disease and disability imposes huge costs, both direct and opportunity costs: the sick must be cared for, and the productive work they could have carried out now goes undone. When people die, their knowledge and their contributions are lost. The cost of this lost human capital is staggering, should you actually sit down to run the numbers.

Increased life expectancy in past centuries was largely a matter of raising the average age at death through better nutrition and control of infectious disease, as well as other improvements in the provision of medicine, such as greater availability of any sort of worthwhile medical services. This was a matter of reducing mortality rates in childhood and early adulthood more than anything else. The future will be quite the opposite, and indeed even today the causes of the upward trend in life expectancy are quite different from those of the 17th and 18th centuries. We will live to see large gains in life expectancy arriving in later life, produced by addressing the causes of aging so as to create rejuvenation and extended vigor.

The effects on economic growth should still be just as profound over time. If stewardship of property is greatly improved by life expectancy at birth growing from 40 to 80, and the costs of aging and disease reduced, then the economic outlook improve again when the expectancy for health life span pushes towards 200 and beyond. I say beyond because if anyone alive today makes it that far, then so much technological progress will have occurred that the state of biotechnology should enable indefinite health by that time. There is no upper limit on human life span given sufficiently capable therapies to repair the causes of aging, and we are now moving into an era in which researchers are just starting to look at doing this, as opposed to patching over the consequences and hoping for the best.

The Longevity Dividend from an Aging Population

Indeed, a central issue with America's aging population - driven by longer lives, lower birth rates and the graying of 78 million baby boomers - is the question of how to manage a society with as many old as young. This is fundamentally a question of economics. The question for all of us is how to square 21st century aging populations with misaligned 20th century policies. Investing giant BlackRock recently addressed this challenge in a white paper and related panel discussion in New York. BlackRock, which manages $4.77 trillion in assets and serves 89% of the largest U.S. retirement plans, brings a compelling set of new ideas to the table.

The most remarkable thing about the new BlackRock report, "Unlocking the Longevity Dividend: How Longer Lives Are Changing Retirement, Investing and the Economy," is that it's not another woe-is-us lamentation on how demographics are going to doom America and the world. Instead, the report argues that if we get things right, longevity and population aging can be a lever of growth for individuals, families, businesses and nations - essentially, everyone on the planet.

BlackRock gets it right by focusing on the fundamentals of human capital: "Longer lives have created a vast pool of experience, capability and wealth that can become a driver for 21st century economic growth. Indeed, the transformative power of the generation now entering retirement should come as no surprise: Baby Boomers, born in the two decades following World War II, have reinvented every phase of life they have entered, often by design and sometimes through sheer force of numbers and economic clout."

To what degree should we expect characteristic changes in behavior observed in the old to have a physical basis in neurodegeneration rather than being an outcome of living in our present cultures for a long time? If the neurodegeneration was prevented or repaired, what behavioral patterns would change, and why? Obviously researchers are a long way from providing defensible answers to those questions, but in this published research the authors provide evidence to suggest that behavioral flexibility is eroded in old age by a physical process, the destruction of a specific class of neuron:

Cholinergic interneurons are rare - they make up just one to two percent of the neurons in the striatum, a key part of the brain involved with higher-level decision-making. Scientists have suspected they play a role in behavioral flexibility, the ability to change strategy when the rules change, and researchers recently confirmed this with experiments. Previous studies tried to identify the role of cholinergic interneurons by recording brain wave activity during behavioral tasks. While that can strongly indicate specific neurons are correlated with a particular behavior, it is not definitive. In this study, researchers killed cholinergic interneurons with a toxin that directly targets them, and then observed how rats reacted to rule changes compared with normal rats with intact neurons. "Our experiments show direct causation, not correlation."

Rats with and without damaged neurons were given tasks for several weeks - they had to press either lever A or B to get a sugar pellet reward. During the first few days, Lever A always resulted in a reward. Both groups of rats had no problem learning the initial strategy to get the sugar pellet - press Lever A. But then, the rules of the game changed. A novel stimulus was introduced - a light flashed above the correct lever, which oscillated between Lever A and B. To get their sugar fix, the rats had to shift strategy and pay attention to this new information. While normal rats quickly responded to the light, rats with damaged neurons could not. The latter group continued to repeat the strategy they had already learned, and were disinclined to explore what the light meant.

"This indicates that cholinergic interneurons throughout the striatum play a common role, namely inhibiting old rules and encouraging exploration, but different regions of the striatum are activated depending on the situation and type of stimulus. Since cholinergic interneurons degenerate with age, this work may provide a clue for understanding the decline in mental flexibility that occurs with advancing age."

Link: http://www.oist.jp/news-center/press-releases/rare-neurons-enable-mental-flexibility

Understanding the storage model for human memory will enable a range of medical technologies relevant to repair and augmentation of the brain, but at present there is only a general consensus on the online of that model. Researchers believe that the data of memory is stored in the architecture of synapses, and here researchers provide more evidence that synapses are indeed the relevant location in mammals. This is perhaps of interest due to recent research in lower animals that seemed to rule out synaptic structures as the location of memory.

Our memories are as fleeting as the brain structures that store them, or so the theory goes. When the connections - called synapses - between neurons break, the memories they hold are thought to evaporate along with them. The idea seemed good, but has been hard to test. Now a team has taken on the challenge, studying a brain region called the hippocampus, which stores "episodic" memories. These are the memories of events or conversations that might be forgotten over time if the memories aren't used. The challenge to studying synapses in this region is that the hippocampus is so deep and the connections so densely packed that no microscope could easily monitor the synapses' longevity.

When mice experience a new episode or learn a new task that requires spatial navigation, the memory is stored for about a month in a structure at the center of the brain called the hippocampus (it is stored slightly longer in people). If mice have hippocampus-disrupting surgery within a month of forming a memory - a memory of meeting a new cage-mate or navigating a maze - that memory is lost. If the disruption occurs after more than a month, then the mouse still retains the memory of a new friend or location of food. That's because the memory had been relocated to a different region of the brain, the neocortex, and is no longer susceptible to disruption in the hippocampus.

In the past, scientists had monitored connections between neurons in the neocortex, nearer the brain's surface and therefore visible with little disruption to the brain. They watched not the connections themselves, but the bulbous projections called spines that form connections at their tips. Watching the spines come and go serves as a proxy for knowing when excitatory connections between neurons are created and broken. Those scientists found that about half of the spines in the neocortex were permanent and the rest turned over approximately every five to 15 days. "The interpretation was that about half the spines in the neocortex are long-term repositories for memories while others retain malleability for new memories or forgetting."

If the same line of thinking held true for the hippocampus as it did for the neocortex, spines in the hippocampus should turn over roughly every 30 days along with the memories they hold. Verifying that idea had been challenging, however, because the hippocampus is deeply buried in the brain and the spines in that region are so densely packed that multiple spines can appear to merge into one. The team overcame that problem with new techniques that allow stable imaging of a single neuron in a living mouse over long time periods, an optical needle, called a microendoscope, that provides high-resolution images of structures deep within the brain, and a mathematical model that took into account the limitations of the optical resolution and how that would affect the image datasets depicting the appearances and disappearances of spines. The researchers found that the region of the hippocampus that stores episodic memories contains spines that all turn over every three to six weeks - roughly the duration of episodic memory in mice.

Link: http://news.stanford.edu/pr/2015/pr-memory-monitor-biox-061715.html

In this post, find some thoughts on costs and risks in the future of regenerative medicine and organ engineering, as well as a pointer to a recent Nature article on the field of tissue engineering. By all accounts researchers have come a long way in the past decade towards the goals of new organs on demand, perfect healing of any injury, and restoration of age-damaged tissues. The reward for all that has been achieved to date is a clear view ahead to show that a great deal more is left to be accomplished. Progress continues, however, and the regenerative treatments and transplants of the next decade will look like the science fiction of past generations - as is only right.

Consider that the shape of the technology landscape is at root determined by costs. After scientists in any given field are far enough beyond fundamental research to understand the bounds of the possible for the next twenty years, research programs then tend to aim downhill at the implementations and outcomes that cost less, are more efficient, and cause less trouble. Why aim to build something that will be an expensive source of problems and few benefits when you don't have to? Of course no group of humans are completely rational, but over the long term economic incentives usually win out.

This is just as true for tissue engineering as for any other field of research and development. A great deal of effort is presently going towards the ability to create organs on demand, with the primary focus neing on decellularization: not growing organs from scratch, but taking a donor organ, possibly not even human, clearing out its cells, and replacing them with new cells derived from a patient. As an implementation this will be a great improvement over the present state of organ transplantation. Yet in the grand scheme of things this is all still a highly expensive, risky, and traumatic set of medical procedures. Organ replacement is major surgery, and major surgeries require highly trained medical teams, extended hospitalization, and an attendant risk of death. This is the standard because there is no better alternative today.

So consider this picture of cost and risk for a moment. It really doesn't seem likely that the advances in tissue engineering needed to be able to grow patient-matched organs from a small skin sample, taking place between now and the 2030s, will then be coupled with extensive transplant surgeries. It's a viable approach in the case of the comparatively rare traumatic accidents suffered by young and robust people, but just won't work as a way to address the consequences of degenerative aging across the entire population. You won't see organ factories churning away to support the old, while everyone undergoes many complex surgeries in their 60s and 70s. It is impractical: excessive cost, excessive risk. We can think about the outer limits of the possible given the ability to regrow any organ, but it seems unlikely that full body replacement or other science-fiction staples will actually happen as a matter of course, rather than being a rare and risky attempt at saving a life when nothing else can possibly work.

Much more likely is that the very same progress in biotechnology that allows for the construction of patient-matched organs from scratch will also allow for considerable regeneration of age-damaged organs in situ. It is all a matter of control over cells, their states, and their signaling to produce a coordinated reconstruction of tissues. This would have to be coupled with other rejuvenation treatments to clear out accumulated metabolic waste in tissues, such as cross-links, lipofusin, and amyloid, and repair other forms of damage in long-lived cells that remain in place throughout the treatment. The business of repairing organs in place, especially those that do not naturally regenerate all that well such as the heart, is probably going to be more complex to achieve than clearance of waste, however. If there is anything that today's investigations into regeneration can teach us, it is that all cellular activities are exceedingly complicated.

The cost in the case of in situ regeneration is a very different picture from that of transplantation. In place of surgeries, hospitalization, and exceedingly expensive medical teams you have mass-produced infusions carried out in out-patient clinics, coupled with diagnostic tests to monitor progress. This is more than an order of magnitude less expensive if you look at today's medical costs for similar treatments, and further the risk of death and complication is far less pronounced. So bear this all in mind when looking at the state of tissue engineering today:

Tissue engineering: Organs from the lab

In their quest to create organs in the laboratory, researchers have come a long way. Engineered tissues are already used in medical research and have even entered clinical trials. But they are much simpler than the real thing. To make a stomach, a lab might use 3D printing to create a mould that could be seeded with the appropriate cells. But without cues provided by blood flow and interactions with other tissues, the result would be simply a stomach-shaped statue, unable to digest or growl. An organ is much more than a mass of cells arranged in a particular configuration: it also has support scaffolds, blood vessels to deliver nutrients and signal molecules, and a hierarchy of intricate control functions that can respond to internal and external cues.

All this makes it tough to build a functional, physiologically relevant organ in the lab. But tissue engineers are making inroads into the problem. To try to tackle the biological complexity of organs, they can choose from various fabrication approaches. One method is to place cells into elaborate, but still simplified models of an organ the size of a microscope slide, which can then be connected together to probe how organs interact. These miniature 'organs-on-chips' provide a unique vantage into organ function and disease, and for applications such as toxicity tests of drug candidates. An alternative approach is to foster the ability of cells to self-assemble, in the hope that they will recapitulate actual organ development and reveal insights into the process.

Whatever the strategy, researchers can start with biologically simple approaches, and then add complexity to the model a little at a time. Just how similar an artificial version of an organ needs to be to its original depends on the questions that are being asked of it. Artificial organs may look very different from their in vivo counterparts but nonetheless be useful for drug testing and basic research. Whether the goal is to understand an organ or to replace it, the eventual aim is an engineered system that functions as reliably as the real thing. Researchers across the world are using these systems to address a wealth of important questions. They can, for example, help to reveal how cancer cells detach from a tumour to invade other tissues, and allow scientists to recapitulate processes in disease and development, such as what might go awry in neurodevelopmental disorders.

Ultimately, the usefulness of the tool is what is important, not the specific approach that is chosen. Engineered tissues are starting to allow incisive experiments and even replacement therapies. And perfectly mirroring nature may not, in all cases, be what is needed. What is critical is that the organ has enough complexity to accomplish its function. Whether it be a patch for damaged hearts, a better toxicity test or an insight into a devastating brain disease, tissue engineering delivers what scientists crave: more understanding, and the potential to help people.

The Argus II is one of a variety of implanted electrode grid devices under development that supply a substitute for vision in the blind by stimulating the retina to produce phosphene patterns. Per this latest news, the device continues to progress much as expected in the clinical trial system. Most users in the latest small trial of several years benefited from the implant, and there were no device failures. Ultimately it might be expected that the research into retinal and optic nerve stimulation that produced the Argus systems will result in something closer to real vision. That, however, will require quite different and more sophisticated approaches than used at present, a process of development that has barely started, and for many types of blindness it may be overtaken by advances in retinal regeneration. It remains to be seen whether prosthetic technologies or regenerative medicine dominate in the years ahead for the alleviation of various types of damage that cause blindness:

Retinitis pigmentosa is an incurable disease that causes slow vision loss that eventually leads to blindness. The Argus II system was designed to help provide patients who have lost their sight due to the disease with some useful vision. Through the device, patients with retinitis pigmentosa are able to see patterns of light that the brain learns to interpret as an image. The system uses a miniature video camera stored in the patient's glasses to send visual information to a small computerized video processing unit which can be stored in a pocket. This computer turns the image to electronic signals that are sent wirelessly to an electronic device implanted on the retina, the layer of light-sensing cells lining the back of the eye.

The Argus II received Food and Drug Administration (FDA) approval as a Humanitarian Use Device (HUD) in 2013, which is an approval specifically for devices intended to benefit small populations and/or rare conditions. To further evaluate the safety, reliability and benefit of the device, a clinical trial of 30 people, aged 28 to 77, was conducted in the United States and Europe. All of the study participants had little or no light perception in both eyes. The researchers conducted visual function tests using both a computer screen and real-world conditions, including finding and touching a door and identifying and following a line on the ground. A Functional Low-vision Observer Rated Assessment (FLORA) was also performed by independent visual rehabilitation experts at the request of the FDA to assess the impact of the Argus II system on the subjects' everyday lives, including extensive interviews and tasks performed around the home.

The visual function results indicated that up to 89 percent of the subjects performed significantly better with the device. The FLORA found that among the subjects, 80 percent received benefit from the system when considering both functional vision and patient-reported quality of life, and no subjects were affected negatively. After one year, two-thirds of the subjects had not experienced device- or surgery-related serious adverse events. After three years, there were no device failures. Throughout the three years, 11 subjects experienced serious adverse events, most of which occurred soon after implantation and were successfully treated. One of these treatments, however, was to remove the device due to recurring erosion after the suture tab on the device became damaged.

Link: http://www.eurekalert.org/pub_releases/2015-06/aaoo-bec062315.php

Researchers have produced a prototype polymer device capable of performing one of the functions of a living neuron, the transmission of neurotransmitter chemicals. This is a small step towards a range of technologies important to very long-term goals in repair of the brain and extension of healthy life.

The brain is distinct from other organs in that we will never be able to outright replace more than small sections of it, which limits tissue engineering as an approach to repair in that portion of the central nervous system. Even when tissue engineers are capable of reproducing brain tissue, they will still have to restore existing cells and connections in situ in order to preserve the data of the mind. Eventually a collection of technologies will be needed to achieve this end, and many of them involve some sort of artificial replacement for living neurons. In the case of early applications in this space, such as bypasses for nerve and brain damage, these artificial neurons do not have to be fully functional or even as small as the real thing, but bear in mind that technologies such as the one demonstrated here are just the first step on a long pathway:

Neurons are isolated from each other and communicate with the help of chemical signals, commonly called neurotransmitters or signal substances. Inside a neuron, these chemical signals are converted to an electrical action potential, which travels along the axon of the neuron until it reaches the end. Here at the synapse, the electrical signal is converted to the release of chemical signals, which via diffusion can relay the signal to the next nerve cell. Scientists have now created an organic bioelectronic device that is capable of receiving chemical signals, which it can then relay to human cells.

"Our artificial neuron is made of conductive polymers and it functions like a human neuron. The sensing component of the artificial neuron senses a change in chemical signals in one dish, and translates this into an electrical signal. This electrical signal is next translated into the release of the neurotransmitter acetylcholine in a second dish, whose effect on living human cells can be monitored." The research team hope that their innovation will improve treatments for neurological disorders which currently rely on traditional electrical stimulation. The new technique makes it possible to stimulate neurons based on specific chemical signals received from different parts of the body. In the future, this may help physicians to bypass damaged nerve cells and restore neural function. "Next, we would like to miniaturize this device to enable implantation into the human body."

Link: http://news.cision.com/karolinska-institutet/r/artifical-neuron-mimicks-function-of-human-cells,c9796303

Cancer is a numbers game, caused by just the right mutationnuclear DNA constantly: you can't put a bunch of complex molecules in close proximity without frequent breakage, and that's even without considering the fact that portions of a cell are involved in the energetic business of converting nutrients into energy stores, a process that generates reactive molecules as a byproduct, or that cells are frequently stressed by heat or exercise. A great deal of a cell's complexity is in fact due to the panoply of mechanisms required for ongoing detection of damage, recycling of damaged components, and building replacement parts as needed. This is a continual process, always attempting to keep up with the pace of damage. Of course all of those mechanisms are also vulnerable to damage and must therefore be capable of repairing themselves, but no repair process is perfectly efficient. DNA repair machinery is some of the most efficient of all of these mechanisms, but it still lets things through: there are so many cells in the body that even a tiny failure rate leads to unrepaired damage.

Fortunately most of the time this just means that at worst a cell will falter or break. Most cells are temporary parts of their tissue, and will die off within days or weeks to be replaced by others. A mutated cell with a more serious breakage may become senescent, removing itself from the cell cycle of replication, or destroy itself. Even in the situation of a potentially cancerous mutation, the cell will still most likely be destroyed by the immune system or its own defenses. But again, there are a lot of cells in the body. It only takes one to slip through all of the layers of defense to start up a tumor. You can develop cancer at any age - you just have to be very unlucky for it to happen in youth, when there is little damage and all of the repair and defense mechanisms are operating a peak efficiency. Later on is a different story, of course, and cancer is an age-related disease because the odds get progressively worse with increasing tissue damage and a growing failure of repair machinery and immune surveillance.

So as I said, this is a numbers game. Count the cells, multiply by mutation rates, and divide by repair efficiency - and there is the scaling factor for your odds of cancer. Or at least in theory, from a naive point of view. Yet here is an interesting thing: mice are little cancer factories in comparison to humans. Yet we humans have thousands of times as many cells as a mouse. Further, what about whales? They have thousands of times as many cells as we do, and some of them seem capable of living twice as long as we do. Yet they don't seem to have any significantly greater cancer incidence. If you compare across other mammals, it turns out that there really isn't any correlation between body mass and cancer rate. This observation is known as Peto's Paradox, proposed with the idea that there is evidently more to the cancer numbers game than first thought.

The motivation for researchers is to be able to identify the differences that exist in the biochemistry of large mammals to explain why they don't have very high cancer rates. There is presumably some chance that this research could result in therapies for humans, though the odds are unknowable in advance. Any sort of investigation of other species could turn up differences that are near impossible to apply to human biochemistry, or differences that could soon lead to therapies, and it's next to impossible to put real numbers to those odds without further research. Still there has been some progress on the basics in recent years, and this open access paper is an example of present thinking on the topic.

Solutions to Peto's paradox revealed by mathematical modelling and cross-species cancer gene analysis

It is an open question why an elephant, with 100× more cells than a human, or a whale with 1000× more cells than a human, has approximately the same (or lower) cancer risk as a human. This is Peto's paradox, and though many potential solutions have been proposed, it remains unsolved. The fact that cancer rates are approximately constant across body sizes and lifespans suggests that there has been selection on the life histories of organisms to prevent cancer in large, long-lived organisms. In order to investigate Peto's paradox, it would be helpful to understand how much evolution would have to change the parameters of somatic evolution to compensate for the evolution of large bodies and long lifespans. For example, we can ask how much the somatic mutation rate must decrease in order for a whale, which has 1000× more cells than a human, to retain the same cancer risk as a human.

There is still much work to be done in the field to obtain more accurate estimates of human somatic mutation rates, as reported values span orders of magnitude. Though the estimates are not perfect, slight differences in mutation rate across species have been observed. For example, one study that derives somatic mutation rates from specific loci across eukaryotes found that the per base mutation rates for human and mouse are a factor of 3.6 apart. This 3.6-fold decrease in mutation rate in human versus mouse is remarkably close to the results of our modelling, which suggest that a two- to threefold decrease in mutation rate can account for a 1000-fold difference in body size between mice and humans. This effective decrease in mutation rate may be accomplished by having better DNA repair in the larger species, more efficient removal of mutated cells, or less endogenous damage as a result of a lower mass-specific basal metabolic rate.

Analysis of previously published models of colorectal cancer suggests that a two- to three-fold decrease in the mutation rate or stem cell division rate is enough to reduce a whale's cancer risk to that of a human. Similarly, the addition of one to two required tumour-suppressor gene mutations would also be sufficient. We surveyed mammalian genomes and did not find a positive correlation of tumour-suppressor genes with increasing body mass and longevity. However, we found evidence of the amplification of TP53 in elephants, FBXO31 in microbats, which might explain Peto's paradox in those species. Exploring parameters that evolution may have fine-tuned in large, long-lived organisms will help guide future experiments to reveal the underlying biology responsible for Peto's paradox and guide cancer prevention in humans.

Numerous scientists in the field of aging research declare their goal to be "healthy aging," which has always seemed to me to be a contradiction in terms. Aging is by definition a process of becoming more frail, more diseased, more damaged. There is a certain amount of politics in all of this, a result of all too many researchers still unwilling to talk in public about extending healthy life spans. Thus healthy aging and compression of morbidity become code phrases to allow these people to discuss the science of aging while pretending that efforts to prevent age-related disease will not extend life spans. Yet successful prevention of age-related disease must extend overall life span. Aging is an accumulation of tissue damage, and age-related disease is the result of that damage. Meaningful treatments for age-related disease will work by reducing levels of damage and thus extend life. An unwillingness to directly engage with this point is a part of the problem we face in finding sufficient funding and support for aging research to make rapid progress.

The current research topic inquires: "Should we treat aging as a disease?" Yet, in this inquiry, the question "Can aging be considered a disease?" is secondary, while the more primary question really must be "Is aging treatable?" Paradoxically, the answer given to the second question largely determines the answer to the first. The perceived unchangeable, and hence untreatable, nature of aging is the root cause for many subsequent rationalizations, even to the point of claiming the desirability of aging-derived suffering and death. This is a well recognized psychological phenomenon sometimes referred to as "apologism" or even "deathism," a ramification of the "sour grapes syndrome," vilifying something that we think we cannot attain, while accepting as "good" or "healthy" something that we believe is inevitable for us (such as degenerative aging). Yet, I argue that, historically, medical tradition has always recognized the morbid character of aging and endeavored to fight it. The rationalizations of aging as "natural," "justified," or "healthy" could never entirely prevail.

I argue that acknowledging the possibility of successful intervention into the aging process, in other words treating aging as a curable disease, has been a long and highly respected tradition of biomedical thought. It may just be observed that the proactive attitudes, aimed to ameliorate degenerative aging, tend to intensify thanks to the advancement of technological capabilities. Presently, the list of supporters of the cause of "curing aging" grows rapidly. The reason for this increase may be objective and tectonic. The world is rapidly aging, threatening grave consequences for the global society, in particular economy, which forces the society to seek solutions. On the other hand, biomedical science and technology are developing rapidly as well, increasing the feasibility of intervention and fostering our hope that a solution may be found.

Those may be "the push and the pull" or "the stick and the carrot" mighty forces that prompt more and more scientists and lay persons to move over to the camp of "treating aging as a disease," toward investing more and more time and effort for its amelioration or even cure, as soon as possible, for the benefit of all. Yet, the very idea of "treating aging as a disease," or some other title given to a morbid, debilitating and deadly condition, is by no means an intellectual novelty. It is a long established commonsensical intellectual tradition and a profound and ancient human desire. With the growing aging population and increasing technological capabilities, this idea is achieving an ever greater prominence. Eventually, the question whether aging should be considered "a treatable disease" may be reduced to technological capacity and semantics. While degenerative aging, that is the accumulation of structural damage, impairment of metabolic balance and functioning, may be seen as a disabling and deteriorative process that requires prevention and treatment, using advanced biomedical technology; the achievement of healthy longevity may be its cure.

Link: http://dx.doi.org/10.3389/fgene.2015.00202

The trouble with cancer research is that all cancers are different; expensive and slow research results in only one therapy for one small group of cancer patients. Real progress would mean finding commonalities between many cancer types, or mechanisms essential to all cancer such as lengthening of telomeres. That is still a minority concern in the research community, but is growing thankfully in recent years. Nonetheless, since various types of cancer spring from specific mutations, it should be expected that with progress in biotechnology researchers will discover the basis for highly effective therapies for at least a few types of cancer:

Up to 90% of colorectal tumors contain inactivating mutations in a tumor suppressor gene called adenomatous polyposis coli (Apc). Although these mutations are thought to initiate colorectal cancer, it has not been clear whether Apc inactivation also plays a role in tumor growth and survival once cancer has already developed. This question has been challenging to address experimentally because attempts to restore function to lost or mutated genes in cancer cells often trigger excess gene activity, causing other problems in normal cells.

To overcome this challenge, researchers used a genetic technique to precisely and reversibly disrupt Apc activity in a novel mouse model of colorectal cancer. While the vast majority of existing animal models of colorectal cancer develop tumors primarily in the small intestine, the new animal model also developed tumors in the colon, similar to patients. Consistent with previous findings, Apc suppression in the animals activated the Wnt signaling pathway, which is known to control cell proliferation, migration, and survival. When Apc was reactivated, Wnt signaling returned to normal levels, tumor cells stopped proliferating, and intestinal cells recovered normal function. Tumors regressed and disappeared or reintegrated into normal tissue within 2 weeks, and there were no signs of cancer relapse over a 6-month follow-up period. Moreover, this approach was effective in treating mice with malignant colorectal cancer tumors containing Kras and p53 mutations, which are found in about half of colorectal tumors in humans.

Researchers continue to investigate why Apc is so effective at suppressing colon tumor growth, with the goal of one day mimicking this effect with drug treatments. "It is currently impractical to directly restore Apc function in patients with colorectal cancer, and past evidence suggests that completely blocking Wnt signaling would likely be severely toxic to normal intestinal cells. However, our findings suggest that small molecules aimed at modulating, but not blocking, the Wnt pathway might achieve similar effects to Apc reactivation. Further work will be critical to determine whether Wnt inhibition or similar approaches would provide long-term therapeutic value in the clinic."

Link: http://www.eurekalert.org/pub_releases/2015-06/cp-asg061115.php

All organs are of course very different from one another, but some are more unusual than others. The heart is largely muscle, but muscle with strange characteristics, one of which is that it does an exceptionally poor job of regeneration following injury. This isn't what you'd like to hear regarding the second most vital organ in the body. As is also the case for the brain, it was only comparatively recently established that the adult heart generates any meaningful number of new replacement muscle cells over time. That flow of replacements is small enough and slow enough that even in old age it is still the case that most of your heart muscle cells were originally created in early childhood. The important thing for researchers in the field of regenerative medicine is that this flow exists at all, however. Given a natural process there will be ways to expand upon it, but this is still very young research even in comparison to similar investigations of ways and means to expand the trickle of neurogenesis in the adult brain.

Current first generation efforts to spur heart regeneration through stem cell therapies skip over all of these subtleties in a brute-force attempt to heal, but regenerative medicine is a field in which the numerous differences between organs matter greatly. Research groups tend to specialize on just a few tissue types at a time, hammering out protocols and knowledge needed to induce regeneration, none of which have immediate application to healing in other tissues. It is similar to the situation in cancer research, in which every cancer is radically different in the ways that matter, but with less of a hope of finding common points of action that should work in many different tissue types. Building tissue is always going to be harder than destroying tissue, and there will be far fewer shortcuts: it is the nature of things. Thus the development of regenerative medicine that builds upon, and eventually goes beyond, stem cell research will be a large and costly field of many specialties for decades. It heralded the start of the era in which degenerative aging will be effectively treated, and I imagine it will still be going strong and with much to accomplish well after the first suite of SENS-like rejuvenation treatments are commercialized.

Back to the heart, here are a couple of recent papers that look at the unusual dynamics of heart cells, particularly in heart muscle tissue:

Most heart muscle cells formed during childhood

New human heart muscle cells can be formed, but this mainly happens during the first ten years of life, according to a new study. Other cell types, however, are replaced more quickly. During a heart attack, when parts of the heart muscle are starved of oxygen, many heart cells die and are replaced by scar tissue. As this impairs functionality, many researchers are interested in the possibility of stimulating the regeneration of lost heart muscle cells. But is it possible?

To examine the regeneration of human heart cells, the team behind this new study used a combination of methods. One such was to measure the radioactive isotope C-14, exploiting the sharp rise in atmospheric levels of carbon-14 in the 1950s and 60s caused by nuclear testing. Levels then declined, which means that cells that were formed after that period give lower C-14 readings than those formed during it. Thus by measuring the amount of C-14 in a cell's DNA, the researchers were able to calculate its age. "We examined the heart tissue from 29 deceased individuals of various ages and found that even by one month after birth, the heart contains the same number of cells as it has in adults."

According to the study, the heart grows during childhood because its cells increase in size rather than in number; in other words, heart cells are generated on only a modest scale, and even during a long life, only forty per cent of muscle cells are replaced. "Our findings suggest that it can be rational and realistic to develop new therapeutic strategies for strengthening the body's own regenerative capacity to treat heart diseases."

Telocytes and putative stem cells in ageing human heart

Tradition considers that mammalian heart consists of about 70% non-myocytes (interstitial cells) and 30% cardiomyocytes. The presence of telocytes has been overlooked, since they were described in 2010. Also, the number of cardiac stem cells has not accurately estimated in humans during ageing. We used electron microscopy to identify and estimate the number of cells in human atrial myocardium. Three age-related groups were studied: newborns (17 days - 1 year), children (6-17 years) and adults (34-60 years).

We found that interstitial area gradually increases with age from 31.3 ± 4.9% in newborns to 41 ± 5.2% in adults. Also, the number of blood capillaries (per mm2) increased with several hundreds in children and adults versus newborns. Cardiomyocytes are the most numerous cells, representing 76% in newborns, 88% in children and 86% in adults. Interestingly, no lipofuscin granules were found in cardiomyocytes of human newborns and children. The percentage of cells that occupy interstitium were (depending on age): endothelial cells 52-62%; vascular smooth muscle cells and pericytes 22-28%, Schwann cells with nerve endings 6-7%, fibroblasts 3-10%, macrophages 1-8%, telocytes about 1% and stem cells less than 1%.

We cannot confirm the popular belief that cardiac fibroblasts are the most prevalent cell type in the heart and account for about 20% of myocardial volume. Numerically, telocytes represent a small fraction of human cardiac interstitial cells, but because of their extensive telopodes, they achieve a 3D network that, for instance, supports cardiac stem cells. The myocardial (very) low capability to regenerate may be explained by the number of cardiac stem cells, which decreases fivefold by age (from 0.5% to 0.1% in newborns versus adults).

Athletes at the top of their fields tend to live longer than the general population. The reasons for this are yet to be determined: for the most part human historical data can only show association, not causation. So it may be that more exercise is beneficial, or it may be that only the most robust people, who were going to live longer anyway, tend reach the heights of professional athletics, or it may be that the wealth, community, and access to medicine that comes with being a successful professional athlete are the critical influences:

To determine whether Olympic medallists live longer than the general population, we carried out a retrospective cohort study, with passive follow-up and conditional survival analysis to account for unidentified loss to follow-up. The study group consisted of 15,174 Olympic athletes from nine country groups (United States, Germany, Nordic countries, Russia, United Kingdom, France, Italy, Canada, and Australia and New Zealand) who won medals in the Olympic Games held in 1896-2010. Medallists were compared with matched cohorts in the general population (by country, age, sex, and year of birth).

More medallists than matched controls in the general population were alive 30 years after winning (relative conditional survival 1.08). Medallists lived an average of 2.8 years longer than controls. Medallists in eight of the nine country groups had a significant survival advantage compared with controls. Gold, silver, and bronze medallists each enjoyed similar sized survival advantages. Medallists in endurance sports and mixed sports had a larger survival advantage over controls at 30 years (1.13) than that of medallists in power sports (1.05). We conclude that Olympic medallists live longer than the general population, irrespective of country, medal, or sport. This study was not designed to explain this effect, but possible explanations include genetic factors, physical activity, healthy lifestyle, and the wealth and status that come with international sporting glory.

Link: http://dx.doi.org/10.1136/bjsports-2015-e8308rep

Cryonics is a form of low-temperature preservation of tissue immediately following death, with the aim of preserving brain structure sufficiently well to allow future revival. Since the necessary technologies for revival can be envisaged in some detail, but remain far in the future, a large focus of the cryonics community is long-term risk and survival of cryopreservation organizations into at least the later decades of this century. A lot of ink has been spilled on this topic over the years, and this article covers some of the high points, such as politics, regulation, the necessity for growth in what is currently a small industry, and so forth:

Cryonics service providers offer their customers perpetual care. This care is meant to continue until medical technology has advanced to the point that their reanimation can be performed safely. While the most optimistic estimates are that reanimation may be possible in as little as fifty years, the time frame is normally considered to be hundreds of years. The poor quality of suspensions received by most persons, however, suggests that many will be reanimated only in the distant future, if at all. One of the greatest unknowns is whether these companies will be able to operate continuously over this period. An organizational failure of even a few months would terminate the experiment in medical time travel by causing irreparable damage to those in storage.

From an organizational standpoint, this offer of perpetual care is similar to that provided by the chantries established in England in the Middle Ages. Chantries were trusts established for the purpose of employing priests to sing a certain number of Masses during a stipulated period of time for the spiritual benefit of the deceased. The first perpetual Mass was established by royalty in the 1180s. Most institutions providing this service were suppressed in 1547 as part of the Reformation. Therefore, the 'perpetual' care lasted for less than four hundred years. This is also a reasonable estimate for the amount of time that a majority of those in cryonic suspension will require before any reanimation becomes possible. However, the chantries were established as part of the Roman Catholic Church or as institutions under its direction and control. During this period, the Roman Catholic Church was as powerful as a state and was considered by many to be the governing body of Europe. In contrast, cryonics organizations are very small businesses with extremely limited resources, subject to regulation by both State and Federal governments. The key question addressed here is whether and how such organizationally inferior institutions can achieve the longevity that the most powerful organization in Europe only barely achieved in earlier times.

Link: http://hplusmagazine.com/2015/06/18/the-growth-and-possible-decline-of-cryonics/

Mechanically speaking, degenerative aging happens for the same underlying reasons in all of us. We all share the same operation of cellular metabolism, generating the same lingering waste products, the same forms of biochemical wear and tear that slowly slip past otherwise comprehensive repair mechanisms. It's all damage, and aging is in effect just a process of damage accumulation. Our organs and tissues react to that damage and waste in the same ways, so much so that you can use patterns of epigenetic markers of cell state to identify age, pulling that out from all of the thousands of changes in cell state that are distinct to a person's unique environment and circumstances.

There is a lot of interest today in identifying the genetic differences and metabolic processes that react to environmental circumstances to determine natural variations in aging and longevity in our species. Some people think that this is the way to produce therapies to extend healthy life spans: figure out what makes some people more likely to live to 100, say a 1% chance rather than a next to 0% chance, and implement some kind of drug that affects similar changes in ordinary people. Take Human Longevity Inc., for example, as representative of the viewpoint of a sizable research contingent. This all seems like a short-sighted approach to me. You're tinkering around in the reaction to the underlying cause of aging, while failing to address the actual problem - which is the damage that causes these reactions. It's like trying to make cars fall apart less frequently by working on oil formulations. There's a much better approach to making cars fall apart less frequently, and that's to repair them every so often. If you don't carry out periodic repair, you aren't going to get much out of better oil. It all seems backwards in a way.

You can make a bunch of money mining, analyzing, and selling genetic data. Human Longevity Inc. will no doubt do just fine as a business, and along the way add to human knowledge in a useful way that incrementally advances the general state of medicine. This just isn't the path to near term meaningful extension of human life spans. It's heading off in entirely the wrong direction for that, missing the forest for the trees, and the same can be said for much of the rest of the research community. They are very focused on mapping aging and its biochemistry in all of its present variations, and largely disinterested in fixing the damage that causes all of this glorious biological complexity. And pain, and suffering, and death. It's the pain and suffering and death on a vast scale that makes this something other than an academic matter in which the research community can be indulged in their desire to produce a complete map of the situation.

In any case, here is an example of the point that aging has root causes, and many age-related conditions spring from the same root causes. There are thousands of failure modes for damaged tissues, but back down the chain of cause and consequence only a handful of those root causes. This is written from the perspective of those who see intervention in the reactions to damage as the way forward, rather than those who look to repair of damage as the way forward - which is to say it is written from the present mainstream view, not the view that needs to supplant it if we are to see meaningful progress in the near future.

Genetic evidence for common pathways in human age-related diseases

It is widely accepted among gerontologists that common processes mechanistically underlie both aging and the pathogenesis of multiple age-related diseases and that targeting common factors in aging will have a significant benefit to human health. A wealth of experimental data from lower organism studies supports this concept, and human progeroid syndromes indicate that disruption of key biological processes can result in the premature onset of multiple age-related pathologies. There has, however, been little direct evidence that this is true in normal human aging and age-related disease, and the role of canonical aging pathways in human age-related pathologies has not been established.

Our gene-based findings suggest that while inflammation, immune regulation, and cholesterol metabolism are all broadly important in human aging, cholesterol metabolism genes alone are strikingly enriched among multiple age-related diseases. Multiple apolipoproteins have been associated with disease, and APOE is a particularly notable genetic loci in human health, as discussed. Consistent with these prior findings, our data suggest that apolipoprotein metabolism is a key underlying pathway in multiple human age-related diseases. Our findings suggest that apolipoprotein metabolism may represent a mammalian-specific underlying pathway in aging and age-related disease, supporting the notion that interventions in lipoprotein metabolism will provide significant benefits to human health. Epidemiological studies already support the adoption of earlier and more widespread statin use, and least one study has suggested that statins broadly affect the aging process. Clearly, apolipoprotein metabolism warrants continued attention as a safe and efficacious clinical target in aging.

In addition to providing further evidence supporting the critical importance of apolipoprotein metabolism in human age-related disease, here, we provide evidence supporting for the model that common, evolutionarily conserved pathways influence many age-related diseases. The data presented here provide new evidence supporting the continued pursuit of interventions designed to combat age-related disease based on genetic pathways of aging discovered in lower organisms. While many of these pathways, such as genome maintenance and IIS/mTOR signaling, have already been implicated in human health, our study provides the first evidence that genome-wide association studies of age-related diseases show a signature of conserved pathways of aging. Finally, while our study focused on age-related disease, our novel pathway-based approach provides a new method for identifying shared pathways of disease. We anticipate that this approach can be applied to traits that are mechanistically poorly defined to provide novel insight into the pathogenesis of human diseases.

Like calorie restriction, the practice of intermittent fasting has been shown to improve measures of health in humans and extend healthy life spans in mice. One research group has in recent years been working on taking a specific implementation of intermittent fasting and running it through the expensive hurdles needed for FDA approval, for instance as an adjuvant therapy for cancer patients. Needless to say, this involves commercialization of a medical diet and industry participation, as otherwise where else will the funding come from for all this work? Arguably despite the long history of calorie restriction research there has been little effort to push approaches like this through the regulatory gauntlet because it requires some ingenuity to link "just eat less" with "some entity can charge lots of money for this." Here is an update on some of that work:

In a new study, researchers show that cycles of a four-day low-calorie diet that mimics fasting (FMD) cut visceral belly fat and elevated the number of progenitor and stem cells in several organs of old mice - including the brain, where it boosted neural regeneration and improved learning and memory. The mouse tests were part of a three-tiered study on periodic fasting's effects - testing yeast, mice and humans. Mice, which have relatively short life spans, provided details about fasting's lifelong effects. Yeast, which are simpler organisms, allowed researchers to uncover the biological mechanisms that fasting triggers at a cellular level. And a pilot study in humans found evidence that the mouse and yeast studies were, indeed, applicable to humans.

Bimonthly cycles that lasted four days of an FMD which started at middle age extended life span, reduced the incidence of cancer, boosted the immune system, reduced inflammatory diseases, slowed bone mineral density loss and improved the cognitive abilities of older mice tracked in the study. The total monthly calorie intake was the same for the FMD and control diet groups, indicating that the effects were not the result of an overall dietary restriction. In a pilot human trial, three cycles of a similar diet given to 19 subjects once a month for five days decreased risk factors and biomarkers for aging, diabetes, cardiovascular disease and cancer with no major adverse side effects.

The diet slashed the individual's caloric intake down to 34 to 54 percent of normal, with a specific composition of proteins, carbohydrates, fats and micronutrients. It decreased amounts of the hormone IGF-I, which is required during development to grow, but it is a promoter of aging and has been linked to cancer susceptibility. It also increased the amount of the hormone IGFBP, and reduced biomarkers/risk factors linked to diabetes and cardiovascular disease, including glucose, trunk fat and C-reactive protein without negatively affecting muscle and bone mass.

Link: http://news.usc.edu/82959/diet-that-mimics-fasting-appears-to-slow-aging/

Researchers are digging into various ways in which stem cells signal other cells to change their behavior, as this this one of the means by which stem cell therapies produce benefits. Identifying the important signalsn would mean that at least some forms of stem cell transplant could be replaced with delivery of the signal molecules instead, probably an easier and cheaper approach to treatment:

The heart, for all its metronomic dependability, has little ability for self-repair. When heart muscle is damaged in a heart attack, the organ cannot replace the dead tissue and grow new. Instead, it must compensate for its lost pumping ability. That compensation comes with a high price: the heart grows large and flabby, and heart contraction weakens. From the start, heart damage seemed a problem custom-made for the burgeoning field of stem cell therapy. As knowledge about stem cells grew, several scientific teams conducted clinical trials on human heart attack victims, injecting damaged hearts with stem cells hoping the cells would take root and make new heart muscle. But results were disappointing.

A little more than a decade ago, researchers discovered that all cells secrete tiny communications modules jammed with an entire work crew of messages for other cells. Researchers renamed these vesicles exosomes. In the current study, researchers used a mouse model of myocardial infarction - heart attack. After infarct, mice received exosomes from either embryonic stem cells or exosomes from another type of cell called a fibroblast; mice receiving the fibroblast exosome served as the control group. The results were unmistakable. Mice that received exosomes from embryonic stem cells showed improved heart function after a heart attack compared to the control group. More heart muscle cells survived after infarct, and the heart exhibited less scar tissue. Fewer heart cells committed suicide - a process known as programmed cell death, or apoptosis. There was greater capillary development around the area of injury in the stem cell exosome group, which improved circulation and oxygen supply to the heart muscle. Further, there was a marked increase in cardiac progenitor cells - that is, the heart's own stem cells - and these survived and created new heart cells. The heartbeat was more powerful in the experimental group compared to the control group, and the kind of unhealthy enlargement that compensates for tissue damage was minimized.

The researchers then tested the effect of one of the most abundant gene-regulating molecules, or microRNAs, found in the stem cell exosome called miR-294. When miR-294 alone was introduced to cardiac stem cells in the laboratory, it mimicked many of the effects seen when the entire exosome was delivered. "To a large extent, this micro-RNA alone can recapitulate the activity of the exosome."

Link: http://www.templehealth.org/content/news.htm?inCtx5news_id=1376

A lot of time and money has gone into the study of sirtuins, a class of a few proteins that participate in numerous cellular processes that influence natural variations in aging and longevity. There was something of a big hype cycle over this back a few years, and like all hype cycles centered on alleged approaches to modestly slowing aging through drugs that alter the operation of metabolism, it all came to nothing exciting in the end. A fair chunk of new cellular biochemistry was mapped, a chunk that it has to be said is in fact a tiny, minuscule slice of the overall space of proteins and genes, something like a few billion dollars were spent, and no reliable demonstrations of extended life in higher animals or viable therapies for age-related disease resulted. It is perhaps worth bearing in mind here that the primary goal of the scientific endeavor in the broader field of cell biology is in fact to map every last complex interaction of cellular biochemistry, and applications of that knowledge are secondary at best, a nagging concern that comes up when writing grants, since the rest of the world has an interest in new technologies and better medicines. I exaggerate, but not greatly.

Large research initiatives have inertia once they are underway and established, and so a broad range of investigations into sirtuin biochemistry continue apace today. Even a brief search of published papers on sirtuins and aging turns up more than a dozen publications in the last couple of months, which is a sizable number for any one narrow subtopic in the life sciences. It is all very interesting, but I think we should continue to assume that there is next to nothing here of any real relevance to the treatment of aging as a medical condition. At the very best this is a long, hard road to drugs that make slight adjustments to the course of aging in any given individual, probably not as large as the adjustments you can make yourself via exercise and calorie restriction. Of course the scientific community should continue along the path of gathering complete understanding of cellular biochemistry, all knowledge will be useful eventually, but we should maintain a realistic view of what various portions of that venture can in fact achieve in the near future.

Here are a selection of recent sirtuin-related papers for you to peruse at your leisure, things that I wouldn't normally take any time to point out. But there is always more going on than is individually newsworthy in my eyes.

Reversing stem cell aging (PDF)

SIRT3 and SIRT7 converge at mitochondrial protection to ensure hematopoietic stem cell maintenance. These protective programs are repressed in aged hematopoietic stem cells and reintroduction of SIRT3 or SIRT7 improves the functional capacity of aged hematopoietic stem cells. Thus, SIRT3 and SIRT7 may modulate the aging process by regulating stem cell quiescence and tissue maintenance. It will be of particular interest to establish whether other tissues use the same mechanism for maintaining stem cell quiescence. It will also be important to identify other genes that mediate mitochondrial protein folding stress to regulate stem cell quiescence.

Sirtuins and Proteolytic Systems: Implications for Pathogenesis of Synucleinopathies

Loss of proteostasis associated with a burden and an impairment of the proteolytic pathways is one of the hallmarks of α-synuclein-induced toxicity. Therefore, modulation of the proteolytic molecular pathways that are deregulated appears as a rational strategy to fight against the harmful effects promoted by α-synuclein. Sirtuins are a family of highly conserved NAD+ dependent histone deacetylases that have emerged as central players in several biological processes, such as transcription, apoptosis, DNA repair, stress cellular response and energetic metabolism. The interest in sirtuins, in the context of proteostasis, emerged with the discoveries that sirtuins have the ability to modulate proteostasis, particularly the autophagy degradation pathway, and aging.

Sirtuin function in aging heart and vessels

Age is the most important risk factor for metabolic alterations and cardiovascular accidents. Although class III histone deacetylases, alias Sirtuins, have been appealed as "the fountain of youth" their role in longevity control and prevention of aging-associated disease is still under debate. Indeed, several lines of evidence indicate that sirtuin activity is strictly linked to metabolism and dependent on NAD+ synthesis both often altered as aging progresses.

SIRTain regulators of premature senescence and accelerated aging

Amongst the seven known mammalian sirtuin proteins, SIRT1 has gained much attention due to its widely acknowledged roles in promoting longevity and ameliorating age-associated pathologies. The contributions of other sirtuins in the field of aging are also gradually emerging. Here, we summarize some of the recent discoveries in sirtuins biology which clearly implicate the functions of sirtuin proteins in the regulation of premature cellular senescence and accelerated aging.

Depletion of SIRT6 causes cellular senescence, DNA damage, and telomere dysfunction in human chondrocytes

SIRT6, a member of the sirtuin family of nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylases, has been implicated as a key factor in aging-related diseases. However, the role of SIRT6 in chondrocytes has not been fully explored. The purpose of this study was to examine the role of SIRT6 in human chondrocytes by inhibiting SIRT6 in vitro. Depletion of SIRT6 in human chondrocytes caused increased DNA damage and telomere dysfunction, and subsequent premature senescence. These findings suggest that SIRT6 plays an important role in the regulation of senescence of human chondrocytes.

Differential expression of sirtuins in the aging rat brain

Although there are seven mammalian sirtuins (SIRT1-7), little is known about their expression in the aging brain. We tested mRNA and protein expression levels of rat SIRT1-7, and the levels of associated proteins in the brain. Our data shows that SIRT1 expression increases with age, concurrently with increased acetylated p53 levels in all brain regions investigated. SIRT2 and FOXO3a protein levels increased only in the occipital lobe. SIRT3-5 expression declined significantly in the hippocampus and frontal lobe, associated with increases in superoxide and fatty acid oxidation levels, and acetylated CPS-1 protein expression, and a reduction in MnSOD level. While SIRT6 expression declines significantly with age acetylated H3K9 protein expression is increased throughout the brain. SIRT7 and Pol I protein expression increased in the frontal lobe. This study identifies previously unknown roles for sirtuins in regulating cellular homeostasis and healthy aging.

Expression of SIRT1 and SIRT3 varies according to age in mice

Sirtuins (SIRTs) are involved in multiple cellular processes including those related to aging, cancer, and a variety of cellular functions including cell cycle progression, DNA repair, and cellular proliferation. SIRTs have been shown to extend the yeast life span, although there is presently little known about SIRT expression in the organs of mice. In the present study, we were especially interested in identifying differences in SIRT expression between young mice and aged mice. Specifically, we investigated the expression of SIRT1 and SIRT3 in the kidney, lung, skin, adipose tissue, and spleens of 6-month-old and 24-month-old mice using immunohistochemical staining. Compared with that in younger mice, the expression of SIRT1 in 24-month-old rats was increased in kidney, lung, and spleen tissue, while that of SIRT3 was decreased in adipose, kidney, and lung tissue. The results of our study suggest that aging is associated with altered patterns of expression of SIRT1 and SIRT3. In addition, we noted that the expression patterns of SIRT1 and SIRT3 varied by organ. Taken together, the results of this study suggest the possibility that SIRTs may be involved in diseases associated with aging.

SIRT1 in the brain - connections with aging-associated disorders and lifespan

SIRT1, the best studied member of the mammalian sirtuins, has a myriad of roles in multiple tissues and organs. However, a significant part of SIRT1's role that impinges on aging and lifespan may lie in its activities in the central nervous system (CNS) neurons. Systemically, SIRT1 influences energy metabolism and circadian rhythm through its activity in the hypothalamic nuclei. From a cell biological perspective, SIRT1 is a crucial component of multiple interconnected regulatory networks that modulate dendritic and axonal growth, as well as survival against stress. This neuronal activity of SIRT1 is also important for neuronal plasticity, cognitive functions, as well as protection against aging-associated neuronal degeneration and cognitive decline.

SIRT1 Deficiency in Microglia Contributes to Cognitive Decline in Aging and Neurodegeneration via Epigenetic Regulation of IL-1β

Aging is the predominant risk factor for neurodegenerative diseases. One key phenotype as the brain ages is an aberrant innate immune response characterized by proinflammation. However, the molecular mechanisms underlying aging-associated proinflammation are poorly defined. Whether chronic inflammation plays a causal role in cognitive decline in aging and neurodegeneration has not been established. Here we report a mechanistic link between chronic inflammation and aging microglia and a causal role of aging microglia in neurodegenerative cognitive deficits. We showed that SIRT1 is reduced with the aging of microglia and that microglial SIRT1 deficiency has a causative role in aging - or tau-mediated memory deficits via IL-1β upregulation in mice. Interestingly, the selective activation of IL-1β transcription by SIRT1 deficiency is likely mediated through hypomethylating the specific CpG sites on IL-1β proximal promoter. In humans, hypomethylation of IL-1β is strongly associated with chronological age and with elevated IL-1β transcription. Our findings reveal a novel epigenetic mechanism in aging microglia that contributes to cognitive deficits in aging and neurodegenerative diseases.

Mitochondria, the power plants of the cell, are implicated as a cause of degenerative aging. Each cell has a herd of mitochondria, dividing like bacteria (mitochondrial biogenesis) and removed by quality control mechanisms when damaged (mitophagy). In an increasing number of cells with advancing age, all mitochondria are damaged, however, fallen into a state that slips past quality control and quickly overtakes the mitochondrial population. This appears to be a fairly rapid transition for an individual cell, but otherwise a rare event. Still, this growing population of dysfunctional cells causes significant harm, such as by exporting reactive molecules that damage lipids and contribute to atherosclerosis.

There are numerous schools of thought on how best to fix this problem, even if very few researchers are actually working on it - the usual state of affairs for anything likely to prove effective in the treatment of aging, sad to say. Gene therapies to deliver replacements for damaged mitochondrial genes, or drug treatments to provide a regular delivery of the proteins those genes produce, for example. Some researchers consider it worth looking into enhanced quality control, or otherwise tinkering with mitochondrial dynamics, but this seems like a comparative poor approach, likely to just slow things down rather than reverse the damage.

Maintenance of mitochondrial function and energy homeostasis requires both generation of newly synthesized and elimination of dysfunctional mitochondria. Impaired mitochondrial function and excessive mitochondrial content are major characteristics of ageing and several human pathophysiological conditions, highlighting the pivotal role of the coordination between mitochondrial biogenesis and mitophagy. However, the cellular and molecular underpinnings of mitochondrial mass homeostasis remain obscure.

In our recent study, we demonstrate that DCT-1, the Caenorhabditis elegans homolog of mammalian BNIP3 and BNIP3L/NIX, is a key mediator of mitophagy promoting longevity under stress. DCT-1 acts downstream of the PINK-1-PDR-1/Parkin pathway and is ubiquitinated upon mitophagy-inducing conditions to mediate the removal of damaged mitochondria. Accumulation of damaged mitochondria triggers SKN-1 activation, which initiates a bipartite retrograde signaling pathway stimulating the coordinated induction of both mitochondrial biogenesis and mitophagy genes.

Taken together, our results unravel a homeostatic feedback loop that allows cells to adjust their mitochondrial population in response to environmental and intracellular cues. Age-dependent decline of mitophagy both inhibits removal of dysfunctional or superfluous mitochondria and impairs mitochondrial biogenesis resulting in progressive mitochondrial accretion and consequently, deterioration of cell function.

Link: http://dx.doi.org/10.1080/15548627.2015.1061172

Researchers have found a single gene intervention that improves heart function and extends life significantly, at least in flies. While looking at the results here, it is worth bearing in mind that a large extension of life in short-lived species via methods used to date, altering the operation of metabolism, does not seems to translate to a large extension of life in long-lived species. This is the case even when the actual mechanism is the same, works well, and seems to produce similar benefits in short term measures of health. Consider calorie restriction, for example. We certainly don't live 40% longer via that method, but mice do.

"More than 80 percent of protein groups found in flies, including vinculin network proteins, are similar to those found in rats and monkeys. We chose to focus on the proteins that naturally increase in expression in the aging hearts of flies, rats and monkeys. Since deletion or mutation of these proteins can lead to cardiomyopathy in patients, we wondered if their age-related upregulation was beneficial to the heart. Moreover, would overexpressing them improve heart function?"

Researchers found that the contractile function of the hearts of fruit flies is greatly improved in flies that overexpress the protein vinculin, which also accumulates at higher levels in the hearts of aging rats, monkeys and humans. In addition, flies genetically programmed to express elevated levels of vinculin lived significantly longer than normal fruit flies. The new study attributes the longer life of the flies to the improved contractile function of the heart due to the presence of more vinculin, which helps with the structure of the heart and connects heart muscle cells. In the study, 50 percent of vinculin-overexpressing flies lived past 11 weeks, to a maximum of 13 weeks. In contrast, 50 percent of control flies only made it to 4 weeks old and none lived past 8 weeks.

"With the average age being projected to increase dramatically in the coming decades, it is more important than ever that we understand and develop therapies for age-related heart failure. The results of this study implicate vinculin as a future candidate for therapy for people at risk of age-related heart failure." For example, if additional research supports these new findings, targeted gene or drug therapies related to vinculin and its network of proteins could be developed to strengthen the hearts of patients suffering from age-related heart failure.

Link: http://www.jacobsschool.ucsd.edu/news/news_releases/release.sfe?id=1765

It seems that after some years of researchers feeling more comfortable talking in public about the goal of treating aging as a medical condition, the community is also beginning to feel constrained by the present regulatory and funding situations. Both are ridiculous. In the US the Food and Drug Administration (FDA) only approves treatments for specific uses and defined medical conditions. Aging is not a defined medical condition, therefore you can't legally deploy new technologies to treat it. That has a stifling effect on the ability to raise funds all the way along the development chain that leads from early stage research to commercialization.

Not that aging research receives anywhere near as much funding as it merits in the first place, regardless of the FDA situation: medical research is in general funded to a fraction of what even a moderately utilitarian view would suggest is a good plan. Aging research makes up a tiny fraction of that medical research funding, and efforts to actually treat rather than merely investigate aging garner a small portion of even that pittance. This is a society of beer and circuses, not one of respect for the sciences, at least if you look at the flows of money and other resources. The amounts spent on the above-board and regulated bribery of the last US presidential election summed to about twice the funding for the National Institute on Aging in that year, for example, and were probably roughly in the same ballpark as the sum of all aging research funding in the US that year, public and private.

In any case, those researchers who consider themselves stuck with working within the institutional funding system are of late gearing up to more seriously lobby the FDA to change the rules. This makes sense in their world: a change opens more doors in the future when it comes to seeking grants or establishing for-profit ventures based on their research. I am not optimistic that this is anything but the start of a very long, expensive, and distracting process for those who take on the lion's share of the responsibility for it, however. We have the example of sarcopenia to consider, this being the name given to the characteristic loss of muscle mass and strength that takes place with aging. Lobbying the FDA to consider this a medical condition and thus allow commercialization of treatments in the US has been underway for a long time indeed, with no sign that FDA bureaucrats are going to do anything more than continue to hold meetings, request expensive data, and waste time.

As I have long said, I think that the better road ahead is to commercialize treatments outside the US on the back of a strong medical tourism industry. The stem cell marketplace could grow into that, but has yet to organize to the point at which it can influence the research community sufficiently to close the funding circle. It absolutely should be any US researcher's expectation that their primary and best avenue for commercial application of medical research is outside the US. Further, a robust trade on that front is the only way to drive back the ever-increasing demands of the FDA. Regulatory competition with other regions is the only argument that bureaucrats reliably listen to: the point at which they look like fools for holding out further. I expect we'd still be waiting on legalization of stem cell treatments of any sort in the US if they hadn't been widely available for years in reliable clinics and hospitals across both land borders and the Pacific.

In any case, here is more on the topic of lobbying the FDA on approval for therapies that might treat aging. This is all some years in advance of anything that can actually effectively move the needle, so far as my view of the situation is concerned, but no harm in getting the groundwork laid early. Though, as noted above, I think they'll be at this for a while, and past the time at which initial treatments to partially treat some aspects of degenerative aging are available overseas via medical tourism.

Anti-ageing pill pushed as bona fide drug, regulators asked to consider ageing a treatable condition

Doctors and scientists want drug regulators and research funding agencies to consider medicines that delay ageing-related disease as legitimate drugs. Such treatments have a physiological basis, researchers say, and could extend a person's healthy years by slowing down the processes that underlie common diseases of ageing - making them worthy of government approval. On 24 June, researchers will meet with regulators from the US Food and Drug Administration (FDA) to make the case for a clinical trial designed to show the validity of the approach.

Current treatments for diseases related to ageing "just exchange one disease for another", says physician Nir Barzilai of the Albert Einstein College of Medicine in New York. That is because people treated for one age-related disease often go on to die from another relatively soon thereafter. "What we want to show is that if we delay ageing, that's the best way to delay disease."

Barzilai and other researchers plan to test that notion in a clinical trial called Targeting Aging with Metformin, or TAME. They will give the drug metformin to thousands of people who already have one or two of three conditions - cancer, heart disease or cognitive impairment - or are at risk of them. People with type 2 diabetes cannot be enrolled because metformin is already used to treat that disease. The participants will then be monitored to see whether the medication forestalls the illnesses they do not already have, as well as diabetes and death.

On 24 June, researchers will try to convince FDA officials that if the trial succeeds, they will have proved that a drug can delay ageing. That would set a precedent that ageing is a disorder that can be treated with medicines, and perhaps spur progress and funding for ageing research.

To be clear, I don't think metformin is going to do much for anyone when it comes to aging. The evidence in human and animal studies for metformin to slow aging is all over the map, and pretty weak overall if you ask me. Even if the best outcomes observed in these studies actually happened in all humans, which they won't, this isn't anything to write home about. It's not even as good as exercise or calorie restriction, both of which are free and backed by the gold standard of weight of evidence when it comes to benefits to health. But you might consider this as an example of reaching for the tools immediately to hand in order to make inroads into the regulatory process.

A fair number of research groups are involved in investigations of the fine details of age-related hair loss. As in most research related to aging, scientists are for the most part much more interested in mapping the chain of change and consequence in cellular biochemistry than in seeking out first causes. The outcome here is that later attempts to build therapies based on new knowledge tend to involve prevention or alteration of downstream consequences of cellular and molecular damage rather than trying to repair or prevent that damage. All other things being equal, this is never going to be the best path forward. For one the consequences of a given form of damage will always be more numerous and more complex than the damage itself: much more effort is involved in chasing down all the loose ends. Secondly messing with the consequences of damage does nothing about the damage itself, which remains to continue causing harm.

During the active phase of the hair growth cycle, stem cell activity sustains an actively dividing population of epithelial cells at the base of the hair follicle called matrix cells. As progeny of the matrix cells move upward from the follicle base (or bulb), they differentiate into a hardened hair shaft, which emerges above the skin surface. Fully differentiated hair shafts consist of dead, but mechanically sound and highly cross-linked, keratin-filled cells. After a period of active hair shaft production, follicles activate an involution program, during which a large portion of epithelial cells die, and the remaining stem cells are reduced to a tight cluster underneath the skin surface. These follicles then remain dormant for some time; however, they can undergo activation and restart active hair shaft production.

The growth, regression, and resting phases together constitute the hair growth cycle, and this cycling can be influenced by a variety of local and systemic signaling factors. Consequently defects in hair cycling can arise from changes in the normal signaling milieu due to disease, aging, or injury. Commonly, in humans, scalp hair follicles enter resting phase prematurely, and hairs shafts become shorter and fall out, resulting in visible baldness. Therefore, identifying new signaling regulators of hair follicle regression will provide a better understanding of the hair loss pathogenesis mechanism and will likely identify novel therapeutic targets.

To test the function of miR-22, we generated a genetic tool to induce miR-22 overexpression in mouse hair follicles, and interestingly, found that increasing miR-22 results in hair loss in mice due to the premature regression of actively growing follicles. Surprisingly, our data reveal that the expression of over 50 distinct keratin genes are markedly reduced by miR-22 and that silencing of keratin-mediated hair shaft assembly by miR-22 is a prerequisite for follicle regression. In the future, our findings are likely to benefit human hair loss research efforts. Androgenic alopecia, where premature regression of scalp hair follicles is induced by increasing androgen levels, is the most common hair loss disorder in humans. Our unpublished data show that two binding sites for an androgen receptor are located in the promoter of both human and mouse miR-22. These findings support the hypothesis that miR-22 functions in the pathogenesis of Androgenic Alopecia, warranting future studies of miR-22 inhibitors as potential anti-hair loss drugs.

Link: http://blogs.plos.org/biologue/2015/06/16/understanding-images-micrornas-contribute-to-hair-loss-and-follicle-regression/

A number of studies propose associations between the solar cycle and aging, or for specific age-related conditions. The mechanisms involved are not clear at all, but it is possible to theorize about levels of radiation damage during embryonic development, for example, or the influence of small variations in solar radiation on the operation of metabolism over the long term. Many forms of autoimmune disease are not age-related conditions, but they can be considered forms of damage, so it is interesting to see even speculative data suggesting a correlation with the solar cycle:

Data shows a "highly significant" correlation between periodic solar storms and incidences of rheumatoid arthritis (RA) and giant cell arteritis (GCA), two potentially debilitating autoimmune diseases. The findings by a rare collaboration of physicists and medical researchers suggest a relationship between the solar outbursts and the incidence of these diseases. RA and GCA are autoimmune conditions in which the body mistakenly attacks its own organs and tissues. RA inflames and swells joints and can cause crippling damage if left untreated. In GCA, the autoimmune disease results in inflammation of the wall of arteries, leading to headaches, jaw pain, vision problems and even blindness in severe cases.

Researchers initially spotted data showing that cases of RA and GCA followed close to 10-year cycles. "That got me curious. Only a few things in nature have a periodicity of about 10-11 years and the solar cycle is one of them." When physicists tracked the incidence of RA and GCA cases, the results suggested more than a coincidental connection. The research, which tracked correlations of the diseases with both geomagnetic activity and extreme ultraviolet (EUV) solar radiation, focused on cases recorded in Olmsted County, Minnesota, over more than five decades. The physicists compared the data with indices of EUV radiation for the years 1950 through 2007 and indices of geomagnetic activity from 1966 through 2007. Included were all 207 cases of GCA and all 1,179 cases of RA occurring in Olmsted County during the periods. Correlations proved to be strongest between the diseases and geomagnetic activity.

The findings were consistent with previous studies of the geographic distribution of RA cases in the United States. Such research found a greater incidence of the disease in sections of the country that are more likely to be affected by geomagnetic activity. Although the authors make no claim to a causal explanation for their findings, they identify five characteristics of the disease occurrence that are not obviously explained by any of the currently leading hypotheses. These include the east-west asymmetries of the RA and GCA outbreaks and the periodicities of the incidences in concert with the solar cycle. Among the possible causal pathways the authors consider are reduced production of the hormone melatonin, an anti-inflammatory mediator with immune-enhancing effects, and increased formation of free radicals in susceptible individuals.

Link: http://www.pppl.gov/news/2015/06/researchers-correlate-incidences-rheumatoid-arthritis-and-giant-cell-arteritis-solar

Modern computer-generated imagery has improved by leaps and bounds at the same pace as biotechnology, both driven by the same underlying trend towards ever-increasing and ever-cheaper processing power. This has led to something of a renaissance in the visualization of cellular biology, conveniently occurring at exactly the same time as researchers assemble far more accurate and complete data on the structures and processes involved. Popular science publications have been able to move far beyond static images, and nowadays high-quality video representations of organs, tissues, and cells are commonplace. Bear in mind that there is a still a great deal of interpretation and artistry involved in the creation of such things, however. They are built based on the best of today's knowledge, which is an ever-changing target these days, false colors are generously employed for clarity, and scenes may be greatly simplified so as to remove other elements that in reality exist but are not essential to the point being made. The map is not the territory.

That said, I think you'll find this selection of short videos interesting. They were commissioned by the SENS Research Foundation, and each gives a high level overview of the cellular biology relating to one particular ongoing research program aimed at producing treatments for the causes of degenerative aging.

Reversing Heart Disease

This video, narrated by actor Edward James Olmos, describes the process that causes heart disease and highlights a promising intervention that SENS Research Foundation is funding. The video begins with an explanation of cholesterol particles that can become trapped in blood vessels and the patrolling macrophages that normally remove them. However, the macrophages struggle to process oxidized cholesterol. This problem causes the macrophages to die, and the resulting foam cells form atherosclerotic plaques, which ultimately cause heart attacks and strokes. SRF is funding research into an enzyme that would enable macrophages to degrade these oxidized cholesterol particles, thereby rescuing the macrophages, preventing plaque buildup, and possibly even reversing the atherosclerotic process.

Stopping Cancer at the Starting Line

Narrated by actor Edward James Olmos, this video describes one of the body's critical anti-cancer defences - the telomeres. These caps on the ends of our chromosomes shorten each time a cell divides and, when they become too short, trigger the cell to self-destruct. When a cell grows too rapidly, it and all of its descendants normally suffer this fate. Such growths are sometimes called "pre-cancer". Since our stem cells need to be able to divide without this constraint in order to replace cells lost across the body, they produce the enzyme telomerase to re-extend their telomeres. Unfortunately, a small number of pre-cancerous cells manage to activate their own copies of the telomerase gene, escaping the limit on their growth. SENS Research Foundation is developing therapies to completely block telomere extension in pre-cancerous cells, ensuring the body's existing defences can function as intended.

Preventing Mitochondrial Aging

Actor Edward James Olmos narrates this short introduction to the mitochondria, the tiny organelles that 'burn' oxygen and nutrients to power our cells, before considering how during aging that same process can damage mitochondrial DNA - eventually causing the host cell to go into decline. Mitochondrial mutations are strongly implicated in several age-related conditions including Parkinson's disease and "sarcopenia", the gradual loss of muscle experienced even by active seniors. SENS Research Foundation is developing a therapy to prevent the failure of all such cells by placing backup copies of key mitochondrial genes in the cell's nucleus, where they are much better protected. With such a backup in place, damage to the mitochondrial DNA becomes irrelevant, and the cell can return to normal healthy function.

The small, four decades old cryonics industry provides long-term low temperature storage for the body and brain immediately following death. Vitrification rather than straight freezing preserves tissues. Provided that the fine structure of the brain is preserved, and evidence to date strongly suggests it is, then the self and memory is preserved along with it. At some point the necessary molecular nanotechnologies will exist to revive a cryopreserved individual, repair their tissue damage, and restore them to a new life. The odds of success are unknown in this endeavor, but infinitely better than all of the other options open to those who will age to death prior to the advent of working rejuvenation therapies. It should be a great mark of shame upon our culture today that cryonics remains a small industry, and that most people reject it out of hand. Billions vanish into the grave and oblivion over the decades, where in a better world they could have been saved.

Max More has heard all of the criticisms. More is the president and CEO of Alcor, the largest of the world's cryonics organizations, which counts 1,033 members - those who have committed, legally and financially, to freezing themselves - and 134 "patients" frozen in aluminum casks at its Scottsdale headquarters. As a 5-year-old, More sat awestruck in front of the TV watching the first moon landing, dreaming of different worlds. While pursuing his doctorate in philosophy at Oxford in the 1980s, he fell in with a group of futurists who believed that humanity's best days lie ahead, courtesy of technology. They introduced him to cryonics, and the idea appealed to him immediately. "It's not about the fear of death," he says, "but the enjoyment of life - and wanting more of it."

More comes across as a reasonable man who is acutely aware that most people think his ideas are insane, or repugnant, or both. Like most of the cryonicists I spoke to, he frames his points as appeals to logic, not emotion. His confidence is infectious. Eventually, he says, the emerging field of nanotechnology will allow us to fix pretty much everything that ails us. He adds that the freezing process itself has evolved from the early haphazard model into rigorous protocols aimed at doing as little damage to the patient as possible. "It really will come to seem crazy to do anything else," he says cheerily. "People will look back on these days and say, 'What was wrong with us? We used to stick people into the ground or shove them into ovens!'"

Then and now, cryonics tended to attract a certain type of seeker: numerically minded males, sci-fi fans, and those with a distinctly non-abstract view of the afterlife. Ralph Merkle, a Xerox PARC alumnus, inventor of computer encryption algorithms, and nanotechnology theorist, is representative of the tribe. Merkle, also a Berkeley alum, says there is no bright line between life and death; science has cured dozens of illnesses that meant certain death a century ago. He reasons that it's just a matter of time before death can be delayed indefinitely. "What we refer to as 'death' is just a set of symptoms that have proven resistant to treatment."

Most cryonicists are impatient with talk of the soul. They believe that the traits that make us unique reside in the brain, so the key is to preserve that organ with as much fidelity as possible. (This approach has led to "neuro" cryopreservations, in which just the brain is frozen in expectation of one day placing it on a cloned body. Half of Alcor members choose neuro, which costs $80,000 versus $200,000 for a whole-body suspension.) "You are nothing more than the signals flitting through your brain," says Robin Hanson, an economics professor at George Mason University who was a UC Berkeley health policy fellow and researcher at NASA's Ames facility in Silicon Valley. "And if we can preserve that, we can save you."

Link: http://alumni.berkeley.edu/california-magazine/summer-2015-confronting-future/deep-freeze-what-kind-person-chooses-get

If you look back far enough for a point of comparison, technological progress has produced astounding results. Life expectancy at birth has in fact more or less doubled since ancient times. This is largely a result of reduced infant mortality and control of infectious disease, however, not any direct strategy of effectively tackling age-related disease. Life expectancy at 60 has climbed much more slowly than overall life expectancy, but it is nonetheless increasing at about a year every decade at the moment. This is an incidental increase, a side effect of general improvements in medicine; the clinical community is still not in any meaningful way trying to treat the actual causes of aging, the reasons why we become frail and diseased in old age. That will change shortly, is changing now in the laboratory, and past trends will shift radically to the upside in the decades ahead.

For thousands of years, the average lifespan of a human being was around 40 years. Evolution holds the explanation: it takes about two decades to grow up and be fully ready to reproduce. Then the offspring come along, and it takes another 20 years to get them ready to leave the nest and repeat the cycle.

"Biologically, we are programmed to live for 40 years, and if we had not been able to do so, the human species would have perished." The improvement in life expectancy over the past two centuries comes from the combined effect of a number of factors. "Sewage systems got better and limited the spread of diseases. Drinking water became cleaner. The industrial revolution provided more people with paid jobs and more money to spend on food and shelter. Housing got better. We got vaccination programmes and managed to limit the number of children dying. Deaths from violence also dropped dramatically as societies became better at organizing social order and protection."

"The importance of medical intervention has been generally overrated when it comes to past increases in longevity. To say that the invention of antibiotics is the reason we've expand­ed our life spans dramatically is false. Of course I am not blind to the enormous impact medical care and treatment can have had. There's no doubt that the decrease in cardiac deaths has significantly contributed to our increased longevity, but there's no consensus on the contribution of specific factors. Nonetheless, the development of human lifespan is an unprecedented story of success on a societal level, and we need to stop being pessimistic about people becoming older. We will live longer and better than ever, and we should each make it our mission to make the most of it."

Link: http://www.technologist.eu/80-became-40/

You will recall that last year we raised $150,000 to expand the work of the SENS Research Foundation on the biotechnologies needed to build a first generation of rejuvenation therapies. Aging is caused by cell and tissue damage and SENS research programs aim at the repair of that damage to bring frailty and age-related disease under medical control. Nine generous donors collaborated to provide a matching fund of $100,000, and the community came together to add another $50,000 in response to that challenge. Those funds are already being put to good use by researchers.

Following on from that success Fight Aging! will run another grassroots fundraiser this year in collaboration with the SENS Research Foundation, with the main event beginning in October and running through to the end of the year. Again, all donations will go towards the early stage research needed to assure healthy longevity and an end to age-related disease. Between now and October we have the time to build a bigger and better matching fund than last year.

Accordingly: Fight Aging! is putting forward $25,000 to start this fund.

I challenge those members of this community with the means to match some or all of this amount: step up and let's make a difference together.

But why do this, you might ask? Thousands of dollars is no small matter, for me just as much for you. I have made the call that a smaller bank account today is a fair trade for a better shot at health and longevity tomorrow, but why should you?

Because SENS Research Programs are of Great Importance

The SENS Research Foundation is perhaps the only organization presently focused on rescuing and speeding up all of the research programs necessary to produce human rejuvenation therapies. A few such fields are, thankfully, doing well today: we can all agree, I'm sure, that stem cell research is progressing at a good pace and there is little that we can do to help. There are a good number of other fields of research that are just as vital when it comes to the treatment of aging, however: clearance of cross-links, mitochondrial repair, senescent cell clearance, and more besides. Unlike stem cell medicine, there are few researchers in these lines of research, and they struggle to find funding and make progress. Yet without them even stem cell therapies will be limited in their benefits to health and longevity.

To bring an end to age-related disease all of the forms of damage that cause aging must be addressed, and it is vital that all of these research programs are brought into the mainstream and funded at a large scale. Few people other than the staff and allies of the SENS Research Foundation are working on this problem, and none of those are doing so in an organized way that allows you and I to make charitable donations to fund their work, confident that our money will go to one of the points of greatest impact.

Because Our Donations and Our Advocacy are Working

It takes time for research funding to make an impact, and few human endeavors are as slow to show progress as medical research. It is not unusual to wait five years or more to hear back on the next development in a long-running line of scientific inquiry. But groups like the Methuselah Foundation, the SENS Research Foundation, and their network of supporters have been at this for more than a decade now. The results of work and funding from earlier years are starting to emerge now, in the form of greater public support, in the form of new large initiatives like Calico, and in the form of meaningful progress in some of the laggard but vital lines of research.

This year, for example, saw publication of the first example of partial senescent cell clearance in normal mice, resulting in clear and impressive health benefits. SENS advocates have been calling for more funding for senescent cell clearance for more than a decade, and predicting that it should show significant benefits when realized, and it is a real shot in the arm to see solid progress emerging today. We are winning - let us not forget that. Past efforts are paying off, the wheel is beginning to turn, and this is exactly the time to pour it on and reinforce that success.

Because Our Donations Make an Immediate Difference to the Research Process

Donations that support grants for promising but poorly funded research have an immediate benefit for the labs involved, as they are frequently forced to delay follow-on work and new investigations. There is a large difference between what researchers want to work on and what they can raise funds for from the standard institutional sources. Philanthropy and organizations like the SENS Research Foundation are very necessary to bridge this divide. Noted researchers Michael and Irina Conboy at UC Berkeley had this to say about our 2014 fundraising:

In 2014 our lab hit a gap in funding and was in dire need of money to keep a postdoc for just a few more months, to finish up work on the rejuvenating effects of oxytocin. The SENS Research Foundation came through with the funds and we were able to finish and publish the work in Nature Communications. While maybe not the direct path to immortality, that project indicated an effective drug for muscle and bone regeneration (and probably other tissues as well), that is generally recognized as safe. Now the SENS Research Foundation funds our postdoc working on a mouse-sized blood-fraction exchange device project, and a cellular senescence collaboration. So we truly appreciate SENS and Fight Aging! and the donors; even a little support at the right time can make a huge difference in outcome.

Because We Light the Way for Larger Donations in the Future

Wealthy donors and large-scale philanthropy are always late to the party. These are the most conservative of funding sources, and do not step in until a field has well-established support. They wait for other people to lead the way by forming communities, raising seed funding, and carrying out proof of concept research programs. That means us. If you want to see more million dollar donations to SENS research, the path to that outcome is through the small donations and day to day advocacy of a thousand individuals, through the discussion, persuasion, and growth of a community to support the goals of rejuvenation research.

If you have a vision for the future, if you can see more clearly than most, then it is your role to light the beacon, to point other groups towards the best and most promising research programs, those capable of bringing an end to the pain and suffering that accompanies aging. The more that we succeed in strengthening SENS research, the greater the number of new allies that will join in to reinforce our success. This is how change happens in medical research: every friend persuaded and every dollar donated makes a difference.

Despite the fact that the public is largely indifferent or even hostile to the prospects for extended healthy longevity in the near future, there has been considerable progress in advocacy and awareness for this cause in recent years. It is now the case that more people than ever outside the scientific community are thinking seriously about this topic. Of course many will have important facts wrong, or misunderstand aspects of published research, or disagree with positions such as support for SENS research being the best way forward, or feel that there is little hope for meaningful progress in the next few decades, but all in all a broader public conversation on aging can only be a good thing. The more often that people encounter these ideas, the more supportive they will be towards research and development in this field:

I am very optimistic regarding my kids. In forty years, they are likely to be still healthy and relatively young. So they should probably plan for a very, very long life. At least 150 years, but possibly a lot more. If you believe that my prediction is silly and unlikely to come true, I am willing to grant you that it is highly speculative. However, from what I can see, lots of highly regarded biologists do take seriously the possibility that we could defeat aging in a few decades. So it is not entirely unreasonable. And the more decades I add to my prediction, the more likely it becomes. I would argue that the probably that I am correct grows exponentially with each decade I add. I have a really hard time imagining that we will still grow old 500 years from now. I do not have a lot of faith in biologists, but there are many of them and they have better and better tools.

But here is something interesting: we never imagine a future where people do not grow old. In Star Trek, James T Kirk grew old. Even the fierce vulcans grow old. In Star Wars, people grow old. Moreover, we still grant public employees pension plans based on limited longevities. There is a very serious risk that we are grossly underestimating the life expectancy of 20-year-old employees. I believe that it is because defeating aging is a taboo. Not even science-fiction writers want to consider it. In a sense, it is not surprising that only a few outliers like de Grey and Kurzweil talk about it. Sure, they are probably wrong in many important ways, but they are not wrong in the way that matters: aging can and will be defeated.

Link: http://lemire.me/blog/archives/2015/06/09/aging-software-bug/

It remains the case that most people are instinctively opposed to the idea of treating aging as a medical condition, bringing an end to age-related disease, and lengthening healthy life spans. No doubt our descendants will look upon this as a sort of transitory mania of the times, but it does make life much harder here and now for those aiming to raise funding and make progress towards that better world of the future. We don't need to persuade everyone, but we do need to persuade enough people to ensure the establishment of a scientific community as well funded and active as the present cancer or stem cell research establishments:

"A 20-year-old male today has a better chance of having a living grandmother than a 20-year-old in 1900 had of having a living mother." That's according to Lauren Carstensen, director of Stanford's Center on Longevity, who spoke during a panel on longevity at FORBES' third annual Women's Summit. The panel also included Longevity Fund partner Laura Deming, AARP CEO Jo Ann Jenkins and Robert Wood Johnson Foundation president Risa Lavizzo-Mourey, were varied: How have our lifespans changed in just a few generations? What's happening in longevity research right now? How can we use technology and policy not only to extend the lives we have, but also to make our golden years more, well, golden?

The panel's title, though, "The Longevity Paradox: Is Living Longer Really Better?", posed a question that was never really on the table. "I think the people on this panel will answer with a resounding yes when you consider the alternative," joked moderator Soledad O'Brien. Yet the fact remains that one of the biggest obstacles to improving longevity is convincing people it's worth the effort. Deming, who says she has been interested in longevity research since she was eight years old, gets plenty of skepticism when she tells people she funds it for a living. "People would be like, 'That is the stupidest thing I've ever heard. Why would you want to live longer?'" she said. "It was this visceral reaction to the idea that you could live a longer life."

All of the women on the panel have seen similar reactions to their work. To Lavizzo-Mourey, it's a question of "how we keep people functional their whole life." Carstensen suspects that when it comes to the years that have been added to average life expectancy, we mentally "tacked it on at the end made old age longer and nothing else." It's changing that culture that poses the biggest problem. "I think that our beliefs have not kept up with the way we are aging," explained Jenkins. "We continue to perpetuate these negative stereotypes of aging when we're not living that way every day."

Link: http://www.forbes.com/sites/sarahhedgecock/2015/06/10/why-longevity-isnt-just-a-numbers-game/

There are many theories of aging, a state of affairs that I would say is really due to past lack of resources put towards building means to treat aging in a targeted way, by addressing specific purported root causes. There has been a great deal of investigation of the biochemistry of aging, and will continue to be given its complexity, and all too little bold experimentation in means to extend healthy life spans. This was in large part cultural for the last generation of researchers, a way to reject any association with the fraud and self-deception of the "anti-aging" marketplace, and thus preserve reputations and the ability to raise funding for legitimate studies of aging. At the same time, however, this meant that greater progress towards longevity enhancement might have happened and did not: talk of treating aging became a threat to careers, an unfortunate state of affairs that has only recently abated.

Ways to increase longevity in laboratory species are the tools by which theories of aging can be winnowed and validated. Unfortunately all of the present means of slowing aging are far too general in their operation to serve as good tools in this sense. Take calorie restriction and its alleged mimetic drugs, for example: these approaches change near every measure of metabolism, to the point at which it remains an enormous puzzle to figure out how and why they act to slow aging. What is needed is a new generation of much more targeted therapies, things like clearance of senescent cells, or clearance of cross-links, or other proposed SENS biotechnologies based on the repair of one single type of tissue damage thought to cause aging. Build the treatment, run the experiment, and a lot will be learned from whether or not it does extend healthy life. If great progress is made by repairing forms of damage thought to cause aging, that tells us that theories painting aging as a process of damage accumulation are more robust and defensible. The types of damage being repaired and the results obtained will help separate out which theories on various types of damage are more robust and defensible.

Ultimately theories of aging matter today because they are used to steer investment in research. This will continue to be important until one group of theories wins out by weight of evidence obtained through extending life in laboratory animals. At the moment the division of greatest importance is between programmed aging theories and stochastic damage theories. Programmed aging theories would have us think that aging is the direct consequence of a set of evolved changes in (say) gene expression and protein levels and cellular operation, and these changes causes damage, dysfunction, and death. The right thing to do if this is true is to work to alter the operation of metabolism, change the gene expression levels, manipulate specific protein levels, to bring them back to a more youthful pattern. In contrast stochastic damage theories of aging tell us that aging is caused by what is effectively biochemical wear and tear, and our bodily systems react to the presence of that damage with altered gene expression and protein levels and cellular operation - but it is the damage that is the root cause of disease and dysfunction. The way forward if this is the case is to repair the damage.

Personally, based on my view of evidence to date, I'm in the latter camp: aging is stochastic damage accumulation. Repairing that damage if following the SENS proposals is very cost-effective, and producing full demonstrations of the various treatments in mice is a $1-2 billion, 10-20 year project at full scale funding. That's less than the cost of developing a single drug candidate in the Big Pharma world these days. Programmed aging on the other hand would direct us into a massive, unending project of trying to fully understand and safely alter swathes of our metabolism. That is a vast project. To give some idea of the scale, about a billion dollars has been swallowed up on research of sirtuins in aging over the past decade or so - just a couple of genes out of thousands worth looking at, and nowhere near a full understanding of their role yet, and no meaningful treatments or ways to alter metabolism resulted from all of that work. So from my perspective, I see programmed aging theories as the road into an endless swamp, a course that might be averted at a low cost by making enough progress on SENS rejuvenation treatments in the laboratory to demonstrate their worth in extending healthy life spans, and thereby showing that aging is mostly likely a process of stochastic damage.

Here is a better than average popular science article that covers many of the aspects of this debate over theories of aging, using a recent paper on programmed aging as a springboard. You should read the whole thing, given that the author took the time to gather opinions from various researchers with different takes on aging, who think that this particular line of research is flawed, and goes on to examine the point I make above, which is that all this theorizing is far from idle and unimportant. It in fact determines the prospects for the near future development of effective means of treatment for degenerative aging, with both sides believing that their road is the more effective one, but only one of them being right:

Are Limited Lifespans An Evolutionary Adaptation?

That aging is a deliberate function of our genetics remains a controversial idea, but it's an idea that's steadily acquiring adherents. One of these adherents is NECSI president Yaneer Bar-Yam, who contends that popular approaches to the aging problem fail to address a very important constraint, namely the ways lifespans are genetically controlled according to the resource limitations of a given environment. Without genetically programmed aging, he argues, animals wouldn't be able to leave sufficient resources for their offspring. And this holds true for all animals, whether they be rabbits, dolphins, or humans.

Bar-Yam and his team reached this conclusion by developing a simple model that analyzed how the lifespans of simulated organisms would change and evolve over time under spatially constrained conditions. Fascinatingly, group selection -- the idea that natural selection acts at the group level -- was never a consideration in the model. Yet the simulations consistently showed that a built-in life expectancy emerged among the simulated organisms to preserve the integrity of their species over time. This is surprising because a pro-group result was produced via an individualized selectional process.

"Beyond a certain point of living longer, you over-exploit local resources and leave reduced resources for your offspring that inhabit the same area," Bar-Yam said. "And because of that, it turns out that it's better to have a specific lifespan than a lifespan of arbitrary length. So, when it comes to the evolution of lifespans, the longest possible lifespans are not selected for."

Programed Death is Favored by Natural Selection in Spatial Systems

Standard evolutionary theories of aging and mortality, implicitly based on mean-field assumptions, hold that programed mortality is untenable, as it opposes direct individual benefit. We show that in spatial models with local reproduction, programed deaths instead robustly result in long-term benefit to a lineage, by reducing local environmental resource depletion via spatiotemporal patterns causing feedback over many generations. Results are robust to model variations, implying that direct selection for shorter life span may be quite widespread in nature.

Based on what we know of the mechanisms by which stem cell therapies produce benefits, it shouldn't be surprising to find that there are signals that can be provided to tissues that enhance the pace of regeneration. We are still in the comparatively early days of the identification and understanding of those signals, but some efforts are further ahead than others:

"We have developed a drug that acts like a vitamin for tissue stem cells, stimulating their ability to repair tissues more quickly. The drug heals damage in multiple tissues, which suggests to us that it may have applications in treating many diseases." The institutions collaborating on this work next hope to develop the drug - now known as SW033291 - for use in human patients. Because of the areas of initial success, they first would focus on individuals who are receiving bone marrow transplants, individuals with ulcerative colitis, and individuals having liver surgery. The goal for each is the same: to increase dramatically the chances of a more rapid and successful recovery.

The key to the drug's potential involves a molecule the body produces that is known as prostaglandin E2, or PGE2. It is well established that PGE2 supports proliferation of many types of tissue stem cells. Researchers had demonstrated that a gene product found in all humans, 15-hydroxyprostaglandin dehydrogenase (15-PGDH), degrades and reduces the amount of PGE2 in the body. The researchers hypothesized that inhibiting 15-PGDH would increase PGE2 in tissues. In so doing, it would promote and speed tissue healing. When experiments on mice genetically engineered to lack 15-PGDH proved them correct, the pair began searching for a way to inactivate 15-PGDH on a short-term basis.

The preliminary work began in test tubes. Researchers developed a test where cells glowed when 15-PGDH levels changed and then combed through a library of 230,000 different chemicals. Ultimately they identified one chemical that they found inactivated 15-PGDH. A series of experiments showed that SW033291 could inactivate 15-PGDH in a test tube and inside a cell, and, most importantly, when injected into animal models. When investigators treated diseased mice, the SW033291 drug again accelerated tissue recovery. In a mouse model of ulcerative colitis SW033291 healed virtually all the ulcers in the animals' colons and prevented colitis symptoms. In mice where two-thirds of their livers had been removed surgically, SW033291 accelerated regrowth of new liver nearly twice as fast as normally happens without medication.

The investigators believe the pathway by which SW033291 speeds tissue regeneration is likely to work as well for treating diseases of many other tissues of the body. However, the next stages of the research will concentrate on diseases where SW033291 already shows promise to provide dramatic improvement.

Link: http://www.sciencedaily.com/releases/2015/06/150611144438.htm

Many types of cancer have been shown to be driven by the existence of a small population of cancer stem cells. This is what leads to the recurrence of cancer following apparently successful treatments to remove tumors, for example: therapies targeting cells making up the bulk of the cancer may not be effective in clearing out the cancer stem cells. On the other hand for cancer types wherein cancer stem cells can be clearly identified, there is an opportunity to strike at the root by attacking these cells:

Some brain tumors are notoriously difficult to treat. Whether surgically removed, zapped by radiation or infiltrated by chemotherapy drugs, they find a way to return. The ability of many brain tumors to regenerate can be traced to cancer stem cells that evade treatment and spur the growth of new tumor cells. But some brain tumor stem cells may have an Achilles' heel, scientists have found. The cancer stem cells' remarkable abilities have to be maintained, and researchers have identified a key player in that maintenance process. When the process is disrupted, they found, so is the spread of cancer.

Scientists have realized in recent years that some cancer cells in glioblastomas and other tumors are more resistant to treatment than others. Those same, more defiant cells also are much better at re-establishing cancer after treatment. "These tumor stem cells are really the kingpins of cancers - the cells that direct and drive much of the harm done by tumors." Researchers identified a protein, known as SOX2, that is active in brain tumor stem cells and in healthy stem cells in other parts of the body. The researchers found that the tumor stem cells' ability to make SOX2 could be turned up or down via another protein, CDC20. Increasing SOX2 by boosting levels of CDC20 also increased a tumor's ability to grow once transplanted into mice. Eliminating CDC20, meanwhile, left tumor stem cells unable to make SOX2, reducing the tumor stem cells' ability to form tumors. "The rate of growth in some tumors lacking CDC20 dropped by 95 percent compared with tumors with more typical levels of CDC20."

When the scientists analyzed human tumor samples, they found that a subset of patients with glioblastomas that had the highest CDC20 levels also had the shortest periods of survival after diagnosis. The researchers are exploring methods to block CDC20 in brain tumors, including RNA interference, an approach in which the production of specific proteins is blocked. That general approach is in clinical trials as a therapy for other cancers, viral infections and other illnesses.

Link: http://news.wustl.edu/news/Pages/Scientists-find-way-to-disrupt-brain-tumor-stem-cells.aspx

I think that it's no great surprise that many people see the US Food and Drug Administration (FDA) and its ilk in other countries as a gargantuan ball and chain dragging down progress. Yet few of these take the fully libertarian position that the FDA should be removed and the demand for safety assurance provided by a marketplace of review and certification organizations. Instead most such advocates argue for a return to the smaller FDA and much less onerous review process that existed in the past. They note that FDA administrators have perverse incentives to block as much progress as possible, and that they have followed these incentives across recent decades to greatly increase the amount of time and money required to obtain approval for new medical technologies.

FDA bureaucrats are blamed for letting through any technology that causes even a tiny amount of harm, while receive no personal benefit for approving something that is safe, and receive no personal penalty from slowing down or blocking perfectly safe technologies from approval. There is no such thing as a perfectly safe medical technology: it is always a cost-benefit analysis for even the most beneficial technologies developed to date, and the mass media tends to inflate every harm done without taking account of the benefits. Everything else proceeds from that, and the consequence is that ever fewer new medicines are approved, there is less funding for development, and many lines of research are abandoned because the cost of regulatory compliance has become too great.

The situation is actually much worse for aging research, as the FDA doesn't recognize aging as a medical condition that can be treated; there is no path through the regulatory process to obtain approval for a treatment for aging, and that fact echoes back down the funding chain to make it much harder to raise money for projects such as SENS rejuvenation research. Potential technologies for the treatment of aging would at best have to be shoved through the approval process as narrow therapies for specific age-related conditions, which may well have a distorting effect on development. Some people are less concerned by this than I am, but changing what the FDA considers to be a disease is a long process of lobbying. This costs money and time that would be better spent on research. Just look at the years of attempts to get FDA bureaucrats to consider sarcopenia a medical condition: that is still going on, with no end in sight.

A number of political advocacy organizations have been founded in past years with the intent of trying to cut down the influence, size, and costs imposed on medical development by the FDA. In most cases they are focused on the time cost rather than the financial cost, possibly because that is an easier rallying cry. These organizations are one of the expressions of frustration with a regulatory process run wild, that serves only itself, and is causing far more harm than good. People don't see the invisible cost of medicines not development and technologies delayed for years. Faster Cures is one of the earlier organizations, now with interests in many approaches to speeding up research, including the venture philanthropy ideals that have been expressed by Peter Thiel for some years. But today I'll point out another lobbying organization created by those frustrated by the FDA and its baleful influence on the pace of medical development:

Tomorrow's Cures Today Foundation

Millions of Americans are in pain and suffer needlessly. Thousands of Americans die unnecessarily as they wait for promising new drugs to make their way through an unnecessarily long approval process. What we see is death and suffering that is attributed to approving drugs with dangerous side effects; but what we don't see is the death and suffering due to regulatory delay. Those victims are invisible.

The Pathway to Faster Cures

Rob Donahue used to ride horses. He was a modern-day cowboy until he was stricken with amyotrophic lateral sclerosis (ALS). Now his muscles are weak. He can't ride horses anymore. And his condition is worsening quickly. ALS will degenerate Donahue's neurons and nervous system, and he will probably die in less than five years. Another ALS sufferer, Nick Grillo, is trying to change all that. He's put together a petition on Change.org to urge the FDA to fast-track approval of a new drug, GM-604, that would help people like Donahue and others like him. "People can't wait five, ten, 15 years for the clinical trial process," said Grillo. "Things need to happen much quicker." But ALS is just one illness, and GM-604 is just one medicine. There are thousands of Americans suffering -- many with terminal illnesses -- while waiting on the FDA approval process.

A paradigm change is essential because FDA culture has led to a situation where it costs an average of $1.5 billion and 12 or more years of clinical testing to bring a new drug to market. Medical innovation cannot thrive when only very large firms can afford to research and develop new drugs. Another problem is that the FDA's first goal is not to maximize innovation, but to minimize the chances that an FDA-approved drug leads to unanticipated adverse side effects and negative publicity. In particular, the FDA's efficacy testing requirements have resulted in an ever-increasing load of money and time on drug developers. We can't count on FDA bureaucrats to fix the broken system they created. Even Congress, whose cottage industry is to regulate, admits that the current FDA system is a roadblock to fast-paced innovation.

The missing seat at the table is for someone who represents freedom -- that is, the right of patients, advised by their doctors, to make informed decisions as to the use of not-yet-FDA-approved drugs. Absent from the congressional hearings over health care, however, has been a freedom agenda, specifically one designed to eliminate the FDA's monopoly on access to new drugs. We hear very little about those who suffer and die because they were not able to access drugs stuck in the FDA's testing pipeline, or about drugs that were never brought to market because FDA procedures made the development costs too high. There is an invisible graveyard filled with people who have died because of drug lag and drug loss. The FDA's deadly over-caution is why venture capitalists shy away from investing in biopharmaceutical startup firms. Venture capitalists are willing to take big risks on ideas that may fail. But failure due to regulatory risk is just too big a hurdle to overcome. Capital providers have other opportunities, even if those opportunities don't involve cures for disease.

High costs and slow innovation are the hallmark of a monopoly. And, as medical science continues its rapid pace of innovation, the cost of lost opportunities for better health will increase even faster. The solution is to introduce consumer choice and competition. FDA proponents would bolster the fear that "unsafe" drugs could flood the marketplace. But the FDA cannot define what is "safe." Only patients with their unique health conditions, treatment profiles, and preferences for taking risk can define what is safe for them.

There is no necessary reason that an artificial organ has to look like or be structured in the same way as the evolved organ it is intended to replace or augment. There are good reasons to try different approaches, largely cost-effectiveness in research and development at the present time, such as by narrowing down work to replicating specific functions rather than trying to encompass everything that a natural organ accomplishes. Further down the line researchers will be aiming to produce improvements on the capabilities of natural biology, however.

This is all especially true of the immune system: so long as it is possible to produce the desired end result of the correct balance of signals in tissues and competent immune cells roaming the body to defend it from pathogens and malfunctioning cells, then it doesn't really matter what the controlling organs look like or where they are in the body. Since immune function can readily be divided up into discrete but interacting portions, there is considerable leeway for researchers to build and augment a bioartificial immune system piece by piece in the years ahead. This sort of work is promising when considering the importance of age-related declines in immune function in frailty and disease. Any means of safely recreating youthful immune system activity in the old is likely to bring considerable benefits.

Beyond that, why shouldn't we all have immune systems that support twice or ten times as many active immune cells, or which are pre-immunized against every known disease, or have other capabilities far beyond the evolved system we're presently stuck with? These and other options are very plausible for the near future:

Engineers have created a functional, synthetic immune organ that produces antibodies and can be controlled in the lab, completely separate from a living organism. The engineered organ has implications for everything from rapid production of immune therapies to new frontiers in cancer or infectious disease research. The synthetic organ is bio-inspired by secondary immune organs like the lymph node or spleen. It is made from gelatin-based biomaterials reinforced with nanoparticles and seeded with cells, and it mimics the anatomical microenvironment of lymphoid tissue. Like a real organ, the organoid converts B cells - which make antibodies that respond to infectious invaders - into germinal centers, which are clusters of B cells that activate, mature and mutate their antibody genes when the body is under attack. Germinal centers are a sign of infection and are not present in healthy immune organs.

The engineers have demonstrated how they can control this immune response in the organ and tune how quickly the B cells proliferate, get activated and change their antibody types. According to their paper, their 3-D organ outperforms existing 2-D cultures and can produce activated B cells up to 100 times faster. The organ could lead to increased understanding of B cell functions, an area of study that typically relies on animal models to observe how the cells develop and mature. "You can use our system to force the production of immunotherapeutics at much faster rates. In the long run, we anticipate that the ability to drive immune reaction ex vivo at controllable rates grants us the ability to reproduce immunological events with tunable parameters for better mechanistic understanding of B cell development and generation of B cell tumors, as well as screening and translation of new classes of drugs."

Link: http://www.news.cornell.edu/stories/2015/06/engineers-synthetic-immune-organ-produces-antibodies

There are hundreds of discrete lines of research within the broad field of regenerative medicine; projects that can be divided up by tissue type, organ, and approach to building therapies. The open access paper quoted below can be taken as an example of the complexity of ongoing work on just one age-related disease in one organ. The large scale funding devoted to stem cell medicine starts to look less large when you multiply the amount of work required to make progress here by all of the varied organs and tissues in the body:

Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible disease of the lung that has no lasting option for therapy other than transplantation. It is characterized by replacement of the normal lung tissue by fibrotic scarring, honeycombing, and increased levels of myofibroblasts. The underlying causes of IPF are still largely unknown, but this disease preferentially affects adults older than 60 years. The focus of the current review is the possible use of stem cell therapy, specifically mesenchymal stem cells (MSCs), a multipotent stromal cell population, which have demonstrated promising data in multiple animal models of pulmonary fibrosis (PF). The most studied source of MSCs is the bone marrow, although they can be found also in the adipose tissue and umbilical cord, as well as in the placenta. MSCs have immunomodulatory and tissue-protective properties that allow them to manipulate the local environment of the injured tissue, ameliorating the inflammation and promoting repair.

Animal models have shown the success of MSC therapy in mitigating the fibrotic effects of bleomycin-induced PF. However, bleomycin, the most commonly used model for PF, is imperfect in mimicking IPF as it presents in humans, as the duration of the illness is not parallel or reversible, and honeycombing is not produced. Furthermore, the time of MSC dosage has proven to be critical in determining whether the cells will ultimately have a positive or negative effect on disease progression, since it has been demonstrated that the maximal beneficial effect of MSCs occurs during the early inflammatory phase of the disease and that there is no or negative effect during the late fibrotic phase. Therefore, all the current clinical trials of MSCs and IPF, though promising, should proceed with caution as we move toward true stem cell therapy for this disease.

Because IPF primarily affects older patients, the issue of aging is intrinsically linked to many aspects of the disease, including the age of the stem cells. In our opinion, an important weakness in the study of IPF is the lack of knowledge of lung aging, which is a main risk factor in IPF. Until now, most of the mouse models have included young animals (less than 3 months), and it is clear that in humans IPF is a pathology of the elderly, and as the association between aging, IPF, and stem cells is well developed, this variable must be taken into account in evaluating preclinical results and in translation to human applications.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4403512/

Irina Conboy is on the SENS Research Foundation's advisory board and is one of the more frequently noted scientists presently working on heterochronic parabiosis and related research. These scientific programs aim at identifying age-related changes in important signal proteins circulating in the bloodstream, with parabiosis being where it all starts: link the circulatory systems of an old and a young animal and observe benefits to measures of health in the elder of the two. This happens because old tissues are exposed to a young blood environment. Once specific proteins in the blood are identified as being of interest, then researchers move on to attempts to alter amounts of these proteins in circulation in old animals. They are in search of the basis for therapies that might make cells and tissues in an old individual behave as if they were younger, despite the damage they have suffered.

The main thrust of this research could probably be considered a branch of stem cell medicine. The signals that differ between young and old tissue appear to be involved in regulating the activity of stem cell populations, and thus the degree to which tissues are maintained, kept supplied with fresh new cells. It is well known that stem cell activity declines with age. Much of the present panoply of stem cell therapies consists of what are, when it comes down to it, ways to bolster regeneration and tissue maintenance in old people. Stem cells transplanted into patients appear to achieve at least some of their beneficial effects by altering the balance of signal proteins in their environment. So why not a future in which the cells are done away with and the therapy consists of directly manipulating protein levels? The only thing needed for that to come to pass is a much better understanding of the signals themselves and how they control cell behavior.

The caveat for all of this is that as an approach it really doesn't address the underlying causes of aging at all. It addresses a consequence of cellular damage without repairing the damage itself. Revving up the activity of a damaged engine obviously bears risks. The greatest risk from a theory point of view is cancer: that damaged cells are doing more has an obvious consequence. In practice, more has been achieved in the field of stem cell medicine and with less cancer as the outcome that was feared at the outset. There may be a fair degree of room in our evolved biology for more regeneration in a damaged system, who knows. Equally these bounds and balances may be very different for short and long-lived species, and so it is an open question as to the degree to which we can trust results in laboratory mice today, even following on from consistency in past results in laboratory mice now translated into human stem cell therapies.

Still, we need stem cell medicine for the old. Stem cell populations will need restoration and repair regardless of success in the rest of the rejuvenation toolkit, as there will be old people awaiting treatment when these therapies are introduced. It is another open question as to whether sufficiently good prevention of other forms of damage will mean that stem cell populations never decline in an individual who has undergone period use of repair therapies since childhood, but that is hardly the most pressing issue in front of us. The first and initial goal of building treatments for aging is to save the people who are old when those treatments arrive.

Engineering the End of Aging

For over a decade, Conboy and her colleagues at UC Berkeley have been searching for ways to slow down or even reverse aging. Their latest discovery - a small-molecule drug that restored brain and muscle tissues to youthful levels in old mice through stem cells - signalled that the prospect of anti-aging therapy for humans may be on the horizon. Published this May, the discovery has been called "fountain of youth" or the "secret to eternal youth" by the media. Comfortably clad in an oversized hoodie, Conboy burst the bubble in her high-pitch, Eastern European accent: Sorry, the drug won't keep us young forever, and we will all eventually die. But what her research hopes to accomplish, Conboy said, is a painless, cost-effective way to live when we are old.

Aging-related diseases like adult-onset diabetes, cancer, Alzheimer's, and Parkinson's disease kill millions every year while draining the economy of billions of dollars on health care costs, and a treatment that keeps people healthier in old age would cut the costs significantly down. A drug that tackles these diseases at its root would also give people more agency how they choose to live late in their lives. "Aging is a synonym with diseases," Conboy said. "When we are young, we don't have these diseases. But when we are old, it doesn't matter what background or gender or culture, we all have them. If we can better understand the aging process, then we don't need to have different hospitals, departments, and institutes that deal with each disease."

The drug, known as Alk5 kinase inhibitor, target a growth factor called TGF-beta1 pathway which, at old age, overproduce itself and inhibits other pathways to stimulate stem cells. As our body breaks down over time, stem cells - which are responsible for repairing the body and live huddled together in pockets called niches - are prevented by TGF-beta1 from doing its job. As the body ages, however, the TGF-beta1 begins to overexpress itself and become a deterrent for yet unknown reasons. What the Alk5 kinase inhibitor sought to do was not rid the body of the pathway but rather regulate it by attaching itself to the pathway and dulling its signal asking for more expression. Now with the TGF-beta1 down to youthful levels, stem cells are able to freely repair the body.

"I look at it as more promising than anything," said Hanadie Yousef, the lead author of the Oncotarget study and currently a postdoctoral scholar at Stanford University. "When I was starting graduate school five years ago, there was absolutely nothing known about how aging actually happened. The field is growing so rapidly that I would bet within the next decade we'll see effective anti-aging therapeutic methods." With the probability of anti-aging therapy on the horizon, death may take a different shape in the future. Death, as Conboy's team hoped to accomplish, would no longer come with pain or suffering at some hospital with wires and machines keeping the body alive. Instead, death will come by more natural causes such as cardiac arrest or a stroke - a relatively quick way to die than fighting years against cancer or similar diseases. "I hope we'll just die in our sleep with no cancer or disease eating up our organs," Yousef said. "The goals of my colleagues and I are not to live forever. Instead of becoming old and becoming a burden on society, we can age ourselves more with integrity."

Persuading researchers to work on treating aging at all has been the major battle of the past fifteen years. We've come a long way when postdocs can now talk in public about treating aging without fearing for their future careers. From here we can build, grow the number of researchers who are willing to aim higher - at rejuvenation, radical life extension, and a complete end to aging. No illness, no loss of vigor or health, and consequently no age-related deaths. That is the future we'd like to see more people working towards.

Cellular quality control mechanisms and their failure modes are important in aging and many diseases. A large number of distinct mechanisms are involved in keeping cell structures in good condition, clearing damaged or unwanted proteins, and other related tasks. Many of these mechanisms are exceedingly complex and far from fully cataloged or understood. It is expected in the research community that therapies will emerge in the near future based on enhancing quality control processes, but while new discoveries are made on a regular basis, I can't say there has been much material progress towards actual treatments over the decade I've been watching the field.

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is a debilitating neurodegenerative disorder that leads to paralysis and death due to the loss of motor neurons in the brain and spinal cord. A primary feature of ALS is an accumulation of the protein TDP43, too much of which is toxic to cells. In the current study, the researchers identified another protein, hUPF1, that keeps TDP43 in check, thereby preventing cell death. "TDP43 is a 'Goldilocks' protein: too much, or too little, can cause cellular damage. Over 90% of ALS cases exhibit TDP43-based pathology, so developing a treatment that keeps protein levels just right is imperative."

Previous investigations had identified hUPF1 as a potential therapeutic target for ALS, but it was unclear how this protein prevented cell death. In the current study, the scientists tested hUPF1's ability to protect against neurodegeneration using a cellular model of ALS. They discovered that genetically increasing levels of hUPF1 extended neuron survival by 50-60%. Digging deeper, the researchers revealed that hUPF1 acts through a cellular surveillance system called nonsense mediated decay, or NMD, to keep TDP43 levels stable and enhance neuronal survival.

This protective mechanism (NMD) monitors messenger RNA (mRNA). If a piece of mRNA is found to be defective, it is destroyed so that it cannot go on to produce dysfunctional proteins that can harm the cell. It now appears that NMD also helps control the levels of proteins, like TDP43, that bind to RNA and regulate splicing. Since hUPF1 is a master regulator of NMD, altering it has a trickle-down effect on TDP43 and other related proteins. "Cells have developed a really elegant way to maintain homeostasis and protect themselves from faulty proteins. This is the first time we've been able to link this natural monitoring system to neurodegenerative disease. Leveraging this system could be a strategic therapeutic target for diseases like ALS and frontotemporal dementia."

Link: http://gladstoneinstitutes.org/pressrelease/2015-06-08/scientists-identify-new-drug-target-to-treat-als

Advanced glycation end-products (AGEs) of various forms are present in the diet, but also generated by our biochemistry as a form of metabolic waste. Some are short-lived and easily cleared by the body, but others are very persistent and form long-lasting cross-links that degrade tissue structure. Their growing presence is one of the contributing causes of degenerative aging, causing a range of effects such as inflammation, stiffening of blood vessels, loss of elasticity in skin, and loss of cartilage and bone strength.

Surprisingly, given how well this cause of aging is understood, there is comparatively little work on the development of therapies to clear the most prevalent AGEs, such as glucosepane in human tissues. Spurring progress in this field is one of the goals of the SENS Research Foundation, and the staff there coordinate early-stage research in a few laboratories, aiming to build the fundamental tools and methodologies needed to encourage a broader participation. The research linked below is one of many examples to demonstrate why we need AGE clearance as a part of any near-future rejuvenation toolkit, here focusing on the role of AGEs in encouraging cellular senescence and fibrosis:

The current study was carried out to evaluate the effect of advanced glycation end-products (AGE) on cardiac aging and to explore its underlying mechanisms. Neonatal rat cardiac fibroblasts were cultured and divided into four groups: control; AGE; AGE + receptor for AGE antibody and AGE + SB431542 (transforming growth factor-β [TGF-β]/Smad signaling pathway inhibitor, 10 μmol/L) group. After being cultured for 48 h, the cells were harvested and the senescence-associated beta-galactosidase expression was analyzed. Then the level of p16, TGF-β, Smad/p-smad and matrix metalloproteinase-2 was evaluated by western blot.

Significantly increased senescence-associated beta-galactosidase activity as well as p16 level was observed in the AGE group. Furthermore, AGE also significantly increased the TGF-β1, p-smad2/3 and metalloproteinases-2 expression in cardiac fibroblasts. Meanwhile, either pretreatment with receptor for AGE antibody or SB431542 significantly inhibited the upregulated cardiac senescence (beta-galactosidase activity and P16) and fibrosis-associated (TGF-β1, p-smad2/3 and metalloproteinases-2) markers induced by AGE. Taken together, all these results suggested that AGE are an important factor for cardiac aging and fibrosis, whereas the receptor for AGE and TGF-β/Smad signaling pathway might be involved in the AGE-induced cardiac aging process.

Link: http://dx.doi.org/10.1111/ggi.12499

A slowly growing group of people are setting forth to publish web sites that aim at similar goals to those of Fight Aging!: regular updates on aging research, advocacy for specific research programs, such as those of the SENS Research Foundation, and original opinion pieces. LifeMAG, the Longevity Reporter, and the Healthspan Campaign are a few of the comparatively recent additions, ranging from amateur to professional and single author to organizational publication. As the field of longevity science grows I expect its associated journalism to grow also, at one end from funded interests putting forward their positions and gathering public support, and at the other from ever more motivated individuals deciding that they cannot possibly remain silent in their support for bringing an end to aging.

Of course there are a very wide range of opinions regarding exactly what research we should be supporting in order to make the best possible progress. Just look at the SENS proposals versus the Hallmarks of Aging proposals, and then the Seven Pillars of Aging proposals from the Trans-NIH Geroscience Interest Group. That's just within some of the fairly well-trafficked portions of the aging research community. Then compare the Fight Aging! support for SENS rejuvenation research based on repair of cell and tissue damage to attain radical life extension versus the advocacy of sites like AgingSciences, which is very focused on near term pharmaceutical strategies to make very slight differences to aging.

Today I thought that I'd point out another new single author effort that is closer to the Fight Aging! position on advocacy and research, a site called Rejuvenaction. It always pleases me to see yet another person motivated to step up and speak out on this topic. Eventually there will be many more voices than is presently the case, no-one will miss mine when I finally sit back down, and that is exactly as it should be, a sign that we are making meaningful progress towards the goal of ending frailty and disease in aging:

Rejuvenaction

Imagine a world where your well-being doesn't depend on your age - a world where your health as a 90-year-old is indistinguishable from your health as a 25-year-old. In this world, once you're an adult you can be whatever you wish whenever you wish. No need to worry about when is the "right time" to have a family or a career, or to leave everything behind and explore yourself. This is not a world where you need to worry about your limited lifespan or about the fact that the more you approach its end, the less able you will be to even just take care of yourself.

This is a world where biological ageing has been cured.

What is biological ageing?

No offense, but you probably don't know what biological ageing actually is; I didn't either, until not too long ago. And maybe just like me, you might never have given much thought about the matter before, or you may be one of those who think that we age because the body "wears out" somehow, or maybe that it's a genetic thing. It isn't any of these things, really. In order to properly understand the matter, we can make use of an example.

Imagine a clean, tidy bedroom. Books are on the shelves, the bed is made, the floor is clean and washed, everything smells nicely and is exactly where it is supposed to be. You can't really expect the room to stay like that forever if you use it, and it will undergo a certain degree of untidiness and dirt even if you don't use it. One day you will take a few books to read off the shelves, and put only two or three back because something distracted you and you left the rest hanging around on the desk. You've been busy and you didn't have time to dust the floor lately. You spilled a drink on the desk and you didn't clean it as thoroughly as you thought you had. And you will have no trouble believing, if your desk is anything like mine, that papers and pens and whatnot tend to accumulate on top of it, without you really knowing how you managed to go from a clear and usable desktop to a complete chaos where you can hardly find anything.

You get the hang of it: there comes a point when the room becomes gradually unusable. Using the room for what it was (more or less) designed has led to causing "damage" to the room itself. The room didn't "wear out" on its own, nor was this programmed. It's a side-effect of using the room in the first place. And you've got to do something about it, if you want to be able to use it again. Of course you might try to prevent havoc from wreaking, by being more tidy, trying to put things back in place as soon as you've done using them, perhaps not to drink anything in the bedroom, and so on; this preventative approach can work really well for some people, but in general, we all know there will come a time when a thorough clean-up of the room is called for, and it will come more than once. If we do it regularly and often enough, we can expect the room to reach only a certain amount of untidiness that still allows to use it comfortably: if we perform regular maintenance to fix up "damage" that has accumulated in the room over time, and we do it before the room becomes a complete mess, we can prevent it from ever reaching a threshold after which is unusable.

Our bodies aren't rooms; however, it's no matter of controversy that the human body is just a machine - a very complex one, with an astronomical amount of tiny moving parts, but still a machine. And just like any human-made machine, the human body does damage to itself, as a side-effect of its normal operations. These are carried out by our metabolism, the incredibly complex set of processes that keep us alive.

Advocacy

During these past few years in which I've been interested in negligible senescence, I've faced many objections to the possibility of human rejuvenation. I must say that the vast majority of people opposing it seemed to be acting out of a gut instinct: a feeling inside them that questioning the inevitability of ageing is somehow a threat to their own mental peace. This is probably due to the fact that all humans need to come to terms with what they consider inevitable, namely ageing and death, and once they've done it they don't really want to go through the trouble of re-examining the case, particularly for the sake of something that still feels like science fiction. Also, I suspect that people tend to repeat what is considered conventional wisdom rather acritically, probably assuming that if nearly everyone says it, it must be true; in addition, it seems that people feel they're being wise and experienced in life by accepting ageing and death as they are.

Memory is not a straightforward function of the brain. There are many different aspects to storing and recalling memories of various types, and all decline in different ways with advancing age, a reflection of the influence of damage on quite different structures and mechanisms in brain tissue.

Researchers conclude that the memory of older adults is not as deficient as has been thought until now. Elderly people remember fewer specific details than younger people and, in general, both groups retain concrete information about events experienced better than abstract information. The main difference is to be found in the capacity to remember more distant facts: youngsters remember them better. "The highly widespread belief that memory deteriorates as one approaches old age is not completely true. Various pieces of neuro-psychological research and other studies show that cognitive loss starts at the age of 20 but that we hardly notice it because we have sufficient capacity to handle the needs of everyday life.This loss is more perceptible between 45 and 49 and, in general, after the age of 75, approximately."

The deterioration does not tend to be either uniform or general: It takes place in certain memory types more than in others. In old age, deterioration appears in episodic memory but not in semantic memory. This type of memory (semantic) and procedural memory are maintained (in some cases they even improve) whereas episodic memory in which detailed memories are retained is reduced. Procedural memory is the one to do with 'skills', the one we need to 'do things' (to drive, for example). In general, it is maintained during old age. Semantic memory, on the other hand, is related to language, to the meaning of concepts and to repetitive facts. Finally, episodic memory preserves the facts (episodes) of the past in our personal life, and it is more specific in terms of time and space.

An individual, both an adult and a young person, has the capacity to remember information relating to facts in his/her private life in detail. The main difference between older adults and younger adults is as follows: the younger ones remember more episodic details. This research shows, however, that this difference only occurred in older recollections, such as of the previous year. No appreciable differences were found in the recollections of the previous month and the previous week, and the older adults were just as capable as the younger adults in providing episodic details relating to the facts.

Link: http://www.alphagalileo.org/ViewItem.aspx?ItemId=153429&CultureCode=en

It is probably a good idea to be skeptical of links claimed between blood type and measures of degenerative aging. The evidence to date is either nebulous or shows little to no correlation. Where correlations are found the effects are not large, or are not reproduced in other study populations. Nonetheless, here is another paper on this topic:

Researchers claim that people with an 'O' blood type have more grey matter in their brain, which helps to protect against diseases such as Alzheimer's, than those with 'A', 'B' or 'AB' blood types. The researchers made the discovery after analysing the results of 189 Magnetic Resonance Imaging (MRI) scans from healthy volunteers. The researchers calculated the volumes of grey matter within the brain and explored the differences between different blood types. The show that individuals with an 'O' blood type have more grey matter in the posterior proportion of the cerebellum. In comparison, those with 'A', 'B' or 'AB' blood types had smaller grey matter volumes in temporal and limbic regions of the brain, including the left hippocampus, which is one of the earliest part of the brain damaged by Alzheimer's disease.

These findings indicate that smaller volumes of grey matter are associated with non-'O' blood types. As we age a reduction of grey matter volumes is normally seen in the brain, but later in life this grey matter difference between blood types will intensify as a consequence of ageing. "The findings seem to indicate that people who have an 'O' blood type are more protected against the diseases in which volumetric reduction is seen in temporal and mediotemporal regions of the brain like with Alzheimer's disease for instance. However additional tests and further research are required as other biological mechanisms might be involved."

Link: http://www.sheffield.ac.uk/news/nr/blood-type-cognitive-disease-1.469296

People are very good at not thinking about the personal inevitability of aging and age-related disease. We all know what happens to the aged. It happens to those we know and care about. It is no big secret that aging causes pain, suffering, and death on a vast scale. Yet here we stand, you and I, consumed by the minutiae of day to day life, in which from moment to moment we put little thought into our future state of frailty and loss of dignity. Across a long history of being unable to greatly influence aging, and the pain and death it causes, this ability to put aside foreknowledge has proven a great strength. It let individuals work and prosper and build despite knowing all too well what was coming down the line. We live in a society of wealth and technology enabled by the toil of our ancestors, the majority of whom suffered and died because of aging.

And now? This talent for looking anywhere but ahead is killing us. What has changed? Medical technology. Unlike every past generation, we stand within reach of means to control and indefinitely delay the aging process. Aging is damage to cells and tissues, and for each of those types of damage researchers can envisage in detail at least one development program to produce a means of repair. The cost of getting to working prototypes in mice for all of these is probably in the vicinity of $1-2 billion spread over 10-20 years, not all that different from the amounts of time and money required to run a single drug candidate through the present regulatory process.

Yet to a first approximation this development isn't happening. Only a tiny amount of funding is presently devoted towards the development of means to repair the causes of aging and thus indefinitely postpone disease and death. There is little support among the public at large for such a goal, little awareness that any work is ongoing, or that there is the potential to strike out for great gains in health and longevity. Indeed there is little thought at all on the topic of medicine to treat and control the processes of aging, the root cause of so much pain and suffering for the old. Ignoring aging is no longer a good thing: it has now become a terrible strategy that is costing lives and costing health.

Ask someone you know today "do you want to suffer Alzheimer's disease?" Or heart disease. Or cancer. The answer is probably no. But why are they not doing something about it? Do they think it is out of their hands? None of their business? Or is it more a case of lapsing back into the daily grind wherever possible, avoiding uncomfortable existential thoughts about the future? The cancer and stem cell research establishments are examples of what should exist for aging: a research community of great size and vigor, aiming to extinguish disease and prevent disability. But it doesn't exist yet for aging, and the behavior of the people you know in response to these questions has a lot to do with that state of affairs. At the large scale and in the long term medical research funding follows the desire of the public. That 10-20 year countdown for treatments to prevent and reverse aging doesn't start at least the first shards of a massive research community do exist.

This is why we advocate and donate. So much is left to be done, and people are suffering and dying in vast numbers each and every day. This is why there must be people of vision leading the way, philanthropists of all stripes and means funding early stage research to bring greater attention to the best paths forward. The bootstrapping of the next generation of medical research for aging, the programs that will ultimately bring an end to all age-related disease, starts with us as much as with the researchers who see clearly enough to put forward their detailed plans in search of support and funding. We hold up the torch and guide the way, helping to bring greater resources to the research that deserves that support.

Do Something About It Poster #1: 4200 x 2800px

Do Something About It Poster #2: 4200 x 2800px

Rougheye rockfish are one of the few species to show negligible senescence, a comparative lack of the usual evident consequences of aging. Other examples include lobsters, naked mole-rats, some tortoise species, and some clam species such as the ocean quahog. Individuals still die after a comparatively long life, and so there are evidently still processes of degeneration gnawing away, but for many of these species it is hard to measure age via the normal metrics of vigor, growth, reproduction, and changes in various aspects of biochemistry. There is little to no meaningful change and decline until close to the end.

Mitochondria are the power plants of the cell, responsible for generating chemical energy stores to power cellular processes. They are descended from symbiotic bacteria and contain a remnant of that bacterial DNA. Damage to this mitochondrial DNA is considered to contribute to aging via a complex chain of conseqeunces that leads to a growing number of malfunctioning cells overtaken by dysfunctional mitochondria. This study of mitochondrial damage and longevity is interesting for having been carried out in a negligibly senescent species:

The mitochondrial theory of ageing proposes that the cumulative effect of biochemical damage in mitochondria causes mitochondrial mutations and plays a key role in ageing. Numerous studies have applied comparative approaches to test one of the predictions of the theory: that the rate of mitochondrial mutations is negatively correlated with longevity. Comparative studies face three challenges in detecting correlates of mutation rate: covariation of mutation rates between species due to ancestry, covariation between life history traits, and difficulty obtaining accurate estimates of mutation rate.

We address these challenges using a novel Poisson regression method to examine the link between mutation rate and lifespan in rockfish (Sebastes). This method has better performance than traditional sister-species comparisons when sister species are too recently diverged to give reliable estimates of mutation rate. Rockfish are an ideal model system: they have long life spans with indeterminate growth and little evidence of senescence, which minimizes the confounding tradeoffs between lifespan and fecundity.

We show that lifespan in rockfish is negatively correlated to rate of mitochondrial mutation, but not the rate of nuclear mutation. The life history of rockfish allows us to conclude that this relationship is unlikely to be driven by the tradeoffs between longevity and fecundity, or by the frequency of DNA replications in the germline. Instead the relationship is compatible with the hypothesis that mutation rates are reduced by selection in long-lived taxa to reduce the chance of mitochondrial damage over its lifespan, consistent with the mitochondrial theory of ageing.

Link: http://dx.doi.org/10.1093/molbev/msv137

Sarcopenia is the name given to age-related loss of muscle mass and strength. Researchers here provide somewhat indirect evidence in support of defects in autophagy, a cellular housekeeping process, being involved in the development of sarcopenia. Autophagy is known to fail with age for reasons that include the accumulation of metabolic waste in cell lysosomes, the structures responsible for breaking down damaged structures to recycle their component parts. Improved autophagy shows up in many of the approaches demonstrated to slow aging in mammals. The practice of calorie restriction improves the state of both autophagy and sarcopenia, for example.

One should always be wary of correlations in aging, of course: aging is caused by damage, and various forms of damage and consequences build up in many tissues at a similar pace. There is no necessary reason for any two correlated aspects of aging to be directly connected simply because they are happening at the same time:

Sarcopenia is the aging-related loss of skeletal muscle mass and strength. Preventing sarcopenia is important for maintaining a high quality of life in the aged population. However, the molecular mechanism of sarcopenia has not yet been unraveled and is still a matter of debate. Determining whether the levels of autophagy-related mediators (e.g., p62/SQSTM1, LC3, etc.) in muscle change with ageing is important to understanding sarcopenia. Such information could enhance the therapeutic strategies for attenuating mammalian sarcopenia.

In previous studies, autophagic defects were detected in the sarcopenic muscle of mice, rats, and humans. However, all these studies involved only western blotting analyses of crude not cell-fractionated muscle homogenates. Thus, these data were insufficient to describe the adaptive changes in autophagy-linked molecules within sarcopenic muscle. Researchers found a marked accumulation of p62/SQSTM1 in the sarcopenic quadriceps muscle of mice using two different methods (western blotting of cell-fractionated homogenates and immunofluorescence). In contrast, the expression level of LC3, a partner of p62/SQSTM1 in autophagy progression, was not modulated. The found autophagic defect improves our understanding of the mechanism underlying sarcopenia. The researchers would like to further study this mechanism with an aim to attenuate sarcopenia by improving this autophagic defect using nutrient- and pharmaceutical-based treatments.

Link: http://www.eurekalert.org/pub_releases/2015-06/tuot-ad060515.php

Cells can become senescent in reaction to a variety of environmental stresses or forms of damage, activating a program that halts cellular replication and triggers the generation of a mix of potent signals that can influence surrounding cells and tissue structure, a state known as the senescence-associated secretory phenotype (SASP). Senescent cells have a role in embryonic development, controlling the shaping of tissues at the extremities, such as the growth of fingers. Their existence in adults is perhaps because the same mechanism, particularly the arrested growth aspect of it, serves to suppress cancer risk - or at least it does so initially and while senescent cells are present in only modest numbers. Evolution tends to lead to complex systems in which every component part is reused in many ways.

Among the signals making up SASP there are those that encourage the immune system to destroy senescent cells, should those cells fail to trigger their own programmed cell death processes. The immune system has its own issues that manifest during the aging process, however, and it becomes ever less effective at all of its tasks, whether that is protecting the body from invading pathogens or destroying unwanted and potentially dangerous native cells. Over a lifetime ever more of the cells in our tissues become senescent and linger rather than being cleared out. Their collective SASP grows in influence, degrading tissue function and contributing greatly to age-related frailty and disease. With enough senescent cells present the original outcome of cancer suppression is swept away and the toxic environment begins to encourage cancer formation.

There is a great deal yet to learn about the nature of the senescent state, exactly why senescent cells accumulate, and how their presence contributes to specific manifestations of age-related disease. There is enough detail yet to be mapped to keep a much larger research community than presently exists occupied for decades. Fortunately all of that can be skipped over if a good way of clearing senescent cells can be developed: periodically remove these cells and you remove the problem. That is a much less complex proposition than reaching a full understanding of senescence, and builds on research already well advanced in other parts of the medical research establishment: how to identify types of cell reliably from their distinctive chemistry, and how to selectively destroy them without harming their neighbors. Cancer researchers are making good progress towards achieving those goals for the types of cell they are interested in, and many of the technologies will be adaptable to senescent cells.

Back to the learning, however. Do we accumulate senescent cells because the immune system falls down on its job? Or it is a matter of there being numerous subtly different types of senescent state, some of which only come into play in a meaningful way in later life? Or perhaps the nature of SASP changes with age for other reasons, such as a reaction to other forms of cellular and tissue damage. At this point any of that might be plausible - and while all interesting, it can all be bypassed by the senescent cell clearance short cut to removing that contribution to degeneration aging. While parts of the aging research community are interesting in removing senescent cells, parts of the cancer research community are interesting in the possibility of creating more of them as a cancer therapy, however. That requires learning enough about senescence to be able to tread the fine line between suppressing and encouraging cancer, and it is not simply a matter of the number of senescent cells present. One thing that is emerging from the intersection of cancer research and senescent cell research is that there is a lot of room to tinker with the mechanisms involved:

The usual SASPects of liver cancer

Cellular senescence is a stable form of cell cycle arrest that limits the propagation of damaged cells and can be triggered in response to diverse forms of cellular stress. This anti-proliferative program was initially considered a cell-autonomous mechanism that promotes tumor suppression and tissue homeostasis. However, several groundbreaking studies performed in the last decade have established that senescent cells can impact their environment through the secretion of growth factors, cytokines, chemokines, immune modulators and extracellular matrix-degrading enzymes. This process, collectively known as the senescence-associated secretory phenotype (SASP), enables the non-cell-autonomous activities of senescent cells. The functions exerted by the SASP are diverse and include the autocrine reinforcement of cell cycle arrest as well as the paracrine transmission of the senescent phenotype to neighboring cells, thereby maintaining and propagating tumor suppression. Moreover, SASP can directly modulate the tissue microenvironment, elicit immune surveillance of senescent cells, and paradoxically, promote tumorigenesis by supporting the proliferation of surrounding malignant or pre-malignant cells.

Many of the findings that illustrate the impact of SASP on the microenvironment stem from in vivo studies in the liver. Upon liver injury, hepatic stellate cells (HSCs) activate, proliferate, and develop a profibrotic secretome. Activated HSCs eventually undergo cellular senescence and produce a SASP enriched in fibrolytic molecules, contributing to fibrosis resolution. Moreover, senescent HSCs also secrete pro-inflammatory cytokines that direct the immune surveillance of senescent HSCs, further limiting liver fibrosis. The production of a proper SASP and subsequent immune-mediated clearance of senescent cells appear to be critical for the beneficial effects of cellular senescence on liver homeostasis and tumor suppression. Accordingly, genetic or chemical abrogation of the immune system leads to increased liver fibrosis, liver cancer, and delayed tumor regression after p53 reactivation in liver cancer cells. Intriguingly, in a murine model of HCC driven by a chemical carcinogen and obesity, senescence of HSCs and the corresponding SASP were associated with hepatocarcinogenesis. These contradictory findings could potentially be explained by differences in the senescence trigger, in the composition of the SASP, or by defective senescence surveillance. In fact, the clearance of senescent HSCs was not observed in the latter study, further emphasizing the importance of efficiently eliminating senescent cells.

Pro-senescence therapy has recently emerged as a novel therapeutic approach for treating cancer and could be applied to liver cancer, a disease that lacks effective treatment. However, if senescent tumor cells are not properly eliminated by the immune system, the SASP can promote the growth of non-senescent adjacent tumor cells. One solution could be to manipulate SASP to restrict its protumorigenic properties and/or enhance its ability to engage the immune system. An elegant work clearly showed how Pten-loss-induced senescence creates an immunosuppressive and protumorigenic microenvironment in prostatic intraepithelial neoplasias. However, pharmacological inhibition of the Jak2/Stat3 pathway reprogrammed SASP, restoring immune surveillance and the anti-tumor effects. Another appealing option is to boost the immune system to improve the surveillance of senescent tumor cells. Treatment with the anti-programmed cell death protein 1 (PD1) immune checkpoint antibodies or ipilimumab, an antibody that enhances the activation of cytotoxic T cells by blockade of the cytotoxic T-lymphocyte associated protein 4 (CTLA-4) receptor, could improve the anti-tumor potential of pro-senescence therapies. Understanding and manipulating the signaling pathways that control SASP as well as identifying the key mediators of SASP will be essential to unleash the full potential of the senescence program.

The small and largely non-profit cryonics industry provides indefinite low-temperature storage immediately following death, so as to preserve the fine structure of neural tissue that stores the data of the mind. For so long as that data remains intact, the possibility remains for the future development of medical molecular nanotechnologies capable of restoring a preserved individual to active life. It is an unknown chance at a future life, but infinitely better than all the other alternatives for those who do not have the time to wait for the defeat of degenerative aging. It is sad and barbaric that cryonics remains on the margins of our society while near all of those who die vanish into oblivion. In a better world they could have been saved.

It is also sad and barbaric that laws in most regions of the world prevent the coordination of death and cryopreservation at a time of the patient's own choosing. Euthanasia is forbidden, leaving patients to suffer horribly in their final weeks, and ensuring that the process of cryopreservation is much more expensive and uncertain than it might otherwise be, involving standby teams and scrambling at short notice to put a complex medical procedure into action. Speed is essential in order to prevent neural damage, but the uncaring laws preventing euthanasia make that hard to do well in all circumstances. Many people understand all of this and do what they can to organize a good cryopreservation over months and years in advance, but there are always those who do not. The cryonics organizations frequently go above and beyond, but why make their lives hard and introduce additional uncertainty and delay when you don't have to? You are the one who will suffer for it in the end.

Mariette Selkovitch, Alcor member A-2830, was pronounced clinically dead on Tuesday May 5, 2015 at 1:30 am in California. Mrs. Selkovitch, a neurocryopreservation member, became Alcor's 136th patient later the same day.

Around 1:16am on Tuesday May 5, 2015, we received an alert from Ronald Selkovitch, a 21-year member of Alcor. His wife, Mariette, had gone into cardiac arrest and resuscitation was being attempted. There was no membership paperwork for her and no funding arranged but he was insisting that we come for her. Normally, the absence of prior arrangements would rule out Alcor accepting such a case. However, on checking our records, some important details emerged. Something similar happened in 2008, when Mr. Selkovitch's 101-year old mother died, also without having any membership paperwork signed or funding arranged. Nevertheless, we accepted the case. Mr. Selkovitch followed through as promised and paid for her. His mother is still our oldest patient at time of clinical death, just short of 102 years old.

Medical Response Director, Aaron Drake, contacted Suspended Animation to put them on the alert. However, SA's Suspension Services manager said that (especially given that any team would likely arrive post-mortem) SA would not deploy without complete paperwork and agreement from the board and from Alcor's Chief Medical Advisor, Dr. Steven Harris. I called and was able to consult with a majority of directors in the middle of the night and secure agreement from everyone, along with Dr. Harris, but the shortage of time meant that it would be impossible to fulfill the conditions for SA and so Alcor deployed a team directly.

It must be stressed that the decision could easily have gone the other way, and in just about any other circumstance, would have. As it was, due to this being a third-party signup (by a member), Mr. Selkovitch was faced with the standard third-party fee (the primary purpose of which is to compensate for family and legal risks). He said he would gladly cover this if we would accept his wife's case. We were fortunate in that the sheriff said that no autopsy was needed and she would be released immediately to a mortuary (the same one where his mother was taken in 2008). The one living son of Mr. and Mrs. Selkovitch was on his way and Mr. Selkovitch said he was on the way there and would very likely sign the Relative's Affidavit (which he did). Mr. Selkovitch was diligent in that he filled out the membership paperwork that I gave Aaron to take with him. Funding followed very rapidly.

The Alcor team set out for California at 5:21 am and were able to administer and circulate medications while packing the head in ice. The team returned to Alcor with Mrs. Selkovitch at 7:38 pm. Cryoprotective perfusion was ended at 12:13 am on May 6 and cool down immediately initiated.

Link: http://www.alcor.org/blog/mariette-selkovitch-becomes-alcors-136th-patient-on-may-5-2015/

Researchers here present the intriguing possibility that the same very same nuclear DNA damage that may be a contribution to degenerative aging is also an essential part of cellular operation in some vital tissues and processes:

Each time we learn something new, our brain cells break their DNA, creating damage that the neurons must immediately repair. This process is essential to learning and memory. "Cells physiologically break their DNA to allow certain important genes to be expressed. In the case of neurons, they need to break their DNA to enable the expression of early response genes, which ultimately pave the way for the transcriptional program that supports learning and memory, and many other behaviors." However, as we age, our cells' ability to repair this DNA damage weakens, leading to degeneration. "When we are young, our brains create DNA breaks as we learn new things, but our cells are absolutely on top of this and can quickly repair the damage to maintain the functionality of the system. But during aging, and particularly with some genetic conditions, the efficiency of the DNA repair system is compromised, leading to the accumulation of damage, and in our view this could be very detrimental."

In previous research into Alzheimer's disease in mice, the researchers found that even in the presymptomatic phase of the disorder, neurons in the hippocampal region of the brain contain a large number of DNA lesions, known as double strand breaks. They discovered that of the 700 genes that showed changes as a result of this damage, the vast majority had reduced expression levels, as expected. Surprisingly though, 12 genes - known to be those that respond rapidly to neuronal stimulation, such as a new sensory experience - showed increased expression levels following the double strand breaks. To determine whether these breaks occur naturally during neuronal stimulation, the researchers then treated the neurons with a substance that causes synapses to strengthen in a similar way to exposure to a new experience. "Sure enough, we found that the treatment very rapidly increased the expression of those early response genes, but it also caused DNA double strand breaks."

Finally, the researchers attempted to determine why the genes need such a drastic mechanism to allow them to be expressed. Using computational analysis, they studied the DNA sequences near these genes and discovered that they were enriched with a motif, or sequence pattern, for binding to a protein called CTCF. This "architectural" protein is known to create loops or bends in DNA. In the early-response genes, the bends created by this protein act as a barrier that prevents different elements of DNA from interacting with each other - a crucial step in the genes' expression. The double strand breaks created by the cells allow them to collapse this barrier, and enable the early response genes to be expressed. "Surprisingly then, even though conventional wisdom dictates that DNA lesions are very bad - as this 'damage' can be mutagenic and sometimes lead to cancer - it turns out that these breaks are part of the physiological function of the cell."

Link: http://newsoffice.mit.edu/2015/dna-breakage-learning-age-related-damage-0604

Investigation of the contribution of stem cells to the process of degenerative aging is a flourishing field of research. As we age our stem cell populations gradually cease their activity, spending more time in periods of quiescence, and becoming more damaged by the wear and tear of continued metabolic activity. The principal role of stem cells is to provide a supply of new cells to keep tissues in working order, and diminished supply results in growing frailty and dysfunction. This is one of the causes of disease and death due to aging.

There are reasons for optimism, however. The stem cell research field is collectively one of the largest and most active scientific institutions in the world today. At present there are many possible avenues towards the development of therapies to slow or reverse those aspects of aging that are directly caused by growing stem cell dysfunction and quiescence. Further, since so many of the first generation regenerative therapies emerging from the study of stem cells are intended to treat age-related diseases, researchers in this field have a strong incentive to find and address all of the major age-related issues associated with stem cell biochemistry. They have to tackle these challenges in order to assure the effectiveness of their stem cell treatments. That said, this is of course only one of a number of fields that must all become this energetic and well funded if we are to see significant progress towards a comprehensive toolkit of rejuvenation therapies, many of which are far removed indeed from that level of support.

It is nonetheless encouraging to see progress on a near weekly basis reported in publications and the press. The latest issue of Cell Stem Cell features a number of open access papers on the role of stem cells in aging, illustrative of a range of current directions in research. I think you'll find them interesting:

Can Metabolic Mechanisms of Stem Cell Maintenance Explain Aging and the Immortal Germline?

Understanding the mechanisms driving aging may lead to innovative strategies to increase health span, an effort that would carry enormous human and economic benefit. The fact that many species (typically, though not exclusively, more slowly developing, longer-lived, and larger species) possess somatic stem cells capable of self-renewal and tissue regeneration calls into question why these organisms and their somatic stem cells do age whereas the germline apparently does not. It is also unclear how evolutionary theories of aging that are currently accepted as at least plausible can be reconciled with the biological properties of somatic stem cells.

It is proposed here that somatic stem cell maintenance mechanisms lead to preferential accumulation, rather than disposal, of damaged stem cells. On the other hand stringent selection in the germline renders this lineage seemingly immortal. Furthermore, use of glycolysis for ATP production in somatic stem cells as opposed to mitochondrial respiration in the germline suggests that mitochondria play a critical role in stem cell maintenance and gamete selection. This hypothesis is consistent with prevailing evolutionary theories of aging, and with a critical role for mitochondria in aging.

Stem Cell Aging and Sex: Are We Missing Something?

A glance at the list of the human individuals currently living over the age of 110 - supercentenarians - reveals a surefire strategy for achieving such exceptional longevity: be female. Out of the 53 living supercentenarians, 51 are female. No other demographic factor comes remotely close to sex in predicting the likelihood of achieving such an advanced age. Sexual dimorphism with respect to longevity is a characteristic of most mammals and has been recorded in human populations since at least the mid-18th century. This dichotomous capacity for resilience has inspired wide-ranging hypotheses to explain the underlying mechanisms. It also raises questions regarding the sexual dimorphism of processes known to sustain tissue regeneration and function throughout life, including adult stem cell renewal.

Most adult stem cell populations undergo an age-related decline, leading to dysfunctional tissue homeostasis, which most likely participates in defining the ultimate lifespan of the organism. Interestingly, sex-specific regulation of stem cell populations has been demonstrated for several stem cell types, and it has long been appreciated that many canonical aging pathways exhibit sex specificity. However, despite the seeming interrelationship between sex, stem cell maintenance, and aging, few studies have sought to directly explore the interaction of these three variables. Here we discuss the sexual dimorphism of adult stem cell populations and how processes regulating the aging of stem cells may also be modified by sex.

Programming and Reprogramming Cellular Age in the Era of Induced Pluripotency

Pluripotent stem cells (PSCs) are characterized by their ability to extensively self-renew and differentiate into all the cell types of the body. We propose PSCs cells as a novel model for studying human aging. Unlike traditional aging paradigms that focus on endpoints such as longevity or the restoration of regenerative capacity, PSCs allow us to monitor and manipulate molecular and cellular hallmarks of aging during both reprogramming and cell differentiation. Capturing the timing and sequence of the steps involved in cellular rejuvenation offers a unique opportunity for subsequent mechanistic studies.

The strong evidence for cellular rejuvenation during induced pluripotent stem cell (iPSC) induction indicates that many aspects of aging are reversible and may represent epigenetic rather than genetic barriers in biology. Therefore, a future is conceivable wherein it will be possible to reliably rejuvenate somatic cells without the need to move them back to pluripotency. In addition to studying rejuvenation, it will be equally important to identify novel induced aging strategies. The ability to direct both cell fate and age in iPSC-derived lineages will allow modeling of human disorders at unprecedented precision. Such studies could yield more relevant disease phenotypes and define novel classes of therapeutic compounds targeting age-related cell behaviors. The ability to program and reprogram cellular age on demand will present an important step forward on the road to decoding the mystery of aging.

Aging-Induced Stem Cell Mutations as Drivers for Disease and Cancer

The incidence of tissue dysfunction, diseases, and many types of cancer, including colorectal cancer and some types of leukemia, exponentially increases with age, and aging represents the single biggest risk factor for most cancers. However, the reasons for this aging-associated failure in tissue maintenance and the increase in cancer are poorly understood. Without a doubt, cancer is largely driven by genome dysfunction, frequently exemplified by specific genetic alterations that drive one or more specific cancer phenotypes. Overwhelming evidence indicates that the genesis and progression of cancer depend on accumulation of genetic alterations.

There is emerging evidence that aging induces changes in molecular pathways that accelerate the initiation and/or clonal dominance of mutations in stem and progenitor cells. The tight connection between aging-associated accumulation of stem and progenitor cell mutations with the failure of tissue maintenance and cancer suppression indicates a causal relationship between these factors. In addition to the cell-intrinsic mechanisms discussed here, there is increasing evidence that cell-extrinsic factors affect stem cell maintenance and possibly the selection of mutant stem and progenitor cells during aging. Likely, and potentially exciting, extrinsic candidates include aging-associated defects in the stem cell niches, alterations in the systemic/blood circulatory environment, changes in proliferative competition among stem and progenitor cells, inflammatory responses, and defects in immune surveillance of damaged cells. The delineation of this interplay of cellular and molecular mechanisms that contribute to the initiation and selection of stem and progenitor cell mutations in the context of aging will undoubtedly help the development of therapies aiming to improve early detection, prevention, and risk assessment of aging-associated diseases, organ dysfunction, and cancer.

The MRL mouse lineage is capable of unusual levels of tissue regeneration for a mammal, an entirely accidental discovery that emerged from an unrelated research program some years ago. Since this came to light, research groups have been chasing down the potential mechanism, and for much the same reason as scientists are interested in the details of salamander regeneration: the possibility of developing therapies to enhance human healing processes. Last I heard, the gene p21 was involved in MRL mouse regenerative capacity, but here researchers are proceeding down a different track, one that seems to have a fairly direct path to a first pass at a regenerative therapy for humans:

"We discovered that the HIF-1a pathway - an oxygen regulatory pathway predominantly used early in evolution but still used during embryonic development - can act to trigger healthy regrowth of lost or damaged tissue in mice, opening up new possibilities for mammalian tissue regeneration." The discovery is the latest development in a long investigation sparked by a chance observation in an unusual mouse strain. Almost 20 years ago, researchers noticed that the MRL mouse can spontaneously regenerate cartilage and other tissues after injury, making it a rare exception among mammals. Years of subsequent research involving the MRL mouse led the researchers to theorize that the HIF-1a pathway, which helps cells respond to low oxygen conditions, may also hold the key to the unique regenerative capability of MRL mice.

Under normal oxygen conditions, HIF-1a is degraded by prolyl hydroxylases (PHDs). Stabilization of HIF-1a levels can be accomplished through inhibition of PHDs. To test their theory, the researchers first experimentally down-regulated HIF-1a in MRL mice, which they found led to a loss of regenerative capability in the mice. Next, they selected a non-regenerating strain of mice to see what would happen when they experimentally up-regulated (stabilized) HIF-1a levels after an ear hole punch injury. The mice received three injections of a PHD inhibitor in a slow-release formulation at 5-day intervals. After 30 days, the researchers observed ear hole healing with closure and regrowth of cartilage and new hair follicles. In addition, the drug-treated mice showed a pattern of molecular changes indistinguishable from that observed in MRL mice during regeneration in response to injury, confirming HIF-1a as a central driver of healthy regeneration of lost or damaged tissue in mice.

"Our experiment shows the possibility of taking mature cells and, with addition of HIF-1a, causing dedifferentiation to a highly immature state where the cells can proliferate, followed by redifferentiation upon withdrawal of HIF-1a. Many researchers in the field see tissue regeneration as a very complex set of events, but some of us look at it more as a process that needs to be turned on and allowed to go to completion. This is what is so exciting about what we saw with drug-induced stabilization of HIF-1a." The researchers plan to move ahead to modify the drug delivery system to achieve an ideal formulation, which they will use to investigate regrowth potential in many types of tissues.

Link: http://www.eurekalert.org/pub_releases/2015-06/mlhl-sal060215.php

The future of retirement in a world of radical life extension achieved via rejuvenation treatments is that there will be no more retirement in the traditional sense. Retirement as an institution exists because of unavoidable frailty and disease in aging, and those outcomes will be ended through progress in medicine. The research and development programs that create effective rejuvenation treatments will take place over less than half a lifetime once things really get going. All too many people today are unaware of the potential for progress towards the medical control of aging, entering their professional careers expecting their lives to have the same shape and duration as those of their grandparents. At least some are waking up, however:

Human life has reached an inflection point - one that matters a great deal for those planning for retirement. People are living longer and trying to stretch their income to make ends meet and stay ahead of inflation, but that's not the inflection point financial advisors are really concerned about - that's just the everyday blocking and tackling on behalf of client portfolios. The emerging challenge goes way beyond that.

Scientists have found the mechanisms that govern aging and are already doing experiments in rats on how to reverse it. They've found species that do not die of old age, such as the jellyfish Turritopsis. "We're adding three months to life per calendar year. It's not an if, it's a when, and the point in time is in the 15- to 20-year range. In a decade or two, or three, there will be a class of people taking treatments who can live for a long time, and that affects employment planning, retirement planning ... Society will never have seen that before. The first person to reach age 150 has already been born. How do I talk to a client preparing to retire at 65 using the traditional model and with planning software that only goes to age 95? The financial model is broken."

The shift from a linear to a cyclical lifeline is already starting to be seen: The average American at age 35 has already had eight jobs. "It's not going to be birth, school, job, retirement, death," he said. Soon individuals will cycle between work, school, sabbaticals, more schooling and more work in a cycle that has never before existed. "It's going to be less about money in the future and more about the future. How do you sit down with someone in their 30s or 40s and tell them that they are going to live to 110 or 120 and haven't prepared financially for that?" At first the challenge won't be that the information is overwhelming; it's that the client won't even believe what the advisor is saying, making it the most difficult and potentially costly conversation an advisor needs to initiate. "They will look at you like you are smoking crack. It's the singularity conversation, and if they think an advisor is crazy, then the advisor will lose the client."

Link: http://www.cnbc.com/id/102730128

Some of the decay of aging is going to happen no matter what you choose do on a day to day basis. Your metabolism is running all the time, and it constantly generates damage as a byproduct of that activity. Metabolic waste accumulates in long-lived cells and in the extracellular matrix. Stochastic DNA damage builds up in the cell nucleus to raise cancer risk and in mitochondria to cause dysfunction there. Cells react to damage and dysfunction by becoming senescent or declining in activity. You could live the perfect life and all of this and more will happen regardless: it is wear and tear as a consequence of the evolved structure of your biology.

There is plenty you can do to hurry this along, however. Happenstance and choices made can accelerate existing forms of damage or add new types of damage that make the situation worse, bringing you to a state of being physically older at a given chronological age than would otherwise have been the case. We tend to live longer than our ancestors in part because we've managed to eliminate a large fraction of the burden of infectious disease and the long-term harm it causes to survivors, for example. Our wealth and technology also provides the opportunity to become fat and sedentary in greater numbers, however, which accelerates the pace of damage, and smoking of course merits a chapter of its own in the annals of killing yourself slowly.

So there is primary aging and there is secondary aging. Primary aging is the damage you can do next to nothing about at the moment, and will only be impacted by the development of therapies capable of repairing the accumulation of damage that causes degenerative aging and all of its attendant medical conditions. Secondary aging is what you do to yourself, most people through some combination of excess fat tissue, lack of exercise, and smoking, and is consequently under your control. The balance of influence here is obviously biased towards primary aging in the end: you can't make lifestyle choices that reliably allow you to live to age 90 in the environment of today's medical technology. Three-quarters of people with the best health are dead by that age, and only medical progress will change that statistic.

You can, however, make simple choices that shift your life expectancy across the range of a decade, out there in the future ahead. You can change your future health for the better and reduce your expected medical expenses at the same time. It seems worth making that effort, especially at this time of very rapid development in biotechnology: a few years here or a few years there might mean the difference between being alive to benefit from the first effective clinical rejuvenation treatments, or dying just on the cusp of that new age of medicine. You never know, and certainly there are those of us trying to speed up the development of those rejuvenation treatments.

Here is an interesting approach to putting some better numbers on the split between primary and secondary aging. All too many people focus on secondary aging when it comes to their health, and that is where their concerns and vision stop. But if we want to see significant progress in funding and support for effective treatment of the causes of aging, then it is very necessary to convince more of these individuals that they are overlooking the most important part of the problem:

Information Theoretical Analysis of Aging as a Risk Factor for Heart Disease

Non-communicable chronic diseases are the greatest cause of mortality in the world, yearly claiming more than 34.5 million lives worldwide (66% or 2/3 of global deaths, or nearly 100,000 deaths daily). Hence major efforts are directed toward their alleviation. Yet, a crucial point is often missing in these considerations, namely, the due emphasis on the fact that these diseases are age-related diseases, and their main risk factor is not necessarily related to environmental risks or life-style choices, but to the aging process itself! There is an appreciation that the incidence of non-communicable diseases increases with age steeply, unlike the effects of other environmental and life-style factors whose influence may be considered steady. Yet, the exact weight of age in relation to other risk factors remains uncertain. Hence, there is a need to be able to determine this weight in order to provide a fuller diagnostic and prognostic assessment for age-related diseases and design interventions that would be able to affect the entire array of risk factors.

Such an ability would be especially valuable for heart disease, the main age-related disease and cause of death in the world. As of 2010, it was estimated that the cardiovascular and circulatory diseases represented the largest proportion among all causes of mortality. Yet, it is also known that cardiovascular diseases, and ischemic heart disease in particular, can be highly susceptible to therapeutic and lifestyle interventions, capable of dramatically extending the health and longevity of the subjects. Hence it is of primary importance to be able to assess the entire array of risk factors as well as the effects of therapeutic interventions on the risk factors, either individually or in combinations, including age. If age is the main risk factor, then it may well be that the primary target of the therapeutic and lifestyle intervention would be the aging process itself.

Here we apply the information theoretical measure of normalized mutual information (uncertainty coefficient) to determine precisely the weight of various risk factors in heart disease, and the particular weight of age as a risk factor, individually and combined with other factors. We show that individual parameters, including age, often show little correlation with heart disease. Yet in combination, the correlation improves dramatically. For diagnostic parameters specific for heart disease the increase in the correlative capacity thanks to the combination of diagnostic parameters, is less pronounced than for the less specific parameters. Age shows the highest influence on the presence of disease among the non-specific parameters and the combination of age with other diagnostic parameters substantially improves the correlation with the disease status. Hence age is considered as a primary "metamarker" of aging-related heart disease, whose addition can improve diagnostic capabilities.

There is a growing realization that a promising and cost-effective strategy to combat severe non-communicable diseases is to give a greater focus of health research from attempting to address individual diseases and symptoms to addressing their underlying root cause and main risk factor - the degenerative process of aging. Such an approach has already yielded in the past valuable strategies to combat non-communicable diseases. Historical examples include probiotic diets, cell therapy and adjuvant immunotherapy that were born from biological research of aging. Further emphasis on treating, delaying or even reversing the seemingly "general" and "systemic" biological processes of aging may likely produce not just a general improvement of the functional state of the aged, but also further advances in the treatment of specific age-related non-communicable diseases, such as heart disease. The current work, for the first time quantitatively demonstrating the weight of age (aging) as a risk factor for heart disease, gives further support to this approach. It further emphasizes the need to intervene into the basic aging processes for developing effective therapies for age-related diseases.

Work on decellularizing different types of tissues to produce patient-matched donor organs proceeds at different rates. Some are much harder than others, not in the step of removing cells from the donor organ, which is fairly consistent for all tissue types, but in the development of methodologies to repopulate the tissue with all of the necessary cell types while ensuring that the correct tissue structures are produced. Last year researchers demonstrated a first pass at recellularized lungs, and suggested that there is a decade to go yet before they'll be ready for human use. More work is underway:

A promising option to increase the donor organ pool is to use allogeneic or xenogeneic decellularized lungs as a scaffold to engineer functional lung tissue. Decellularization of mouse, rat, goat, sheep, pig, non-human primate and human lung tissue has been accomplished, and resulted in three-dimensional acellular scaffolds that are generally devoid of detectable residual DNA. Repopulation of decellularized lungs has been reported using a number of different cell types. However, only partial recellularization of alveoli, airways and pulmonary vasculature has been achieved.

One potential approach to improve recellularization of decellularized lung scaffolds is to use the dynamic rotating wall vessel (RWV) bioreactor, which has been shown to promote growth and differentiation of stem and/or epithelial cells. The RWV is an optimized form of continuous suspension culture wherein cells are cultured in horizontally rotating bioreactors that are completely filled with media. The bioreactor rotation offsets sedimentation, creating a constant, gentle fall of cells and their growth substrate/scaffolds through the culture medium.

We demonstrate that decellularized mouse lungs recellularized in a rotating wall vessel contained more cells with decreased apoptosis, increased proliferation and enhanced levels of total RNA compared to static recellularization conditions. These results were observed with two relevant mouse cell types: bone marrow-derived mesenchymal stromal (stem) cells (MSCs) and alveolar type II cells. In addition, MSCs cultured in decellularized lungs under static but not bioreactor conditions formed multilayered aggregates. Gene expression and immunohistochemical analyses suggested differentiation of MSCs into collagen I-producing fibroblast-like cells in the bioreactor, indicating enhanced potential for remodeling of the decellularized scaffold matrix. In conclusion, dynamic suspension culture is promising for enhancing repopulation of decellularized lungs, and could contribute to remodeling the extracellular matrix of the scaffolds with subsequent effects on differentiation and functionality of inoculated cells.

Link: http://dx.doi.org/10.1371/journal.pone.0126846

Decellularization is a process that strips all the cells from tissue leaving behind the extracellular matrix and its chemical guides. If suitably repopulated with new cells from a patient, the optimal result is living and fully functional tissue matched for transplantation without the possibility of immune rejection. This approach is a stepping stone on the way to generating new complex tissues from scratch, a way to work around the fact that the research community cannot yet produce artificial scaffolds of sufficient complexity and quality to match the natural extracellular matrix structure present in organs. Most work on decellularization to date has involved internal organs such as hearts, livers, and lungs, but there is no reason why it cannot be applied to a limb, as is the case here:

Researchers have used an experimental approach previously used to build bioartificial organs to engineer rat forelimbs with functioning vascular and muscle tissue. They also provided evidence that the same approach could be applied to the limbs of primates. "The composite nature of our limbs makes building a functional biological replacement particularly challenging. Limbs contain muscles, bone, cartilage, blood vessels, tendons, ligaments and nerves - each of which has to be rebuilt and requires a specific supporting structure called the matrix. We have shown that we can maintain the matrix of all of these tissues in their natural relationships to each other, that we can culture the entire construct over prolonged periods of time, and that we can repopulate the vascular system and musculature."

The same decellularization process used in whole-organ studies - perfusing a detergent solution through the vascular system - was used to strip all cellular materials from forelimbs removed from deceased rats in a way that preserved the primary vasculature and nerve matrix. After thorough removal of cellular debris - a process that took a week - what remained was the cell-free matrix that provides structure to all of a limb's composite tissues. At the same time, populations of muscle and vascular cells were being grown in culture.

The research team then cultured the forelimb matrix in a bioreactor, within which vascular cells were injected into the limb's main artery to regenerate veins and arteries. Muscle progenitors were injected directly into the matrix sheaths that define the position of each muscle. After five days in culture, electrical stimulation was applied to the potential limb graft to further promote muscle formation, and after two weeks, the grafts were removed from the bioreactor. Analysis of the bioartificial limbs confirmed the presence of vascular cells along blood vessel walls and muscle cells aligned into appropriate fibers throughout the muscle matrix.

Functional testing of the isolated limbs showed that electrical stimulation of muscle fibers caused them to contract with a strength 80 percent of what would be seen in newborn animals. The vascular systems of bioengineered forelimbs transplanted into recipient animals quickly filled with blood which continued to circulate, and electrical stimulation of muscles within transplanted grafts flexed the wrists and digital joints of the animals' paws. The research team also successfully decellularized baboon forearms to confirm the feasibility of using this approach on the scale that would be required for human patients.

Link: http://www.eurekalert.org/pub_releases/2015-06/mgh-mgt060215.php

It is always pleasant to see more people writing seriously about aging and medicine, even if they omit what I see as some of the important viewpoints, or fail to end up advocating for massive funding of SENS research so as to make best speed towards an end to age-related frailty and disease. Certainly all too few people are willing to make that last leap at the moment. However, that there is more interest these days in treating aging as a medical condition and in the biological details of aging is a sign that the tide of public awareness is rising. In turn this should mean that it will become ever easier to raise funds in the years ahead - certainly I hope so, since I'll be doing my part to try to pull in grassroots funding for some of the more important lines of early-stage research.

At the grand scale this is all about persuasion, as is the case for all bootstrapped advocacy for a cause. You might recall a scientific study published a few years back on the tipping point of inevitability: where is the line that divides an opinion that remains forever fringe from an opinion that will become mainstream? The researchers suggested that the division is somewhere near 10% of the populace. I think we're getting there for important sections of the public when it comes to support for the medical control of aging in the same sense as the presently mainstream support for the medical control of cancer. Progress along this road accelerates rapidly as the tipping point nears, which is certainly a relief after the painfully slow early stages of talking people around to see common sense on medicine and aging, one individual at a time, and with frequent rejection. Certainly these past two years have seen things moving along at a much faster pace than the decade that preceded them.

Why We Age - Part I: The Evolution Of Aging

If you had to guess how you were going to die, you could narrow it down pretty quickly. It takes only a handful of diseases to account for over half of the deaths of Americans each year. Only five in fact - heart disease, cancer, stroke, Alzheimer's disease, and diabetes. Though these disparate diseases affect different organ systems and develop as a result of different mechanisms, they all share a common underlying cause - the aging of the human body. It is aging that is the real killer here - aging kills more people on Earth than anything else. Maybe that's obvious, maybe it's not.

For a condition that kills so many, most of us don't have the slightest understanding of how aging works or why it happens. This series will ask the deceptively simple question, "Why do we age?" To tackle this, we will break this question into three distinct parts: "Why do we age?", "How do we age?", and "Is it possible to live longer?" The first will explore aging from the perspective of evolution, the second will delve into the actual mechanisms within our bodies that cause us to age, and the third will discuss scientific research into lifespan extension.

Why We Age - Part II: A Comprehensive View Of The Aging Process

In general, the biological theories of aging can be split into two types: stochastic and programmed (stochastic just means random). Stochastic theories suggest that damage to our cellular components accumulates over time, leading to functional decline, and ultimately, death. On the other hand, programmed theories propose that aging arises from a set biological timetable, possibly the same one that regulates childhood growth and development.

Though stochastic and program theories are frequently presented as mutually exclusive, in reality they are connected, complementary, and deeply embedded in the interwoven, complex biological network that regulates all of life. To foster a holistic appreciation for the aging process, I will first layout the various theories of aging, and will then connect the pieces to construct a comprehensive map of aging.

Why We Age - Part III: Can We Live Forever?

Amazingly, the most widely studied method of lifespan extension requires no drugs, no supplements, no organ replacement. All that is required is reducing your caloric intake - just eat less. This practice, known as calorie restriction, has been observed to extend the lifespan of many species, from yeast to mice. Remarkably, initial findings have even shown that it can decrease the onset of age-related diseases in primates as well. To be clear, calorie restriction does not mean starving yourself, just reducing your caloric intake from a baseline level, typically by around 30%.

So why does calorie restriction work? From an evolutionary perspective, it is thought that in times of famine, organisms forgo reproducing, instead holding out for more prosperous times. As a result, it is advantageous to up-regulate genes involved in protection and repair and wait for better days to come. Essentially, we have specific genes that sense the availability of nutrients in the environment, and in times of scarcity, slow the process of aging, so that we may reproduce in more favorable conditions.

Tissue engineering is a field of many diverse research groups, each specializing in just a few types of tissue or organ structures. There is a great deal going on, and some of it is out of the public eye simply due to language barriers and the fact that more obscure or less important tissues are involved. It all still needs to be done, however: all of the body fails with age, and thus all tissues are a target for regenerative treatments. Take the work of this Japanese research group, for example:

Salivary gland hypofunction, or xerostomia (dry mouth syndrome), induces various clinical problems, such as dental decay, bacterial infection, and swallowing dysfunction. Xerostomia caused by autoimmune disease and aging affects an increasing number of patients. The development of novel functional treatments for xerostomia is needed, as currently available therapies are only palliative in nature. Tissue stem cell transplantation and gene therapy are currently being investigated as potential approaches to the restoration of salivary gland function. The final goal of regenerative therapy is fully functional regenerative organ replacement for dysfunctional organs.

Previously, we developed a technology to reconstitute the organ germ (Organ Germ Method) using epithelial and mesenchymal stem cells. We have recently reported the regeneration of fully functional organs, such as teeth, hair and lacrimal glands, can be achieved by the transplantation of bioengineered organ germs. In this review, we describe the regeneration of the salivary gland as part of a feasibility study of a next-generation regenerative therapy.

Link: https://www.jstage.jst.go.jp/article/jsci/38/2/38_93/_article/-char/en/

It isn't widely appreciated that many of the organs donated for transplant are discarded as unsuitable. In the near future tissue decellularization will be used to expand the pool of viable organs, though it may also lead to enabling xenotransplantation of organs farmed from pigs or other large animals, a step that would largely remove present limits on available organs. In the longer term decellularization and donor organs, human or animal, will be replaced by the growth of complex tissues such as whole organs on artificial scaffolds or completely from scratch, starting only with cells. For now, however, decellularization is the hot topic:

Researchers report progress in their quest to build replacement kidneys in the lab. The teams' goal is to make use of the more than 2,600 kidneys that are donated each year, but must be discarded due to abnormalities and other factors. The scientists aim to "recycle" these organs to engineer tailor-made replacement kidneys for patients. The process begins by washing the discarded organs in a mild detergent to remove all cells. The idea is to replace these cells with a patient's own kidney stem cells, making a tailor-made organ that would not be rejected and wouldn't require the use of powerful anti-rejection medication. But are the organs a suitable platform for engineering after going through the process to remove cells?

To help answer that question, the researchers evaluated whether the washing process affects a small sac of capillaries in kidneys called the glomerulus. The researchers screened the kidney structures to see if they retained growth factors that play an important role in function. The research team reports that the size, structure and function of the micro-vessels in the glomerulus are preserved after the cell-removal process. In addition, vital proteins known as growth factors that regulate cell growth and function are retained within the kidney structures. "These growth factors play a vital role in the formation of new vessels and kidney cells. The fact that they are preserved means they can potentially facilitate the repopulation of cells into the structure and reduce the potential of clot formation."

In a separate study, the team reported on the interactions that occur when stem cells are placed on kidney structures that have been through the cell removal process. The team seeded stem cells derived from amniotic fluid onto sections of kidney structures. In this first study to describe the long-term results of this process, the scientists observed that the stem cells proliferated when placed on the structures and were functionally active as demonstrated by the fact that they secreted chemicals and growth factors involved in such critical pathways as inflammation and the formation of new blood vessels. "These results indicate that discarded human kidneys are a suitable platform for engineering replacement kidneys and that when cells are added, the structures behave as an effective and viable biosystem."

Link: http://www.wakehealth.edu/News-Releases/2015/New_Discoveries_Advance_Efforts_to__Build_Replacement_Kidneys_in_the_Lab.htm

The future of cancer treatments is, one way or another, all about two things: (a) the ability to identify and target common mechanisms in a broad range of cancers so that one technology platform, one research initiative, can be useful for many patients rather than just a few, and (b) targeting cancer cells so that treatments are far more effective and have few and negligible side-effects. Today's cancer treatments are highly specific to cancer types and subtypes, the result of a large number of parallel lines of development undertaken at great cost, and are also damaging to the patient's healthy tissue. At the most blunt even the application of the best of chemotherapies are an art that involves finding the optimal point in the range lying between too little to degrade the cancer and too much for the patient to bear. Yet the transition is underway to a world in which cancer treatments are something you walk into a clinic to obtain, and walk right out again a hour later feeling no worse for the experience.

There are many ways in which this goal might be achieved, coupling the knowledge needed to distinguish the chemistry of cancer cells from ordinary cells with any one of a number of possible delivery systems. Over the past decade researchers have demonstrated the use of nanoparticle assemblies that glue together sensors for cancer cell characteristics and cell-killing compounds, but why build new molecular machinery when there so much of the stuff is already evolved and waiting to be used as raw materials? Take immune cells, for example, which already handily perform the function of attacking and destroying unwanted cells and other invaders. The use of engineered and trained immune cells is prevalent in modern cancer research, and trials of immunotherapies for cancer are in some cases a fair way along the road to widespread clinical availability. This may well win out to be the basis for most of the next generation of cancer treatment technology.

Beyond immunotherapies, however, there are bacteria and viruses to consider. These can also be engineered to attack cancer cells in a discriminating fashion, and self-replication is a powerful weapon in the therapeutic arsenal if it can be harnessed and controlled. While receiving less attention than immunotherapy these days, there are still a goodly number of impressive demonstrations in the laboratory of the ability of bacteria and viruses to mop up cancer when everything goes right. In clinical trials, there are still hurdles to overcome far more often than not, but it is perhaps encouraging that the same was true for immunotherapies not so very long ago.

Personalized virotherapy in cancer

The use of engineered oncolytic viruses (OVs) is a promising new therapy for cancer treatment. Different OVs have been engineered to express immune stimulatory molecules indicating that OVs can act at two levels, by directly killing malignant cells in concurrence with the simultaneous activation of the host anti-tumor immunity. OVs can be also combined with chemotherapeutic agents providing an aggressive platform for cancer attack. One of these OVs, a Herpes Simplex virus named T-VEC armed with GM-CSF has just completed a phase III trial in advanced melanoma with promising results and might reach the clinic after FDA approval.

Conditionally Replicative Adenoviruses are oncolytic adenoviruses (OAV) engineered to selectively replicate within and kill tumor cells. Selectivity is obtained through the use of ''cancer cell''-specific promoters (CCSP) that are selected to replace viral promoters and drive the expression of genes essential for OAV replication. OAVs replicate essentially in malignant cells with positive expression of the gene from which the CCSP was selected. OAVs efficacy can be also improved through the exchange of the capsid fiber of the virus or addition of specific moieties that will retarget vectors to enter the cell through alternative receptors.

As for other therapeutic modalities, viral spread and therapeutic efficacy is hampered by the extracellular matrix (ECM) barrier. The high resistance to conventional and targeted therapies in desmoplastic tumors of adults is largely due to the dense ECM. The ECM distorts blood and lymphatic vessels structure that hampers the possibility of systemically delivered therapies to reach the tumor mass. With this in mind, we started engineering OAVs whose replication was driven by CCSPs active both in the stroma and in the malignant compartment of the tumor mass. More recently we have shown that the OAV AV25CDC combined with gemcitabine exhibited a large efficacy and complete absence of toxicity in preclinical models of pancreatic cancer in mice and syriam hamsters. AV25CDC was able to disrupt tumor architecture by inducing an increase in MMP-9 activity that would have facilitated gemcitabine penetration deeply inside the tumor mass.

Since little if anything works in isolation inside a cell, many of the varied methods discovered over the past twenty years to modestly slow aging in laboratory species are in fact acting on a much smaller set of underlying mechanisms. Thus a steady flow of new discoveries like the one below continue to take place, a step by step exploration of the vast complexity of metabolism that will likely still be far from done by the time viable rejuvenation technologies exist, built based on a repair approach that bypasses the need for a complete understanding of cellular biochemistry in aging:

Long noncoding RNAs were until recently thought to exist and function predominantly in the nucleus. It is now fast becoming realized that they effusively associate with cytosolic ribosomes. Several functions for short noncoding RNAs bound to ribosomes have been described, such as those that derive from both mRNAs and tRNAs and function as stress-induced inhibitors of protein translation. It is thus becoming clear that ncRNAs, both short and long, are playing roles in protein translation that are only beginning to be fully appreciated.

The biogenesis of ribosomes and their coordination of protein translation consume an enormous amount of cellular energy. As such, it has been established that the inhibition of either process can extend eukaryotic lifespan. Here, we used next-generation sequencing to compare ribosome-associated RNAs from normal strains of Caenorhabditis elegans to those carrying the life-extending daf-2 mutation. We found a long noncoding RNA (lncRNA), transcribed telomeric sequence 1 (tts-1), on ribosomes of the daf-2 mutant. Depleting tts-1 in daf-2 mutants increases ribosome levels and significantly shortens their extended lifespan. We find tts-1 is also required for the longer lifespan of the mitochondrial clk-1 mutants but not the feeding-defective eat-2 mutants. In line with this, the clk-1 mutants express more tts-1 and fewer ribosomes than the eat-2 mutants.

The precise mechanism of the tts-1 lncRNA remains to be determined. One intriguing possibility is that it is specifically regulating the translation of ribosomal protein mRNAs. Supporting this notion is the observation that despite the marked reduction of ribosomal proteins in the daf-2 mutant proteome, expression levels of ribosomal protein mRNAs in the daf-2 mutants are actually higher than in wild-types. This suggests that a specific block of ribosomal protein gene expression at the level of translation is imposed in mutants undergoing lifespan extension, and we believe this will be an interesting area of future study. In sum, we propose that the tts-1 lncRNA is able to reduce ribosome levels in a manner that is necessary for lifespan extension. Since many recent reports demonstrate that both genetic and pharmacological manipulations of the translation machinery can extend longevity in eukaryotes, our study puts lncRNAs forward as a compelling area in the field of aging research.

Link: http://dx.doi.org/10.1016/j.celrep.2014.12.029

The klotho enzyme can be manipulated to slow aging in laboratory animals, and more circulating klotho is associated with enhanced cognitive function. Like many of the mechanisms found to modestly slow aging in short-lived species in the laboratory, the activities of klotho touch on many systems in the body and are far from completely cataloged. This is an example of some of the more speculative areas of investigation:

Klotho-deficient mice manifest a phenotype resembling accelerated human ageing. Klotho-deficient mice have a short lifespan, and overexpression of Klotho in mice extends lifespan significantly in comparison with normal mice, which is taken as proof of the concept that Klotho is associated with longevity. In a human population study, Klotho gene variations were found to be associated with life extension. Of particular interest was the finding that Klotho deficiency in mice was associated with a severe vascular phenotype of arteriosclerosis, impaired endothelial function, and impaired angiogenesis.

Klotho protein in mammals is present in different isoforms, as a membrane-bound protein and as a soluble form. Membrane Klotho confers tissue target specificity for FGF23. The function of Klotho as an obligatory coreceptor for FGF23 explains the nearly identical phenotypes that are observed in knockout mice lacking either Klotho or FGF23. Soluble Klotho is secreted into serum, urine, and cerebrospinal fluid. Serum Klotho or Klotho fragments can have humoral actions on tissues far distant from the site of biosynthesis. This is based on the observation of generalized involvement of tissues and organs outside the Klotho expression tissues in the prematurely ageing phenotype of Klotho-deficient mice and on the finding that administration of soluble Klotho ameliorated the premature ageing-related features, such as growth retardation, organ atrophy, and vascular calcification.

Experimental studies have shown that soluble Klotho, when delivered as a humoral factor, can protect the vasculature. Klotho gene delivery by adenoviral vector increased endothelium-dependent nitric oxide synthesis and prevented adverse vascular remodeling in an arteriosclerotic, obese rat model. Results from several in vitro models point toward a direct effect of soluble Klotho on vascular tissue. Recently, soluble Klotho has been shown to regulate vascular tonus, and a nitric oxide stimulatory ability was confirmed in vitro.

Uremia is potentially a state of Klotho deficiency based on decreased concentrations both at the tissue level and in the circulation, although determinations of serum Klotho levels are problematic. It is of high priority to better understand whether deficiency of Klotho contributes to the reduced longevity and other many severe complications in patients with chronic kidney disease, which are accompanied by a dramatic increase in the rate of cardiovascular morbidity and death.

In different experimental models soluble Klotho has been shown to protect against acute kidney injury, renal fibrosis, uremic cardiomyopathy, vascular calcification, and endothelial dysfunction. These observations are very important not only to understand the pathogenetic mechanisms involved, but also with respect to the development of future and more effective treatments and prophylactic measures, including replacement/substitution of the potentially missing hormone. In this context it is essential to know whether the uremic state is associated with reduced circulating levels of Klotho, whether local vascular production is reduced, and whether vascular tissue is an additional source of humoral Klotho. It is still an open question whether Klotho is present in the vasculature under physiological conditions, and, if so, whether it is changed in the uremic state.

Link: http://www.nature.com/ki/journal/v87/n6/full/ki201580a.html