Fight Aging!

Today, I'll point out the early stage company Retrotope, more out of curiosity than as an example of a research and development strategy that I'd favor pursuing. They don't make it terribly easy to see exactly what they're up to, as seems to be the trend for the online presence of young biotech companies these days, but the digest is that the staff there are trying to build therapies based on substituting deuterium for hydrogen in some of the molecules employed in cellular structure and machinery.

As long-time readers will no doubt recall, a slow trickle of evidence has arrived over the past decade to suggest that replacing a small fraction of hydrogen atoms with deuterium atoms in the proteins and other molecular machinery of a living organism produces a slight beneficial outcome to health and longevity. Deuterium is an isotope of hydrogen, with a nucleus containing a proton and a neutron rather than just a proton. So it is twice as heavy, but with the same single electron as hydrogen it has similar chemical properties. Molecules in which this substitution has been made have broadly similar characteristics, but there is enough of a difference to ensure that, for example, heavy water is toxic, more so to lower animals than to mammals, and, apparently, that a low level of deuterium substitution in cellular machinery can be slightly beneficial. In studies of deuterium substitution a common methodology is to culture worms, flies, and so forth, with a diluted dose of heavy water and then observe the results. You'll find examples back in the Fight Aging! archives.

This exploration has to date been anemic and far from conclusive, for all that it is a fascinating topic, and this is why I point out Retrotope. I imagine that the efforts to run a potential isotope substitution treatment through a clinical trial, currently in the recruitment phase, may prove to be the sharp edge of work that advances the state of knowledge regarding the effects of isotope substitution on cellular biology. It is undeniably interesting stuff from a life science perspective, regardless of its likely poor best possible outcome in comparison to damage repair approaches to treating aging. Even the current trial is for the inherited condition Friedreich's ataxia, with only vaguely similar mechanisms to aging involved in its pathology.

In any case, the basic plot here is based on the view that the presence of heavier isotopes helps to resist the effects of oxidative stress, the damage to molecular machinery caused by the presence of free radicals, whether produced by disease processes, aging processes, or less common issues such as radiation exposure. Somewhere between an absence of deuterium and enough deuterium to be toxic lies a level at which enough of a benefit is produced to be worth turning it into a treatment. This, at least, is the hope. Various other strategies aimed at ameliorating oxidative stress should give us some idea as to the plausible range of expected outcomes for this sort of approach. For example, you might look at the results from gene therapies to boost levels of the antioxidant catalase in cells. These are not large positive effects in the grand scheme of things, I'm sorry to say.

Pill of super­protective 'heavy' fat

Mikhail Shchepinov, director of Retrotope, a biotech company based in Los Altos, California, wants eventually to slow down the ageing process. But he is starting with a related problem - treating the inherited movement disorder Friedreich's ataxia, with which ageing shares a mechanism. They are both caused, in part, by a molecular attack on our cells. Shchepinov's idea is to counteract this assault by reinforcing our cells' defences, slowing the progression of this incurable disease. If it works, it should demonstrate that the approach is also suitable for tackling ageing.

He reckons we can protect our cells from free radicals simply by strengthening the bonds between molecules that make up our cell membranes. This can be done by swapping the hydrogen in the fatty acids for a different form known as deuterium. Because deuterium has an extra neutron, it is heavier than hydrogen and forms stronger bonds.

Targeting lipid peroxidation and mitochondrial imbalance in Friedreich's ataxia

Oxidative stress can be the cause and/or the consequence of mitochondrial energy imbalance, leading to cell death. Fibroblasts from two mouse models were used to analyse two different categories of protective compounds: deuterised poly-unsaturated fatty acids (dPUFAs) and Nrf2-inducers. The former have been shown to protect the cell from damage induced by lipid peroxidation and the latter trigger the well-known Nrf2 antioxidant pathway. Our results show that the sensitivity to oxidative stress of mouse fibroblasts, resulting in cell death and lipid peroxidation, can be prevented by d4-PUFA and Nrf2-inducers.

Retrotope: Products

Retrotope is currently assessing technical proof of principle, regulatory requirements, and viability of several products in multiple market segments. The company has a pipeline of products, including single agent and multiple stabilized polyunsaturated fatty acids (PUFAs), stabilized amino acids, each in a variety of indications. Pharmaceutical candidates include:

1) Fortified lysine: Anti-metastatic agent against cancer proliferation and fibrotic disease, downregulating the effects of LOX, a well documented target for pathological collagen crosslinking.

2) Stabilized fatty acids: Treatment and high risk mitigation of diseases involving oxidative mitochondrial membrane damage. Anti-proliferative for protein damage and aggregation in Parkinson's and other orphan central nervous system diseases, using stabilized fatty acid mimetics.

3) Episodic or regular intervention for radiation exposure events or at high radiation- risk populations (e.g. security personnel, military, etc).

In the most simplistic view, aging is little more than a matter of damage accumulation. The more damage you have, the worse your health, and eventually it kills you. At a very high level, this is in fact the way things are, but living organisms are extremely complex systems, and "damage" is made up of numerous primary causes, direct results of the normal operation of cellular metabolism. These spiral out into hundreds or thousands of secondary and later consequences: further damage, evolved reactions to damage, and so forth. The middle portion of the intricate web of biochemistry that links damage at one side to specific age-related diseases at the other is still comparatively poorly mapped, precisely because it is hugely complex. It is also surprisingly variable from individual to individual, for all that the basic root causes of aging are comparatively simple processes that occur in the same way for everyone.

Thus our situation is that frailty in aging is inevitable in the long run for any individual managing to somehow evade all of the late stage system failures of aging that kill without frailty, but over the present median human life span many people do avoid becoming frail before succumbing to those other ends. So there is some distinction between processes of aging and processes of frailty, for all that the latter is absolutely a function of the former. You might consider this to tie back into the fact that genetic differences have little effect on mortality and health until later in life. The effect of genetic variations on longevity is to a first approximation a matter of how your system manages to cope with being damaged.

Over the next few decades a great deal of effort will be devoted to understanding how exactly all of this works - mapping the middle of the linkage between damage and end results. This is effort that I hope to see side-stepped and evaded via the approach of repairing this fundamental damage, thus creating a toolkit of first generation rejuvenation therapies. How human biology reacts to being very damaged by the causes of aging is a field of research that I would like to live to see become an academic curiosity, along the lines of how human biology reacts to smallpox - something of interest, but neither vital nor important, because it will no longer be the case that people suffer in that state. We have the opportunity to make this happen in the years ahead, but that very much requires greater support and funding for SENS and similar lines of rejuvenation research.

Older people are at risk of developing frailty with advancing age. The prevalence of frailty increases from 2.5-3% in adults aged 65 years to 30-35% in those older than 85 years. These results suggest that an association exists between longevity and frailty. However, at the same time, even at advanced age, the majority of older adults are free of frailty, suggesting that factors different from those contributing to or produced by the life length are involved in producing frailty.

Genetic and epigenetic factors, nutrient-sensing systems, mainly the so-called insulin/insulin-like growth factor-1 signaling pathway, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, inflammation, and some hormonal systems are involved in longevity. However, factors involved in frailty are mainly inflammation and hormones, with an anecdotal role for genetic and other potential factors, but even these two common factors seem to regulate longevity and frailty in different ways. Moreover, their effect on frailty seems to change when they are acting in combination.

Link: http://www.karger.com/?DOI=10.1159/000382057

Since regular exercise extends healthy life span in mice, it isn't surprising to find it slowing the progression of specific manifestations of damage in aging:

Researchers found that structural changes that make the blood-brain barrier leaky and result in inflammation of brain tissues in old mice can be mitigated by allowing the animals to run regularly, so providing a potential explanation for the beneficial effects of exercise on dementia in humans. Old age is the major risk factor for Alzheimer's disease, like many other diseases. Age-related cognitive deficits are due partly to changes in neuronal function, but also correlate with deficiencies in the blood supply to the brain and with low-level inflammation.

Physical activity is already known to ameliorate the cognitive decline and sensorimotor deficits seen in old age in humans as well as in mice. To investigate the impact of long-term physical exercise on the brain changes seen in the aging mice, the researchers provided the animals with a running wheel from 12 months old (equivalent to middle aged in humans) and assessed their brains at 18 months (equivalent to about 60 years in humans, when the risk of Alzheimer's disease is greatly increased).

Young and old mice alike ran about two miles per night, and this physical activity improved the ability and motivation of the old mice to engage in the typical spontaneous behaviors that seem to be affected by aging. This exercise significantly reduced age-related pericyte loss in the brain cortex and improved other indicators of dysfunction of the vascular system and blood-brain barrier. Exercise also decreased the numbers of microglia/monocytes expressing a crucial initiating component of the complement pathway that others have shown previously to play are role in age-related cognitive decline.

Link: https://www.jax.org/news-and-insights/2015/october/exercise-prevents-age-related-changes

ALZFORUM is a long-running, industry-supported site covering Alzheimer's research, and the staff there turn out a good line in explanatory and popular science articles on the topic. This is something that we need a lot more of in the field of aging research, and especially for those portions of the field focused on SENS or SENS-like strategies of damage repair. Efforts like LIFEmag, the Longevity Reporter, the Rejuvenation Biotechnology Update quarterly emails to supporters of the Methuselah Foundation and SENS Research Foundation, and the publications of the Healthspan Campaign and similar are steps in the right direction, but there is still a sizable gap to be filled here.

Some of that gap is, I think, conceptual. People who are developing the symptoms of Alzheimer's - and their supporters and their caregivers - will do exactly what everyone else faced with currently intractable medical issues does: go online, network, find a community, read up on research. People suffering from aging, which is to say everyone, don't really exhibit all that much of the same behavior, however. Convincing the rest of the world to think of aging itself as a medical condition, amenable to near-future treatment, rather than a fact of life is perhaps still a hurdle to be overcome. In any case, today I'll point out a couple of articles recently published at ALZFORUM; see what you think:

Does the Blood-Brain Barrier Stand Up to Alzheimer's? Study Finds No Breach

The blood-brain barrier shields the brain from potentially harmful things, and some findings have suggested that this protective border weakens with age or disease. However, a study now reports that the barrier remains largely intact in multiple mouse models of neurodegenerative disease. The researchers also found that brains from healthy aging people bore the scars of just as many barrier breaches as those from Alzheimer's disease (AD) patients. This study contradicts previous work that has called disruption of the blood-brain barrier (BBB) both a cause and a consequence of AD pathology.

Researchers wanted to formally test the idea that AD disrupts the BBB. They are developing a strategy to smuggle therapeutic antibodies across the brain's border, hence evidence of an intact barrier would further support the need for such a trafficking route. The researchers previously developed bispecific antibodies, which recognize a different target with each of their two arms. While one arm recognizes BACE1, the other latches on to the transferrin receptor (TfR) expressed on endothelial cells lining the barrier, which then transport the antibody across via transcytosis. In plaque-ridden, 10- to 13-month-old PS2-APP mice, the researchers found that, as in wild-type mice, only the bispecific TfR antibody crossed the barrier efficiently, while BACE1 or control antibodies remained largely outside. This indicated that a barrier disruption large enough to let antibodies across did not occur in these AD mice. The same held true for two transgenic mouse models expressing disease-associated forms of human tau despite extensive tauopathy and neurodegeneration.

The authors' conclusion that the blood-brain barrier remains largely intact across models of neurodegenerative disease and in humans with AD contradicts many studies using differing techniques that say otherwise. What do results from AD mouse models say about the state of the BBB in human disease? Maybe the import of antibodies is limited because one big difference between animal models and human AD is the presence of cerebral amyloid angiopathy (CAA). In some people, the vascular amyloid deposits of CAA cause vessels to bleed, but most mouse models have no CAA.

Reinforcement, or Replacement? Stem Cell Strategies Divide to Conquer

Behind every successful neuron, there is a support crew of glia. Stem cell researchers are aiming to replace both types of cell in an effort to slow neurodegenerative disease. The defining characteristic of neurodegenerative disease is the death of neurons, and researchers have long searched for ways to either replace the fallen cells or bolster support for those that remain. Stem cell therapy offers opportunities to try both. Scientists have developed protocols to transform stem cells or induced pluripotent stem cells (iPSCs) into neurons of various persuasions, or into the glial cells that support them.

Another approach is to skip the complexity of the stem cell altogether and directly deliver trophins such as brain-derived neurotrophic factor (BDNF) or nerve growth factor (NGF). The latter has a long history. In 2001, researchers delivered NGF to people with probable AD by injecting directly into the striatum either patient-derived fibroblasts engineered to pump out NGF, or adeno-associated virus (AAV) expressing NGF. Recently, the scientists reported postmortem results from 10 patients who died between one and 10 years later. The researchers observed neurons undergoing a growth spurt - putting out axonal projections and expressing key signaling molecules - in the areas near the injection. In the viral gene therapy recipients, both healthy neurons and degenerating cells riddled with tau tangles expressed NGF, indicating that even sickly neurons retain the capacity to produce trophic factors. While the results did not reveal whether the trophic support slowed the pace of AD in these patients, they suggest that when such therapy is delivered, neurons respond.

Viral delivery of BDNF has shown promise in rodent models of neurodegenerative disease as well as in aging primates. However, the treatment is still in its preclinical stages as researchers grapple with the challenge of efficiently delivering the trophin to specific regions in the brain. Some researchers believe that the factors might work best when delivered by professionals (i.e., by glial cells that normally produce them). This was tried this in ASO mice, a model of dementia with Lewy bodies (DLB) that overexpresses human α-synuclein. These animals are riddled with Lewy bodies and develop both motor and cognitive deficits. The researchers transplanted neural stem cells (NSCs) derived from normal mice directly into the striata of 12-month-old ASO mice. They found that the transplanted cells differentiated into astrocytes and oligodendrocytes, and six weeks after the injection had migrated throughout the striatum and even into the neighboring cortex and amygdala. The transplanted cells restored the animals' deteriorating motor function, as well as learning and memory.

Last year, researchers demonstrated restoration of youthful activity of the thymus in old mice via increased levels of FOXN1. Rejuvenation of the thymus is one possible path towards at least partial rejuvenation of the immune system, as its decline in adulthood limits the supply of new immune cells, and that limit is one of the factors that creates dysfunction and dysregulation of the immune system in old people. In this paper researchers further characterize the age-related decline in FOXN1 levels in the thymus:

In human, the thymus-derived naïve T cell repertoire, capable to exert effective protection to foreign antigens, is established during early embryonic life and it reaches maximal size in childhood, subsequently, as antigen specific T cells are generated, the naïve T cell pool is gradually depleted. Thus, the limited naïve T-cell repertoire in elderly individuals is a major contributor to age-related immunodeficiency, a frequent cause of death. The immune compromised status results in the lack of effective immune response against pathogenic microrganisms and malignant cells. Because age related immunodeficiency is often life limiting as the cause of frequent nosocomial infections of the elderly, and because current treatment is insufficient, moreover it represents a significant medico-economic burden, there is a strong interest to develop effective and economically sound therapies. One possible strategy is the restoration of the naïve T cell repertoire via therapeutic regeneration of thymic activity.

In humans, as the thymus ages, thymic epithelial mesh is gradually replaced by adipose tissue. The process is thought to start at the first year of life and continues during aging, being accompanied by a decreasing export of naive T cells. The underlying molecular mechanisms responsible for the impairment of thymopoiesis in the aging thymus remains unclear. One possibility is that intrinsic mechanisms related to thymic epithelial cells (TEC) physiology are impaired in old individuals, since bone marrow precursors from old animals are able to colonize the thymus.

Studies in rodent models pointed out that the transcriptional factor forkhead box protein N1 (FOXN1) is both necessary and seemingly sufficient to induce differentiation of functional TEC. For the first time, we report here a striking three-fold decrease of FOXN1 expression over time in the human thymus, when comparing the "Postnatal" group with the "Adult" group. In fact, the decrease of TEC associated expression levels may be markedly higher, as due to the relatively lower lymphocyte content of the aging thymus, the relative abundance of TEC is increasing. We thus suggest that FOXN1 expression may limit thymopoiesis and its reduced expression may be responsible for thymic senescence.

To model age-related changes, we tested a human thymus derived epithelial cell line, hTEC, for expression of FOXN1. One of the most important epigenetic mechanisms that is often involved in transcriptional regulation during development is CpG methylation. To investigate the methylation status of CpG residues in the FOXN1 gene in the hTEC, we tested a candidate regulatory region (we named C20). In the C20 candidate region FOXN1 expressing skin cells show minimal methylation in 8 of the 13 candidate CpGs of the C20 region, while FOXN1 non-expressing leukocyte is highly methylated. Overall methylation is decreasing with age, and hypermethylation of the C20 segment of the hTEC provides a strong clue supporting our hypothesis, namely that hypermethylation may gradually silence the FOXN1 ultimately leading to decreased thymopoesis.

Link: http://dx.doi.org/10.1186/s12979-015-0045-9

Researchers here identify a possible way to identify and target T-cells that clutter up the aged immune system, impacting its effectiveness. A sizable part of immune decline in aging seems to result from the accumulation of large numbers of memory T-cells and exhausted or anergic T-cells at the expensive of naive T-cells capable of attacking threats. This may be due to the presence of cytomegalovirus, CMV, which is very prevalent and largely harmless, except for the fact that it cannot be cleared from the body and over the years the immune system devotes ever more of its limited resources to the problem.

This issue has a blunt solution: destroy the useless and the excess T cells, freeing up space for new competent immune cells to be generated as replacements. The basic concept has been demonstrated for other parts of the immune system; destruction of old, bad B cells led to the creation of fresh new B cells in animal studies, for example. A range of targeted cell destruction technologies are at various stages of development in the cancer research community, many of which can be coupled to arbitrary detection and delivery mechanisms. A whole field of research revolves around building future standards for platforms that can join a cell-killer to a sensor and delivery mechanism that discriminates targets by their particular surface chemistry. The first step on this road is finding a useful characterization of the target:

In acute infections, antigen-specific T cells differentiate into activated effector cells and then into memory T cells which rapidly gain effector functions and re-expand on subsequent encounter with the same pathogen. In contrast, during chronic infections, pathogen-specific T cells gradually lose effector functions, fail to expand, and can eventually become physically deleted. These traits are collectively termed T cell exhaustion, and have been described both in animal models of chronic viral infection as well as in human infections with hepatitis C virus (HCV) and human immunodeficiency virus (HIV). Identifying reversible mechanisms of T cell exhaustion is therefore a major goal in medicine.

Discovering surface markers of exhausted T cells is important for both to identify exhausted T cells as well as to develop potential therapies. We report that the ectonucleotidase CD39 is expressed by T cells specific for chronic viral infections in humans and a mouse model, but is rare in T cells following clearance of acute infections. In the mouse model of chronic viral infection, CD39 demarcates a subpopulation of dysfunctional, exhausted CD8+ T cells with the phenotype of irreversible exhaustion.

In this study, we demonstrate that, in contrast to CD8+ T cells from healthy donors, antigen-specific CD8+ T cells responding to chronic viral infection in humans and a mouse model express high levels of biochemically active CD39. CD39+ CD8+ T cells co-express PD-1 and are enriched for a gene signature of T cell exhaustion. In the mouse model of chronic LCMV infection, high levels of CD39 expression demarcate terminally differentiated virus-specific CD8+ T cells within the pool of exhausted CD8+ T cells. Thus, CD39 provides a specific, pathological marker of exhausted CD8+ T cells in chronic viral infection in humans and mouse models of chronic viral infection.

Link: http://dx.doi.org/10.1371/journal.ppat.1005177

Researchers have recently mapped a specific mechanism by which autophagy is connected with the onset of cellular senescence. Both autophagy and cellular senescence are important topics in aging research, associated with aging and longevity.

Autophagy is a set of complex recycling processes used by cells to eliminate damaged components and some forms of unwanted waste. In its most familiar form, autophagy involves tagging a cellular component such as a damaged mitochondrion, wrapping it in a membrane, and transporting it to a lysosome where it is dismantled. Enhanced autophagy has been observed in many of the methods and interventions shown to modestly slow aging in animal studies, though as is the case for calorie restriction it is very hard to pick out the degree to which any one change is responsible for slowing the pace of aging. Everything in the operation of cellular metabolism is interconnected, it is an enormously complex set of feedback loops and relationships, and nothing can be altered in isolation. That said, some studies in which researchers deliberately set out to increase the level of autophagy have shown life extension in lower animals, and it is not unreasonable to believe that increased cellular housekeeping should result in slower aging. Some researchers believe that autophagy is the important mechanism in most methods of slowing aging demonstrated to date. There is some interest in the research community in producing treatments based on enhancement of autophagy, but as yet there has been little concrete movement in this direction beyond early-stage investigations.

Cellular senescence is an evolved response to stresses, toxicity, and damage in tissues that, among other things, serves to reduce the risk of cancer by removing cells from the cycle of replication. A senescent cell ceases to divide and secretes signals that encourage nearby cells to also become senescent. Unfortunately this only works when comparatively few senescent cells exist. Once many of them accumulate, as happens by the time later life rolls around, their presence produces a range of very harmful effects on organs and tissues, and they even corrupt the local environment to the point of encouraging cancer growth. Senescent cells are removed by the immune system to some degree, but this also fails with aging. One of the most promising near-future rejuvenation therapies involves clearance of senescent cells, which might be achieved via any form of targeted cell destruction technology that can clearly identify the characteristic senescent cell chemistry from that of a normal cell. A proof of concept in mice showing improved health as a result of clearance was published earlier this year, and separately Oisin Biotechnology was seed funded to develop another method of clearance applicable to humans. A clearance method that reduces senescent cell levels to those present in a 30-something adult can be repeated as needed and can in principle completely remove this contribution to the aging process.

Given all this it is interesting to see one of the modes of autophagy and initiation of cellular senescence linked as described below, though the researchers' ideas for turning their work into potential treatments sound a lot more complicated and less likely to succeed than the easier target of simply destroying senescent cells every so often. One of the great advantages of senescent cell clearance as an approach is that it sidesteps an awful lot of work; figuring out exactly how and why senescent cells are produced and cause harm becomes an optional nice-to-have if you can just get rid of them.

Autophagy Works in Cell Nucleus to Guard Against Start of Cancer

The material that autophagy can digest ranges from a single molecule to a whole bacterium. Previously, all known substances consumed by autophagy took place outside the nucleus in the cell's cytoplasm. In the new study autophagy is shown, for the first time, to digest nuclear material in mammalian cells. "We found that the molecular machinery of autophagy guides the degradation of components of the nuclear lamina in mammals." The nuclear lamina is a network of protein filaments lining the inside of the membrane of the nucleus. It is a crucial network in the nucleus, providing mechanical support to the nucleus and also regulating gene expression by making some areas of the genome less or more available to be transcribed into messenger RNA.

In response to cellular stress that can cause cancer, the team found that LC3, chromatin, and laminB1 migrate from the nucleus - via nuclear blebs - into the cytoplasm and are eventually targeted for disposal. This breakdown of laminB1 and other nuclear material leads to a cellular state called senescence. Human cells have complicated ways to protect themselves from becoming cancerous, and one way is to drive themselves to become senescent, so that the cells can no longer replicate.

The team showed that when a cell's DNA is damaged or an oncogene is activated (both of which can cause cancer), a normal cell triggers the digestion of nuclear lamina by autophagy, which promotes senescence. Inhibiting this digestion of nuclear material weakens the senescence program and leads to cancerous growth of cells. "The nucleus is the headquarters of a cell. When a cell receives a danger alarm, amazingly, it deliberately messes up its headquarters, with the consequence that many functions are completely stopped for the cell. Our study suggests this new function of autophagy as a guarding mechanism that protects cells from becoming cancerous."

Although senescence suppresses cancer, which is the good side of this physiological balance, there is also a dark side. Senescence is associated with normal aging, and senescent cells accumulate in aged tissues, which impair the normal functions of the tissue and contribute to age-related diseases. The team noted that while autophagy digestion of the nucleus is able to restrain cancer, this machinery is improperly turned on during normal aging. "There is a short term 'tactical' advantage, but a long term 'strategic' defeat. This mechanism makes a normal cell, even without cancer stress, get old much faster, and in a detrimental way."

In support of this notion, the team found that in late middle-aged normal cells, blocking the autophagy-driven breakdown of the nuclear lamina can make cells live 60 percent longer. Looking toward the future, the team reasons that specific manipulation of the nuclear digestion by autophagy holds promise to intervene in age-related diseases. The team showed that a blocking peptide, which inhibits LC3-laminB1 interaction, is able to slow cell aging. The implications are that a small molecule could be made to stop the long-term dark side of the senescence pathway, and to treat age-related diseases, especially those related to chronic inflammation as seen in human aging.

Autophagy mediates degradation of nuclear lamina

Macroautophagy (hereafter referred to as autophagy) is a catabolic membrane trafficking process that degrades a variety of cellular constituents and is associated with human diseases. Although extensive studies have focused on autophagic turnover of cytoplasmic materials, little is known about the role of autophagy in degrading nuclear components. Here we report that the autophagy machinery mediates degradation of nuclear lamina components in mammals. The autophagy protein LC3/Atg8, which is involved in autophagy membrane trafficking and substrate delivery, is present in the nucleus and directly interacts with the nuclear lamina protein lamin B1, and binds to lamin-associated domains on chromatin. This LC3-lamin B1 interaction does not downregulate lamin B1 during starvation, but mediates its degradation upon oncogenic insults, such as by activated RAS. Lamin B1 degradation is achieved by nucleus-to-cytoplasm transport that delivers lamin B1 to the lysosome. Inhibiting autophagy or the LC3-lamin B1 interaction prevents activated RAS-induced lamin B1 loss and attenuates oncogene-induced senescence in primary human cells. Our study suggests that this new function of autophagy acts as a guarding mechanism protecting cells from tumorigenesis.

Recent historical data for the harm done due to the incidence of stroke in the old is similar to that gathered for many age-related diseases. With progress in medicine the risk of suffering a stroke is falling, and the following consequences are becoming less severe. To be clear, it is still a life-threatening, potentially fatal, crippling biological structural failure. Yet your odds are better today than they were last year, and continue to improve. Because there are more people in the world, and more of those people are living longer, the overall incidence and cost of stroke is increasing, however. An optimist might see this as a spur that will lead to more interest in treating the causes of aging, the collection of processes that are the underlying reason for stroke and all of the other catastrophic age-related failures of the cardiovascular system.

The objective of this study is to show geographic patterns of incidence, prevalence, mortality, disability-adjusted life years (DALYs) and years lived with disability (YLDs) and their trends for ischemic stroke and hemorrhagic stroke in the world for 1990-2013. Stroke incidence, prevalence, mortality, DALYs and YLDs were estimated following the general approach of the Global Burden of Disease (GBD) 2010 with several important improvements in methods. Data were updated for mortality (through April 2014) and stroke incidence, prevalence, case fatality and severity through 2013. Death was estimated using an ensemble modeling approach. All rates were age-standardized to new GBD estimates of global population.

Age-standardized incidence, mortality, prevalence and DALYs/YLDs declined over the period from 1990 to 2013. However, the absolute number of people affected by stroke has substantially increased across all countries in the world over the same time period, suggesting that the global stroke burden continues to increase. There were significant geographical (country and regional) differences in stroke burden in the world, with the majority of the burden borne by low- and middle-income countries. Global burden of stroke has continued to increase in spite of dramatic declines in age-standardized incidence, prevalence, mortality rates and disability. Population growth and aging have played an important role in the observed increase in stroke burden.

Link: http://www.ncbi.nlm.nih.gov/pubmed/26505985

This open access paper from some of the researchers involved in parabiosis research, aiming for at least partial restoration of youthful stem cell activity and tissue maintenance in old individuals, is a reminder that there is a lot of politics and happenstance in research, as in every other human endeavor:

It has been 10 years since the paradigm-shifting observations that in heterochronic parabiosis, the young systemic milieu rapidly and broadly rejuvenates organ stem cells in muscle, brain/hippocampus and liver, while the old systemic milieu rapidly and broadly ages myogenesis, liver regeneration and neurogenesis, with the responsible biochemical pathways being re-set to their young or old states. Before this work, the prevalent theories of tissue decline in aging focused on cumulative cell intrinsic changes as culprits: telomere attrition, DNA damage, oxidative damage, mitochondrial dysfunction, etc.). While all of the above continue to be true for differentiated cells, it is important to realize that organ stem cells age "extrinsically", and maintain a relative "youth" that could be due to the state of quiescence, which is default for most if not all postnatal stem cells. As such, stem cell regenerative capacity persists throughout life, but sadly, the biochemical cues regulating organ stem cells change with age in ways that preclude productive regenerative responses, causing the abandonment of tissue maintenance and repair in the old.

If all this has been known for 10 years, why is there still no therapeutics? One reason is that instead of reporting broad rejuvenation of aging in three germ layer derivatives, muscle, liver, and brain by the systemic milieu, the impact of the study published in 2005 became narrower. The review and editorial process forced the removal of the neurogenesis data from the original manuscript. Originally, some neurogenesis data were included in the manuscript but, while the findings were solid, it would require months to years to address the reviewer's comments, and the brain data were removed from the 2005 paper as an editorial compromise. The phenomenon and its magnitude were replicated, expanded and elegantly described in a 2011 paper, but if the friendly neighbor of the original lab had not been interested in this project after learning of our findings, this important result could have been lost or remained on a "back-burner" indefinitely. While it is certainly better late than never and even if the data are more elaborated than in the original manuscript, one can argue that the scientific community could already have been working on the extrapolation of these results and translating them into therapeutics against neuro-degeneration for 10 years.

Another reason for the slow pace in developing therapies to broadly combat age-related tissue degenerative pathologies is that defined strategies, which are "beyond parabiosis", for the rejuvenation of multiple old organs have been very difficult to publish in high impact journals; only the magic of "heterochronic parabiosis" seems to keep the editors' and reviewers' attention. As the result, in the current dynamically raging scientific waters, significant work that is directly relevant to attenuation or even reversal of human tissue aging (e.g., molecules that work in mice and are FDA approved or in clinical trials for human applications) can sadly get washed over, particularly, when relevant publications from lower impact journals are not always noticed or cited.

Link: http://www.impactaging.com/papers/v7/n10/full/100819.html

Here I'll point to a recent selection of news and research relating to tissue engineering and organ regeneration. If you look around at the state of this field, organoids and proto-organs and pseudo-organs are everywhere. Many laboratories are making strides in the generation of small sections of functional or partly functional complex organ tissue. Alongside and overlapping this work is the young field of bioprinting, the use of 3-D printers to create tissue from scratch, layer by layer, depositing scaffold biomaterials, protein solutions, and cells in precise locations and amounts to form complex structures that themselves self-assemble in further growth. Further, there is the parallel approach of regenerating and rebuilding existing organs in situ, built on the same underlying knowledge, but aiming to deliver cells and protein signals to spur regrowth inside the body that would otherwise not happen.

These lines of work are entwined with one another, linked together in often novel ways. For example, much of the present focus in organ engineering is not in fact to produce complete and fully functional tissues for transplantation, as that still lies a way in the future for most complex organs, but rather to create tools to speed up life science research. Organoids and proto-organs, even if only partly functional, are a much better and cheaper option than animal models when it comes to studying both diseased and healthy tissues. Anything that lowers the cost and increases the quality of the tools needed for research will speed up progress. So the researchers aiming to understand the molecular biology of regeneration sufficiently well to steer it in the body will in years ahead be working with tissue engineering organoids for their early stage research and initial technology demonstrations.

I don't think it overly ambitious at this point to expect the late 2020s to be a time of comprehensive organ engineering, with the production of most tissues - to order, as needed - being a widely available option in clinical practice. It will be interesting to see the degree to which transplantation flourishes in the face of the growing ability to instruct cells in the body to repair existing organs. After all, removing the need for potentially traumatic, expensive, and risky major surgery is a big incentive to improve stem cell therapies and regenerative medicine to their theoretical limits rather than focus on building new patient-matched organs for transplant.

Researchers hack off-the-shelf 3-D printer towards rebuilding the heart

"We've been able to take MRI images of coronary arteries and 3-D images of embryonic hearts and 3-D bioprint them with unprecedented resolution and quality out of very soft materials like collagens, alginates and fibrins. 3-D printing of various materials has been a common trend in tissue engineering in the last decade, but until now, no one had developed a method for assembling common tissue engineering gels like collagen or fibrin. The challenge with soft materials - think about something like Jello that we eat - is that they collapse under their own weight when 3-D printed in air. So we developed a method of printing these soft materials inside a support bath material. Essentially, we print one gel inside of another gel, which allows us to accurately position the soft material as it's being printed, layer-by-layer." One of the major advances of this technique, termed FRESH, or "Freeform Reversible Embedding of Suspended Hydrogels," is that the support gel can be easily melted away and removed by heating to body temperature, which does not damage the delicate biological molecules or living cells that were bioprinted.

Lab-grown guts show promise in mice and dogs

Starting with stem cells from the small intestines of human infants and mice, Hackam and his colleagues have for the first time grown intestinal linings on gut-shaped scaffolds that could one day treat bowel disorders like necrotizing enterocolitis and Crohn's disease. They have found that the tissue and scaffolding are not rejected, but instead readily assimilate in lab animals. Most strikingly, the scaffold allowed dogs to heal from damage to the colon lining, restoring healthy bowel function. The scaffold is made from a material similar to surgical sutures that can be formed into any desired intestinal size and shape, and is tube-shaped like a real gut, with tiny projections on the inner surface to help the tissue grow into functional small intestine villi, tiny fingers of tissue that help absorb nutrients. To grow the gut lining in the lab, the researchers painted the scaffold with a sticky substance containing collagen, dribbled it with a solution of small intestine stem cells, and then let it incubate for a week. They found that adding connective tissue cells, immune cells, and probiotics - bacteria that help maintain a healthy gut - helped stem cells mature and differentiate.

Study Finds Thyroid Function May Be Restored by Using Patient-Derived Human Cells

"With this paper, we've identified the signaling pathways in thyroid cells that regulate their differentiation, the process by which unspecialized stem cells give rise to specialized cells during early fetal development." After deciphering this natural differentiation process, the investigators duplicated it in the laboratory dish by adding a sequence of proteins, called growth factors, to the fluid bathing the stem cells. The team then used murine pluripotent stem cells to regenerate thyroid function in a murine model of hypothyroidism.

Tissue-engineered colon from human cells develop different types of neurons

A study has shown that tissue-engineered colon derived from human cells is able to develop the many specialized nerves required for function, mimicking the neuronal population found in native colon. These specialized neurons, localized in the gut, form the enteric nervous system, which regulates digestive tract motility, secretion, absorption and gastrointestinal blood flow. In healthy intestines, food is moved along the digestive tract through peristalsis - a series of wave-like contractions. Special nerve cells called ganglion cells are required for this movement, but there is also a rich mixture of other types of nerve cells. "The diversity of neuron types that grew within the human tissue-engineered colon was a revelation to our team, because previously we had only documented that some ganglia were present."

An accessible approach to making a mini-brain

If you need a working miniature brain - say for drug testing, to test neural tissue transplants, or to experiment with how stem cells work - a new paper describes how to build one with relative ease and low expense. The little balls of brain aren't performing any cogitation, but they produce electrical signals and form their own neural connections - synapses - making them readily producible testbeds for neuroscience research. Just a small sample of living tissue from a single rodent can make thousands of mini-brains. The recipe involves isolating and concentrating the desired cells with some centrifuge steps and using that refined sample to seed the cell culture in medium in an agarose spherical mold. The mini-brains, about a third of a millimeter in diameter, are not the first or the most sophisticated working cell cultures of a central nervous system, the researchers acknowledged, but they require fewer steps to make and they use more readily available materials.

The research noted here, in which scientists transplant young stem cells into old mice, is a logical exploration of the bounds of the possible along the lines of parabiosis studies, in which the circulatory systems of old and young individuals are linked. The results demonstrate that regular cell transplants incorporating young bone marrow stem cells can extend life when provided to older individuals, provided there is a close genetic match between donor and recipient. Without that match there was no effect on life span:

The method of lifespan extension that is a practical application of the informational theory of aging is proposed. In this theory, the degradation (error accumulation) of the genetic information in cells is considered a main cause of aging. According to it, our method is based on the transplantation of genetically identical (or similar) stem cells with the lower number of genomic errors to the old recipients. For humans and large mammals, this method can be realized by cryopreservation of their own stem cells, taken in a young age, for the later autologous transplantation in old age.

To test this method experimentally, we chose laboratory animals of relatively short lifespan (mouse). Because it is difficult to isolate the required amount of the stem cells (e.g., bone marrow) without significant damage for animals, we used the bone marrow transplantation from sacrificed inbred young donors, males and females of 1.5-3 months. Bone marrow transplantation (2 × 10^6 cells) was performed with the intervals of 3 months to the death of the animal. Experiments were started at age of 7-8 months for the recipients of the first and the second experimental groups and at age of 6-10 months for those of the third group.

It is shown that the lifespan extension of recipients depends on level of their genetic similarity (syngeneity) with donors. We have achieved the lifespan increase of the experimental mice by 34% when the transplantation of the bone marrow with high level of genetic similarity was used. The value of lifespan increase in our experiments varies from 34% for high-level syngeneic transplantation to 0% for allogeneic transplantation.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4605449/

In this paper the author looks ar the oucomes of past efforts to modestly extend life, mostly in the laboratory only, via the traditional drug discovery and development process, or pharmacology. I'd argue that any debate over targeting lifespan versus healthspan is an artifact of focusing on strategies that can do very little in the grand scheme of things, either slightly slowing aging or slightly compensating for one or more aspects of aging without addressing its causes. Only in this realm is it possible to produce therapies that could extend life without extending health to match. It becomes moot for true rejuvenation therapies that repair the underlying cell and tissue damage that causes aging, and are capable in principle of extending life by decades if made effective enough at that repair. At that scale of life extension, and by that methodology of damage repair, healthspan and lifespan are extended in tandem - it isn't possibly to move one independently of the other. Present damage determines both current health and future trajectory of health and mortality absent future repair.

The main goal of this paper is to present the case for shifting the focus of research on aging and anti-aging from lifespan pharmacology to what I like to call healthspan pharmacology, in which the desired outcome is the extension of healthy years of life rather than lifespan alone. Lifespan could be influenced by both genetic and epigenetic factors but a long lifespan may not be a good indicator of an optimal healthspan. Without improving healthspan, prolonging longevity would have enormous negative socioeconomic outcomes for humans. The goal of aging and anti-aging research should therefore be to add healthy years to life and not to merely increase the chronological age.

This paper summarizes and compares two categories of pharmacologically induced lifespan extension studies in animal model systems from the last two decades: those reporting the effects of pharmacological interventions on lifespan extension alone, versus others that include their effects on both lifespan and healthspan in the analysis. The conclusion is that the extrapolation of pharmacological results from animal studies to humans is likely to be more relevant when both lifespan and healthspan extension properties of the pharmacological intervention are taken into account.

Link: http://dx.doi.org/10.1089/rej.2015.1774

The so-called accelerated aging conditions, fortunately rare, are better thought of as DNA repair deficiency disorders, caused by specific inherited or spontaneous mutations that interfere with normally very efficient DNA repair processes. The results don't encompass all of the symptoms of aging, even if the outcome appears superficially similar to the late stages of normal aging, characterized by declining stem cell activity, faltering tissue maintenance, and the resulting failure of vital organs. This is perhaps best illustrated by the fact that it is not possible to just turn the situation around and generate enhanced healthy longevity via gene therapies that aim to boost the operation of DNA repair processes. This is demonstrated by the authors of the open access paper quoted below; they tested a variety of genes associated with different parts of the DNA repair infrastructure present in cells, and obtained quite mixed results on life span.

Engineering greater longevity in animal studies should be the first choice for a minimum standard of proof for the relevance of any particular cellular mechanism to aging, with other minimum standards involving many more mutually supporting lines of evidence for those cases where the life extension studies cannot yet be carried out for technical reasons. There are all too many papers out there in which researchers claim importance in aging on the basis of breaking a mechanism and observing reduced life span as a result. This isn't good enough, as the much more likely explanation in most cases is that breakage causes damage and dysfunction of forms that are irrelevant in normal aging, but which nonetheless raise mortality risk and shorten life. To create an exaggerated example, if you disable the operation of someone's liver, their life expectancy falls dramatically, but that doesn't put the liver at the center of the aging process, and nor does it mean that adding an extra liver to a healthy individual is going to significantly extend life.

This study of mixed results from attempts at DNA repair enhancement is interesting in that it is a step forward, but nonetheless fails to add clarity to the debate over the degree to which stochastic nuclear DNA damage is a meaningful cause of aging. The damage certainly grows with age and certainly increases cancer risk, but does it do more than this? Some researchers think that it dysregulates cellular metabolism to a large enough degree to matter, some do not. The research community is still in search of a definitive study that tips the evidence one way or another, but as this work shows that is likely to prove a complex undertaking:

Lifespan and Stress Resistance in Drosophila with Overexpressed DNA Repair Genes

Aging is a complex process that is far from being fully understood. Of the many factors that contribute to aging and the multiple changes on many levels that take place, one in need of further study at this time is the role of DNA repair. Because DNA damage does accumulate with age and appears to be associated with some of the detrimental aspects of aging, including neurodegeneration, boosting DNA repair mechanisms may be one approach to intervention.

Here, we investigated the potential life-extending effects of increasing the expression of genes known to be involved in DNA repair in Drosophila. We compared the overexpression of these genes throughout the body versus in the nervous system alone and throughout the lifespan versus in adulthood alone. We also included three known stressors. We found both positive and negative effects on lifespan, with many important variables, including gene, sex, stress exposure, extent of overexpression, developmental stage, and distribution of overexpression in the body.

The most pronounced effects of overexpression on lifespan occurred with Hus1, mnk, mei-9, mus210, spn-B, and WRNexo, which control the processes of DNA damage recognition and repair. Lifespan and stress resistance were interrelated, moreso in males than females, in that increased lifespan was associated with increased resistance to hyperthermia and oxidative stress, while decreased lifespan was associated with decreased resistance to all three stressors tested. Overexpression of DNA repair genes throughout development leads to opposite effects on lifespan when compared to adult-specific overexpression, and the direction of this dichotomy depends on whether the overexpression was ubiquitous or limited to the nervous system.

It is difficult to explain these effects on the basis of the available experimental or published data. Aging research is still in need of basic studies to address a wide variety of unanswered questions. This study presents a valuable set of preliminary data on the role of DNA repair in aging and points to a promising set of DNA repair genes and experimental conditions to pursue in greater detail in future studies that incorporate both transcription-level and protein-level effects on a wider variety of lifespan- and aging-related parameters.

A range of research groups are presently working on the development of biomarkers based on gene expression changes that occur with aging. Insofar as everyone suffers the same forms of cell and tissue damage that causes aging, it should be expected that cellular reactions to rising levels of that damage have similar patterns, albeit mixed in with environment effects and individual differences. A robust biomarker of aging would be a very useful thing to have to hand, as without it the only way to prove that a potential rejuvenation therapy in fact extends healthy life is to wait and see. That is slow and expensive, even in mouse studies, and this cost is a ball and chain holding back the pace of progress.

Researchers examined expression of genes in blood samples from 15,000 people across the world. They found 1,450 genes that are linked to ageing, and also uncovered a link between these genes and factors such as diet, smoking and exercise. The research team specifically looked for changes in gene expression, a process in which the information contained in genes is 'expressed' by reading the DNA sequence and creating RNA, and subsequently proteins. By looking in blood, the researchers aimed to find easy to measure markers of human ageing. This technique allowed them to develop a new method to predict people's 'biological age' and show that people with a biological age older than their actual age were more likely to have conditions such as high blood pressure or cholesterol. Many of the genes work together in pathways such as generating the energy supply of the cells (mitochondrial function), metabolic processes, and the stability and flexibility of the cells.

"This study has discovered many genes that change in their patterns of expression with age. This study has not only given insights into ageing mechanisms - such as mitochondrial function - but these techniques have potential use in prediction and treatment. Large, observational, and collaborative projects such as these provide a great platform to focus ageing research in the future, with the hope that predictive tests can be developed, and treatment strategies for age-related conditions improved."

Link: http://www.exeter.ac.uk/news/featurednews/title_478415_en.html

Several distinct lines of ongoing (but unfortunately poorly funded) research aim to restore at least some degree of youthful activity to the thymus in old individuals, and researchers here demonstrate one of them: a process of introducing young thymus cells into an old thymus. The thymus plays a vital role in the generation of immune cells, and during childhood the rate of production is high. In early adulthood the thymus atrophies in a process known as involution, however, and the supply of new immune cells diminishes to a trickle. This is one of the important limiting constraints that determine the way in which the immune system ages. Restoring an old thymus should improve immune function in adults, and given that the degeneration of immune function in the old is a large component of the frailty of old age, this is an important and much underrated goal.

The thymus reaches its maximum size early in life and then begins to shrink, producing fewer T cells with increasing age. This thymic decline is thought to contribute to age-related T cell lymphopenias and hinder T cell recovery after bone marrow transplantation. Although several cellular and molecular processes have been implicated in age-related thymic involution, their relative contributions are not known.

Using heterochronic parabiosis, we observe that young circulating factors are not sufficient to drive regeneration of the aged thymus. In contrast, we find that resupplying young, engraftable thymic epithelial cells (TECs) to a middle-aged or defective thymus leads to thymic growth and increased T cell production. Intrathymic transplantation and in vitro colony-forming assays reveal that the engraftment and proliferative capacities of TECs diminish early in life, whereas the receptivity of the thymus to TEC engraftment remains relatively constant with age. These results support a model in which thymic growth and subsequent involution are driven by cell-intrinsic changes in the proliferative capacity of TECs, and further show that young TECs can engraft and directly drive the growth of involuted thymuses.

Link: http://dx.doi.org/10.4049/jimmunol.1403158

Here I'll point out news of a recent study carried out in old rats, wherein the scientists involved claim a partial reversal of cognitive decline resulting from, probably, a reduction in chronic inflammation and increase in neurogenesis in the brain. The researchers pulled an existing drug from the rack for this experiment because it is known to affect the particular molecular targets they had in mind, but the results should be taken as a demonstration of the importance of inflammation and neurogenesis to brain aging, not as a sign that everyone should jump in and take that drug. It is only the particular tool of convenience for this study, and it is always wise to wait on replication of results and studies with larger numbers of animals in any case.

Neurogenesis is the term given to the production and integration of new neurons into the brain. It was only comparatively recently in the history of neuroscience, twenty to thirty years ago, that this process was proven to occur in adults. The consensus now is that a supply of new neurons is vital to learning and other forms of mental flexibility, and they have an effect on the overall behavior of neural networks that is large in comparison to their numbers. Unfortunately the pace of neurogenesis, like the pace of generation of new cells by stem cell populations throughout the body, declines with aging. This may be part of an evolved balance between death by cancer on the one hand and death by increasing frailty on the other. As molecular damage accrues to cells and tissues, created as a byproduct of the normal operation of cellular metabolism, too much cellular replication would speed the slow rise in the risk of fatal cancer. Conversely too little cellular replication will accelerate the slow decline into various forms of organ failure, nowhere more complex and subtle than in the brain.

Chronic inflammation contributes to a wide range of issues in aging, including most neurodegenerative conditions. The immune system runs awry and malfunctions with age, becoming ever more overactive and yet failing to accomplish its job at the same time. This excessive activity has consequences, including signals sent and received that change the behavior of cells and tissues. In short bursts this is necessary for regeneration and defense against pathogens, but when always on it causes harm. Higher levels of chronic inflammation resulting from metabolic dysregulation are probably one of the more important ways in which excess visceral fat tissue raises the risk of early death and of suffering all of the common age-related medical conditions along the way to that fate.

Will medical science produce the means to rescue people from the consequences of poor health and lifestyle choices? Yes, in the fullness of time. But that level of control - and reliability - remains a couple of decades away at least, I suspect. Metabolism is ferociously complex and still far from understood to the degree needed in order to create such science fiction staples such as safe obesity with perfect health. For the foreseeable future it is better not to get into that position in the first place, since at least some means of rejuvenation through repair of cell and tissue damage will probably arrive more rapidly. These are the important technologies to keep an eye on, as rising inflammation and lost neurogenesis are indirect consequences of this damage.

Old rat brains rejuvenated and new neurons grown by asthma drug

As we get older, most of us will experience some kind of brain degeneration. Typically, we lose the ability to make new neurons. Another problem is chronic, low-grade inflammation in the brain, which is implicated in many age-related brain disorders. To tackle both problems in one go, researchers targeted a set of receptors in the brain that, when activated, trigger inflammation. High numbers of these receptors are found in areas of the brain where neurons are born, suggesting they might also be involved in this process, too.

A drug called montelukast, regularly prescribed for asthma, blocks these receptors, so the researchers tried it on young and old rats. The team used oral doses equivalent to those taken by people with asthma. The older animals were 20 months old - roughly equivalent to between 65 and 75 in human years. The younger rats were 4 months old - about 17 in human years. The animals were fed the drug daily for six weeks, while another set of young and old rats were left untreated. There were 20 young and 14 old rats in total.

The rats took part in a range of learning and memory tests. By the end of their six-week drug regime, old animals performed as well as their younger companions. "We've restored learning and memory 100 per cent, to a level comparable with youth." When the team studied the brains of the animals, they found that old rats that had been given montelukast had 80 per cent less inflammation. They also had an enhanced level of new neuron growth compared with untreated old rats - about 50 per cent of that seen in young rats. The team also found that the blood-brain barrier - which stops infectious agents reaching the brain and which weakens in old age - was stronger in treated old rats. "Structurally, the brain had rejuvenated." The drug had no effect on young animals, probably because it targets inflammation associated with age and disease.

The researchers say the results from the rat study are significant enough to warrant a clinical trial, and will start by testing the drug in people with Parkinson's disease.

Researchers here demonstrate a more efficient path to the production of large numbers of patient-matched immune cells. Delivering large numbers of immune cells via infusion on a regular basis may prove to be a useful treatment for older individuals suffering the characteristic immune dsyfunction that accompanies aging, a near-term way to restore vital immune functions ranging from clearance of unwanted cells to defense against pathogens, a stop-gap to be used until the underlying causes of immune aging can be reversed. The cost of generating the necessary cells is a big determinant of whether or not a therapy is developed for widespread use, however.

Though immune therapy and regenerative medicine are promising areas of research for future medical therapies, they are limited today by the difficulty of creating stem cells, and scientists around the world are searching for ways to create somatic stem cells in the easiest way possible. Researchers have now found that in immune cells, simply blocking a transcription factor that leads to differentiation is sufficient to keep cells in a multipotent stem cell-like state where they can continue to proliferate and can later differentiate into various cell types. Efforts in the past to create stem cells have typically involved finding ways to take target cells and "dedifferentiate" them into multipotent cells, but this is typically a painstaking process.

The team took mouse hematopoetic progenitor cells - cells that give rise to white blood cells - and modified them to overexpress a protein called Id3. Id3 inhibits the expression of E-proteins, which are involved in differentiation in somatic cells. They then placed the cells into culture conditions containing certain cytokines, and instead of differentiating into B-cells, the cells continued to divide as stem cells. When placed in a culture that did not contain those cytokines, the cells differentiated into various immune cells. To test whether the cells would maintain their multipotency in living animals, the researchers transplanted them into mice whose white blood cells had been depleted, and showed that the new cells could expand and differentiate into various types of white blood cells.

To explore the potential for application, the group then attempted a similar experiment using human blood stem cells taken from umbilical cords, which they transfected with a vector encoding human Id3. They found that like the mouse cells, these human cells could be maintained in a dividing state and then prompted to differentiate by changing the conditions. "This is both a useful tool for giving us a better understanding of the genetic and epigenetic program controlling the self-renewal of stem cells, and on a practical side, it could allow us to inexpensively produce large numbers of immune cells, which could then be used for regenerative medicine or immune therapy."

Link: http://www.riken.jp/en/pr/press/2015/20151023_1/

An interesting study here correlates physical fitness to a specific measure of cognitive function and age-related change in brain activity in older individuals. There are numerous mechanisms that might link degree of fitness to the pace of change and neurodegeneration in aging, such as the structural integrity of blood vessels in the brain, which in turn connects to blood pressure, degree to which stiffening occurs in blood vessel walls, and so forth:

A new study shows, for the first time, the direct relationship between brain activity, brain function and physical fitness in a group of older Japanese men. They found that the fitter men performed better mentally than the less fit men, by using parts of their brains in the same way as in their youth. With tasks involving the temporary storage and manipulation of memory, long term memories and inhibitory control, young adults favor the right side of the prefrontal cortex (PFC), while older adults engage both the right and left PFC. In fact, with aging, we tend to use both sides of the PFC during mental tasks, rather than just one. This phenomenon has been coined HAROLD (hemispheric asymmetry reduction in older adults) and reflects the reorganisation of the brain as compensation for reduced brain capacity and efficiency due to age-related structural and physiological decline.

60 older men (aged 64-75 years) underwent an exercise test to measure their aerobic fitness. The men, whose physical fitness was found to vary widely, then performed a test to measure their selective attention, executive function and reaction time. This well-known color-word matching Stroop test involved showing the men words meaning color, such as blue, green, red, but asking them to name the color of the letters rather than read the word itself. When the color of the letters does not match the word - blue, red, green - it takes the brain longer to react. This reaction time is used as a measurement of brain function. Activity in the PFC region of the mens' brains was measured throughout the test.

As predicted for older adults, during the Stroop test both sides of the PFC are active, with no difference between right and left, verifying the HAROLD phenomenon amongst this group of men. Previous studies have shown that young adults favour the left side of the PFC for this task. Analysis of the relationship between brain activity and Stroop reaction time revealed that those men that favored the left side of the PFC while performing the Stroop test had faster reaction times. This indicates that older adults who use the more youth-like, task-related side of the brain perform better in this test. Next, the association between aerobic fitness and Stroop reaction time was analysed. Fitter men had shorter reaction times. Based on these findings, the researchers correctly predicted that higher aerobic fitness would be associated with higher left-PFC activity. In other words, fitter men tend to use the more youth-like side of their brains, at least while performing the Stroop test. "One possible explanation suggested by the research is that the volume and integrity of the white matter in the part of brain that links the two sides declines with age. There is some evidence to support the theory that fitter adults are able to better maintain this white matter than less fit adults, but further study is needed to confirm this theory."

Link: http://www.eurekalert.org/pub_releases/2015-10/uot-aba102215.php

Alzheimer's research is comparatively well funded, but the production of therapies based on the presently dominant amyloid hypothesis is proving to be a hard, slow grind. The most promising involve directing the immune system to break down amyloid-β or related proteins, but even this line of work is a litany of failed early stage trials at this point. Since theorizing and preliminary investigation of new theories is a lot cheaper than contributing to the messy and very complicated late stage development of potential amyloid clearance treatments, a lot of theorizing is taking place. This is human nature at work; any faltering steps for the majority position in a field will lead to more work on alternative theories, even if it is just a matter of it being harder than expected to turn science into medicine in this case.

The failures haven't dented the primacy of amyloid and tau as targets: the consensus is that this is a hard problem, and the Alzheimer's research community is essentially having to build all of the technology and infrastructure to make immune therapies for clearance of misfolded proteins work at all, never mind work for amyloid. Still, Alzheimer's research is indistinguishable at the edges from general research into understanding the biochemistry of the brain. The pathology of Alzheimer's is entangled with the way in which the brain works in quite fundamental ways, and this is one of the reasons why this research is so well funded: it is driving much of the progress towards a greater understanding of neural biochemistry at all levels.

That is the background. Here I'll point out a couple of minority hypotheses on the causes and pathology of Alzheimer's disease. These are often quite interesting in and of themselves, such as the painkiller hypothesis, but you should probably take both of these papers with a grain of salt. All research has to be critically considered, and not just for the details of a specific paper - small sample size, possible errors, other interpretations that would also explain the data, and so forth - but also in the context of the bigger picture. Does it connect to other well-supported research? Does it stand alone, with no other groups looking into it? Being both alone and associated with a large and active field is usually not a good sign; it's a quiet rejection on the part of other researchers, who would otherwise comment, experiment, and write their own variant theories based on it.

Different Brain Regions are Infected with Fungi in Alzheimer's Disease

The possibility that Alzheimer's disease (AD) has a microbial aetiology has been proposed by several researchers. Here, we provide evidence that tissue from the central nervous system (CNS) of AD patients contain fungal cells and hyphae. Fungal material can be detected both intra- and extracellularly using specific antibodies against several fungi. Different brain regions contain fungal material, which is absent in brain tissue from control individuals. Analysis of brain sections from ten additional AD patients reveals that all are infected with fungi. Fungal infection is also observed in blood vessels, which may explain the vascular pathology frequently detected in AD patients. Sequencing of fungal DNA extracted from frozen CNS samples identifies several fungal species. Collectively, our findings provide compelling evidence for the existence of fungal infection in the CNS from AD patients, but not in control individuals.

Divalent Copper as a Major Triggering Agent in Alzheimer's Disease

Alzheimer's disease (AD) is at epidemic proportions in developed countries, with a steady increase in the early 1900 s, and then exploding over the last 50 years. This epidemiology points to something causative in the environment of developed countries. This paper will review the considerable evidence that that something could be inorganic copper ingestion. The epidemic parallels closely the spread of copper plumbing, with copper leached from the plumbing into drinking water being a main causal feature, aided by the increasingly common use of supplement pills containing copper.

Inorganic copper is divalent copper, or copper-2, while we now know that organic copper, or copper in foods, is primarily monovalent copper, or copper-1. The intestinal transport system, Ctr1, absorbs copper-1 and the copper moves to the liver, where it is put into safe channels. Copper-2 is not absorbed by Ctr1, and some of it bypasses the liver and goes directly into the blood, where it appears to be exquisitely toxic to brain cognition. Thus, while aggregation of amyloid-β has been postulated to be the cause of AD under current dogma, the great increase in prevalence over the last century appears to be due to ingestion of copper-2, which may be causing the aggregation, and/or increasing the oxidant toxicity of the aggregates.

An alternative hypothesis proposes that oxidant stress is the primary injuring agent, and under this hypothesis, copper-2 accumulation in the brain may be a causal factor of the oxidant injury. Thus, irrespective of which hypothesis is correct, AD can be classified, at least in part, as a copper-2 toxicity disease. It is relatively easy to avoid copper-2 ingestion, as discussed in this review. If most people begin avoiding copper-2 ingestion, perhaps the epidemic of this serious disease can be aborted.

Of course a great many things parallel the past century of economic development, not just copper plumbing. This is one of the problems with the painkiller hypothesis as well: near everything associated with wealth, technology, and progress has an upward curve that happens to correlate with Alzheimer's incidence.

Resulting from parabiosis studies in mice, GDF-11 is one of the significant proteins identified to vary with age in blood. When augmented to youthful levels in old mice it produces partial reversal of some measures of degeneration via boosted stem cell activity. The underlying mechanisms for these findings were disputed, however, and here is the latest in that discussion:

Back in the 1950s scientists first showed that connecting the circulatory systems of old and young mice seems to rejuvenate the more elderly animals. A handful of labs have recently been racing to find factors in young blood that may explain this effect. Researchers claim that a specific protein, GDF11, may explain young blood's beneficial effects. They have reported that blood levels of GDF11 drop in mice as the animals get older and that injecting old mice with GDF11 can partially reverse age-related thickening of the heart.

Last May, however, another group reported that the antibody the Harvard team used to measure levels of GDF11 also detected myostatin (also known as GDF8), a similar protein that hinders muscle growth. This group concluded from a different assay that GDF11 levels in blood actually rise with age in rats and people. And in their lab, GDF11 injections inhibited muscle regeneration in young mice. Now, the original researchers say that this assay used to detect GDF11 and GDF8 was itself flawed. They found that the main protein detected by the antibody test is immunoglobulin, another protein that rises in blood level with age. Mice lacking the gene for immunoglobulin tested negative for the active form of GDF11/8 that the assay was thought to reveal. "They actually had very consistent findings to ours with respect to the blood levels of GDF11/8 with the antibody we all used, but their interpretation was confused by this case of mistaken identity."

A recently published study finding that GDF11/8 blood levels decline with age in people and are low in those with heart disease supports the contention that GDF11 has an antiaging role. To back up their earlier results, the original researchers again show in a new paper that daily GDF11 injections can shrink heart muscle in both old and new mice. But this time they note another observation: The mice also lost weight. "We don't have much insight into that right now, but we're looking into it." The findings suggest that as with other hormones, GDF11 may have "a therapeutic window" for beneficial effects - too much may cause harm.

Link: http://news.sciencemag.org/biology/2015/10/antiaging-protein-real-deal-harvard-team-claims

I had no idea that the the Milken Institute included a Center for the Future of Aging. In nature it is more AARP than Healthspan Campaign, which might explain the oversight. Here I'll point out an article published by the organization earlier this year, one of a number on the future of retirement that appeared around the same time. The bottom line is that change is upon us, and younger adults are largely planning for a future that won't happen: they will live far longer and in better health than the present common wisdom suggests, and most likely far longer than is predicted by the current actuarial models based on a continuing gentle upward trend in life expectancy. This is a time of great progress in biotechnology and medicine, a leap upwards and fundamental shift in the relationship between medicine and aging. In the past researchers were not trying to treat the causes of aging. Now they are.

Many see aging only in negative terms, with the talk about entitlement costs, dependency ratios, and the challenges of disease and financial insecurity. But increased longevity has contributed to unprecedented economic growth and opportunities for personal fulfillment that previous generations could only dream of. Innovations in genomics, personalized medicine, and digital health will mean more time to work, learn, contribute, and recreate. Respected leaders in science are focused on the possibilities of dramatic life extension. The odds are that millennials and the generations that follow will experience significantly longer lives. So conversation about the future of aging is not just about "boomers." It's about all of us. While there is no certainty that scientists will succeed in enabling radical life extension, that possibility alone should change the thinking of millennials about their futures. How should members of this generation prepare? Here are a few points to consider.

Plan for lifelong learning. Whether on campus or on-line, millennials will return to school several times in their lives to learn new skills, develop fresh perspectives, and expand their general knowledge and relationship networks. They'll benefit by learning with and from older adults, and older adults will, in turn, benefit from lessons they learn from millennial teachers. The habit of establishing intergenerational relationships and shared learning experiences will bring lifetime benefits.

Plan for lifelong work. Traditional retirement is ready to be retired. Millennials will continue to work for financial security in longer life and because the stimulus of work can enhance both health and well-being. Many millennials already understand the challenges of changing workplaces and professions. Flexibility and comfort with new environments will serve this generation well. Millennials should join with older adults to fight workplace ageism and advocate for part-time, shared, and flexible work options, knowing they'll be the beneficiaries of progressive workplace policies as they age.

Save and invest for the long term. Many in the current generation of older adults have not saved enough to support themselves and their families, with devastating consequences. Millennials came of age during the Great Recession, and many carry the burden of student loan debt. But by planning responsibly and effectively, and investing early, millennials can be better prepared than their parents for longer lives. Big cars and bigger houses may be appealing to some, but there are far more important priorities in life for all of us.

Link: http://www.milkeninstitute.org/publications/view/708

The Methuselah Foundation volunteers are setting up a new podcast series, to be published at the Bristlecone and available on mobile devices via the standard channels such as iTunes; you'll find links to the first few editions below.

The Methuselah Foundation continues to be very influential in that part of the research community interesting in making significant progress towards rejuvenation therapies and related technologies, and among the supporters of this work. Since spinning off the SENS Research Foundation into its own organization back in 2009, the Methuselah Foundation has focused as much on tissue engineering as on other needed advances in longevity-related medicine, such as through initiatives like the New Organ prizes and providing seed funding to bioprinting startup Organovo in its early stages. An eclectic range of other projects have also been funded, such as bowhead whale sequencing, funding for Oisin Biotechnology's work on senescent cell clearance, and of course the original Methuselah Mouse Prize to encourage the creation of greater healthy longevity in animal studies is still running.

Perhaps of greater importance is what you don't see. The networking and influence applied behind the scenes by Methuselah Foundation co-founders David Gobel and Aubrey de Grey, and by numerous allies inside and outside the scientific community, has played a large role in the transformation of the aging research community and the public perception of its work over the past decade, most importantly in the acceptance of treating aging as a medical condition, and the willingness of researchers to speak out in public on this topic. Fifteen years ago was a very different time, in which to talk seriously about extending human longevity was to risk your professional future in the research community. Forcing that to change was a necessary first step on the road to ending aging as a threat to health.

And now here we are, on the verge of prototype versions of several rejuvenation biotechnologies, with stem cell and genetic medicine advancing rapidly alongside, equipped with the ability to get out there and raise funds, to convince people that the golden future is just around the corner, if only the support is found. It's a whole new age in comparison to just a few short years ago, and a lot of people should be waking up to ask how they can help, and what will happen next. In the second and third podcast linked here you'll find an interview with David Gobel; I think you'll find it an interesting look at what the Methuselah Foundation is doing to help advance the cause of human longevity, accelerating progress towards numerous facets of the treatment of aging as a medical condition.

Episode 001 of the Methuselah 300 Podcast

An introduction to a new way of staying in touch with the the Foundation's work. In this episode, you'll learn what the podcast will be about and what you can expect to see in the future.

Episode 002 of the Methuselah 300 Podcast

In this episode of the Methuselah 300 Podcast, we'll interview founder Dave Gobel and learn what planted the seed for the idea that would grow into the Methuselah Foundation. You'll also learn the specifics of some of the innovations the foundation is working hard to create.

Episode 003 of the Methuselah 300 Podcast

In this episode of the Methuselah 300 Podcast, we'll continue our interview with founder Dave Gobel as he explains more of the areas of regenerative medicine that the foundation is working toward, some new partnerships and backers -including NASA - and how he believes future life will be impacted in the near and mid term by exciting progress currently being made in medical research.

Here I'll point out an article on research into nutrition and some of the aspects of aging that contribute to neurodegenerative conditions, such as chronic inflammation. The article discusses one representative program in a broader field that devotes significant resources to the study of nutrition and aging, something that I think is a waste of potential given what could be done instead with all that time, training, knowledge, and funding. We are in the midst of a revolution in biotechnology. Are investigations of altering diet really worth it? I think not.

It is my conjecture that there is a deep conceptual chasm separating science from the application of science. Science in medicine is the business of mapping what is, the bounds of the present situation, how things progress, how things work. The application of science to construct new medical technologies is all about changing all these things for the better. People enmeshed in the scientific community, the research funding community, and the ethos of the scientific method are largely absolutely terrible at stepping beyond what is to what might be. I think that's probably true of the population at large, as well, but in this particular portion of the larger human endeavor the result is a selection of very inefficient, stumbling strategic approaches to the application of science.

One of these, I think, is any attempt to consider nutrition a useful approach to manipulating aspects of aging. It is true that this is probably helpful if you are interested in mapping metabolism and the way in which metabolism and aging interact to cause disease and death due to accumulating damage and dysfunction. It provides points of comparison, slightly different paths of progression, and that's always a benefit when trying to decipher a very complex system. Calorie restriction research has certainly produce mountains of data on this front. But it has also failed to produce meaningful ways to extend healthy life after billions of dollars and two decades of research. In principle the approach of developing calorie restriction mimetic drugs cannot do more than slightly slow aging in humans, even if that line of research was going anywhere these days, and this is the absolute best of what can be done with altered nutrition. We have examples all around us, a century or more of very good data on what exactly the bounds of the possible are in terms of altering human aging via diet. The results are marginal, tiny in the grand scheme of things.

In summary these are all distractions. They are not legitimate paths towards healthy life extension, but in reality bad strategic choices by people who have not stepped beyond their primary goal, the scientific goal of obtaining more data on how aging happens here and now, in the present situation. If you don't like how aging happens today, then you need to look elsewhere for people who are trying to do something about it, such as to SENS research.

There has been widespread speculation that stem cells could be used to repair neurons damaged by degenerative diseases such as Alzheimer's and Parkinson's. In other cases, however, these cells could be part of the problem. "They do try and repair disease and aging. But when they do that too much, they can lead to brain tumors." The question was how could these neural stem cells be stimulated to produce more healthy cells without overproducing and creating tumors - and how could they continue to make cells as they aged? "Their aging involves many, many gene and protein networks, and to try and get a handle on that influence through a single gene or protein is very difficult." While some drugs have been shown to be effective in stimulating growth of new brain cells, results have been inconsistent.

A few years ago, the researchers began investigating a new angle: nutrition. "Food is medicine. Nutrition has the ability to affect many of those pathways at the same time. When we went looking for a director for our new laboratory, we were looking for a translational scientist who was conducting cutting-edge research related to nutrition and prevention of age-associated cognitive impairments - someone who would bring in new areas of research to the center and help move the field of nutrition and brain disease forward. I believe we found exactly the right person we are looking for. What's become very clear is that the regenerative capacity diminishes as you age. The question we will probably ask and answer is how do these nutritional requirements change and how do they tie into the regenerative ability. Once we answer that question, we can ask how we alter nutrition to achieve that."

To home in on those questions, researchers have focused on the role that inflammation plays in the aging of stem cells, as well as in neurodegenerative diseases. Research has shown that inflammation produces small proteins, or cytokines, in brain cells. Two of these types of proteins - amyloid and tau proteins - have been associated with Alzheimer's disease. "Particular genetic mutations can't process these proteins very well. The cells try and spit them out to get rid of them, but when they can't do that, the cells themselves can die." When they are able to expel them into the environment in the brain, they can affect other cells, which may not function properly, contributing to Alzheimer's. A similar protein called alpha-synuclein may be associated in a similar way with Parkinson's. The researchers have focused on the role that inflammation plays in the aging of stem cells, as well as in neurodegenerative diseases such as Alzheimer's and Parkinson's. By changing diet and nutrition, patients may be able to limit inflammation of brain tissue and prevent or even reverse these degenerative diseases by giving neural stem cells the ability to heal the damage.

Link: http://now.tufts.edu/articles/feed-your-stem-cells

Josh Mitteldorf here reports on the presentations given at a recent conference on the comparative biology of aging. He has a programmed aging point of view, considering aging to be an evolved genetic program that produces damage and dysfunction. On the other hand I as a long-time observer of the field, along with the majority the research community, consider the evidence to point to aging to be the result of accumulated cell and tissue damage, and where epigenetic and other changes are observed in old individuals, these are reactions to that damage. To the degree that this division steers research and development priorities, it is the most important debate in aging research.

Comparative biology is a field that has grown with advances in genetic biotechnology, and the plummeting cost of good genetic data is producing a wealth of information on long-lived species for those researchers who want to better understand how exactly age-related degeneration progresses from first cause to final outcome at the most detailed level of genetic and cellular mechanisms. The purpose of science is to generate knowledge, so all this is good and according to plan, but it seems to me to be largely unlikely to lead to great breakthroughs in methods to build rejuvenation therapies. We already know how to do that, which specific forms of cell and tissue damage to repair, and the problem there is directing more funding and attention to that work, not a need for more data. The comparative biology community may be well placed to answer questions about which forms of damage are more important than others, aiding prioritization in repair approaches, but even there it would be faster just to spend more efforts on repair and then see what happens as a result.

The conference was opened by a theoretical lecture by Tom Kirkwood, father of one of the more popular theories of aging. He admonished us that evolution is a mathematical science that yields specific and quantitative information about what aging can and cannot be. These provide a powerful mathematical underpinning for the understanding of aging.

The next morning, Annette Baudisch told us that in reality, nature has produced every combination of aging strategy that you can imagine, and some that you probably never imagined. The kind of aging that humans know is gradual and accelerating, leading to death on a timetable that is predictable within about 10-15%. But this brand of aging is a small minority in nature. There are salmon and octopuses and annual plants that reproduce in a burst and then die suddenly. There are beetles and jellyfish that are able to "age backward", reverting to a larval state under stress, then beginning life again with a fresh start. Baudisch coined the term "negative senescence" for a phenomenon that is not the same thing as this: most trees and some turtles and lobsters just grow ever larger and more fertile over decades or even centuries.

Closing the conference was a keynote address by Steven Austad. Austad warned us that much of what we have long assumed about the biology of aging is not to be taken literally without exception; and some of it is merely persistence of myth. He showed us the classic plot of animal size versus lifespan. In mammals, life span rises slowly, with about the 1/4 power of an animal's weight, which corresponds to a slope of 0.25 in the log plot. There are outliers where animals have managed to find strategies to suppress their death rates from predators and disease. Most birds live longer than comparably-sized mammals, and the most dramatic examples are people and bats. I had known that mice are outliers on the downside. Since mice provide food for a great number of predators, and they freeze to death over the winter; their life spans are below the trend line. What I learned from Austad is that the exceptions extend to all small rodents. For rodents less than 8 kg, there is no correlation at all between size and life span. No one, to my knowledge, has explained this.

As in his past work, Austad offers so much useful good sense in his keynote, and yet he clings to a view that aging is driven by an accumulation of damage, that it can be slowed but never reversed, that there are no genetic mechanisms that have evolved solely for the purpose of assuring a fixed (shorter) life span. The three points are related but not identical. Curiously the idea that damage is the root of aging is not the influence of evolutionary theorists, but far older, rooted in ancient concepts of impermanence. I know it is theoretically possible, and hope that it will prove generally true in practice, that the body knows how to repair all the important kinds of damage that accrue in aging, and is capable of restoring itself to a youthful state, given the appropriate signaling environment.

Austad's present research is based on the observation that misfolded proteins tend to accumulate in our cells, and are related to dysfunction and disease, most prominently Alzheimer's. Long-lived varieties need to keep proteins in the right conformation, with "chaperone" molecules that are particularly effective. Austad is isolating and transplanting some of these chaperone molecules from his menagerie of 500-year-old clams. Despite differences in theoretical perspective, I have found the community of aging biologists to be especially personable and gracious. I have known Austad and Kirkwood in the deep past, and Baudisch more recently because she belongs to the next generation. Before I had any reputation or credibility in the field, all of them responded to me personally and respectfully.

Link: http://joshmitteldorf.scienceblog.com/2015/10/19/from-roscoff-with-rotifers/

In mammals, reduced levels of myostatin or increased levels of follistatin, which acts to inhibit myostatin production, can be achieved by a variety of methods ranging from gene therapy to RNA interference, the standard panoply of technologies used to adjust the amounts of a particular protein in animal studies. Suitably altered levels of myostatin or follistatin result in greatly increased muscle growth, lower amounts of body fat, and in mice at least a possible but disputed modest life extension to go along with it. The most direct methodology is knockout of the myostatin gene, and this is the path chosen of late by Chinese researchers in their work on dogs, using CRISPR, one of the latest advances in genetic editing technology.

The creation of genetically altered, heavily muscled dogs is not an isolated line of research. There is at least one dog breed in which a myostatin mutation has occurred naturally, and the same goes for cows, another species heavily influenced by centuries of quite sophisticated human breeding strategies. There are even a few human natural myostatin mutants presently alive, as well-muscled as their animal peers. Gene therapies have been used for nearly a decade to create "mighty mouse" myostatin and follistatin mutants. Early this year scientists demonstrated myostatin knockout pigs using TALENs, another modern improvement on older methods of gene therapy.

Obviously this is a road that at some point branches away from the production of improved animal lineages towards the production of enhancements and therapies for humans. The conventional view is that enhanced muscle production is a viable therapy for the collection of wasting diseases known as myopathies and sarcopenia, the characteristic progressive loss of muscle mass and strength that occurs with aging. This would be a compensatory approach, a way to improve quality of life by overriding some of the results of damage or disease on the natural balance of muscle tissue repair and regeneration, but without actually fixing the damage itself.

I have in the past argued that myostatin or follistatin gene therapies look very much like an all upside treatment, something that everyone should undergo in an ideal world, not just older or sicker people, after it has been developed for use in humans. On the other hand SENS Research Foundation staffer Michael Rae has suggested more caution; if you look back at some of the archived posts on animal studies of myostatin knockout you'll see some of the data to back up that point of view. A decade of animal studies, naturally occurring mutant lineages, numerous mammalian examples of successful gene therapy, and early human trials of the same for myopathies is enough for some people, however. It is interesting to note that BioViva CEO Liz Parrish recently became the first publicly acknowledged healthy recipient of follistatin gene therapy, carried out as a first step towards spurring greater progress towards human clinical trials and treatments aimed at slowing or reversing the effects of aging.

All in all, if you were going to pick one gene therapy to move on with today, myostatin or follistatin would be near the top of the list given the present state of the art and the level of experience present in the scientific community. This is no doubt why the researchers here chose it as a first step in their program of producing genetically altered dog lineages. Their ultimate goal is the production of new models for disease research, not enhancement or treatments per se, but work on myostatin is sufficiently well advanced that it makes a good test case for the newer technologies and methodologies used along the way.

First Gene-Edited Dogs Reported in China

Scientists in China say they are the first to use gene editing to produce customized dogs. They created a beagle with double the amount of muscle mass by deleting a gene called myostatin. The dogs have "more muscles and are expected to have stronger running ability, which is good for hunting, police (military) applications. The goal of the research is to explore an approach to the generation of new disease dog models for biomedical research. Dogs are very close to humans in terms of metabolic, physiological, and anatomical characteristics."

Genome editing refers to newly developed techniques that let scientists easily disable genes or rearrange their DNA letters. The method used to change the beagles, known as CRISPR-Cas9, is particularly inexpensive and precise. Last month, the work was highlighted as part of a large Chinese effort to modify animals using CRISPR. The list of animals already engineered using gene editing in China includes goats, rabbits, rats, and monkeys. The efforts were described as a national scientific priority and part of China's effort to establish world-class research.

The dog researchers took much the same approach, directly introducing the gene-editing chemicals - a DNA snipping enzyme, Cas9, and a guide molecule that zeroes in to a particular stretch of DNA - into more than 60 dog embryos. Their objective was to damage, or knock out, both copies of the myostatin gene so that the beagles' bodies would not produce any of the muscle-inhibiting protein that the gene manufactures. In the end, of 65 embryos they edited, 27 puppies were born, but only two, a female and a male, had disruptions in both copies of the myostatin gene. They named the female Tiangou, after the "heaven dog" in Chinese myth. They named the male Hercules. In Hercules the gene editing was incomplete, and that a percentage of the dog's muscle cells were still producing myostatin. But in Tiangou, the disruption of myostatin was complete and the beagle "displayed obvious muscular phenotype," or characteristics.

Some of the SENS Research Foundation supporters in the Bay Area have organized a charity benefit party in Brisbane, just down the road a little from San Francisco, to be held on November 3rd. If you're in the area, give some thought to attending: your donations to SENS rejuvenation research programs will be matched dollar for dollar by this year's Fight Aging! matching fund. All these funds go towards advancing the state of the art in repairing the cell and tissue damage that causes aging.

This event is a great idea, and I'd love to see more of this sort of thing taking place. Charitable fundraising for medical research is hard work, but also largely a solved problem at the detail level. A wide array of time-proven strategies exist when it comes to raising modest amounts of money through your own personal network. You just have to get out there and persistently put in the time and effort, be willing to be known as someone who raises funds for a good cause.

SENS Research Foundation volunteer Walter Crompton and Johnny Adams will be hosting a Benefit Party for SENS Research Foundation on November 3rd at the 7 Mile House in Brisbane, CA. The party will include dinner, a live band, and a silent auction. Aubrey de Grey will be there to meet and greet all the attendees. Space is limited to 30 people, so book your tickets now.

When: November 3, 2015, 6:30 - 9:00 pm
Where: 7 Mile House
2800 Bayshore Blvd
Brisbane, CA

"You are invited to the first of a series of events dedicated to slowing and ultimately reversing aging (specifically the diseases of aging) in humans! Each event will benefit a different organization. Our premiere event will be held in the San Francisco Bay Area benefiting SENS Research Foundation. You can enjoy a luscious dinner and drinks, live jazz, a silent auction, and meet & greet celebrities - Aubrey de Grey, Irina Conboy and Michael Conboy - and get a tax deduction."

Link: https://www.eventbrite.com/e/eat-meet-tap-your-feet-2015-sens-research-foundation-benefit-party-tickets-19049821529

As this article points out, despite the fact that much is left to be determined in neurobiology, based on the current evidence and understanding it is reasonable to expect that cryopreservation of the brain via vitrification preserves the data of the mind. When considering cryonics as an end of life option this is the critical question: the whole point of the exercise is to prevent the pattern that is you from decaying away to nothing. While that pattern continues to exist, most likely encoded in the molecular structure of synapses, a preserved individual can wait for as long as it takes for technology to advance to the point at which restoration is a possibility.

Can any technology, even in principle, preserve the unique features of an individual's mind? We agree there is more to the mind than the synaptic connections between neurons. The exact molecular and electrochemical features of the brain that underlie the conscious mind remain far from completely explored. However, available evidence lends support to the possibility that brain features that encode memories and determine behavior can be preserved during and after cryopreservation. Cryopreservation is already used in laboratories all over the world to maintain animal cells, human embryos, and some organized tissues for periods as long as three decades. When a biological sample is cryopreserved, cryoprotective chemicals are added and the temperature of the tissue is lowered to below the glass transition temperature (typically about -120 C). At these temperatures, molecular activities are slowed by more than 13 orders of magnitude, effectively stopping biological time.

Although no one understands every detail of the physiology of any cell, cells of virtually every conceivable kind are successfully cryopreserved. Similarly, while the neurological basis for memory, behavior, and other features of a person's identity may be staggeringly complex, understanding this complexity is a problem largely independent of being able to preserve it. Direct evidence that memories can survive cryopreservation comes from the roundworm Caenorhabditis elegans. For decades C. elegans have commonly been cryopreserved at liquid nitrogen temperatures and later revived. This year, using an assay for memories of long-term odorant imprinting associations, one of us published findings that C. elegans retain learned behaviors acquired before cryopreservation. Similarly, it has been shown that long-term potentiation of neurons, a mechanism of memory, remains intact in rabbit brain tissue following cryopreservation.

It is easy to dismiss controversial practices such as cryonics and gloss over the research surrounding them, but we should remember and even respect that prevailing views are often shown to be incorrect, and that what is impossible now may be possible in the future. For example, Ignaz Semmelweis, the father of germ theory, was widely ignored when he proposed in the 19th century that nurses and doctors should wash their hands before treating patients. Even today, physicians are frequently incorrect when predicting outcomes in end-of-life situations. Cryonics deserves open-minded discussion, as do mainstream efforts to understand the nature of consciousness, preserve human tissue and organs for life-saving transplants, and rescue critically injured patients by understanding the boundaries between biological life and death.

Link: http://www.technologyreview.com/view/542601/the-science-surrounding-cryonics/

The SENS Research Foundation has released videos of the keynote addresses given at the Rejuvenation Biotechnology 2015 conference held earlier this year. The SENS Research Foundation is one of the very few organizations focused on speeding up progress towards medical technologies capable of repairing the cell and tissue damage that causes aging. This has been a neglected area of research and development, scattered across many fields in medicine, and with little coordination between research groups working on aspects of the same form of damage and degeneration. As a consequence the basic science is far ahead of its application; for more than twenty years now more than enough has been known to make real inroads into repairing the causes of aging and age-related disease. Yet all too little of that has happened, despite tremendous progress in biotechnology and its tools. What is needed today is much more work on turning what is known about cell and tissue damage - and how to fix it - into therapies, and this rather than the generation of ever more data on the detailed interactions between metabolism and aging, which is the present focus for the majority of the aging research community.

Fortunately significant progress on the basis for rejuvenation therapies has been made in the labs in recent years, even given the struggles for funding and attention. Senescent cell clearance has been demonstrated, as have methods of working around the consequences of mitochondrial DNA damage, and more besides. For organizations like the SENS Research Foundation this means that it is time to devote more energy to making connections with the for-profit medical development industry. More technologies will be arriving at the point of readiness for development in the years ahead, but the hand-off from research group to company to clinic is not something that just magically happens. It all requires organization, raising awareness, making connections, giving clear signals as to what is coming down the line. This is the purpose of the Rejuvenation Biotechnology conference series, to help smooth the path and build the network of relationships that will needed for what is to come. The next step is to bring large-scale funding to bear on creating the first generation of effective therapies to treat aging out of technology demonstrations of rejuvenation carried out in the laboratory.

Chas Bountra RB2015 Keynote

Chas Bountra is Chief Scientist at the Structural Genomics Consortium (SGC). Bountra's keynote provides an overview of how new medicines are commonly discovered and researched today, citing organizational and scientific challenges as the causes behind a process that is slow, costly and risky. In light of these factors, Bountra is developing - and succeeding with - a new approach to drug discovery at the University of Oxford's Nuffield Department of Clinical Medicine. The group works with a consortium of labs in Canada, US, Brazil, Sweden and Germany, collectively called the SGC. He outlines key initiatives that are accelerating the development of new medicines:

Pooling resources: Because there is high risk associated with this business, it is unrealistic to think that any one organization, group or individual can succeed alone. The SGC is working with a consortium of 10 large pharmaceutical companies, benefitting from their financial resources as well as their expertise in medicinal chemistry, screening, and drug discovery.

Crowdsourcing and transparency: the group freely shares its outputs (data, knowledge, reagents) with the academic, pharmaceutical and biotech world because such transparency creates trust, facilitates collaboration, and catalyzes science and drug discovery. This form of crowdsourcing science is opening up new areas of biology and disease understanding.

Immediate disclosure: Everything that the SGC does is immediately released to the world, disclosing its data, knowledge and new reagents (high quality tools for early target discovery). Making these assets publicly available helps to reduce unnecessary replication and wastage.

Frances Colón RB2015 Keynote

Frances Colón is the Acting Science and Technology Advisor to the Secretary of State, United States Department of State. Colón outlined the importance of advising political leaders in the areas of science and technology so they can make better, more informed decisions that lead to greater peace, stability and prosperity. Colón explained that science diplomacy is the interaction between science policy and foreign policy, or the translation of technology and scientific trends to political leaders who aren't particularly well versed in these areas. Bridging this gap allows for change in business and the way in which foreign affairs are handled. She noted that scientists working within the White House, are engaging with non political tools. While policy may dictate the nature of relationships between the U.S. and other countries, scientists cooperate across borders and political divides. As such, science diplomacy has been an excellent asset in many situations.

Researchers here demonstrate a stem cell therapy that produces improvements in a mouse model for dementia with Lewy bodies, a common form of neurodegenerative condition in which the mechanisms and progression overlap with those of Parkinson's disease to some degree. This looks like a compensatory therapy, partially restoring some of the lapse in necessary function in the brain that occurs due to damage without actually addressing the damage itself. In that it is an incremental improvement in the present mainstream approach to therapies for age-related disease, but still cannot possibly be as effective as approaches that succeed in repairing the damage. In synucleinopathies like dementia with Lewy bodies, that most likely means the development of methods to safely clear alpha-synuclein aggregates from brain tissues:

Neural stem cells transplanted into damaged brain sites in mice dramatically improved both motor and cognitive impairments associated with dementia with Lewy bodies. DLB is the second-most common type of age-related dementia after Alzheimer's disease and is characterized by the accumulation of a protein called alpha-synuclein that collects into spherical masses called Lewy bodies - which also accumulate in related disorders, including Parkinson's disease. This pathology, in turn, impairs the normal function of neurons, leading to alterations in critical brain chemicals and neuronal communication and, eventually, to cell death.

The researchers transplanted mouse neural stem cells into genetically modified mice exhibiting many of the key features of DLB. One month later, the mice were retested on a variety of behavioral tasks, and significant gains in both motor and cognitive function were observed. The researchers examined the effects of the stem cells on brain pathology and circuitry connecting neurons. They found that functional improvements required the production of a specific growth factor - called brain-derived neurotrophic factor - by neural stem cells. The team examined two of the key brain structures that become dysfunctional in DLB - dopamine- and glutamate-making neurons - to determine how BDNF might drive recovery. "Our experiments revealed that neural stem cells can enhance the function of both dopamine-and glutamate-producing neurons, coaxing the brain cells to connect and communicate more appropriately. This, in turn, facilitates the recovery of both motor and cognitive function."

To further confirm the importance of BDNF in these effects, the researchers modified the stem cells so that they could no longer produce the growth factor. When these modified cells were transplanted, they failed to improve behavioral function and no longer enhanced dopamine and glutamate signaling. Testing the possibility that BDNF alone might be an effective treatment, the researchers used a virus to deliver the growth factor to the brains of DLB mice. They found that this treatment resulted in good recovery of motor skills in the test rodents but only limited recovery of cognitive function. This suggests that while BDNF is critical to stem cell-mediated motor and cognitive recovery, it does not achieve this outcome alone.

Link: http://news.uci.edu/research/stem-cell-treatment-lessens-impairments-caused-by-dementia-with-lewy-bodies/

Supporters of the DRACO (double-stranded RNA activated caspase oligomerizer) approach to antiviral medicine have launched a crowdfunding campaign, seeking enough philanthropic funding to move forward from the excellent results in cell and animal studies. DRACO represents an entirely novel approach to the problem of viral infection, potentially applicable to near all viruses, including those that currently cannot be effectively treated. The SENS Research Foundation is acting as a sponsoring organization, allowing donations to be tax deductible. The legal side of setting up a non-profit takes a couple of years these days, so this sort of assistance is pretty common for new initiatives. DRACO has been featured at SENS conferences in past years, so it seems like a good match.

Viruses must infect human or animal cells in order to replicate, and virtually all virus-infected cells contain long double-stranded RNA, whereas healthy cells do not. DRACOs detect double-stranded RNA inside the infected cells and then cause those cells to commit suicide before the viruses can replicate and spread to other cells. DRACOs do not harm uninfected cells because DRACOs are only looking for the general structure of double-stranded RNA that is made by a wide variety of viruses. By the process of efficiently eliminating only virus-infected cells, DRACOs may be able to permanently cure viral infections that can currently only be controlled. When tested in human and animal cells, DRACOs have been nontoxic and effective against 15 different viruses, including rhinovirus (the common cold) and dengue hemorrhagic fever.

Currently, DRACOs are in the well-known Valley of Death - the financial and experimental gap between the previously funded National Institutes of Health (NIH) proof of concept experiments and the threshold for convincing major pharmaceutical companies to advance DRACOs toward human trials. This campaign has been set up to raise the funding necessary to bridge that gap. With your assistance, we hope to raise enough funding to test and optimize DRACOs against clinically relevant viruses in human cells. If successful, the results of those experiments should persuade pharmaceutical companies and other major sponsors to commit their own resources to advance DRACOs through large-scale animal trials and hopefully human trials. Without your assistance, DRACOs may never progress further, and their potential to revolutionize the treatment of viral infections may remain unfulfilled.

Link: https://www.indiegogo.com/projects/help-end-viral-diseases-with-dracos/

Good news from the SENS Research Foundation arrived today: the programs targeting harmful cross-links in human tissues are starting to make concrete progress. The occasion is marked by a publication in the prestigious journal Science that covers the establishment of one of the first basic tools needed to work with glucosepane, the most important constituent of age-related human cross-links.

Cross-links are sugary compounds known as advanced glycation end-products that form in the extracellular matrix as a natural byproduct of metabolic processes. They glue together proteins and alter the physical properties of the tissue as their numbers grow. Fortunately most are short-lived, but some hardy forms of glucosepane cross-link can linger for a lifetime, as our biochemistry hasn't evolved the mechanisms needed to remove them. These cross-links are a major cause of the reduced elasticity in skin and blood vessels that occurs with aging, among many other issues, but even blood vessel stiffening taken on its own is enough to kill people through hypertension, distortion of cardiovascular system tissues, and eventual catastrophic failure of the heart or blood vessel integrity.

The important thing to realize about glucosepane and research into cross-links is that next to no tools and methodologies exist to allow researchers to work with this compound in tissues and cell cultures. This is one of many small blind spots in the life sciences, places where the lack of basic development, documentation, and tooling has led to company after company, research group after research group deciding to do something else with their limited funds rather than be forced into building every last part of the basic toolkit they'd need to even get started. So while biotechnology has advanced by leaps and bounds on every side, every individual along the way made a rational short-term decision not to touch this area of research - and this despite the fact that it is a big, obvious target for the development of therapies that could help to extend healthy life and treat or prevent a wide range of age-related conditions that cause a great deal of suffering and death. Getting on with the thankless work of building the tools needed for glucosepane research was taken up some years ago by the SENS Research Foundation as a part of their efforts to unblock the road to rejuvenation therapies.

As for all such research programs coordinated by the SENS Research Foundation, this work was funded by philanthropic donations, including yours and mine made in past years. If you like what you see here, note that we're matching your donations to SENS rejuvenation research dollar for dollar for the rest of this year. Giving money to SENS research is a great way to help ensure that more progress occurs in the years ahead, moving down the road towards therapies capable of bringing aging under medical control, preventing age-related disease, and greatly extending healthy life.

As an aside, you'll see that the publicity materials quoted here talk about diabetes front and center. This is because the lifestyle disease of type 2 diabetes is where the funding is for cross-link research: yet another example of aging as the red-headed stepchild of medical science, locked in a closet and fed scraps, ignored in comparison to its potential for alleviating suffering and preventing death. In reality the real relevance is aging and the treatment of aging. Arguably the cross-link biochemistry of diabetic patients is somewhat removed from that of a healthy individual, as short-lived cross-links, including those that arrive in the diet, become much more important as a source of harm to organs in such a dysfunctional metabolism. It is a whole different picture, in which some facets overlap, but of course research establishments must ever follow the funding.

SRF-Funded Glucosepane Paper in Science

A new study funded by the SENS Research Foundation sheds greater light on diabetes and aging through a synthetic process. The new process will allow researchers to study glucosepane, a key molecule involved in diabetes, inflammation, and human aging. Glucosepane is considered to be a critical chemical link in both diabetes and aging. It is also an independent risk factor for long-term microvascular complications in diabetes. With access to synthetic glucosepane, scientists will now be able to generate tools to examine the role this molecule plays in human health and perhaps, develop molecules to inhibit or reverse its formation.

Glucosepane contains a rare isomer of imidazole, which has never before been observed in natural molecules, other than those in the glucosepane family. The researchers developed a new methodology for synthesizing this imidazole form that requires only eight steps.

"We are extremely proud to have supported this project and the developments leading to better insights on diabetes and aging. To have Science recognize the accomplishment of this team doesn't just demonstrate the value of our contribution to medical research; it helps raise awareness that the SENS Research Foundation approach can lead to better insights about aging and age related disease."

Concise total synthesis of glucosepane

Glucosepane is a structurally complex protein posttranslational modification that is believed to exist in all living organisms. Research in humans suggests that glucosepane plays a critical role in the pathophysiology of both diabetes and human aging, yet comprehensive biological investigations of this metabolite have been hindered by a scarcity of chemically homogeneous material available for study. Here we report the total synthesis of glucosepane, enabled by the development of a one-pot method for preparation of the nonaromatic 4H-imidazole tautomer in the core. Our synthesis is concise (eight steps starting from commercial materials), convergent, high-yielding (12% overall), and enantioselective. We expect that these results will prove useful in the art and practice of heterocyclic chemistry and beneficial for the study of glucosepane and its role in human health and disease.

Researchers here advocate one of the many varied theories on Alzheimer's disease, in this case that the mitochondrial dysfunction that occurs with age is an important root cause of the condition. Over the past twenty years, a sufficient understanding of Alzheimer's to make good progress in producing therapies has expanded to include the need to understand a fairly large chunk of the cellular biochemistry of the brain: it is a complex condition, and given the ongoing struggles to make the initial approach of amyloid clearance work in any practical way, alternative hypotheses are springing up. You might take note of the point made in this paper on the dubious relevance of genetic studies to much of the prevalence of Alzheimer's, given the tiny proportion of cases that are familial versus sporadic. It is worth bearing in mind when reading other research reports from the field:

Alzheimer's disease (AD) is a progressive neurodegenerative disease that represents the most common form of dementia among the elderly. Despite the fact that AD was studied for decades, the underlying mechanisms that trigger this neuropathology remain unresolved. Since the onset of cognitive deficits occurs generally within the 6th decade of life, except in rare familial case, advancing age is the greatest known risk factor for AD. To unravel the pathogenesis of the disease, numerous studies use cellular and animal models based on genetic mutations found in rare early onset familial AD (FAD) cases that represent less than 1% of AD patients. However, the underlying process that leads to FAD appears to be distinct from that which results in late-onset AD. As a genetic disorder, FAD clearly is a consequence of malfunctioning/mutated genes, while late-onset AD is more likely due to a gradual accumulation of age-related malfunction.

Normal aging and AD are both marked by defects in brain metabolism and increased oxidative stress, albeit to varying degrees. Mitochondria are involved in these two phenomena by controlling cellular bioenergetics and redox homeostasis. In the present review, we compare the common features observed in both brain aging and AD, placing mitochondria in the center of pathological events that separate normal and pathological aging. We emphasize a bioenergetic model for AD including the inverse Warburg hypothesis which postulates that AD is a consequence of mitochondrial deregulation leading to metabolic reprogramming as an initial attempt to maintain neuronal integrity. After the failure of this compensatory mechanism, bioenergetic deficits may lead to neuronal death and dementia. Thus, mitochondrial dysfunction may represent the missing link between aging and sporadic AD, and represent attractive targets against neurodegeneration.

Link: http://dx.doi.org/10.1007/s10522-015-9618-4

Complaining about the way in which the popular press garbles and misrepresents aging research is evergreen. The economic incentives operating on professional journalists mean that they garble and misrepresent everything; it is how they operate. When you can make money by selling garbled, misrepresented stories as news, and spending more to get it right doesn't cause you to make more money, then it is inevitable that the end result is of low quality. Specialist knowledge and effective fact checking are not cheap propositions when compared with the cost of paying for writers. Some people argue that the situation has become worse in this modern age of low-cost communication, but I suspect that it has just become easier to see the true scope of the problem. After all, these days we have easy access to both original source materials and the specialists who know what is actually going on under the hood.

I don't agree with all of the article quoted below, in particular the matter of whether or not advocates and scientists should avoid talking about greatly extending human longevity. I think that it is useful and necessary to talk about radical life extension of decades or centuries. The bounds of any discussion fall somewhere in the middle of its far extremes, and if no-one is talking about complete medical control over aging, then the middle ends up being support for some mediocre goal such as the original Longevity Dividend proposal of finding drug candidates to slightly slow aging in ways that might add five years to the healthy human life span, assuming you're not already old when the drugs arrive. So much more than that is possible and plausible - actual rejuvenation treatments based on repair of the damage that causes aging - but only if there is widespread support and large-scale funding for the work.

The last few years have seen a dramatic increase in the attention given to science intended to increase healthy human lifespan. This increased coverage, as anyone would assume, should have represented a step forward. With astronomically wealthy private entities such as Google in support, many predicted a move toward a more legitimate and widely accepted status for both the industry and its advocates, investors, and experts. However, coverage of research and developments is still being taken out of context and hyped up to the point of farce. The main issue being the media's fixation with the notion of immortality.

The media's obsession with immortality is of course rooted in the need for an attention-grabbing headline. Ignoring the science and focusing on the possible fantastical outcome of living forever is an easy way to reel in readers. The problem with this coverage is that it doesn't show any interest in the actual progress of science, and further alienates the industry, associating the bizarre with the real and critical.

Furthermore, for readers, these attention grabbing headlines are neglecting the actual scientific processes and complexities of anti-aging research. What we are left with is a stripped down version of the industry, which doesn't reflect the developments in healthy life extension, and withdraws from any real in depth analysis. Advocacy coming from among those who are interested in immortality will no doubt increase, but not the awareness amongst the general population, what the industry is really aiming for.

Rather than being seen as a single issue subject, life extension science wants to be seen for what it is, an important and complex area of science aiming to eradicate age-related disease. Real and, in many ways, awful diseases and conditions which blight us later in life, no matter how much our lifespan has increased. For journalists and news outlets covering life extension, instead of conceding in creating clickbait titles which attract one-time readers on the subject, why do they not engage in a debate and provide real analysis, which would more than likely, over time, establish a base of returning readers.

Life extension has been granted its place in mainstream media, which many areas of science would still love to acquire, but this elevated position is currently not doing anyone any favours. With this obsession with immortality, people who could be potential supporters and advocates of healthy life extension are put off. By asking the question 'do you want to live forever?' rather than 'do you want to see more investment in cures for age-related disease?' the media faces the reader with a fantastic and in many ways terrifying notion, instead of one which is entirely practical and more likely to be universally supported. Greater exposure then, of this kind, has a direct negative impact on advocacy.

Link: http://lifemag.org/article/the-media-s-fixation-with-immortality-is-it-becoming-a-problem

It is by now the established model for crowdfunding efforts to keep going for the full span of time allotted at launch and add stretch goals if the original target is reached early. The mitochondrial repair research project running at Lifespan.io hit its $30,000 goal at the end of last month, and so now we have stretch goals - see below for the updates.

The funds raised by this initiative will be used by the SENS Research Foundation to further in-house efforts at their Bay Area research center to apply allotopic expression to the whole mitochondrial genome. This involves gene therapy to introduce versions of all mitochondrial genes of interest into the cell nucleus, while amending the proteins produced in ways that ensure they will be transported back into the mitochondria where they are needed. This in effect creates a backup source of protein machinery needed for correct mitochondrial function and should make mitochondria, the cell's power plants, immune to the consequences of accumulating damage to their DNA, something that is thought to be a significant contributing cause of aging. Working allotopic expression therapies for all mitochondrial genes should be a cheap one-shot rejuvenation treatment, mass produced infusions that are the same for everyone and effective for everyone.

The groundwork for this approach has been laid over the past decade, some of it funded by early donors to the SENS Research Foundation. Across the pond those years of research have blossomed into commercial efforts at Gensight, where allotopic expression of a single mitochondrial gene is being developed as a therapy for the inherited condition Leber's hereditary optic neuropathy. A lot of money is going towards that effort, which should go a long way towards making the underlying technology robust and palatable to regulators. That in turn allows researchers interesting in treating the damage to mitochondrial DNA in aging to focus on expanding the application of allotopic expression to all relevant portions of the mitochondrial genome.

Since donations to this crowdfunding initiative go to the SENS Research Foundation, the Fight Aging! matching fundraiser will match all such donations made on the 1st of this month or later, the date on which our fundraiser launched. The generous philanthropists who put up the funds for our $125,000 matching fund will match dollar for dollar all donations made to the SENS Research Foundation until the end of this year - or until the fund runs dry, which I hope will happen first. There is $90,000 or so left in the fund at this time. What are you waiting for?

MitoSENS Mitochondrial Repair Project: Updates

Hi everyone, thanks so much for your support in reaching our initial goal! I'm proud to announce that we have just received a donation from a local company in the form of a large quantity of free DNA primers. We used the donation to design a huge set of primers that we can use to make dozens more mitochondrial targeting sequences (MTSes) to test for their ability to target proteins to the mitochondria. So instead of the 3 that we've tested so far we could test many different ones that we suspect might be good candidates as stretch goals for this campaign.

If we reach a total of $45,000 we can test all of these MTSes on ATP6 and see if we can bring it up to full activity.

If we reach a total of $60,000 we can also test all of these targeting signals on a 3rd gene, Cytochrome B, which has long been a challenging gene for us and others in the field to make functional. If we can get this gene working, we should be able to make any gene in the system work.

In addition, we are excited to announce matching funds! Several of you have asked for this. For every dollar that you donate to the Mitochondrial Repair Project another dollar will go directly into the SENS Research Foundation general fund to support all the great research we do at SRF. Thanks to Fight Aging! for helping to organize this fund to match your donations!

Smokers have significantly worse health and die younger than the rest of us, with much of this thought to be due to inflammation and other immune system effects. Researchers here look at some of the proteins for which altered levels are already known to be associated with aging and longevity in humans and mice, in particular FGF-21, finding differences between smokers and non-smokers:

The average life span of smokers is more than 10 years shorter than that of non-smokers, and it is said that smoking is a factor which accelerates aging. However, the details of the mechanism which accelerates aging due to smoking was not yet clear. A research group found that smoking habits affected the aging-related molecule α-klotho (αKl) in blood serum. In addition, this group also elucidated that smoking causes a rise in blood serum concentration of fibroblast growth factor (FGF)-21, a factor related to metabolism which has gained attention in recent years.

The group focused on the relationship between smoking and aging, examining the involvement of Klotho in the advancement of aging due to smoking. It was found that the levels of FGF-21 related to metabolism, α-Klotho, and interleukin(IL)-6, a cytokine related to inflammation, were significantly higher in smokers than in never-smokers. In addition, the blood serum concentration of α-Klotho rose in stressful conditions such as lack and sleep and being under emotional stress outside of smoking. FGF-21 is negatively-correlated to adiponectin, which is known as a cytokine related to metabolism, and the rise in FGF-21 in smokers is thought to suggest a metabolic disorder.

By contrast, it was shown that in never-smokers, α-Klotho has a positive correlation with IL-6, but this correlation was not found in smokers. Past reports have stated that α-Klotho holds anti-inflammatory effects, so it is thought that the lack of this correlation between α-Klotho and IL-6 in smokers is possible due to the weakening of anti-inflammatory effects of α-Klotho brought about by smoking stress.

Link: http://www.alphagalileo.org/ViewItem.aspx?ItemId=157275&CultureCode=en

Here, a few notes on the study of sea anemones, among which are examples of negligibly senescent species. These are comparatively rare species in which individuals do not seem to suffer the effects of degenerative aging, or where they do it is considerably less pronounced than in their near relatives. In lower animals the degree to which individual immortality is possible in principle appears to be greater. The continual and highly proficient regeneration of the sort seen in lower animals such as hydras and anemones, in which every body part can be regrown from a remnant, falls by the wayside somewhere on the way to the evolution of a complex brain and central nervous system, however. It remains an open question as to what of use to medicine can be learned from the study of the biochemistry of negligibly senescent species that are very distant from us:

Sea anemones are soft bodied animals that attach themselves to rocks and coral reefs in shallow waters. There are more than 1,000 species of anemone, varying in size from a few centimetres to more than a metre across. They live in every ocean, from the warmest to the coldest. "As far as we know, these are immortal animals. They live a very long time - one was documented to have lived 100 years. They don't have old age. They live forever and proliferate, just getting bigger." If you cut off their tentacles, they grow new ones. Even if you cut off their mouths they grow new "heads." As long as they are not poisoned or eaten, as is often the case, they seem to go on and on.

They appear to avoid ageing and the adverse effects that humans experience over time. "You should see tumours in these animals, but we have very few descriptions of that. They are constantly replenishing themselves without getting cancer." Instead of ageing, anemones seem to stay young and fully functioning. "If I look at a sea anemone today and compare it to a week later the same structure will be there but many of the cells will have been replaced." How it does this isn't clear. "We would love to be able to find a gene or pathway that allows it to avoid ageing. Sea anemones are the simplest animals we know of that have a nervous system - it's not organised in the same way as ours, but they do have a network of neurons that allows them to respond to stimuli and be very active predators. Genetically, sea anemones share a lot with us. We found a lot of similarities we had not seen when comparing humans to fruit flies or nematodes."

Link: http://www.bbc.com/news/magazine-34454844

Today I'll point out a study whose authors believe that the the fairly new consensus on sitting as a bad influence on long-term health is essentially mistaken. That there is a correlation between time spent sitting and mortality has been one of the more interesting results to emerge in recent years from the sea of statistical data on long-term health in humans. If this was just a matter of more time spent being sedentary correlating with higher mortality rates this would not be remarkable; that is the expected outcome in the middle range of the dose-response curve for moderate levels of exercise. No, what drew attention was the fact that time spent sitting seemed to be an independent risk factor for common causes of mortality, unrelated to the time spent exercising. In that model, you can be diligently jogging every day, but spend an extra hour in a chair while your equally diligent peers are standing and your life expectancy is worse.

If you look at the last five years you'll see a sudden blossoming of studies correlating time spent sitting down with telomere length, cancer rates, arterial stiffness, and all sorts of other measures of health and the slow slide into old age and disease. Given that people who are more sedentary do sit more we should probably take it as read that many of these studies are essentially unrelated to the interesting point above - they are picking up on the standard, well-worn correlation between poor health, lower life expectancy, and sedentary behavior. Still, some very large data sets show signs of this independent relationship between sitting and higher mortality rates.

One of the other interesting results to come out of large statistical studies of health in the past few years is the degree to which low levels of activity appear to make a difference. Things along the lines of puttering around in the garden or washing dishes have only been well quantified in large studies with the comparatively recent advent of low-cost accelerometers such as those present in mobile devices nowadays. With that data in hand, this sort of low-level exercise seems to be beneficial enough to need to be taken into account.

This leads us back to sitting: is it is the sitting, or is it the lack of puttering around that is contributing to this correlation, assuming that causation is involved and flows from the level of activity to quality of health? The researchers here argue that past conclusions on sitting are misinterpreting the issue, and immobility is the problem - sitting makes no difference if considered independently of exercise levels. That said, this is one study of a few thousand people, which at the moment is to be weighed against opposing studies with probably somewhere near a hundred times as many participants. As ever, more research is needed, but hopefully the whole business of how to eke out an extra year or three of health in old age via lifestyle choices of this sort will become a moot point soon enough to matter for those of us considering it today.

Sitting for long periods not bad for health

New research has challenged claims that sitting for long periods increases the risk of an early death even if you are otherwise physically active. The study followed more than 5000 participants for 16 years, making it one of the longest follow-up studies in this area of research, and found that sitting, either at home or at work, is not associated with an increased risk of dying. The participants included 3720 men and 1412 women drawn from the Whitehall II study cohort.

The study participants provided information on total sitting time and on four other specific types of sitting behaviour (sitting at work; during leisure time; while watching TV; and sitting during leisure time excluding TV) as well as details on daily walking and time spent engaged in moderate to vigorous physical activity. Age, gender, ethnicity, socioeconomic status, general health, smoking, alcohol consumption and diet were all taken into account. The study showed that over the 16 year follow-up period none of these five sitting measures influenced mortality risk. Future work will consider whether long periods of sitting are associated with increased incidence of diseases such as heart disease and type II diabetes, and will investigate the biological mechanisms that underpin previously observed associations between sitting time and health outcomes.

Associations of sitting behaviours with all-cause mortality over a 16-year follow-up: the Whitehall II study

Sitting behaviours have been linked with increased risk of all-cause mortality independent of moderate to vigorous physical activity (MVPA). Previous studies have tended to examine single indicators of sitting or all sitting behaviours combined. This study aims to enhance the evidence base by examining the type-specific prospective associations of four different sitting behaviours as well as total sitting with the risk of all-cause mortality.

Over 81,373 person-years of follow-up (mean follow-up time 15.7 ± 2.2 years) a total of 450 deaths were recorded. No associations were observed between any of the five sitting indicators and mortality risk, either in unadjusted models or models adjusted for covariates including MVPA. Sitting time was not associated with all-cause mortality risk. The results of this study suggest that policy makers and clinicians should be cautious about placing emphasis on sitting behaviour as a risk factor for mortality that is distinct from the effect of physical activity.

Researchers here investigate copy number variations in the context of a long-lived human study population, finding similar results to those obtained from other studies. Copy number variations in the genome are one of the forms of inherited difference between individuals. Stretches of DNA have duplications or deletions, leading to more or fewer copies of specific DNA sequences. In recent years, with the growing availability of genetic data, an increased frequency of copy number variations has been shown to correlate with higher mortality rates in human studies, and some specific variations seem to be sufficiently uncommon in older people to suggest that they cause harm over the long term in some way.

It is worth considering that the purpose of progress in science is to gain more knowledge of this sort of intricate relationship between DNA differences and natural variations in life span - to understand how the system works if left to its own devices. The purpose of progress in medicine, however, is to make these differences irrelevant by intervening in our biology to prevent disease and dysfunction. Methods of repairing the causes of aging will in due course lead to rejuvenation treatments and people who never enter the late stage of life, heavily damaged, in which genetic variations become important determinants of how far a failing body can limp along. There isn't all that much of an overlap between the genetics of aging and the effective treatment of aging: the former is the study of what happens when you cannot treat aging, and all of our attention should be focused on efforts to dig ourselves out of that position.

In this study, we explored the impact of copy number variation on mortality at the extreme end of life by performing a genome-wide investigation of the association between CNVs and prospective mortality in nonagenarians and centenarians. As our main result, we found that an increase in the average CNV length significantly associated with a higher mortality, as did an increase in the total part of the genome occupied by deletions. These findings are consistent with the results of a previous study in which the burden of large deletions was found to be associated with higher mortality, suggesting that longer CNVs, especially deletions, are more disadvantageous. The identified association between a higher CNV burden and increased mortality is generally in line with the proposed role of genome instability, that is, a decrease in genome maintenance and hence an accumulation of genomic changes, in lifespan and suggests that even among the very old, the load of genomic alterations is linked to differences in mortality.

Among the specific deletions and duplications, four deletions were consistently associated with higher mortality across the study populations, as were a single deletion in women and two deletions in men. These seven nominally significant CNVs are surrounded by numerous genes, of which two, TRPM3 and STARD13, have previously been implicated in the regulation of human lifespan. The STARD13 gene has moreover been associated with plasma levels of amyloid beta peptides that, among other things, play a role in Alzheimer's disease and hypertension. In addition, also the CCDC3 and IRAK1BP1 genes could be speculated to play a role in human lifespan, as they have been reported to inhibit inflammation, and the majority of the other genes are involved in cell adhesion, which has previously been linked to longevity and age-related diseases. In addition to their more direct effect on genes, for example, alteration of gene dosage and gene disruption, CNVs may also affect regulatory regions or other functional regions that influence gene expression. Only a few of the seven CNVs found to potentially associate with mortality in long-lived individuals in this study contain known regulatory elements, however.

In conclusion, we found that the genomewide CNV burden, specifically the average CNV length and the total CNV length, associates with higher mortality in long-lived individuals. Our results indicate that CNVs might be important contributors to the genetic component of human longevity and prompt further investigation.

Link: http://onlinelibrary.wiley.com/enhanced/doi/10.1111/acel.12407/

Transposable elements are parasitic DNA sequences that have attached themselves to the genome over the course of evolutionary history. They are rigorously suppressed in normal cellular operation, but that suppression appears to fail with age, leading more cells to suffer replication of these transposable elements. This activity shows up in senescent cells, for example.

Some researchers, such as the authors of the paper linked here, argue that rising activity of retrotransposons - or transposable elements - in our DNA are a cause of aging. This is a subgroup of those who think that, more generally, accumulated stochastic nuclear DNA damage is a cause of aging above and beyond paving the way to higher levels of cancer. It is thought to disarray the activities of cells to a large enough degree to disrupt tissue function. As for transposable elements, the data can be argued either way: while the correlations are strong and DNA damage is shown to raise cancer risk, there is no good experimental evidence to demonstrate that nuclear DNA damage in isolation significantly contributes to aging in other ways across the current length of a human life span, nor to definitively answer the question of whether transposable element mobilization is closer to being a root cause or closer to being an end consequence in aging.

As in many of these mechanisms, the best and fastest approach to obtaining that answer would be to repair the damage and see what happens - assuming that repair to be feasible. For stochastic DNA damage, this is becoming somewhat more practical as a future possibility with the falling cost of gene therapy and improved techniques such as CRISPR, but the challenge here is substantial: how to fix different forms of damage in every cell. Short of full-blown molecular nanotechnology, the development of complex programmable machines built of DNA or similar, capable of figuring out what to fix in situ inside a cell, I see few options.

Understanding the molecular basis of ageing remains a fundamental problem in biology. In multicellular organisms, while somatic tissue undergoes a progressive deterioration over the lifespan, the germ line is essentially immortal as it interconnects the subsequent generations. Genomic instability in somatic cells increases with age, and accumulating evidence indicates that the disintegration of somatic genomes is accompanied by the mobilisation of transposable elements (TEs) that, when mobilised, can be mutagenic by disrupting coding or regulatory sequences. In contrast, TEs are effectively silenced in the germ line by the Piwi-piRNA system.

Here, we propose that TE repression transmits the persistent proliferation capacity and the non-ageing phenotype (e.g., preservation of genomic integrity) of the germ line. The Piwi-piRNA pathway also operates in tumorous cells and in somatic cells of certain organisms, including hydras, which likewise exhibit immortality. However, in somatic cells lacking the Piwi-piRNA pathway, gradual chromatin decondensation increasingly allows the mobilisation of TEs as the organism ages. This can explain why the mortality rate rises exponentially throughout the adult life in most animal species, including humans.

Link: http://dx.doi.org/10.1007/s00018-015-1896-0

Here I'll point out a technology demonstration of mitochondrial gene editing via CRISPR, something that should be of general interest, though debatable relevance to work on mitochondrial repair at the present time. The development of CRISPR, an efficient low-cost method of genetic editing, has opened a lot of doors. In the course of a few short years since the first practical demonstration, use of CRISPR has made genetic engineering projects accessible and affordable to a vastly greater number of researchers than was previously the case. As an infrastructure advance it is about as transformative as the development of induced pluripotency was for the stem cell research community. Cost and difficulty are very important determinants of the pace of progress in a field, and sharp reductions in both of those for genetic engineering suggests that the next decade is going to be very interesting indeed.

The use of transcription activator-like effector nucleases (TALENs) is one of the candidate next generation genetic engineering technologies that was developed prior to CRISPR, though work continues even now. It is promising, but clearly not starting fires to the same degree that CRISPR is: again, it is all about relative degrees of cost and difficulty. Still, you may recall that it was quite exciting to see TALENs working for mitochondrial DNA back when that was first demonstrated.

Mitchondrial DNA (mtDNA) is distinct from nuclear DNA. It is a circular genome made up of a few leftover genes that is resident in each of the hundreds of mitochondria present in every cell. Mitochondria are the evolved descendants of symbiotic bacteria, and their primary - but far from only - activity is to act as power plants, generating chemical energy store molecules that are used to power cellular activities. They still behave much like bacteria: fusing, dividing, passing molecules and even large portions of their internal structures back and forth between one another. Other processes within a cell monitor the state of mitochondria, and flag damaged ones for destruction, recycling their component parts. Somewhere in all of these interacting processes of generation and destruction, there are ways in which mitochondrial DNA can be come damaged, losing the blueprints for vital protein machinery used in some modes of energy store generation. These damaged mitochondria are in some way privileged, more able to evade destruction at the hands of quality control mechanisms despite their dysfunction. They quickly overtake the entire mitochondrial population of a cell - so quickly that researchers don't have a good view of how exactly the process happens; they only see before and after snapshots. That cell then becomes harmful and dysfunctional, exporting damaged proteins and reactive molecules into the surrounding tissue. The accumulation of such cells over time is one of the contributing causes of degenerative aging.

So as you can see, the ability to edit mitochondrial DNA to fix it is of potential interest. But what can be done here? Can the existence of these dysfunctional cells be fixed for a long enough period of time via a global gene therapy of some sort that directly delivers replacement genes to mitochondria? Or will the continued presence of broken variants just quickly overwhelm any freshly delivered working variants? After all, the damaged variants already achieved that goal in the cells they have taken over, and they are still there in large numbers. There has been sufficient doubt on that front for the research groups involved in efforts to repair damaged mitochondria to adopt other, less direct approaches. These include allotopic expression, in which copies of mitochondrial genes are placed into the cell nucleus, altered in ways that ensure the proteins produced can find their way back to the mitochondria where they are needed. Development of that approach for inherited mitochondrial diseases is at a fairly advanced stage, but it has yet to be applied to aging. With a large fall in the cost and difficulty of mitochondrial gene editing, it may be worthwhile revisiting this picture, however. I'm sure some researchers will do just that in the years ahead.

Efficient Mitochondrial Genome Editing by CRISPR/Cas9

Mitochondria play roles in many important cellular functions. Mitochondria contain their own genome, which encodes 13 proteins that are subunits of respiratory chain complexes, as well as two rRNAs and 22 mitochondrial tRNAs. Due to the critical roles of genes encoded by mtDNA, maintenance of mitochondrial genome integrity is quite important for normal cellular functions. Mitochondrial DNA are, however, constantly under mutational pressure due to oxidative stress imposed by radicals generated by oxidative phosphorylation or an imbalance in the antioxidant defense system in aging or disease processes. Damage to mtDNA, such as point mutations or deletions, contributes to or predisposes individuals to a variety of human diseases.

Despite the huge potential of mitoTALEN-mediated mtDNA editing, more user-friendly and efficient alternative methods are necessary to overcome difficulties in mtDNA modification either for correction of dysfunctional mtDNA or for producing dysfunctional mtDNA in order to create mitochondria-associated disease models.

Here we report a novel approach to generate mtDNA dysfunction with the CRISPR/Cas9 system. Cas9, widely used for genome editing, showed distribution to mitochondria as well as the nucleus. Expression of FLAG-Cas9 with gRNAs designed to target mtDNA resulted in cleavage of mtDNA and alterations in mitochondrial integrity as determined by Western blots for some mitochondrial proteins. Moreover, regular FLAG-Cas9 was modified to contain mitochondrial targeting sequence instead of nuclear localization sequence (NLS) in order to localize it to mitochondria (namely, mitoCas9). MitoCas9 robustly localized to mitochondria; together with gRNA targeting of mtDNA, specific cleavage of mtDNA was observed, demonstrating its functional application for mtDNA editing.

These results together demonstrate the successful application of CRISPR/Cas9 in mitochondrial genome editing and suggest the possibility for in vitro and in vivo manipulation of mtDNA in a site-specific manner.

Christine Peterson is co-founder of the Foresight Institute, one of the oldest of the numerous research and advocacy organizations that emerged from the transhumanist community of the 1980s and 1990s, focused on the development of molecular nanotechnology. Based on her public statements, her position on longevity and technology has in recent years appeared to me to be similar to that of Ray Kurzweil, in that there is too much of an emphasis on taking action now via optimization of supplements and diet, something that I think cannot produce sufficient benefits to merit the investment in time required. In addition you'll never in fact know whether or not your investment in time is actually helping, and the size of the best possible result in terms of healthy life gained is still tiny.

If you look at the comments on this post, however, you'll see that Peterson rejects this interpretation, and notes her position to be much the same as mine, which is to say that SENS-style rejuvenation research is front and center as the primary goal. From my point of view, and apparently Peterson's as well, the only way out of the hole we're in with respect to aging is medical research after the SENS model that aims at repairing the cell and tissue damage that causes aging. Everything else is a distraction.

The October 1, 2015 podcast of The Optimized Geek featured Foresight Co-Founder and Past President Christine Peterson: A Glimpse at the Future Lifespan of Humans (55 minutes). Christine explained the development of nanotechnology in three stages. Currently we are moving from the first stage focus on nanomaterials, like stain-resistant pants, into the second phase, dominated by nanoscale devices. The most exciting change change will come with the third stage, in which systems of molecular machines will operate with atomic precision. In responding to a question on what we might see in the next ten years, Peterson suggested that although nanotechnology in that time frame would still be mostly about nanomaterials and simple nanodevices, one of the most interesting applications would be in health, giving the example of more effective diagnosis, imaging, and treatment of cancer through enhanced targeting specificity.

What might advanced nanotechnology look like 30 years from now? Peterson began with the question: What limits do the laws of physics set on what we can build with systems of molecular machines able to build with atomic precision, including inside the human body? One of many applications would be correcting DNA mistakes and mutations cell by cell. Other targets could be damaged proteins and plaques from Alzheimer's, etc. With this level of technology, lifespans would not be limited by aging or traditional diseases, but only by accidents that destroyed the brain, leading to estimated lifespans on the order of 10,000 years. With technology to record the molecular structure of brain, back-up copies of individual brains could be made, eliminating even the 10,000 year limit.

Peterson described "the quantified self" and "biohacking" as taking an engineering approach to making changes and improvements in our bodies. Approaches range from the traditional, like diet, exercise, and stress reduction, to the more exotic, like supplements to improve brain chemistry, or to improve health and longevity. Peterson cautions however, that while taking supplements is easy, figuring out which supplements to take is difficult. Although not of immediate use for those who want to take action now to improve their health and longevity, for those who want to advance research in longevity, Peterson recommended Aubrey de Grey's SENS Research Foundation.

For those who, due to illness or advanced age, will not be able to survive until the future when aging is cured and disease eliminated, Peterson addressed the question of whether there is available today some form of suspended animation to maintain a body until it can be repaired. In the early days of "cryonics", recently deceased bodies were placed at low (liquid nitrogen) temperatures for preservation. Later, certain chemicals were introduced as antifreeze to reduce biological damage caused by freezing. More recent technology has introduced improvements that have been tested on donated organs that are reversible; that is, a viable organ can be recovered from low temperature preservation. Arrangements can be made with cryonics organizations - the largest one is Alcor Life Extension Foundation - to implement for you the best suspended animation technology available at the time that you need it. Peterson shared that she is signed up for it because "I do not see a down side."

Link: http://www.foresight.org/nanodot/?p=6812

Researchers here reinforce the point that, yes, being obese is bad for your health, and that a few prior studies that suggested otherwise were mistaken. In any field there are always going to be studies that appear to go against the grain to provide contradictory results. Most of the time these are errors of interpretation; scientific research is hard and complicated, and as a consequence a lot of published work is incorrect in some way. That is why one should never take any single paper in isolation, but look at it in the context of the broader field. In the case of excess fat the broader field has provided a mountain of evidence to show that adding and maintaining more fat tissue causes worse health, greater medical expenditures, and a shorter life expectancy.

It is unfortunate that some factions within our society are willing to cherry pick research to support and propagate the mistaken belief that being overweight is safe and has no effect on health. Everyone who has managed to get themselves into a deep hole wants to be told that they are just fine and haven't caused any harm, but that doesn't make it true.

Researchers set out to solve a puzzle: Why is it that study after study shows obese or overweight people with cardiovascular disease outliving their normal weight counterparts? Would this phenomenon, referred to as the obesity paradox, hold up when approached within different parameters? According to their latest research, the answer is no. When accounting for weight history in addition to weight at the time of survey and when adding in smoking as a factor, obesity is harmful, not helpful, to someone with cardiovascular disease. "There are claims that ... it's good to be obese when you have cardiovascular disease, that if you have fat stores, maybe you'll live longer. It's conceivable that there are health advantages. But we show they are overwhelmed by the disadvantages of being obese, once you control for these two sources of bias."

The researchers started with data from more than 30,400 participants of the National Health and Nutrition Examination Survey between 1988 and 2011. The survey is a nationally representative sample considered the gold standard in the United States. Of those participants, 3,388 had cardiovascular disease. Most research of this type looks only at weight at time of survey. For example, if a participant who long weighed 300 pounds lost one-third of his mass by the time he weighed in, he would be counted at 200 pounds. Not including weight history, however, "would be like classifying a lifelong smoker who quit the day before the survey as a non-smoker, even though we know that if you're a lifelong smoker you carry those risks over even if you stop smoking."

Adding weight history "turns out to have a profound effect on the findings," eliminating the mortality advantage for those who are overweight or obese. Incorporating the second factor, smoking, also contributed to resolving the paradox. Smokers are less likely to be obese, and those who are obese are less likely to smoke. This correlation is much stronger for those with cardiovascular disease, so the researchers limited their pool to lifelong non-smokers. Accounting for weight history makes the obesity paradox disappear. Excluding smokers? That's when being obese equates to significantly higher mortality for those with cardiovascular disease.

The researchers said these results could improve disease treatment, since some clinicians may use the obesity paradox in patient care decisions. "There's every reason to imagine that clinicians are at least confused, and in some cases, are believing that being overweight or obese is a good thing among people with cardiovascular disease, diabetes and other conditions for which a paradox has been demonstrated." Conditions like stroke, kidney disease and high blood pressure, for example. "This may be trickling down into clinical decision making, which is concerning because we don't think it's a real finding."

Link: http://www.upenn.edu/pennnews/news/obesity-does-not-protect-patients-with-cardiovascular-disease

Front and center, the primary plan for longevity for people in middle age and younger today is to help push through enough of the right medical research. Your body is aging, accumulating damage, but methods of repairing that damage are slowly edging their way towards clinical application. Once in the clinic they will slowly become better. At some point the improvement in repair methodologies will add healthy life expectancy for older people faster than a year with every passing chronological year. Everyone with access to the latest stable medical technology at that point will have beaten the curve: they will no longer suffer and die due to aging. The question is where that point occurs in your life span, indeed whether it occurs in your life span, and that is where activism and funding comes in. You can't make yourself younger (yet), but you can help to speed up the development process: it is certainly moving at far below optimal speed at the present time.

That is the primary plan, and for every primary plan there must be a backup plan. Never bet on just one horse. The backup plan for evading the end that comes with death by aging is cryonics: low-temperature preservation of the fine structure of the brain on clinical death. Cryopreservation organizations will maintain the data of your mind in its physical form for the decades it will take for restoration to active life to become a viable possibility. That will, at minimum, require near complete control over cellular biochemistry and regeneration, as well as a mature molecular nanotechnology industry capable of repairing broken cell structures, removing cryoprotectant from tissues, and similar tasks. None of these goals are impossible or unforeseen, it is just that the necessary technologies don't exist today. Preserved individuals have all the time in the world to wait, of course.

A backup plan is never as good as the primary plan. That is why it is the backup plan. In order to be cryopreserved you have to undergo a very unpleasant set of experiences; you have to age and you have to die, and do so naturally with little help, since our backwards legal systems don't allow for assisted euthanasia in a constructive way that can mesh with cryonics protocols and organizational procedures. Further, in comparison to remaining alive and healthy thanks to the development of working rejuvenation treatments, cryonics will for a long time to come be a leap into the dark with an unknown chance at ultimate success. It is still infinitely better than any of the other possible choices open to the billions who will die too soon to benefit from near future rejuvenation therapies.

Strangely, after four decades of organized operation cryonics remains a tiny, niche, non-profit industry. This is the case for reasons that remain unclear and much debated. Cryopreservation is certainly a far better option than the many strange things people choose to have happen to their bodies following clinical death, usually for no better reason than everyone else does it. Is it little more than the fact that you have to prepare some time in advance to make it cost-effective via life insurance? The reluctance to embrace cryopreservation over the grave and oblivion may have some of the same roots as the reluctance to support research into the treatment of aging as a medical condition and extension of healthy life spans. At root all it would really require for cryonics to grow to become a dynamic and competitive industry is for more people to sign up and express interest.

In recent years the popular press have transitioned from ridicule to balanced respect on the topic of cryonics, and the level of attention has increased. I think at least some of this has to do with growing interest in treating aging as a medical condition, though the relationship may be indirect: people who influence opinions tend to support both life extension and cryonics research and development. In the past decade we've seen a growing acceptance of the transhumanist ideals for longevity and the defeat of death that were first discussed realistically and robustly over the course of the 1960s to the 1980s. Many more people are now on the inside of what was once a small intellectual circle, and visionary thinking from that time is now taken as a foregone conclusion for technological development. That said, journalists are ever journalists and still largely miss the very important difference between freezing, which is something that cryopreservation seeks to avoid, and vitrification, which is the goal of modern procedures. Freezing produces ice crystals which are highly damaging to tissues, whereas vitrification minimizes that outcome.

Dying is the last thing anyone wants to do - so keep cool and carry on

Call the headquarters of Alcor in Scottsdale, Arizona, and you are greeted by a recorded message. "If you would like to report the death or near-death of an Alcor member," says a chirpy midwestern voice, "please press two." The Alcor Life Extension Foundation - to give it its full title - has an unexceptional grey concrete exterior that resembles a regional bank branch. Inside, however, are the bodies or brains of 138 dead people, stored in vats of liquid nitrogen in the hope that, at some point in the future, advances made in science will be capable of bringing them back to life.

This is cryonics - the preservation of animals and humans at extremely low temperatures. And in America, business is booming. Last month, Alcor took receipt of its 138th patient: Du Hong, a Chinese science-fiction writer who died of pancreatic cancer at the age of 61 and whose family contacted Alcor shortly before her death to have her brain preserved. Brain-freezing starts at $100,000 and is cheaper than the full-body option, which costs more than twice that amount. Alcor, which describes itself as a not-for-profit organisation, insists that all fees go directly back into running costs.

Brain Freeze: Those looking to cheat death turn to cryonics - being frozen in liquid nitrogen - to one day live again

"I believe that my identity is stored inside my physical brain," says Carrie Wong, president of the Lifespan Society of British Columbia, an advocacy group that works to promote and protect access to cryonic preservation. "So if I can somehow preserve that, maybe at a future time technology and medical science will advance to such a point that it may be possible to repair the damage of freezing me in the first place and also what killed me back then," says the 27-year-old, who concedes such a feat could be hundreds of years in the future. "It's not possible now, but nobody can really argue it's not possible in the future because that's arguing about what future technology is capable of."

The Cryonics Institute, a non-profit organization founded in 1976 by Robert Ettinger, operates a preservation facility near Detroit, where about 100 pets and 135 humans are suspended in tanks called cryostats. "The actual cryostats are just giant thermos bottles with liquid nitrogen, there's no electricity to fail," says president Dennis Kowalski, a 47-year-old Milwaukee firefighter and paramedic who became interested in cryonics in his 20s.

About 1,250 people, including a number of Canadians, are signed up for CI's service. Membership costs US$28,000, which is typically paid for through life-insurance policies. While acknowledging that he and others who intend to be frozen are often "looked at as a bunch of kooks," Kowalski views cryonics as being like a clinical experiment - and one that beats the alternative. "I'll be the first to admit it may not work. And everyone who's signed up should understand cryonics may not work and there are no guarantees."

BioViva is a small group that recently announced they have moved ahead with a human test of telomerase and myostatin-related gene therapies as a potential method to modestly slow the effects of the aging process. Their initial goals are to get things moving in this part of the field by taking this step forward, observing the results, and raising funding for further development efforts to try to lower the costs of this sort of approach. The BioViva CEO Liz Parrish, who is also the initial test subject, recently hosted an AMA (ask me anything) event at Reddit's /r/futurology community. Her comments below are lightly edited for continuity, since they are pulled from numerous distinct answers to questions posted by the community:

I am patient zero. I will be 45 in January. I have aging as a disease. To take on this role myself was the only ethical choice. I am happy to step up. I do feel we can use these therapies in compassionate care scenarios now but we will have to work them back into healthier people as we see they work as preventive medicine.

The genes targeted are human telomerase reverse transcriptase (hTERT) and follistatin (FST). In animal models neither FST nor hTERT have increased the risk of cancer. We expect to see the same result on myself, and to that effect we are measuring all known cancer biomarkers. The gene therapies on my body are to measure the effects on humans. There is plenty of animal research to support these gene therapies but no one was conducting human tests. We are using both visual biomarkers, MRI and a panel of blood and tissue testing including work on telomere length and epigenetic testing. We are collecting as much data as we can, but unfortunately we currently don't have the coverage rate for this therapy, how much of the tissue of the body is affected. Depending on the tissue and vector used we ultimately expect to see similar rates of transfection as seen in mice, which is somewhere between 5 to 60%.

We are working as hard as we can to bring it to the world as quickly and safely as possible. We will will evaluate monthly and within 12 months we will have more data. If the results are good we hope to have something to the general public, that is cost acceptable, in 3-5 years. Our goal is to build laboratories that will have the mission of a gene therapy product at a reduced cost. Gene therapy technology is much like computing technology. We had to build the super computer which cost $8 million in 1960. Now everyone has technologies that work predictably and at a cost the average person can afford. We need to do the same with these therapies. What you will get in 3-5 years will be vastly more predictable and effective that what we are doing today and at a cost you or your insurance can cover .

We need a lab that works solely to bringing those costs down. We would need about $1 - 1.5 million to build one lab to focus on this. We can expand as needed. I would love to crowdfund this project but I do not know how to get good results at that scale - I think the price tag is high for that modality. We are raising investment to do offshore clinical trials. Many USA companies do this. If we can cut costs we will be able to bring back a treatment that people can afford.

Link: https://www.reddit.com/r/Futurology/comments/3ocsbi/ama_my_name_is_liz_parrish_ceo_of_bioviva_the/

James Bedford was the first person to be cryopreserved following death, and unlike the others from that early era of cryonics he remains preserved today, nearly fifty years later, at the Alcor facility. It is an open question as to the degree to which the crude preservation methodologies of the time damaged the fine structure of his brain due to ice crystal formation, making restoration a far more complex project, requiring far more advanced future technologies. Even taking that into account restoration is a theoretical possibility, a project that lies within the bounds of the laws of physics as we understand them, which is more than can be said for all of Bedford's peers. They are gone to the grave and oblivion, beyond any hope of a renewed life in the future.

Jeanne Louis Calment is listed as the longest-living (verified) human being in history. She was born on February 1875 and died on 4 August 1997, at the age of 122 years, 164 days. As of October 2, 2015, Ms. Calment's record has been broken by cryonaut Dr. James Bedford, who is maintained in cryopreservation by the Alcor Life Extension Foundation.

Bedford was born on April 20, 1893. As of today, October 6, 2015, he has survived for 122 years, 167 days. It is true that Bedford is not currently alive. But neither is he dead. When Alcor transferred him from an old, customized vessel back in 1991, it was clear that the original ice cubes created at the time of preservation were intact. We have no good information on the quality of the ultrastructural preservation of his neural tissue. But we can say that he has remained cryopreserved since 1967, and so deserves the title of longest-surviving human being in history!

Link: http://www.alcor.org/blog/james-bedford-first-cryonaut-is-now-the-longest-surviving-human-being-ever/

Below find links to a few recent papers relating to the genetics and epigenetics of aging. Aging is a byproduct of the normal operation of cellular metabolism, due to damage generated and not repaired. Many genes will have some impact on the progression of aging because they govern the operation of metabolism and thus influence the pace at which unrepaired damage accumulates. As time progresses and the damage of aging builds up, cells react to that damage with changes to the epigenetic regulation of the production of proteins. Thus old individuals have more of some proteins and less of others in circulation and present in various tissues, changing the way in which cells and tissues function. Some of this is compensation, and aging would be faster and worse without it, but some of it is just more dysfunction piled on top of that caused directly by damage to cells and their component parts.

Much of the aging research field is involved in cataloging: firstly finding genes associated with the pace of aging by dint of altering them one by one in short-lived and well-characterized species such as yeast or nematode worms, and secondly finding genes whose output of proteins changes with age by precisely measuring the molecules present blood and other bodily fluids at various different ages. Gathering information about how exactly aging progresses at the detail level still has a higher priority for most researchers in comparison to moving beyond that to try to treat aging.

There are some necessary tools that will emerge from cataloging efforts, however. One is a good biomarker of biological age, a measurement that must be cheap and easy to carry out given simple patient samples such as skin or saliva, and comprehensive enough to pick up the beneficial effects of a partial rejuvenation therapy soon after it is applied. For rejuvenation based on repair of cell and tissue damage after the SENS model, researchers can always identify how much of the specific form of damage has been repaired by their treatment, but there is still the need to link that to some reliable and accepted measure of overall biological age for the organism as a whole. Without that biomarker the only way to prove that rejuvenation has happened is to wait and see: run the life span study, which even in mice requires years and millions of dollars, never mind in longer-lived mammals. The need for life span studies as proof is a real drag on the pace of progress.

Identification of ageing-associated naturally occurring peptides in human urine

In a first small scale study, we investigated the urinary proteome in a cohort of 324 healthy individuals between 2 to 73 years of age showing the feasibility to obtain high resolution molecular information from readily available body fluids such as urine. Meanwhile, we have accumulated multiple high-resolution urine peptidomics datasets that enable the investigation of ageing-associated changes in a large cohort. In the present study, we therefore investigated the unique urinary proteome profiles of 11,560 individuals in an attempt to identify specific ageing-associated alterations and investigate pathological derailment of normal ageing. This showed that perturbations in collagen homeostasis, trafficking of toll-like receptors and endosomal pathways were associated to healthy ageing, while degradation of insulin-like growth factor-binding proteins was uniquely identified in pathological ageing.

Length of paternal lifespan is manifested in the DNA methylome of their nonagenarian progeny

The heritability of lifespan (age at death) has been estimated to be approximately 20-30%, and it has been shown to increase with advancing age. Healthy aging is also heritable, and the offspring of long-lived parents show delayed onset of aging-associated diseases. Much of the research studying the heritability of lifespan has focused on extreme age (nonagenarians, centenarians, supercentenarians), but recently it has been shown that every decade of parental age after the age of 65 reduces the mortality and incidence of cancer of their offspring. Even though the heritability of the lifespan is acknowledged, only one genomic locus (on chromosome 3) and a few genetic variants, such as in APOE and FOXO3, have consistently been shown to be associated with longevity. To explain this discrepancy, the inheritance of epigenetic features, such as DNA methylation, have been proposed to contribute to the heritability of lifespan.

We investigated whether parental lifespan is associated with DNA methylation profile in nonagenarians. A regression model, adjusted for differences in blood cell proportions, identified 659 CpG sites where the level of methylation was associated with paternal lifespan. However, no association was observed between maternal lifespan and DNA methylation. The 659 CpG sites associated with paternal lifespan were enriched outside of CpG islands and were located in genes associated with development and morphogenesis, as well as cell signaling. The largest difference in the level of methylation between the progeny of the shortest-lived and longest-lived fathers was identified for CpG sites mapping to CXXC5. In addition, the level of methylation in three Notch-genes (NOTCH1, NOTCH3 and NOTCH4) was also associated with paternal lifespan.

The role of Hsp70 in oxi-inflamm-aging and its use as a potential biomarker of lifespan

The heat-shock protein 70 (Hsp70) acts as a cellular defense mechanism its expression being induced under stressful conditions. Aging has been related to an impairment in this induction. However, an extended longevity has been associated with its increased expression. According to the oxidation-inflammation theory of aging, chronic oxidative stress and inflammatory stress situations (with higher levels of oxidant and inflammatory compounds and lower antioxidant and anti-inflammatory defenses) are the basis of the age-related alterations of body cells. Since oxidation and inflammation are interlinked processes, and Hsp70 has been shown to confer protection against the harmful effects of oxidative stress as well as modulating the inflammatory status, it could play a role as a regulator of the rate of aging.

Mapping the Genes that Increase Lifespan

Following an exhaustive, ten-year effort, scientists have identified 238 genes that, when removed, increase the replicative lifespan of S. cerevisiae yeast cells. This is the first time 189 of these genes have been linked to aging. These results provide new genomic targets that could eventually be used to improve human health. "This study looks at aging in the context of the whole genome and gives us a more complete picture of what aging is. It also sets up a framework to define the entire network that influences aging in this organism." Researchers began the painstaking process by examining 4,698 yeast strains, each with a single gene deletion. To determine which strains yielded increased lifespan, the researchers counted yeast cells, logging how many daughter cells a mother produced before it stopped dividing. "We had a small needle attached to a microscope, and we used that needle to tease out the daughter cells away from the mother every time it divided and then count how many times the mother cells divides. We had several microscopes running all the time."

These efforts produced a wealth of information about how different genes, and their associated pathways, modulate aging in yeast. Deleting a gene called LOS1 produced particularly stunning results. LOS1 helps relocate transfer RNA (tRNA), which bring amino acids to ribosomes to build proteins. LOS1 is influenced by mTOR, a genetic master switch long associated with caloric restriction and increased lifespan. In turn, LOS1 influences Gcn4, a gene that helps govern DNA damage control. "Calorie restriction has been known to extend lifespan for a long time. The DNA damage response is linked to aging as well. LOS1 may be connecting these different processes."

It remains an open question as to the degree to which the mechanisms that cause progeria are relevant in normal aging. They are present at very low levels in old people, a very different picture from the upheaval and dysfunction taking place in the cells of progeria patients. Are those low levels meaningful over the course of a normal human life span, and in comparison to the known causes of degenerative aging? Time will tell, but it can't hurt to keep an eye on progress in progeria research, which seems to be on the verge of a more effective class of therapies:

Though researchers identified the abnormal protein behind progeria - progerin - the exact way in which it causes the accelerated aging remains elusive. Progerin, a protein present in very high concentration in progeria cells, is known to be responsible for many of the characteristics of the disease. It is a mutant version of lamin A, a protein crucial for the stability of the nucleus and involved in many essential nuclear functions. "A few years ago, we and others found that progeria cells have much less LAP2α than normal cells. LAP2α is a protein that interacts with lamin A to regulate cell proliferation, the process that produces new cells. Interestingly, LAP2α levels also decrease during normal aging. The cells that produce progerin had really low LAP2α levels compared to normal cells. But when we re-introduced LAP2α we could completely rescue the proliferation defect of the progeria cell line. The same actually happened in cells from patient samples."

Further experiments revealed a real surprise: LAP2α functions very differently in progeria cells compared to normal cells. Usually it binds to a distinct nuclear pool of lamin A and slows proliferation, so low LAP2α levels result in hyperproliferation. But in progeria the opposite is the case, cells proliferate much slower and prematurely enter the cellular aging process. The reason for this is that progeria cells do not have the nuclear lamin A pool. This hinted that LAP2α uses a different route to exercise its function in progeria cells. In the end, data from previous experiments gave the researchers the clue to solve the puzzle. "Cells are surrounded by material that structurally supports them. It is called extracellular matrix or in short ECM. It was reported before that progerin negatively affects the production of ECM proteins, leading to a disrupted cellular environment and slower proliferation. Now we connected this to the low LAP2α levels and when we reintroduced LAP2α into progeria cells they again produced normal ECM and proliferated normally and didn't enter the cellular aging process."

The study's insights why and how progerin impairs the production of ECM proteins and normal proliferation opens new avenues towards the development of more specific therapeutic strategies for the treatment of progeria. As the premature aging disease resembles in many aspects normal aging, the results also allow drawing conclusions on the cellular processes during normal aging.

Link: http://www.meduniwien.ac.at/homepage/1/news-and-topstories/?tx_ttnews[tt_news]=6044

Researchers here demonstrate a method of generating reprogrammed cell lines from old patients that retain the age-related changes and damage in the cells, a useful tool for further research. The technique of induced pluripotency has in recent years been used to generate cells of arbitrary specific types from, for example, a patient skin cell sample: the skin cells are reprogrammed to be pluripotent, and then differentiated into the desired cell type. Reprogramming to pluripotency has been shown to rejuvenate some of the aspects of old cell lineages, such as by clearing out damaged mitochondria, and removing age-related epigenetic markers, possibly reflecting other forms of repair. This may be related to the early stage of embryonic development in which age-related damage is abruptly repaired, the cells reset to a youthful state. This is all very interesting to some factions of the research community, but frustrating for those scientists who are trying to build patient-matched models of old tissue to better understand what is going wrong in age-related diseases.

For the first time, scientists can use skin samples from older patients to create brain cells without rolling back the youthfulness clock in the cells first. The new technique, which yields cells resembling those found in older people's brains, will be a boon to scientists studying age-related diseases like Alzheimer's and Parkinson's. "This lets us keep age-related signatures in the cells so that we can more easily study the effects of aging on the brain. By using this powerful approach, we can begin to answer many questions about the physiology and molecular machinery of human nerve cells - not just around healthy aging but pathological aging as well."

Over the past few years, researchers have increasingly turned to stem cells to study various diseases in humans. For example, scientists can take patients' skin cells and turn them into induced pluripotent stem cells, which have the ability to become any cell in the body. From there, researchers can prompt the stem cells to turn into brain cells for further study. But this process - even when taking skin cells from an older human - doesn't guarantee stem cells with 'older' properties. "As researchers started using these cells more, it became clear that during the process of reprogramming to create stem cells the cell was also rejuvenated in other ways."

Researchers decided to try another approach, turning to an even newer technique that lets them directly convert skin cells to neurons, creating what's called an induced neuron without passing through a pluripotent state. They collected skin cells from 19 people, aged from birth to 89, and prompted them to turn into brain cells using both the induced pluripotent stem cell technique and the direct conversion approach. Then, they compared the patterns of gene expression in the resulting neurons with cells taken from autopsied brains. When the induced pluripotent stem cell method was used, as expected, the patterns in the neurons were indistinguishable between young and old derived samples. But brain cells that had been created using the direct conversion technique had different patterns of gene expression depending on whether they were created from young donors or older adults. For instance, levels of a nuclear pore protein called RanBP17 - whose decline is linked to nuclear transport defects that play a role in neurodegenerative diseases - were lower in the neurons derived from older patients.

Link: http://www.salk.edu/news/pressrelease_details.php?press_id=2119

Here I am going to ramble a little about patterns of human behavior. "Arcane" is one of those words sorely abused by generations of people involved in the most fanciful of modern pastimes, which is to say the creation of alternative magical and religious beliefs and practices, both in earnest and for fun. As a consequence it has gathered a broad wake of connotations and cultural baggage. Cut all that away and it has an unbiased, simple, and straightforward meaning, however. To be arcane is to be obscure, to be hidden, to be known only to a few.

We humans have evolved a strong urge to pattern recognition. It is a key part of our intelligence as it applies to the business of surviving the rigors of natural selection. Clearly the benefits of identifying and acting on real patterns far outweighed the disadvantages of incorrectly seeing patterns that are not real. How else to explain magical thinking, the tendency for people to fit everything they observe into simple models of cause and effect regardless of accuracy, and then search for the truth later, if at all? The world about us is so very complex that there will always be things that any given group of people cannot understand or model accurately with the resources at their disposal, but put in that situation they will build the models anyway, because that is more comfortable than acknowledging ignorance. So we have religion, magical traditions, the ridiculous marketing that emerges from the snakeoil "anti-aging" marketplace, and generations of people attaching extra saddlebags of meaning to workhorse words such as "arcane," "esoteric," and the like.

Every present culture has very deep roots, stretching back at least centuries into eras in which it was universally accepted that an arcane world lies underneath the mundane, steering it, providing the rules that make sense of what seems senseless. In search of patterns, any patterns, people looked for guidance to whomever was bold enough to claim to see into the arcane world, and since we are a hierarchical species, like our fellow primates, that form of leadership was institutionalized into power structures very early on. Thus we have a history of shamans, priesthoods, temples, the Hero's Journey, and the endless, ever more baroque theology that commenced as soon as things advanced to the point of fighting with words and concepts rather than weapons. All of that lies underneath the thin veneer of modernism, a bone mountain, the legacy of the dead.

Now, here is an interesting thing about modern science and technology: its complexity and importance has in effect created a real arcane world that lies alongside the mundane, steering its future, determining who will live and who will die, what changes and what persists, how the rules of everyday life will differ tomorrow. The present state of technology is the greatest determinant of how we live our mundane lives, and technological progress is the greatest determinant of what tomorrow will bring. Yet few people choose to undertake the work needed to peer from their daily grind into the arcana of technology, even in this age of enormously rapid change, in which the formative lives of each new generation are appreciably different from those of their parents.

Medicine and medical research, especially into aging, shape the rules that will determine the portents for the rest of our lives. How long will we live, will we suffer, what must we do to have the best odds of success? Two thousand years ago people went to priests and burned offerings. A thousand years ago they petitioned physicians who had more in common with priests than with today's practitioners. Today they go clinics and understand about as much of the underpinnings of what they are told to do, for all that it is a lot more effective. The behaviors and organizations laid down to deal with the imaginary arcana of mysticism and religion continue for the real arcana of technology. Very few people go beyond talking to researchers to lift the veil and seek to understand why medicine is the way it is, why the answers to their questions are what they are. They accept the patterns that are explained in shorthand, and are comforted by them, right or wrong. That the patterns offered are better and more effective because of the changing tides of the arcane world of medical research is almost beside the point.

It is always too easy to castigate, however. We who do look further, who place ourselves with a foot in the arcane and a foot in the mundane, drifting from day to day activities on the one hand to presenting the logical outcome of human agelessness resulting from effectively treating aging as a medical condition on the other - we can forget just how distantly removed from all this we once were, or how much of an accident it is that we are where we are today. Ponder just how little thought you gave to medicine and where it came from when you were young, immersed in the mundane: back when you thought aging was set in stone, and the sum of the world was school, shopping, relationships, the changing of the seasons, a job, a hobby. The sum of an unremarkable, unique life. That is most people, unaware of what actually sways their futures.

All of this is why you see similar patterns of human organization at the high level emerging at the boundary of medical science and the world at large as at the boundary of organized religion and the world at large. The data is vastly different, and the importance vastly different. But the same underlying incentives and facets of human nature are at work, driving the small decisions that snowball into organizations and initiatives. For preference I'd like to see this change. The arcane world of medical research, and particularly that related to ending frailty and disease in aging, cannot continue to be as arcane as it is today if we are to see the growth we need in funding and support. The scale of applied resources and pace of progress that is justified by the grand panoply of suffering caused by disease and aging is hard to sustain when no-one thinks about medicine until they are sick. Research and development of new therapies is slow, and leaving education and support for that process until it is needed is leaving it far too late to make a difference.

If we could just bootstrap medicine to much the same position in the public eye as the automobile or the personal computer, where there is some breakdown of the veil between the arcane world of progress and development and the mundane world of use, even that would be a great gain. Unfortunately doing this is an uphill battle against our own evolutionary history and evolved preferences: threatened by complexity, and worse, by the time needed to make a dent in that complexity, most people retreat and direct their limited attention elsewhere. It is a hard sell to persuade anyone to outlay their precious time to understand something that will be important a decade or two from now. In effect those of us closer to the inside of the veil of the arcane for medical research are something like reverse Cassandras: knowing that wondrous, golden futures lie ahead, if only people will listen, understand, and help. More are taking notice with each passing year, but it still far more slowly than they might. Changing the world is not easy.

Here I'll point out some of the latest work on adenylate cyclase 5 (AC5), a longevity gene in mammals, which is now shown to boost exercise performance as well as longevity in mice. It is an open question as to the degree to which the longevity effects are secondary to the exercise effects. The authors of this paper note that there has been little study of exercise effects for most of the other methods of enhancing longevity in laboratory mice, which is an interesting oversight. Perhaps this will change with a growing interest in the development of exercise mimetic drugs.

Disruption of AC5, such as through gene knockout, is one of the many methods shown to modestly slow aging and extend healthy life in mice. As for all of these approaches, much work is yet needed to understand exactly how it works under the hood. The present high level understanding of single gene longevity enhancements in laboratory animals varies from sketchy theory to fairly robust outline, and getting any further than that is proving to be a slow, expensive, and time-consuming business. Every mechanism influences every other mechanism inside a cell, nothing happens in isolation, and so understanding any one life-extending genetic alteration blurs at the edges into the much, much larger project of understanding the enormous complexity of cellular biochemistry as a whole.

The major finding of this investigation is that disruption of AC5, which actually decreases sympathetic tone, increases exercise performance. This is novel, as the most common mechanism mediating enhanced exercise is via increased sympathetic stimulation and catecholamines, resulting in increased AC activity and augmented cardiac output. This was not the mechanism in AC5 knockout mice, where AC activity is actually reduced, and there was no greater increase in cardiac output during exercise compared with WT mice, based on direct measurements of ascending aortic blood flow with implanted ultrasonic flow probes and heart rate in chronically instrumented mice. Further confirming the lack of a cardiac mechanism, the cardiac-specific AC5 knockout did not exhibit enhanced exercise. Accordingly, the mechanism resided at the level of the exercising skeletal muscles, which was confirmed, when we found that exercise performance was also elevated in the skeletal muscle-specific AC5 knockout.

Another key finding of the current investigation was demonstrating that protection against oxidative stress, by increased MnSOD levels and activity in AC5-deficient skeletal muscles, is also involved in the mechanism of enhanced exercise capacity in AC5 knockout mice, as exercise capacity of AC5 knockout mice was significantly attenuated in AC5 knockout / MnSOD heterozygous knockout bigenic mice. One question that arose is whether these effects of enhanced exercise in AC5 KO mice are simply due to a decrease in AC, which might be evoked in a knockout from any of the 9 AC isoforms, or are they due to unique signaling in AC5. To address this question, we examined exercise in 10 AC6 KO mice and 7 wild type controls. The AC6 KO mice did not show increased distance or speed with exercise compared to their wild type. Therefore, the enhanced exercise was not simply due to a reduction in AC, but was rather unique to the AC5 KO and its signaling pathway noted above.

Exercise plays an essential role in longevity, in general, and healthful aging, in particular, as it protects not only against obesity, diabetes, and cardiovascular disease, but also reduces the risk of cancer and improves bone health and even mental diseases that impair aging. Therefore, the demonstration of improved exercise performance in the AC5 knockout model is particularly germane, as this is also a model for longevity, and protects against cardiovascular stress, diabetes, and obesity. In view of the important link between exercise and longevity, it is surprising that of 20 mouse models we reviewed, only two studied exercise and found it to be increased.

Link: http://onlinelibrary.wiley.com/enhanced/doi/10.1111/acel.12401/

Over the last five years considerable progress has been made in the tissue engineering of intestines. Researchers have created sections of intestine, grown intestine organoids, and regenerated damage to intestines in laboratory animals. Here is the latest example:

Working with gut stem cells from humans and mice, scientists have successfully grown healthy intestine atop a 3-D scaffold made of a substance used in surgical sutures. The tube-shaped scaffold was a big first step on the quest to develop an implantable replacement intestine. But the new work pushes that effort further because it shows how stem cells, when mixed with immune and connective tissue cells, can grow into normal gut tissue around the scaffold and function inside a living mammal. Researchers caution that a fully functioning replacement intestine for humans is far off, but they say their results have laid the critical groundwork to do so. "Our experiments show that the architecture and function of our lab-made intestine strikingly resemble those of the healthy human gut, giving us real hope that our model could be used as the backbone for replacement intestine."

In an initial set of experiments researchers took stem cells from the colons of babies undergoing intestinal surgeries and from mice, then added immune cells called macrophages, the body's scavengers that seek out and engulf debris along with foreign and diseased cells. To this mix, they added cells called fibroblasts, whose function is to form collagen and other connective substances that bind tissues and organs together. The idea, the scientists say, was to create a mixture that closely mimics the natural composition of the gut. In another set of experiments, researchers added probiotic bacteria to the newly created intestinal tissue. Doing so further amplified the growth and differentiation of new gut cells, specifically the growth of Paneth cells responsible for production of infection-fighting proteins that guard against intestinal infections.

Next, researchers implanted the newly created intestine into the bellies of mice. In a matter of days, the implanted intestine began producing new intestinal stem cells and stimulated the growth of new blood vessels around the implant. That observation, researchers say, affirmed the ability of the 3-D intestine to spur the growth of new tissue not only in lab dishes, but also in living organisms. In a final step, the investigators implanted pieces of the newly created intestine - about 1.6 inches in length - into the lower portion of dog colons lacking parts of their intestinal lining. For two months, the dogs underwent periodic colonoscopies and intestinal biopsies. Strikingly, the guts of dogs with implanted intestines healed completely within eight weeks. By contrast, dogs that didn't get intestinal implants experienced continued inflammation and scarring of their guts.

Link: http://www.hopkinsmedicine.org/news/media/releases/lab_grown_3_d_intestine_regenerates_gut_lining_in_dogs

Neurogenesis is name given to the creation of new neurons in the central nervous system, and particularly the brain. Only within the last thirty years, quite recently in the grand scheme of things, have researchers proved that neurogenesis occurs at a low level in adults, that the brain is not a fixed set of long-lived and non-dividing cells, but is augmented with new arrivals on an ongoing basis. Once verified, this became a topic of considerable interest for the growing fields of regenerative medicine and stem cell research. Can the rate of neurogenesis be safely increased, and will this produce benefits for patients suffering neurodegenerative conditions, or postpone the onset of such conditions? Can investigation of neurogenesis be used to guide improvements in first generation stem cell therapies based on transplanted cells?

With more research into the biology of the brain, aided by the rapid improvement in the tools of biotechnology since the 1990s, there is an increased realization of the importance of adult neurogenesis. Few evolved processes exist without serving multiple ends, and this one is no exception in that regard. More than a mere repair and replacement mechanism, neurogenesis in adults is necessary to the correct functioning of the brain. Couple that to the discovery that rates of neurogenesis decline with age, and the processes of slow growth and change in the brain become ever more attractive as an area of medical research. It is worth noting that some of the recent work emerging from parabiosis studies, in which alterations are made to levels of some of the molecular signals in the circulatory system, have shown preliminary signs of being able to reduce the age-related decline in neurogenesis.

The article linked below is a good read, and goes some way to providing the high-level context and background to explain why research into neurogenesis is so important to those parts of the life science community focused on aging, age-related diseases of the brain, neurobiology, and regenerative medicine. Clearly there is a lot more to be done before an initial set of therapies emerge via the traditional drug development approach, and those therapies will likely be pretty marginal at the outset if history is any guide, but it is an interesting field to watch.

Brain Gain: Young Neurons in the Adult Human Brain are Likely Critical to its Function

At a lab meeting in the mid-1990s a neuroscientist told his team that he wanted to determine whether new neurons are produced in the brains of adult humans. At the time, adult neurogenesis was well established in rodents, and there had been hints that primate brains also spawned new neurons later in life. But reports of neurogenesis in the adult human brain were sparse and had not been replicated. Soon enough, a clear picture emerged: the human hippocampus, a brain area critical to learning and memory and often the first region damaged in Alzheimer's patients, showed evidence of adult neurogenesis. In November 1998, the group published its findings. "When it came out, it caught the fancy of the public as well as the scientific community. It had a big impact, because it really confirmed neurogenesis occurs in humans."

Fifteen years later, in 2013, the field got its second (and only other) documentation of new neurons being born in the adult human hippocampus - and this time learned that neurogenesis may continue for most of one's life. Neuroscientistists took advantage of nuclear bomb tests carried out during the Cold War. Atmospheric levels of carbon-14 have been declining at a known rate since such testing was banned in 1963, and researchers were able to date the birth of neurons in the brains of deceased patients by measuring the amount of carbon-14 in the cells' DNA.

In the late 1990s and early 2000s, researchers delved into the cell biology of neurogenesis, characterizing the populations of stem cells that give rise to the new neurons and the factors that dictate the differentiation of the cells. They also documented significant differences in the behavior of young and old neurons in the rodent brain. Most notably, young neurons are a lot more active than the cells of established hippocampal networks, which are largely inhibited. "For a period of about four or five weeks, while the newborn neurons are maturing, they're hyperexcitable. They'll fire at anything, because they're young, they're uninhibited, and they're integrating into the circuit."

To determine the functional role of the new, hyperactive neurons, researchers began inhibiting or promoting adult neurogenesis in rodents by various means, then testing the animals' performance in various cognitive tasks. What they found was fairly consistent: the young neurons seemed to play a role in processing new stimuli and in distinguishing them from prior experiences. This type of assessment is called pattern separation. While some researchers quibble over the term, which is borrowed from computational neuroscience, most who study hippocampal neurogenesis agree that this is a primary role of new neurons in the adult brain. The basic idea is that, because young neurons are hyperexcitable and are still establishing their connectivity, they are amenable to incorporating information about the environment. If a mouse is placed in a new cage when young neurons are still growing and making connections, they may link up with the networks that encode a memory of the environment.

While studying the function of hippocampal neurogenesis in adult humans is logistically much more difficult than studying young neurons in mice, there is reason to believe that much of the rodent work may also apply to people - namely, that adult neurogenesis plays some role in learning and memory. "Given that the dentate gyrus is so highly conserved and that the mechanisms of its function are so similar between the species - and given that neurogenesis is there in humans - I would predict that the general principle is the same." And if it's true that hippocampal neurogenesis does contribute to aspects of learning involved in the contextualization of new information - an ability that is often impaired among people with neurodegenerative diseases - it's natural to wonder whether promoting neurogenesis could affect the course of Alzheimer's disease or other human brain disorders. Epidemiological studies have shown that people who lead an active life - known from animal models to increase neurogenesis - are at a reduced risk of developing dementia, and several studies have found reduced hippocampal neurogenesis in mouse models of Alzheimer's. But researchers have yet to definitively prove whether neurogenesis, or lack thereof, plays a direct role in neurodegenerative disease progression.

Of course, the big question is whether researchers might one day be able to harness neurogenesis in a therapeutic capacity. Some scientists say yes. "I think the field is moving toward that. Neurogenesis is not something de novo that we don't have at all - that would be much harder. Here, we know it happens; we just need to enhance it."

Researchers here crunch the numbers to suggest that people who exercise for longer are better off in terms of risk of suffering age-related cardiovascular disease. One of the emerging themes in epidemiology in recent years is an attempt to pin down the dose-response curve for exercise. How is long term health and life expectancy affected for different levels of exercise, and do these differences reflect correlation or causation? Is it a matter of people obtaining health benefits through exercise or a matter of more healthy people tending to exercise more? These are hard questions to answer for human populations, but as technology lowers the cost of obtaining and using large data sets, ever more research groups are taking a stab at it. As with all such statistical studies, it is wise to wait for more data and the work of different teams before taking anything published by one group at face value, however:

Doubling or quadrupling the minimum federally recommended levels of physical activity lowered the risk of developing heart failure by 20 percent and 35 percent, respectively, according to researchers. "Walking 30 minutes a day as recommended in the U.S. physical activity guidelines, may not be good enough - significantly more physical activity may be necessary to reduce the risk of heart failure." The researchers found that the current U.S. physical activity guidelines recommendation of a minimum of at least 150 minutes of moderate intensity physical activity a week was associated with only a modest reduction in heart failure risk, and suggest that higher levels of physical activity, up to twice the minimum recommended dose, is needed to reduce the risk of heart failure.

They also found a "dose-dependent" inverse association between physical activity and heart failure, that is, higher levels of physical activity were associated with a lower risk of heart failure. This relationship was consistent across all age, sex, race, and geographic location based subgroups studied. Although the role of physical activity in coronary heart disease - the narrowing of the arteries that causes heart attacks - has been comprehensively studied, this study focused exclusively on the quantitative relationship between the amount, or specific "dose" of regular physical activity and the risk of heart failure.

The researchers pooled data from 12 studies from United States and Europe that collectively included 370,460 individuals with varying levels of physical activity at baseline and 20,203 heart failure events over a mean follow-up of 15 years. Physical activity was measured by self-reported levels of activity by study participants using standard questionnaires. "Future physical activity guidelines should take these findings into consideration, and potentially provide stronger recommendations regarding the value of higher amounts of physical activity for the prevention of heart failure."

Link: http://blog.heart.org/physical-activity-more-is-better-for-heart-failure-prevention/

The present best approach to enabling xenotransplantation of pig organs into human patients is decellularization: strip all the cells and repopulate the extracellular matrix scaffold of the organ with human cells. However, with the existence of cheap and efficient genetic alteration based on CRISPR it may be possible to edit all of the genes in pig cells that produce problem proteins instead of replacing these cells. My first thought on this is that decellularization is still a better option; after any reasonable number of genetic edits on pig cells the result remains an organ built out of edited pig cells, not human cells, and not matched to the patient. Still, this is an interesting demonstration of the cost-effectiveness of CRISPR, making genetic alterations in much larger batches than have been achieved to date:

For decades, scientists and doctors have dreamed of creating a steady supply of human organs for transplantation by growing them in pigs. But concerns about rejection by the human immune system and infection by viruses embedded in the pig genome have stymied research. By modifying more than 60 genes from pig embryos - ten times more than have been edited in any other animal - researchers believe they may have produced a suitable non-human organ donor.

The researchers used CRISPR gene-editing technology to inactivate 62 porcine endogenous retroviruses (PERVs) in pig embryos. These viruses are embedded in all pigs' genomes and cannot be treated or neutralized. It is feared that they could cause disease in human transplant recipients. They also modified more than 20 genes in a separate set of embryos, including genes encoding proteins that sit on the surface of pig cells and are known to trigger the human immune system or cause blood clotting. Eventually, pigs intended for organ transplants will have both these modifications and the PERV deletions.

A biotech company founded to produce pigs for organ transplantation, eGenesis in Boston, is now trying to make the process as inexpensive as possible. The team released few details about how they managed to remove so many pig genes. But both sets of edited pig embryos are almost ready to implant into mother pigs. eGenesis has procured a facility at Harvard Medical School where the pigs will be implanted and raised in isolation from pathogens.

Link: http://www.nature.com/news/gene-editing-record-smashed-in-pigs-1.18525

Today I'll point out a couple of recent research publications on the topic of the molecular mechanisms of exercise: how it might work to improve health, how it extends healthy life span but not maximum life span in animal studies, and how the response to exercise might be safely improved or otherwise manipulated. Researchers nowadays tend to comment on future directions for drug discovery based on their investigations of exercise, and in that this slice of the field is becoming much like calorie restriction research ten to fifteen years ago.

Take a moment to think about how much work and funding has gone into investigations of calorie restriction and the search for drug candidates that can mimic even just a fraction of the beneficial metabolic alterations and extension of healthy life spans that occur in response to calorie restriction: probably a few billion dollars and year after year of dedicated investigations by hundreds of scientists in the past decade alone. Yet at the end of all that, and after the collection of enormous amounts of data, there is only a small number of drug candidates, few of which are anything other than marginal in animal studies, none of which can reproduce all of the beneficial changes observed in calorie restriction, and there is still no comprehensive accounting of how calorie restriction works under the hood, just an outline of ever-growing complexity.

It has taken fifteen years to get that far. Processes like the reaction to restricted calorie intake and exercise are enormously complex. They impact near every aspect of metabolism and cellular biology, and the quest to understand them well enough to manipulate them is more or less the same thing as the quest to understand cellular biology completely. This and the past history of calorie restriction mimetic drug research is why I'm not holding my breath waiting on exercise mimetic drugs. Researchers will talk about this as a goal, just as they have talked about calorie restriction mimetic drugs, but the reality is that the inherent complexity involved makes this is a very long-term project, one that tends to produce marginal outcomes at great expense. Exercise mimetics and calorie restriction mimetics that are safe and reliable would be a pleasant thing to have around, to be sure, but it seems to me that at the present time there are better and more cost-effective approaches to the treatment of aging as a medical condition.

Exercise Pills: At the Starting Line

Excessive caloric intake and limited physical activity contribute to the current explosion of 'modern' chronic diseases such as obesity, type 2 diabetes, muscle atrophy, and cardiovascular diseases. By contrast, regular physical exercise maintains glucose homeostasis and induces physiological adaptations that effectively prevent, and often reverse, these diseases. Recognizing the human and economic burdens these diseases cause, and taking into account the health benefits of exercise, have led many exercise scientists to suggest that physical exercise may be the preferred method in the treatment and prevention of these 'modern' chronic diseases.

Unfortunately, exercise compliance levels are almost universally low, especially for people using home-based exercise programs. A variety of factors including poor physical condition, weakness, sickness, lack of time, and poor motivation contribute to low exercise compliance. The much publicized poor compliance begs the question: is there an alternative approach that both induces the health benefits of physical exercise and overcomes the problem of low compliance rate? Regular physical exercise activates a number of molecular pathways in whole organ systems and reduces the risk of developing numerous chronic diseases. Although nothing can fully substitute for physical exercise, candidate exercise pills that have emerged in recent years may be an attractive alternative.

Exercise in a bottle could become a reality

Researchers exposed a thousand molecular changes that occur in our muscles when we exercise, providing the world's first comprehensive exercise blueprint. "Exercise is the most powerful therapy for many human diseases, including type 2 diabetes, cardiovascular disease and neurological disorders. However, for many people, exercise isn't a viable treatment option. This means it is essential we find ways of developing drugs that mimic the benefits of exercise." The researchers analysed human skeletal muscle biopsies from four untrained, healthy males following 10 minutes of high intensity exercise. Using a technique known as mass spectrometry to study a process called protein phosphorylation, they discovered that short, intensive exercise triggers more than 1000 changes.

"Exercise produces an extremely complex, cascading set of responses within human muscle. It plays an essential role in controlling energy metabolism and insulin sensitivity. While scientists have long suspected that exercise causes a complicated series of changes to human muscle, this is the first time we have been able to map exactly what happens. This is a major breakthrough, as it allows scientists to use this information to design a drug that mimics the true beneficial changes caused by exercise. Most traditional drugs target individual molecules. With this exercise blueprint we have proven that any drug that mimics exercise will need to target multiple molecules and possibly even pathways, which are a combination of molecules working together. We believe this is the key to unlocking the riddle of drug treatments to mimic exercise."

For some years a faction of researchers have argued that Alzheimer's disease really should be considered a type 3 diabetes, based on the shared risk factors and what is known of the way that it ties into the mechanisms associated with insulin resistance. It is certainly the case that based on epidemiological data Alzheimer's, like type 2 diabetes, is enough of a lifestyle disease that you should add it to the list of very good reasons not let yourself become fat and sedentary. But is the connection with insulin metabolism relevant enough to class Alzheimer's as a form of diabetes, or is this just a good example of the way in which everything connects to everything else in the operation of our cellular biology?

Aging is known to be one of the top risk factors for both Alzheimer's disease (AD) and Type 2 Diabetes (T2D). The pathologies of these disorders are somewhat understood, with AD being associated with the accumulations of amyloid-β plaques and/or phosphorylated tau tangles (two proteins involved in neuron structure and development) and T2D being associated with resistance to insulin (the growth factor that controls glucose uptake by cells). For many years these two diseases have been treated separately, with few overlaps. In more recent years, however, the overlap between them has become more prominently recognized. The rate of AD in diabetic individuals is elevated, and it may be worth considering these two "separate" disorders as a related problem.

The first suggestion of AD being a previously unrecognized type of diabetes was in 2005, where it was noted that insulin signaling and insulin-like growth factor (IGF) expression were greatly affected in the instance of AD. It has since been shown that in the instance of AD, IGF, insulin receptor, and insulin expression are all reduced in the temporal cortex and hippocampus of the brain. Further, as AD progresses the levels of these gene transcripts continue to decrease. These inhibited insulin-related signals result in a deficiency and similar symptoms to those shown in other cases of diabetes. This deficiency also contributes to a vicious cycle, as impaired insulin receptor expression can contribute to further AD-like pathology such as hyperphosphorylation of tau and increased amyloid-β deposits as well as decreased clearance of these deposits from the brain.

Although seldom considered a metabolic disorder, it is clear that AD is metabolically affected in a similar fashion to diabetes. Although frequently treated separately, the same basic principles which are used for diagnosing an individual as diabetic may also be applied to understand some of the mechanisms affected in AD. As such, it may be appropriate to consider AD as a type of diabetes of the brain.

Link: http://sage.buckinstitute.org/food-for-thought/

An important factor in the speed of development, cost, and availability of future stem cell therapies is the existence of an efficient, reliable way to create large numbers of the specific cell types needed. This is one of the main limiting factors for many areas of medical development in cell-based regenerative medicine. Here, researchers establish a methodology for generation of photoreceptor cells that could be used to rebuild retinal tissue, which is good news for progress towards regenerative therapies for conditions such as macular degeneration:

Age-related macular degeneration (ARMD) is due to the degeneration of the macula, which is the central part of the retina that enables the majority of eyesight. This degeneration is caused by the destruction of the cones and cells in the retinal pigment epithelium (RPE), a tissue that is responsible for the reparation of the visual cells in the retina and for the elimination of cells that are too worn out. However, there is only so much reparation that can be done as we are born with a fixed number of cones. They therefore cannot naturally be replaced. Moreover, as we age, the RPE's maintenance is less and less effective - waste accumulates, forming deposits.

A research team has developed a highly effective in vitro technique for producing light sensitive retina cells from human embryonic stem cells. "Our method has the capacity to differentiate 80% of the stem cells into pure cones. Within 45 days, the cones that we allowed to grow towards confluence spontaneously formed organised retinal tissue that was 150 microns thick. This has never been achieved before."

In order to verify the technique, researchers injected clusters of retinal cells into the eyes of healthy mice. The transplanted photoreceptors migrated naturally within the retina of their host. "Cone transplant represents a therapeutic solution for retinal pathologies caused by the degeneration of photoreceptor cells. To date, it has been difficult to obtain great quantities of human cones." The discovery offers a way to overcome this problem, offering hope that treatments may be developed for currently non-curable degenerative diseases, like Stargardt disease and ARMD. "Researchers have been trying to achieve this kind of trial for years. Thanks to our simple and effective approach, any laboratory in the world will now be able to create masses of photoreceptors. Even if there's a long way to go before launching clinical trials, this means, in theory, that will be eventually be able to treat countless patients."

Link: http://www.alphagalileo.org/ViewItem.aspx?ItemId=157027&CultureCode=en

Last week we launched the Fight Aging! fundraiser for SENS rejuvenation research programs, work on the biotechnologies needed to repair the cellular and molecular damage that causes aging and all age-related disease. Do we want to see meaningful progress towards the defeat of degenerative aging in our lifetime? Yes, yes we do. We will be matching dollar for dollar all donations to the SENS Research Foundation until either the end of the year or our $125,000 matching fund runs out - whichever happens first. Obviously we'd love to see the community hit this target, as that would mean an extra quarter of a million dollars for the best lines of early stage research into ending frailty and disease in aging. As of today, 94 donors have given $22,542 since the fundraiser launched on the 1st. A good start!

The SENS Research Foundation has a track record of producing results, as I outlined recently. The philanthropy of past years has blossomed into a first round of startups, clinical development, and greater ongoing funding: Gensight is commercializing an approach to mitochondrial repair, Oisin Biotech is working on senescent cell clearance, and Human Rejuvenation Technologies was formed to further develop the use of bacterial enzymes to remove of some of the metabolic waste compounds that contribute to atherosclerosis. The wheel is turning and now is the time for greater efforts, to remove the hurdles and fund the groundwork needed for the next round of biotechnologies for human rejuvenation.

I ran up a pair of new fundraising posters over the weekend, sticking to this year's simple motif of text and color, suitable for signs and more visible from a distance. This year's fundraiser is a stretch goal for our community, based on how we've been doing over the past couple of years. We need to get out there and wave the flag, track down new supporters and expand our corner of the world, the small community interested in actually getting something done about aging.

2015 Fundraiser #1: 4200 x 2800px

2015 Fundraiser #2: 4200 x 2800px

Researchers are now able to compare the mutational damage to nuclear DNA in individual long-lived cells such as neurons, which is a step towards measuring how much of this damage there is and how it varies over time and from cell to cell. That in turn is a step towards getting a handle on whether or not this damage has any meaningful effect over the course of a human life span beyond raising the risk of cancer. For example is the presence of stochastic mutational damage causing large enough alterations in the day to day operation of metabolism across enough cells to matter? There is some debate on this issue, and certainly a lack of good enough data to nail down a proof one way or another.

A single neuron in a normal adult brain likely has more than a thousand genetic mutations that are not present in the cells that surround it, according to new research. The majority of these mutations appear to arise while genes are in active use, after brain development is complete. "We found that the genes that the brain uses most of all are the genes that are most fragile and most likely to be mutated." It's not yet clear how these naturally occurring mutations impact the function of a normal brain, or to what extent they contribute to disease.

Cells of many shapes, sizes, and function are intimately intertwined inside the brain, and scientists have wondered for centuries how that diversity is generated. Scientists are further interested in genome variability between neurons due to evidence that mutations that affect only a small fraction of cells in the brain can cause serious neurological disease. Until recently, however, scientists who wanted to explore that diversity were stymied by the scant amount of DNA inside neurons: Although researchers could isolate the genetic material from an individual neuron, there was simply not enough DNA to sequence, so cell-to-cell comparisons were impossible. However, technology has become available in the last few years for amplifying the full genomes of individual cells. With plenty of DNA now available, the scientists could fully sequence an individual neuron's genome and scour it for places where that cell's genetic code differed from that of other cells.

The scientists isolated and sequenced the genomes of 36 neurons from healthy brains donated by three adults after their deaths. For comparison, the scientists also sequenced DNA that they isolated from cells in each individual's heart. What they found was that every neuron's genome was unique. Each had more than 1,000 point mutations (mutations that alter a single letter of the genetic code), and only a few mutations appeared in more than one cell. What's more, the nature of the variation was not quite what the scientists had expected. "We expected these mutations to look like cancer mutations, in that cancer mutations tend to arise when DNA is imperfectly copied in preparation for cell division, but in fact they have a unique signature all their own. The mutations that occur in the brain mostly seem to occur when the cells are expressing their genes. To what extent do these mutations normally shape the development of the brain, in a negative way or a positive way? To what extent do we have a patch of brain that doesn't work quite right, but not so much that we would call it a disease? That's a big open question."

Link: http://www.hhmi.org/news/study-examines-scale-gene-mutations-human-neurons

This article paints a picture of David Sinclair as one of the important researchers in the move towards treating aging as a medical condition. I'd say that he's certainly good at publicity and fundraising, and has more than done his part to make drug development for the treatment of aging plausible in the eyes of the public, but it is a pity that all of this is coupled to lines of research (such as the investigation and manipulation of sirtuins) that to my eyes have no hope of producing meaningful therapies. Even if sirtuin-based therapies could do all that the original hype promised, the end result would be a marginal, slight slowing of the aging process. As an end goal for the investment of billions and years of time, that simply isn't worth it when there are far better approaches to the problem such as SENS that can in principle lead to actual rejuvenation and the addition of decades of healthy life.

Today, Sinclair's work on slowing the ageing process, and even reversing some aspects of it, could lead to the most significant set of medical breakthroughs since the discovery of antibiotics nearly a century ago. At the heart of what motivates him is a deceptively simple notion: if the greatest driver of disease in old age is old age itself, then why not find a cure for ageing, which he describes as being "the greatest problem of our time". Sinclair's statement is borne out by the World Health Organisation's Global Burden of Disease Project, which estimates that the number of years lost to premature death or compromised by disability in 2010 was 2.5 billion, meaning that about a third of potential human life goes to waste. The toll from crime, wars and genocides does not come close to matching this. Yet, as Sinclair points out, just one per cent of medical research funding is spent on understanding why we age and even less on doing something about it. His goal is to find the "master control switch" that can regulate the pathways that contribute to ageing itself. "It could be one pill for 20 diseases at once. It would be the most profitable drug ever made."

Extending the generally accepted limits of human life is now being taken seriously by some of the world's top scientists. Backed by wealthy philanthropists and tech giants such as Google, billions of dollars are being poured into longevity research. Press releases and PowerPoint presentations come laced with terms such as health-span, not lifespan. The elderly, we are told, will become the wellderly. There will be fewer bedridden geriatrics taxing our overstretched medical systems. The ever-growing list of billionaires funding research into longevity includes PayPal co-founder Peter Thiel, who has set up Breakout Labs, a non-profit organisation that supports early-stage companies, and Oracle founder Larry Ellison, who has donated more than $US430 million ($600 million) to anti-ageing research.

Sinclair is decidedly reticent when it comes to passing judgment on the work of other scientists such as Craig Venter at Human Longevity Inc. and Cynthia Kenyon at Calico: "I think it's going to take a lot of resources to find the needle in the haystack, but it's helpful that more people are getting involved in ageing research. If Craig and his associates tackle it from the sequencing side and we tackle it from the fundamental biology side and Google's Calico attacks it from bioinformatics side, then there's more chance of finding the right medicines." Circumspection is embedded in Sinclair's DNA. He speaks slowly and deliberately, giving his audiences time to absorb both the complex science behind his discoveries and to underline what motivates him. "How sad would it be if we, after 10,000 generations, we were the last ones to live a normal lifespan? Imagine if we were born one generation too early to reap the benefits of this technology."

Link: http://www.smh.com.au/interactive/2015/never-say-die/

Given the BioViva press release I pointed out earlier today, you may be interested in listening to a Longevity Day roundtable held yesterday, since Elizabeth Parrish of BioViva was participating, as well as Keith Comito of the Life Extension Advocacy Foundation, and a few other names you might recognize. From my perspective it is great to see so much going on that I only find out about after the fact: one of the signs of a healthy and growing community is that people are off doing things and I have no idea, since there is too much to keep track of in any reasonable amount of time.

What can be done to raise public support for the pursuit of indefinite life extension through medicine and biotechnology to the same level as currently exists for disease-specific research efforts aimed at cancers, heart disease, ALS, and similar large-scale nemeses? In this panel discussion, held on October 1, 2015 - International Longevity Day - Mr. Stolyarov asks notable life-extension supporters to provide input on this vital question and related areas relevant to accelerating the pursuit of indefinite longevity. This panel is coordinated in conjunction with MILE, the Movement for Indefinite Life Extension.

Panelists: Adam Alonzi, Sven Bulterjis, Keith Comito, Roen Horn, B. J. Murphy, and Elizabeth Parrish

A set of presentation slides was put together by Butlerjis, and is worth a few minutes of your time. In particular, one of the lessons to take away here is that big budget cancer research didn't just magically happen overnight. Rather it was the culmination of many failed attempts to create such a state of affairs over the course of half a century. Prior to the 1970s cancer research in fact looked quite similar to the situation for aging research today: little interest, little funding, large gaps in the scientific understanding of the fine details of the disease, but the clear potential to make a big difference to patients and therapies with what was known at the time.

Aging Research Needs Marketing: What Can We Learn from Cancer Research?

1910: The American Association for Cancer Research convinces president Taft to ask congress to build a national lab for cancer research: failure.

1927: Senator Matthew Neely asks congress to give 5 million USD for information that could lead to a cure for cancer: he got 50,000 USD.

1937: Neely, Senator Homer Bone and Representative Warren Magnuson : National Cancer Institute Act, success signed by president Roosevelt: NCI founded, but the war in Europe soon ended funds for the NCI.

1946-47: Neely and Senator Claude Pepper: 3rd proposal for nation wide cancer research: rejected.

Solomon Garb said in 1969: "A big obstacle in the fight against cancer is the severe an chronic lack of money, something that is not known to most people. We won't get there by repeating this. It is also necessary to explain how it will be used, what kind of projects will be financed with it, why these projects deserve our support, and where the scientists and technicians that have to execute them will come from."

Why do some diseases have a big impact only in a given era? Theory: the society couples diseases to psychological crises. For Cancer: in the '70s when the focus changed from external (USSR) to internal (cancer). For AIDS: in the '80s when the generation was obsessed with sexuality and freedom. For SARS: in the 21st century alongside the fears of globalization. But what about aging?

To conclude: cancer has a similar history to aging, we also need marketing, business people, and celebrities on our side, and aging has to be recognized as a disease.

Gene therapy to raise levels of the natural antioxidant catalase in mitochondria is one of many methods shown to modestly extend life in mice. Cancer is so very prevalent in mice that it is frequently worth asking whether or not life extension is a matter of slowing aging or a matter of suppressing cancer - though there is certainly a lot of room for argument as to whether or not these are just two ways of stating the same thing, based on the details of the mechanisms involved. See the debate over whether rapamycin slows aging or suppresses cancer, for example. Given all this, the paper linked here is interesting:

The antioxidant enzyme catalase targeted to mitochondria (mCAT) has been shown to delay aging and cancer in mice, and the progression of transgenic oncogene and syngeneic tumors was suppressed, helping support the notion that attenuation of mitochondria-generated hydrogen peroxide signaling is associated with an antitumor effect.

In order to determine if mCAT has any effect on naturally occurring lung cancer of the adenocarcinoma type in old mice, the tumor incidence and progression were examined in the lungs of old mCAT transgenic and wild-type (WT) mice with a CB6F1 background. CB6F1 mice with a WT genotype were found to have a high incidence of adenomas at 24 months of age, which progressed to adenocarcinomas at 32 months of age. CB6F1 mice with the mCAT genotype had significantly reduced incidence and severity of lung tumors at both ages.

Fibroblasts isolated from the lungs of old mCAT mice, but not WT mice, were shown to secrete soluble factors that inhibited lung tumor cell growth suggesting that stromal fibroblasts play a role in mediating the antitumor effects of mCAT. The aged CB6F1 mouse, with its high incidence of K-ras mutant lung cancer, is an excellent model to further study the anticancer potential of mitochondria-targeted therapy.

Link: http://dx.doi.org/10.3402/pba.v5.28776

BioViva is one of the small groups interested in bringing telomerase therapies to humans sooner rather than later. It seems they have started in on their small long-term trial of human gene therapy for telomerase activation, and have treated the first volunteer.

I should say that at any given time there is a fairly large gap between what can be done in human medicine, the technology that actually exists and works, and what is being done in trials. Most of this gap is due to regulation, and the rest of it because development groups want to have a reasonable certainty that what they are doing actually works, does more good than harm, and so forth. The regulatory process might last a decade, while the actually useful part of that testing (does it basically work, and is the risk profile sufficiently defined and acceptable to patients) is only a few years. As the cost of research and development in the life sciences falls, it will become increasingly untenable that a huge ball and chain slows progress thanks to regulatory risk aversion, and a growing number of initiatives will forge ahead and build anyway. Some years ago I proposed the Vegas Group fable, something that I think will happen in the fullness of time: alternative roads that bypass official regulation in favor of faster progress, an inevitability in an environment of low-cost research. Also, I think, a necessity.

What about the science here? I've never been a big fan of telomere lengthening approaches, as average telomere length as it is measured today in immune cells looks very much like a marker of the progress of aging, an end stage consequence far removed from root causes. Telomeres shorten with cell division and new long-telomere cells are delivered into tissues by stem cell populations. Thus average telomere length in immune cells reflects some combination of immune health and stem cell activity, both of which are known to decline with age. You can't argue with the fact that telomerase gene therapy has been shown to extend life in mice, however, though you can certainly note that the size of the effect has been getting smaller as the research groups have refined their data and approaches.

How does this work to slow aging in mice? At this point I lump enhanced telomerase activity into the general category of approaches that either probably work or intend to work by boosting the activation of old stem cell populations, resulting in increased repair and tissue maintenance and thus a slower decline into frailty and organ failure. More telomerase doesn't seem to raise cancer risk in mice, but mice have very different telomere dynamics and cancer risk profiles than we humans. The fastest way to figure out what is going to happen in humans is of course to try it, and kudos to anyone volunteering at this stage, but I'd be waiting for a few more years of testing first in animal or tissue models closer to human telomere dynamics. In part that decision would be driven by the fact that I don't think that this is the best approach to move ahead with practical applications, to push ahead and get things done. I absolutely agree that pushing ahead to get things done needs to happen, but I'd rather see this sort of boldness for SENS treatments like senescent cell clearance.

BioViva USA, Inc. has become the first company to treat a person with gene therapy to reverse biological aging, using a combination of two therapies developed and applied outside the United States of America. Testing and research on these therapies is continuing in BioViva's affiliated labs worldwide. BioViva CEO Elizabeth Parrish announced that the subject is doing well and has resumed regular activities. Preliminary results will be evaluated at 5 and 8 months with full outcome expected at 12 months. The patient will then be monitored every year for 8 years.

Gene therapy allows doctors to treat disease at the cellular level by inserting a gene into a patient's cells instead of using the regular modalities of oral drugs or surgery. BioViva is testing several approaches to age reversal, including using gene therapy to introduce genes into the body. Although not generally considered a disease, cellular aging is the leading cause of death in the developed world. Side effects like muscle wasting (sarcopenia), grey hair and memory loss are the well-known hallmarks. And the aging cell is also responsible for the diseases of aging, including Alzheimer's disease, heart disease and cancer. BioViva is leading the charge to treat the aging cell and reverse aging. "The aging cell is a key factor that has been overlooked for too long. Companies have put millions of dollars into treating the diseases of aging, such as dementia, frailty, kidney failure and Parkinson's disease, and we still do not have a cure. Aging involves multiple pathways. We wanted to target more than one for a better outcome."

Link: http://www.prweb.com/releases/2015/10/prweb12995323.htm

Today I'm pleased to announce the launch of this year's Fight Aging! matching fundraiser in support of the work of the SENS Research Foundation, funding scientific programs to speed progress towards working rejuvenation therapies and an end to frailty and disease in aging. In 2013 we raised $60,000, in 2014 $150,000, and this year we're shooting at a cool quarter of a million dollars. You never know where the limits really are unless you forge ahead, and support for the treatment of aging as a medical condition is growing more rapidly today than at any time since the creation of Fight Aging!

• View the Fundraiser Page at Fight Aging!
• Donate at the SENS Research Foundation

We have kicked things off with a Reddit /r/futurology post this year, as we did last year. Please do take a look and share the link and this fundraiser with those who might appreciate it. The /r/futurology community has been a great help in the past, and a source of many new supporters of longevity science.

Front and center, I'd like to thank Josh Triplett, Christophe and Dominique Cornuejols, Michael Greve of forever-healthy.org, and Stefan Richter for joining Fight Aging! in putting money on the table to set up a $125,000 matching fund for this event. From today until December 31st 2015, we will match every donation to the SENS Research Foundation dollar for dollar. I'd also like to thank David Gobel at the Methuselah Foundation for leaping in to be the first donor, providing an additional $15,000 for SENS research this year. Only another $110,000 to go, and three months to do it in!

How do we create a real, actual medical rejuvenation industry? By building technologies capable of repairing the known forms of cellular and molecular damage that cause aging. These types of damage are well-cataloged, and there is broad consensus on their relevance to age-related disease, but surprisingly little work takes place in the research community when it comes to making use of this knowledge to create treatments. This is even more surprising given that where progress has been made, such in amyloid clearance, senescent cell clearance, and mitochondrial repair, even early stage outcomes are of great quality, and clearly well worth further attention.

Funding for SENS technologies has been underway at a modest level for a decade now, and I can point to concrete progress occurring as a result. The wheel is starting to turn, and prospective SENS and SENS-like damage repair treatments targeting the causes of aging are beginning to leave the labs for clinical translation. Our community created this achievement, through advocacy and a comparatively small amount of funding directed to speed and enable to most promising scientific programs. One of the great secrets of our age is that early stage research is very cheap, but next to no-one other than philanthropists is willing to fund it. Just as soon as a prototype can be built, however, other institutions flock to fund the next stages. When looking at this is seems pretty clear that creating new and far more effective medical technologies really does fall upon the shoulders of the average person with a little vision, and the willingness to stand up and make a difference.

For example, all of these growing lines of development were originally seeded by small amounts of funding at critical times over the past decade, all of it provided by philanthropic donations. You can find further details in the latest SENS Research Foundation annual report.

Firstly: from 2008, donors to the Methuselah Foundation and then SENS Research Foundation collectively helped fund the work of the Marisol Corral-Debrinski lab on mitochondrial DNA damage. That was successful and in the years since then these researchers founded, grew, and found venture funding for Gensight, a company that is now devoting tens of millions of dollars to establishing the first clinical trials of this technology for inherited mitochondrial disease. Yet without the funding at the earliest stage, provided by forward-thinking SENS supporters, that early stage work struggled to find a patron. This is the sort of difference that we can make.

Secondly: The SENS Research Foundation has for years been using donor funds to support efforts to clear senescent cells from tissues, to remove their insidious contribution to the aging process. In 2015 the Methuselah Foundation and SENS Research Foundation have provided seed funding for the startup company Oisin Biotech that will be further developing one of these methodologies: these clearance technologies are leaving the lab and starting on their own journey to the clinic, one that will see them attract far greater funding. But again, without the years of low-level philanthropy, these are projects that languished unfunded by the institutional research establishment in their early stages.

Thirdly: One of the first and longest-running SENS programs was aimed at clearing age-related chemical junk from the cellular recycling organelles called lysosomes. With age, these organelles become clogged and faulty, and cells drown in garbage and broken components. The SENS Research Foundation has produced drug candidate molecules from studies of bacteria known to consume these compounds, and the long-time supporter Jason Hope has founded Human Rejuvenation Technologies to develop the first round of treatments based on this technology, aimed initially at removing the characteristic blood vessel plaques of atherosclerosis.

This is how the world is changed, a weight of small decisions to help, snowballing into significant projects. This is how, step by step, we can build a near future in which being old isn't accompanied by pain, suffering, disease, and death.

There is something about the prospect of treating the causes of aging and greatly extending healthy life spans that makes otherwise sensible people throw common sense out of the window. If I had a dime for every time I saw incoherent predictions and conspiracy theories suggesting that rejuvenation therapies would be developed in secret and restricted to the wealthy elite, I'd have a lot of dimes. There is something ugly and irrational in human nature when it comes to this sort of topic.

In reality it is impossible to build new medical science in secret. It is impossible to build anything in secret that requires a community of tens of thousands, an entire supporting industry, global collaboration in research and development, and the active participation of the scientific community, relentlessly focused on papers and publication. The rejuvenation treatments that will result from from SENS-style repair approaches will be mass-produced infusions akin to biopharmaceutical medicines that today cost a few thousand dollars for a course of treatment, administered by a bored clinician once every few years. After a couple of decades of market action they will be far less costly, like the older drugs produced today that are so cheap even the third world has access.

In short we all win together or we all lose together. This is a cooperative game, not a competitive one. This is all obvious and right in front of our noses; there are scores of examples in medicine today, demonstrating exactly how development and price works out over the years. Yet people are still willing to believe strange things about the future of treatments for aging, building castles of fearful fancy in the clouds.

Concerns about the advance of life extension science research and development frightens many people. Particularly, the level of private investment pouring into the industry. The most extreme of prophecies argue that there will be an absolute divide between the handful of super rich who can afford life extension treatments, and those who can't. The fear is that this divide will permit a world in which a new social order is established planted in financial wealth, but rooting from access to life-prolonging medicine.

Life extension science is at the forefront of this debate, with critics arguing that scientific research should be led by a social contract, rather than a fiscal objective. However, supporters believe that commercial input, especially in life extension, is accelerating the overall momentum of scientific research.

Ultimately though, life extension science is suffering from a complete lack of federal funding, and so if an anti-aging community is to be created, whether the result will benefit us all or just the richest in society, it must first be born out of big business and philanthropy. So then, if this is the case, how much truth and evidence are there in the claims from either side of the debate, and should we be afraid of private entities taking hold of the anti-aging industry?

Link: http://lifemag.org/article/lifespan-inequality-are-we-heading-toward-a-dystopia-or-does-it-already-exist

Researchers here propose that the domestic dog population is overlooked as a cost-effective source of data on aging. It is certainly the case that there is a broad variation in life span as well as size between canine breeds, and comparative biology between and within species with disparate life spans is a strong thread in aging research these days:

With many caveats to the traditional vertebrate species pertaining to biogerontology investigations, it has been suggested that a most informative model is the one which: 1) examines closely related species, or various members of the same species with naturally occurring lifespan variation, 2) already has adequate medical procedures developed, 3) has a well annotated genome, 4) does not require artificial housing, and can live in its natural environment while being investigated, and 5) allows considerable information to be gathered within a relatively short period of time.

The domestic dog unsurprisingly fits each criterion mentioned. The dog has already become a key model system in which to evaluate surgical techniques and novel medications because of the remarkable similarity between human and canine conditions, treatments, and response to therapy. The dog naturally serves as a disease model for study, obviating the need to construct artificial genetically modified examples of disease. Just as the dog offers a natural model for human conditions and diseases, simple observation leads to the conclusion that the canine aging phenotype also mimics that of the human.

Genotype information, biochemical information pertaining to the GH/IGF-1 pathway, and some limited longitudinal investigations have begun the establishment of the domestic dog as a model of aging. Although we find that dogs indeed are a model to study aging and there are many independent pieces of canine aging data, there are many more "open" areas, ripe for investigation.

Link: http://dx.doi.org/10.1016/j.exger.2015.08.008