Fight Aging! Newsletter, March 7th 2016

March 7th 2016

Fight Aging! provides a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress towards the medical control of aging in order to prevent age-related frailty, suffering, and disease, as well as improvements in the present understanding of what works and what doesn't work when it comes to extending healthy life. Expect to see summaries of recent advances in medical research, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more.

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  • Clearing Microglia Without Clearing Amyloid Produces Benefits in a Mouse Model of Alzheimer's Disease
  • A Chapter Excerpt from the Forthcoming Longevity Cookbook
  • Cellular Senescence Presented as the Causal Nexus of Aging
  • A Selection of Recent Calorie Restriction Research
  • Is the Growing Presence of Fragmented Nucleic Acids in Aging Tissues a Contributing Cause of Aging?
  • Latest Headlines from Fight Aging!
    • New Problems in Nematode Life Span Studies
    • Engineered Calcium Receptors in the Heart Improve Function
    • Considering Healthy Longevity and Retirement Planning
    • Should We Treat Aging as a Disease?
    • Even Small Differences in Exercise in Older People Are Associated with Greater Remaining Life Expectancy
    • How the Immune System Recognizes Senescent Cells
    • ACE Inhibition Extends Life in Nematodes
    • More ARGK-1 Increases Nematode Life Span
    • Commercialization of Mitochondrially Targeted Antioxidant Plastinquinones Continues, Slowly
    • A Recent Example of Cryonics Coverage in the Popular Press


Researchers have reduced inflammation and cell death in a mouse model of Alzheimer's disease by reducing the numbers of microglia present in brain tissue, an approach that doesn't reduce amyloid-β levels associated with the progression of Alzheimer's disease even though it results in functional benefits. Microglia are a class of immune cell specific to the brain, where portions of the immune system have more roles and more complicated roles than is the case elsewhere in the body. Types of immune cell only found in the brain are responsible for supporting neurons in many ways, not just by attacking pathogens. Dysfunction in microglia has long been implicated in the chronic inflammation that accompanies many neurodegenerative conditions, and microglia are a target for numerous lines of research related to potential Alzheimer's therapies, which in some cases include increasing microglial activity or otherwise altering their behavior rather than the approach of removal tried here.

Animal models are never the same as the human disease they are trying to mimic, and that can mean garbage in, garbage out. Judging relevance of results must always be on a case by case basis, and while considering all of the fine details, because just as it is possible to learn a great deal from a good animal model, it is also possible to create states and scenarios in that same animal model that have no real relevance to human biochemistry. For example, researchers have in the past created scenarios in which mice are heavily loaded with amyloid-β and yet show few or no signs of neurodegeneration, and it has never been entirely clear as to the degree to which that helps in understanding Alzheimer's disease in humans. This microglia study might help shed some further light on those results, at least in mouse models, given the inflammation angle. It is generally accepted that inflammation is important in the progression of Alzheimer's disease, and there are certainly other studies in mice models in which reductions in inflammation have been shown to reduce Alzheimer's-like symptoms.

On the whole, this study does well as supporting evidence for those who are trying to build treatments for neurodegenerative conditions based on targeting microglia. As is the case for a lot of the work on Alzheimer's in animal models, it raises at least as many questions as it answers, however.

Blocking inflammation prevents cell death, improves memory in Alzheimer's disease

Researchers found that flushing away the abundant inflammatory cells produced in reaction to beta-amyloid plaques restored memory function in test mice. Their study showed that these cells, called microglia, contribute to the neuronal and memory deficits seen in this neurodegenerative disease. "Our findings demonstrate the critical role that inflammation plays in Alzheimer's-related memory and cognitive losses. While we were successful in removing the elevated microglia resulting from beta-amyloid, further research is required to better understand the link among beta-amyloid, inflammation and neurodegeneration in Alzheimer's."

The neurobiologists treated Alzheimer's disease model mice with a small-molecule inhibitor compound called pexidartinib, or PLX3397, which is currently being used in several cancer studies. The inhibitor works by selectively blocking signaling of microglial surface receptors, known as colony-stimulating factor 1 receptors, which are necessary for microglial survival and proliferation in response to various stimuli, including beta-amyloid. This led to a dramatic reduction of these inflammatory cells, allowing for analysis of their role in Alzheimer's. The researchers noted a lack of neuron death and improved memory and cognition in the pexidartinib-treated mice, along with renewed growth of dendritic spines that enable brain neurons to communicate. Although the compound swept away microglia, the beta-amyloid remained, raising new questions about the part these plaques play in Alzheimer's neurodegenerative process.

Eliminating microglia in Alzheimer's mice prevents neuronal loss without modulating amyloid-β pathology

In addition to amyloid-β plaque and tau neurofibrillary tangle deposition, neuroinflammation is considered a key feature of Alzheimer's disease pathology. Inflammation in Alzheimer's disease is characterized by the presence of reactive astrocytes and activated microglia surrounding amyloid plaques, implicating their role in disease pathogenesis. Microglia in the healthy adult mouse depend on colony-stimulating factor 1 receptor (CSF1R) signalling for survival, and pharmacological inhibition of this receptor results in rapid elimination of nearly all of the microglia in the central nervous system.

In this study, we set out to determine if chronically activated microglia in the Alzheimer's disease brain are also dependent on CSF1R signalling, and if so, how these cells contribute to disease pathogenesis. Ten-month-old 5xfAD mice were treated with a selective CSF1R inhibitor for 1 month, resulting in the elimination of ∼80% of microglia. Chronic microglial elimination does not alter amyloid-β levels or plaque load; however, it does rescue dendritic spine loss and prevent neuronal loss in 5xfAD mice, as well as reduce overall neuroinflammation. Importantly, behavioural testing revealed improvements in contextual memory. Collectively, these results demonstrate that microglia contribute to neuronal loss, as well as memory impairments in 5xfAD mice, but do not mediate or protect from amyloid pathology.


You might recall that last year longevity science advocate Maria Konovalenko raised more than 50,000 via crowdfunding to create the Longevity Cookbook, an examination of the state of research and development for aging and longevity. My impression from the materials at the time was that this will be something analogous to Kurzweil and Grossman's Fantastic Voyage, in which a mix of the irrelevant and the interesting are presented. In that work, diet, supplements, and existing pharmaceuticals, all of which are near completely irrelevant to the future of human life extension, are given a lot of space, and discussed alongside some of the latest lines of research that might in the future be relevant once developed into clinical therapies, such as the SENS research programs. The public fixates on diet and supplements, encouraged by relentless "anti-aging" industry propaganda, and much of the aging research community focuses on slow and expensive pharmaceutical development aimed at metabolic adjustment that might, one day, slightly slow the pace of aging. None of that will add a decade of additional healthy years to human life any time soon, but it certainly sucks up all of the oxygen in the room when it comes to talking about human longevity.

The only path ahead that can produce radical life extension in the near future, an addition of decades or more, is the path of damage repair: SENS-like therapies capable of fixing the fundamental forms of cell and tissue damage that cause aging. Senescent cell clearance, removal of metabolic wastes, and so forth. The work needed to produce these therapies has far less support and funding, and receives far less attention than slow and expensive efforts to slightly slow down the pace of aging via metabolic tinkering, however. Nonetheless, SENS rejuvenation therapies are the future, because they are the only way to succeed in this game. Sooner or later all of the other approaches and hobbies will fall by the wayside because they cannot extend life. They will be discarded in favor of the SENS approaches that work, on an ongoing basis as the data is produced.

Work on the Longevity Cookbook is proceeding apace, and I see that an excepted chapter is now available to read online. It is focused on pharmacology, one of the areas where I think that the current mainstream research focus is of little relevance to the end goal of greatly enhanced human longevity. Obviously small molecule and enzyme development has tremendous promise for rejuvenation based on clearance of specific forms of metabolic waste, such as amyloids, cross-links, and lipofuscin constituents, but that isn't what is taking place in the industry. Similarly, outside of cancer research, there isn't a great deal of effort put towards pharmacology for destruction of other types of unwanted or harmful cells, such as senescent cells or errant immune cells. Most pharmacological work related to aging and longevity involves scanning existing drug catalogs for things that might do a little good by altering metabolism into a state more like that of the calorie restriction response: researchers would be pretty excited to obtain a two year statistical gain in life span in humans via this strategy. Not a useful approach to my eyes, since it has a high cost and poor expected outcomes even if wildly successful. That doesn't stop it from being interesting, but bear in mind the low expectation value given the past decade of work on dead ends like sirtuins.

Longevity Cookbook: Pharmacological Extension of Lifespan

Can we impact lifespan with pharmaceuticals? The average lifespan of humans has increased unevenly throughout history, but since the beginning of the industrial revolution it has taken rapid and steady strides upward. Much of this increase has been due to better sanitation, nutrition and living standards. Improvements in medicine, such as vaccines and antibiotics, have been very successful in combating infectious disease. This used to be the main cause of death for humanity but we have been so successful in combating them (world wide) that the main causes of death are now chronic age-related disease and cancer. These are what we hope to tackle now.

We will not cover all of the compounds that have been studied to extend lifespan, but those that I find most promising or most interesting. We will also discuss compounds that possibly work through different mechanisms. This could mean that we are neglecting some potentially important compounds, so we will try to explain what we think constitutes good evidence for a compound being promising. Extending lifespan in a model organism is certainly an important factor.

Combinatorial interventions are used for treating different diseases in the clinic. In cancer therapies, combinatorial treatments are used with success. The cancer can be attacked from different angles with multiple targeted therapies and cytotoxic agents. So what is the difference between testing one compound and testing a combination of compounds? At some level a single compound may act as a combination of compounds. Single compounds can bind to many targets. But aren't those off-target effects just creating negative side effects? Often that may be true, but some compounds might work well, precisely because they have multiple targets.

If two compounds can extend lifespan separately, together they must be even better, right? Well, it might not be that simple. The only published combination of compounds that has successfully extended lifespan to my knowledge is valproic acid and trimethadione in C. elegans. On their own, valproic acid extended the mean lifespan by 35% and trimethadione extended it by 45% at optimal dose. Together they extended the mean lifespan by 61%. This same study from the Kornfeld lab also shows that combining two compounds that on their own extend lifespan, can produce toxic effects. This was the case when mixing ethosuximide with trimethadione. So why is this? One explanation can be that they are both acting on the same pathway. Too much of a good thing is not always good.

So how do we know which compounds will work well together? The truth is we don't really know. We can try to make educated guesses though. Perhaps targeting different pathways is the way to go. However, sometimes targeting the same pathway can yield very potent effects with genetics. The insulin/IGF1 signaling pathway can be targeted from different angles in C. elegans yielding very long lived worms. There is also the possibility that two compounds targeting the same pathway can maximize the beneficial outcome while minimizing the side effects. Targeting different pathways can also work very well. In C. elegans the TOR and insulin signaling pathway were targeted genetically to produce a worm with nearly 5 times its normal lifespan.

Rapamycin and metformin are two drugs that could potentially work well together to extend longevity. A side effect of rapamycin is insulin resistance but metformin improves this condition. A combination of rapamycin and metformin treatment was started by the NIA Interventions Testing Program in 2011. No results are yet published, but rumor has it, it's working. One combination of compounds that was reported to be working in mice to combat one aspect of aging is quercetin and dasatinib. The combination is for killing senescent cells. They were each effective in killing senescent cells in different tissues but worked better together. No lifespan was measured, but health was improved. The mice were able to run farther on a treadmill.

Testing different compounds in combination is certainly a daunting task. How many compounds do you want in your longevity cocktail? Lets say we want to test 100 promising geroprotectors in combination. Perhaps we are assaying lifespan of C. elegans in a 96-well format. If we are just doing pairwise combinations it is almost manageable. 10,000 combinations performed in triplicate make 30,000 wells to be assayed. Only very large effects will be noticed in these types of screens if we are to eliminate false positives. If we are combining 3 or 4 compounds together in our screen we need to assess 3,000,000 or 300,000,000 wells respectively. In this setup, we are only using one concentration per compound. We have seen that sometimes concentrations of drugs need to be lowered when used together with another drug. A way to get around some of the problem is to first do a pairwise screen and use your best combination as the base for the next screen. This way you can keep adding compounds to your cocktail with a manageable amount of screening. This will of course miss some combinations that would be in the massive 300,000,000 well screen but some compromises always have to be made.

One of the main problems with research in general is the reliability of the data. Many times a finding is not repeatable when tried by another lab. This is usually not due to fraud or anything as nefarious as that. It is mainly that research is hard and there are many ways to fool yourself. One way to easily fool yourself is to use too small a sample size. This is quite common. Using a small sample size when looking at lifespan increases the chance that a long-lived or short-lived population was picked by chance. Generally around 100 animals should give around 80% chance of detecting a 10% difference in lifespan. By detecting I mean the difference being statistically significant (if they indeed are). But not only large sample sizes and statistical significance are important. Large effects are generally more reproducible than small effects. What I like to see is a large effect with a large sample size with a good statistically significant result. It is always nice to see if can be replicated by other groups. However, many small badly designed studies do not equal one large well-designed study.


In the open access paper I'll point out today, a group of researchers who focus on the phenomenon of cellular senescence present their argument for cellular senescence to be the central process in aging. It has to be said that I'm bullish on the clearance of senescent cells as a strong first step towards a toolkit of therapies for human rejuvenation, especially now that startup companies are working on it, but it is important to recognize that the accumulation of senescent cells is just one of a number of fairly independent mechanisms that contribute to aging. Yes, the damage caused by these mechanisms interacts, but the sources of that damage are very different. Removing one only helps to the degree that you have removed one. The others will still get you, because all of them are associated with at least one fatal age-related disease. You can take a look at the introduction to the SENS vision for rejuvenation therapies for a list of the forms of cell and tissue damage that contribute to degenerative aging.

I think we've all heard the fable of the blind men and the elephant deployed in connection with aging research. The life sciences are overwhelmingly populated by specialists, as biochemistry and medicine are both so very complex that productive work requires a narrow focus. Investigating one tiny area of cellular biochemistry can be the focus of an entire career. Even when you can see what you are doing, when poised two centimeters from an elephant's face, the creature is essentially a trunk - and maybe some other stuff back there that obviously can't be as important as the giant trunk occupying your field of vision. The elephant of aging is surrounded by hundreds of researchers, each of whom is focused intently upon a small piece of the whole. There are far too few generalists working to link parts of the field and make otherwise disconnected researchers aware that they are looking at the same biochemistry through different lenses.

In any case, this is a very long-winded way of saying that one should be cautious about any analysis that places one particular mechanism at the center of aging. It isn't at all clear to me that aging has a center, and the research community is still unable to say with confidence that any one of the the forms of cell and tissue damage listed in the SENS view of aging is more or less important than the others. The way we will find out which of the forms of age-related damage is the most important is by firstly developing the means to repair that damage and then secondly watching the results of repair therapies in animal models - which is exactly what is happening at the moment for senescent cell clearance. The try it and see approach will get to answers a lot faster than any of the much more analytical alternatives.

Cellular Senescence as the Causal Nexus of Aging

In 1881 the evolutionary biologist August Weismann proposed that "Death takes place because a worn-out tissue cannot forever renew itself, and because a capacity for increase by means of cell division is not everlasting but finite." How did he arrive at such a bold conclusion? Weismann observed that during evolution, simple multicellular organisms such as Pandorina Morum, which were immortal, gradually evolved into mortal organisms such as Volvox Minor. The absolutely crucial difference between these two organisms is that while Pandorina's cells were undifferentiated and divided without limit, Volvox's cells had differentiated into two very different types: the Somatic (body) cells, and the Germ (reproductive) cells. Thus, while the germ line has retained the capacity for infinite renewal, the body cells have not; they age and expire. While Weismann's hypotheses were remarkably prescient, at that time neither DNA nor cultured cells were sufficiently understood to allow his theory to be adequately tested. In fact, it was not until nearly one hundred years later, following the development of sophisticated animal cell culture protocols, that he was proven correct: it was shown that somatic cells grown in culture have limited growth potential. After approximately forty passages, human cells stop proliferating and undergo cellular senescence.

Besides Weismann's evolutionary theory, many additional theories have been proposed to explain the complexity of aging. These include the antagonistic pleiotropy theory, the free radical theory, age-associated shortening of telomeres, development of insulin resistance, decreased immune function, the mitochondrial theory, as well as deregulation of the circadian clock. While these theories indicate functional diversity in the etiology of aging, it must be stressed that each one relies on the concept of internal alterations in individual cells, and does not explain how the microscopic cellular damage manifests as macroscopic aging and tissue breakdown in the organism (with a few exceptions, such as changes in hormone function and declines in immune function). Theories of mutation accumulation and antagonistic pleiotropy address the genetic causes of aging, and environmental stress or lack of it contributes to modulation of the epigenome as well as physiological alterations in different tissues of the whole organism, but each theory revolves around the functional competence of different components of cells and again does not explain how this manifests as macroscopic organismal aging. Experimental evidence unifying the interactions of some components has started to emerge, but we propose that all of the changes described by diverse theories ultimately converge on the cellular senescence theory.

Since aging is a progressive condition that steadily advances from invisible to visible and localized to ubiquitous, the central question as to the direct cause of the entire process is key. The answer has been elusive due to its complex nature. Our model proposes that the process of aging results from a sequential passage through three distinct phases and can be described by the following blueprint: (1) molecular damage which results in (2) cessation of proliferation leading to cellular senescence followed by (3) body-wide aging of the organism. The first step occurs when localized, microscopic damage accumulates to a point where the burden to repair overwhelms the system. Despite the tissue source or broad input of molecular damage, crossing of this threshold results in the second phase, the crux of the entire process - arrest of cellular proliferation, acquisition of the senescence-associated secretory phenotype (SASP), and imminent cellular senescence. Once this occurs, the third phase of aging begins. This final phase is marked by tissue dysfunction and breakdown that results in the visible signs of comprehensive organismal aging.

The incremental advance proposed by our model is that while there are many undisputed factors that trigger the onset of cellular senescence and result in cessation of proliferation and SASP, the first phase in the model (cumulative molecular damage) is a precursor, rather than a final cause of aging. The complexity normally imposed by countless variables (i.e., age of onset, site of damage, affected cell type, mechanism of damage, and even species) that need to be overcome is rendered manageable by eliminating the first phase in the aging schematic. And since organismal aging can be artificially and reversibly induced by blocking and restarting cellular proliferation, this indicates that the second phase in the model - cessation of proliferation followed by cellular senescence - clearly represents the essential cause of aging. Placing cellular senescence in the pivotal junction between cause and effect, the causal nexus, to yield an integrated model of aging will serve to advance identification of crucial targets for future therapeutic investigation. By identifying cellular senescence as the causal nexus of aging, the process of treating, reversing and possibly even eventually eliminating this once inevitable outcome draws closer to reality.


Calorie restriction is a growing area of research these days, linked to diverse fields ranging from aging to diabetes to pharmaceutical development, and above all to the overarching quest to produce a grand map of cellular metabolism. Calorie restriction is of greatest interest outside the scientific community for the fact that it reliably slows aging and extends healthy life in most species and lineages tested to date. This effect, like all methods of slowing aging through altered metabolic state, is much more pronounced in short-lived species. The additional life gained as a proportion of life span falls as the species life span increases: we all know that calorie restriction in humans, while it produces impressive short-term benefits for basically healthy individuals that have yet to be matched by medical science, doesn't extend human life span by 40% or more as it does in mice. We would have noticed by now.

Messing with metabolism, however it is done, isn't a great approach to life extension. It has a limited upside, and has proven very hard and very expensive to achieve successfully via drug development. Calorie restriction itself already exists, however, is reliable, and even though it has a limited upside, it is free. Just as for exercise, it seems silly not to take advantage. The cost-benefit analysis for metabolic alteration via drugs is terrible because it will cost an enormous amount of time and money to produce results, and those resources would be better devoted to SENS rejuvenation research. The cost-benefit analysis for calorie restriction is completely different because it costs nothing and is here now - something for nothing, even if it is not much of a benefit in the grand scheme of things.

Moving away from considerations of enhanced longevity, inside the scientific community calorie restriction is perhaps of greatest interest as a reliable tool with which to interrogate the operation of cellular metabolism. The ability to reliably adjust that operation into a different stable state is very useful if the aim is to try to understand the function of this complex system. Two operating states provides points of comparison and analysis that don't exist for one state. This is of particular interest in aging research, and calorie restriction is used by some groups in much the same way as comparisons between species with different life spans: to try to identify important mechanisms relevant to aging and understand how the operation of metabolism determines natural variations in life span.

Nevertheless, some research groups are attempting to refine the application of calorie restriction as a formal treatment, largely to augment existing approaches to diabetes and cancer, as that is where the ability to raise funding best overlaps with potential benefits for patients. This involves a lot more careful categorization of short-term results for human calorie restriction, and a classification of different types of calorie restriction, some of which don't involve a reduction in overall calorie intake at all, but rather focus on timing and dietary content, such as intermittent fasting or protein restriction. The first of the papers linked here is a review along these lines:

Dietary restriction with and without caloric restriction for healthy aging

Caloric restriction is the most effective and reproducible dietary intervention known to regulate aging and increase the healthy lifespan in various model organisms, ranging from the unicellular yeast to worms, flies, rodents, and primates. However, caloric restriction, which in most cases entails a 20-40% reduction of food consumption relative to normal intake, is a severe intervention that results in both beneficial and detrimental effects. Specific types of chronic, intermittent, or periodic dietary restrictions without chronic caloric restriction have instead the potential to provide a significant healthspan increase while minimizing adverse effects. Improved periodic or targeted dietary restriction regimens that uncouple the challenge of food deprivation from the beneficial effects will allow a safe intervention feasible for a major portion of the population. Here we focus on healthspan interventions that are not chronic or do not require calorie restriction.

Newer antidiabetic drugs and calorie restriction mimicry

In rhesus monkeys unsurprisingly one of the most potent mechanisms of longevity was the reduction of cardiovascular risk factors and glucose intolerance in calorie-restricted monkeys. In the University of Wisconsin cohort, none of the individual calories restricted animals developed any degree of glucose impairment at the time of the interim analysis in contrast with the control monkeys who developed diabetes in a fairly good number. The animal data suggests the long-term CR in adult animals is a potent way to prevent the development of glucose impairment.

There are no comparable human studies with CR. Type 2 diabetes mellitus in humans is currently described as a progressive disease with a pathophysiology that involves over eight different organ systems. However, this understanding of disease does not really give a valid explanation to the reversibility and induction of normal glucose tolerance in patients with type 2 diabetes who undergo bariatric surgery. The improvements in glucose control happen within a few days after surgery much before there is any significant reduction in body weight. There are many explanations offered for early improvement in glucose tolerance like changes in gut hormone profile, changes in gut bacteria, etc., Both these overlook the most logical explanation for the phenomenon which is an acute profound decrease in calorie intake.

However, considering the difficulties in getting healthy adults to limit food intake science has focused on understanding the biochemical processes that accompany calorie restriction (CR) to formulate drugs that would mimic the effects of CR without the need to actually restrict calories. Drugs in this emerging therapeutic field are called CR mimetics. Some of the currently used anti-diabetic agents may have some CR mimetic like effects. This review focuses on the CR mimetic properties of the currently available anti-diabetic agents.

Sex difference in pathology of the ageing gut mediates the greater response of female lifespan to dietary restriction

Women live on average longer than men, but have greater levels of late-life morbidity. We have uncovered a substantial sex difference in the pathology of the ageing gut in Drosophila. The intestinal epithelium of the ageing female undergoes major deterioration, driven by intestinal stem cell (ISC) division, while lower ISC activity in males associates with delay or absence of pathology, and better barrier function, even at old ages. Males succumb to intestinal challenges to which females are resistant, associated with fewer proliferating ISCs, suggesting a trade-off between highly active repair mechanisms and late-life pathology in females. Dietary restriction reduces gut pathology in ageing females, and extends female lifespan more than male. By genetic sex reversal of a specific gut region, we induced female-like ageing pathologies in males, associated with decreased lifespan, but also with a greater increase in longevity in response to dietary restriction.

The effects of graded levels of calorie restriction: VI. Impact of short-term graded calorie restriction on transcriptomic responses of the hypothalamic hunger and circadian signaling pathways

Food intake and circadian rhythms are regulated by hypothalamic neuropeptides and circulating hormones, which could mediate the anti-ageing effect of calorie restriction (CR). We tested whether these two signaling pathways mediate CR by quantifying hypothalamic transcripts of male C57BL/6 mice exposed to graded levels of CR (10 % to 40 %) for 3 months. Hunger signaling, circadian rhythms and their downstream effects are far more complex than the results described here. Although limited by using a knowledge based signaling network, we were able to gain insights into the potential mechanisms underpinning the action of CR. Associations between gene expression and physiological outcomes such as body temperature and food anticipatory activity established by linear models and correlations are obviously only descriptive and causality cannot be assumed. Nevertheless these individual mice have been subjected to an unprecedented level of phenotyping allowing us to tie together the complex transcriptomic changes to alterations in body composition, circulating hormones and physiological outcomes.

Overall, our study has demonstrated that increasing levels of CR lead to a graded expression of genes involved in both hunger signaling and circadian rhythms. The expression of genes in these pathways wwere correlated with circulating levels of leptin, insulin, TNF-α and IGF-1, but not resistin or IL-6. We also demonstrated the phenotypic responses to CR (body temperature and physical activity) were significantly associated with the key hunger and core clock genes. Our results suggest that under CR modulation of the hunger and circadian signaling pathways, in response to altered levels of circulating hormones, drive some of the key phenotypic outcomes, such as activity and body temperature, which are probably important components of the longevity effects of CR.


Cells use the bloodstream as a way to communicate with one another, and blood in an old individual has many differences when compared to that of a young individual. The amounts of numerous important signal molecules are different, for example. By the evidence to date, obtained from parabiosis studies in which the circulatory systems of an old and a young individual are linked, this appears to be connected to the age-related decline in stem cell activity, and probably to many other systems as well. These signal molecules are just one class of change in the blood over the course of aging, however. Here is another: fragments of DNA sequences, the nucleic acids that make up DNA, are another type of molecule found in the bloodstream in greater amounts in old individuals. Researchers are presently debating whether and how this molecular debris might cause harm.

These circulating nucleic acids are thought to arise from the destruction of cells, though given that cells are capable of creating and releasing quite complex structures into the surrounding tissues - consider extracellular vesicles for example - it is perhaps plausible that dysfunctional cells could be exporting nucleic acids while still intact. The theorized problem caused by extracellular nucleic acids is that cells will take them up and integrate them into their DNA, and that this could be a significant source of stochastic mutational damage.

This might be considered a part of the broader argument as to whether nuclear DNA damage is significant in aging over a normal human life span in any way other than generating an increased risk of cancer. It is indisputably the case that mutational damage occurs, and is a distinguishing feature of old tissues, each cell with its own unique pattern of damage. What is hard to prove is that this actually causes significant problems in and of itself, absent any of the other changes of aging. A large enough level of mutation will definitely change the behavior of cells in ways that degrade tissue function, but is the present mutation rate in aging anywhere near high enough to get to that point? The studies needed to definitively answer that question have yet to take place.

The dark side of circulating nucleic acids

Billions of cells in the adult human body are eliminated daily through cell death processes, such as apoptosis and necrosis; especially necrotic cells, which unlike apoptotic cells are not generally removed cleanly by phagocytosis, are thought to be a source of degraded DNA fragments released to the blood plasma or serum as cell-free DNA or circulating free DNA (cfDNA). Some aspects of the biology of cfDNA are still unexplored and several key questions remain. One question with high relevance to aging is whether or not cfDNA fragments can behave as mobile genetic elements, illegitimately integrating in the chromosomal DNA of healthy cells in its own host, thereby contributing to genome instability and possibly causing age-related functional decline and age-related pathophysiological processes.

Recently evidence was provided that the integration of cell-free nucleic acid with host cells occurs in vivo as well as in vitro. Mice were injected intravenously with human cfDNA and Cfs and analysis of heart, lung, liver, and brain of the mice sacrificed 7 days after injection revealed genomic localization of nucleic acids, with Cfs localizing more efficiently than cfDNA. Of note, genomic integration of Cfs in the mouse brain indicated that chromatin particles are able to cross the blood-brain barrier. This recent work offers a fascinating new mechanism of age-related mutagenesis, highlighting the fate and effects of free nucleic acids within our body. However, many questions remain. Probably the most interesting question is whether cfDNA truly behaves as mobile genetic elements under normal conditions. That is, rather than extracting concentrated cfDNA from heterogenic serum samples and intravenously injecting that in the mouse, integration of its own cfDNA should be studied, for example, as a function of age. Because integrated DNA fragments can then no longer be uniquely aligned as foreign DNA to a reference sequence, single cells or clones should be studied for insertion events as compared to the germline sequence, which is considerably more difficult than screening for reads containing human sequences.

While still lacking in important details, this recent work opens up the intriguing prospect of a new, endogenous source of genome instability that could well contribute to increased genome mosaicism with age. In this respect, cfDNA could act similarly to the previously described age-related derepression of endogenous retrotransposons in the somatic genome during aging. In this respect, there is evidence that cfDNA becomes increasingly frequent in the circulation as a function of age, for example, due to increased vulnerability of aged and damaged cells to cell death. Its activation of the DNA damage response could increase the level of genome instability considerably, contributing to aging-related degenerative processes, such as cellular senescence, cancer, and inflammation. Further research on the biological and pathological roles of cell-free nucleic acids will help to elucidate its importance as an intrinsic mechanism of aging.


Monday, February 29, 2016

Researchers have uncovered a new way in which many past studies of extended life span in nematode worms have been distorted by a part of the experimental process. This isn't the first time this has happened in recent years. The metabolic processes and life spans of short-lived species are very plastic in response to all sorts of circumstances, and thus smaller effects are easier to produce, intentionally and otherwise. As a general rule these effects are irrelevant to longer-lived species, where life span is much less plastic. Even large extension of life in short-lived species via methods of metabolic alteration that have also been tried in humans, such as calorie restriction or growth hormone receptor loss of function, have no such matching effect in humans.

In matters of the fundamental molecular biology of aging, we mammals are not so different from tiny C. elegans worms. Some of the biggest differences only serve to make them convenient research models. But one distinction - their ability to asexually reproduce exact copies of themselves - may have led to many research discrepancies. The reason, according to a new study, is that the drug scientists use prevent such confusing reproduction turns out to help aging worms rebound from stress, thereby significantly lengthening their lifespan in some cases. In the study researchers identify the human chemotherapy drug FUdR as the culprit. Their detailed experiments show that the drug goes well beyond squelching worm reproduction. It also triggers stress response and turns on DNA repair pathways (that are also found in mammals) that allow the worms to better endure adverse conditions such as saltiness, heat, or low oxygen.

"We can explain a lot of the disagreement in the C. elegans aging field by realizing that FuDR can dramatically change the answer. There were very different effects in published papers that had different doses of FUdR in them. Sometimes it's a very profound disagreement." Moreover, some other studies may involve FUdR-related discrepancies but insufficient documentation of the methods prevented researchers from being sure.

In the absence of any stress, FUdR makes no difference to lifespan in normal worms, they confirmed. But when worms were exposed to a modest concentration of salt, animals who were not exposed to FUdR had only half the lifespan of those who were exposed to the drug. Meanwhile, adding even more FUdR caused even longer lifespan under salt stress. A tenfold increase in FUdR concentration extended lifespan by a factor of three. Other experiments suggested that FUdR causes better stress resistance in hot or low-oxygen conditions. Further research revealed details of how FUdR protects the worms from stress. They found evidence that the drug turns on the gene that produces the protein FOXO, a master regulator of stress resistance in many organisms that is often central in longevity studies. They also found that exposure to FUdR forced DNA mutations that then activated a DNA-repair process. That process, once activated, also fixes a lot of DNA damage caused by environmental stresses, including dreaded double-strand breaks, a clean severing of the DNA molecule.

Monday, February 29, 2016

Researchers here demonstrate that using gene therapy to introduce a modified calcium receptor into the heart can improve the calcium signaling that drives the heartbeat, and that the effects are measurable even for a small uptake of the new receptor in heart cells. In the context of heart disease and degenerative aging of the heart, this approach could partially compensate for progressive failure of function in the organ, though it doesn't fix any of the underlying cell and tissue damage, or the prior remodeling of the heart caused by arterial stiffening and consequent hypertension.

Researchers have engineered new calcium receptors for the heart to tune the strength of the heartbeat in an animal model. The team developed a protein engineering approach by tailoring the heart's ability to respond to calcium, which is the signal for contraction. Using a modified version of troponin C (TnC L48Q), their study showed it can enhance or therapeutically preserve heart function and cardiovascular performance in mice without harmful effects commonly seen with other agents that increase heart muscle contraction.

Most heart muscle diseases involve problems with contraction. Many strategies increase the calcium signal to improve heart contraction. However, they do so at the expense of other functions. This can cause negative side effects, such as arrhythmias and cell death, and ultimately increase mortality. The team evaluated TnC L48Q in a common heart pathology - myocardial infarction, or a heart attack. Compared to the infarcted control group, TnC L48Q mice had better heart function and cardiovascular performance. There were also no signs of congestive heart failure or increased mortality, both of which were observed in the control group. When assessing the long-term effects and therapeutic potential of TnC L48Q, the researchers observed steady and significant improvement in heart function, cardiovascular performance, and significantly less detrimental remodeling compared to the control group. This resulted in better survival.

"It's long been presumed that altering the receptor would be ineffective, that it was better to change the calcium signal. We're seeing strong evidence that's not the case. Changing the calcium receptor does have a significant and safer impact." The scientists report these results were achieved by replacing only a modest amount of the original TnC receptor through gene therapy. This makes it more likely that this strategy will be a viable and personalized treatment option in the future. The researchers believe these findings could open the door for new treatments against cardiac diseases. In previous in vitro work, the team has customized several TnC receptors designed to combat various cardiac disorders. The team is also working on engineering other calcium receptors for a variety of diseases, such as high blood pressure and heart arrhythmias.

Tuesday, March 1, 2016

To the degree that rejuvenation therapies are successfully developed, retirement will become a thing of the past. It and all of its surrounding institutions and traditions exist because, in the environment of today's medical technology, everyone eventually becomes too frail to work and maintain their own lives. When health can be sustained for far longer, people will continue to work and engage with the world for far longer, but that longevity opens up many other options for lifestyle and planning besides simply working indefinitely. For example, saving and investment over much longer timeframes will ultimately allow anyone to take a few decades out of the normal flow of work here and there to do whatever it is that they desire before returning to gainful employment.

This article isn't a particularly deep or insightful discussion of the topic of retirement and longevity, and, given the source, isn't all that applicable to people of modest means and ordinary employment, but I point it out its existence as an indication of the degree to which the concepts of radical life extension are spreading in the media and the public at large. The more that people think about this sort of thing, and realize that the science makes it plausible for the near future, the more support we find for the necessary research and development.

While the new longevity Americans now savor seems to offer nothing but an upside - you're cheating death longer, right? - the downside of retirement, if it can be called that, is the absolute need to do more planning and budget in many more expenditures. And that's just for starters, because no one knows how long "longevity" will eventually extend, given the scientific world's ongoing research into stem cells. With stem cells, engineered tissues and organs may someday replace our disintegrating originals. "You could get an 'oil change,' an upgrade to your cells every few years. If, 20 or 30 years into the future, your heart is defective, maybe you can grow a new heart in a dish. The underlying biology and access to cells is getting there."

It's hard for anyone to put a number on it. Depending on whom you talk to, those estimated ages of longevity - again, 81.4 years for men and 84.3 for women, according to 2011 actuarial tables - may be just so much hokum. As the science of human longevity continues to accelerate, this will likely translate into improved life expectancy across the board.

Heart disease, cancer and other terminal illnesses can all be traced back to the natural wear and tear that comes with living. As we age, our bodies break down: Tissues and organs become defective and the likelihood increases that our cells will fail us. "Ninety percent of us will die of diseases that do not kill 20-year-olds," says George Church, a professor of genetics at Harvard Medical School. Advances in medicine - which over the past century raised the average lifespan in the United States from 47 to 77 - simply delay the inevitable certainty that we will grow old and, eventually, die. But what if we could reverse aging? According to Church, "That's already happening." Remember those stem cells? Other body parts are figuring into the mix, too. To be clear, Church is talking about mice. Still, the research is compelling.

Such experiments, along with advancements in regenerative medicine, stem cell therapy and gene editing, mean that in a hazy but potentially not-too-distant future, we will no longer die from natural causes. Death, in other words, will be relegated to the realms outside age and disease. Plan to live longer than you expect to. After all, the anecdotal evidence out there supports it.

Tuesday, March 1, 2016

This scientific editorial summarizes and provides links to many of the papers published of late on the topic of whether or not aging should be classified as a disease. This is primarily a question of regulation and advocacy, and how those issues interact with the pace of progress and the ability to bring more money to bear on research into treating aging as a medical condition. That present regulatory systems don't recognize aging as a medical condition has greatly impacted the ability to raise funds at all levels of development. Given the present state of the science, with the first actual, real rejuvenation treatments already under clinical development in startups, there is much more willingness in the scientific community to call for funding and work towards changing the present system.

The quest to increase healthy lifespan is becoming a pressing economic priority required to preserve the current standards of living. Rapidly increasing dependency ratios and unfunded social security and healthcare liabilities are an enormous and growing burden on the economies of developed countries. But the situation, if handled properly, is not hopeless; with advances in anti-aging treatments and preventative care, the negative economic impact of aging could be at very least reduced, while increases in productive longevity in developed countries could actually stimulate significant economic growth. One of the impediments to industry transformation is the way aging is treated. While no doubt exists that aging is a complex multifactorial process leading to a progressive decline in function with no single cause or treatment, the issue of whether aging can be classified as a disease is widely debated by gerontologists, medical doctors, demographers, philosophers, policy makers, and the general public. This disagreement has until now hindered classification of aging as a disease and, consequently, the fitting of potential treatment options into established research, regulatory, insurance, and marketing frameworks.

Some prominent biogerontologists have provided comprehensive weighted responses explaining the dangers of separation of aging from disease and benefits of proactive preventative approaches that are likely to result from recognizing the pathological nature of aging. In spite of the many breakthroughs providing proof of concept for successful interventions in aging in model organisms, human progress has been surprisingly slow. One major cause of inaction is a widely held, but flawed, conceptual framework concerning the relationship between aging and disease that categorizes the former as "natural" and the latter as "abnormal". One comprehensive review of the many arguments for and against classifying aging as a disease with a definite and eloquent recommendation that calls for a complete quote: "We must draw aside the rosy veil of tradition and face aging for what it is, and in all its horror: the greatest disease of them all."

Bulterijs et al. explained the many benefits of classifying aging a disease, while Stambler provided a historical perspective arguing that acknowledging the possibility of successful intervention into the aging process, in other words treating aging as a curable disease, has been a long and highly respected tradition of biomedical thought. Dubnikov and Cohen provided an overview of multiple theories of aging and recommended further research to understand the relationship between aging and disease. Advocates for longevity research provided new survey data indicating that the majority (74.4%) of Americans are interested to live to 120 or longer if health was guaranteed, but only 57.4% wished to live that long if it wasn't, contradicting previous surveys that used different approaches to surveying the general population and generally indicated negative attitudes toward increased longevity and longevity-boosting interventions.

The main international agency responsible for disease classification is the World Health Organization (WHO), which maintains and publishes the International Statistical Classification of Diseases and Related Health Problems (ICD) since 1948. The 10th revision of the ICD, referred as ICD-10, was first published in 1992, and the 11th revision (ICD-11) is expected to be released in 2018. WHO classifies aging as a disease in the ICD-10 with the R54 code. However, this code is generally regarded by the Global Burden of Disease (GBD) statisticians as a "garbage code" and cannot be considered to be actionable. Actionable classification of aging as a disease may lead to more efficient allocation of resources by enabling funding bodies and other stakeholders to use quality-adjusted life years (QALYs) and healthy-years equivalent (HYE) as metrics when evaluating both research and clinical programs. In order to classify aging with an actionable code or set of codes linked to specific age-related diseases, we propose an international task force to be organized to develop and communicate proposals to the WHO at the national and international levels.

Wednesday, March 2, 2016

One of the interesting results that has emerged from the growing use of accelerometers in studies of exercise is that even small differences in activity levels have an noticeable correlation with mortality rates and life expectancy:

Even for people who already exercised, swapping out just a few minutes of sedentary time with some sort of movement was associated with reduced mortality. Researchers looked at data from approximately 3,000 people aged 50 to 79 who participated in the National Health and Nutrition Examination Survey (NHANES). For the study, subjects wore ultra-sensitive activity trackers, called accelerometers, for seven days. For these same people, the agency then tracked mortality for the next eight years. The results were striking. The least active people were five times more likely to die during that period than the most active people and three times more likely than those in the middle range for activity. "When we compare people who exercise the same amount, those who sit less and move around more tend to live longer. The folks who were walking around, washing the dishes, sweeping the floor tended to live longer than the people who were sitting at a desk."

Previous activity-tracking studies have drawn similar conclusions. But such studies usually ask participants to monitor their own exercise frequency and quantity, numbers they notoriously over-report. Also, the trackers used for NHANES have a higher level of precision than what's typically employed. "Because the device captures the intensity of activity so frequently, every minute, we can actually make a distinction between people who spent two hours a day doing those activities versus people who spent an hour and a half." To account for chronic conditions or illness influencing mortality rates, researchers statistically controlled for factors like diagnosed medical conditions, smoking, age and gender. They also completed a secondary examination from which they entirely excluded participants with chronic conditions. Though the scientists didn't discover any magic threshold for the amount a person needs to move to improve mortality, they did learn that even adding just 10 minutes per day of light activity could make a difference. Replacing 30 minutes of sedentary time with light or moderate-to-vigorous physical activity produced even better results.

Wednesday, March 2, 2016

Researchers here investigate one of the mechanisms by which the immune system recognizes senescent cells, targeting them for destruction. Accumulating numbers of senescent cells are one of the contributing causes of aging, and the age-related decline of the immune system probably accelerates this process in later life. In theory, given a good enough understanding of the biochemistry involved, it should be possible to greatly increase the efficiency with which the immune system destroys senescent cells. This is not the direction taken by the first companies to work on senescent cell clearance technologies, however, so this approach may never be developed, as it will prove to be unnecessary.

Senescent cells are specifically recognized and eliminated by natural killer (NK) cells. In this study we investigated the mechanisms which control the recognition of senescent cells by NK cells. We found that senescent cells up-regulate the expression of NKG2D ligands MICA and ULBP2 regardless of the senescence-inducing stimuli. The mechanisms regulating the expression of NKG2D ligands in senescent cells are partly attributed to a DNA damage response and activation of ERK activity. MICA and ULBP2 were found to be localized at the cell membrane where they can interact with NK cells to mediate efficient killing of senescent cells. Interaction of the ligands with the NKG2D receptor on the NK cells is necessary for the recognition of senescent cells by the NK cells in vitro. Importantly, NKG2D receptor-ligand interaction is essential for efficient elimination of senescent cells in vivo and thus for restraining fibrosis development. Overall, our findings demonstrate that NKG2D ligands on senescent cells are necessary for efficient recognition and elimination of senescent cells in vitro and during tissue damage in vivo.

The increase in expression of NKG2D ligands, particularly MICA and ULBP2, is likely a general feature of human senescent cells. A number of other studies have demonstrated the expression of MICA and/or ULBP2 in senescent cells derived from different cell types. Furthermore, senescent cells also acquire unique NKG2D ligand expression profiles consisting of several additional NKG2D ligands that result from differences between cell types (or cell-strains) and the mechanism by which senescence was induced. The repertoire of NKG2D ligands in mice is vast and similar to human cells, however based on sequence comparisons, mouse ligands are not homologous to the human ligands. Of note, NKG2D ligands are present on mouse cells that become senescent following p53 reactivation, and participate in the interaction of these cells with NK cells. In addition to their expression in senescent cells, NKG2D ligands are upregulated in other cell contexts related to cellular stress, including cancer, virally infected cells or following DNA damage. Therefore, the expression of these ligands might be part of a general stress response of cells that is utilized by senescent cells.

Our findings add to the emerging conceptual idea that the senescent program might represent a change in cell state that is associated with conversion to an immunogenic phenotype, functioning to remove damaged cells by immune clearance rather than through apoptosis. In addition to the upregulation of NKG2D ligands, the secretion of chemoattractants or the expression of adhesion molecules are further examples by which senescent cells become immunogenic. Immune clearance of senescent cells is likely beneficial in complex organisms where the regenerative capacity is dependent on non-resident stem cell populations and therefore temporal preservation of tissue architecture is necessary. Elimination of senescent cells following short-term insults, mediated by immune clearance, has physiological functions in tumor suppression and wound healing. Moreover, inefficient clearance might lead to the long-term persistence of senescent cells in tissues that has been associated with promotion of cancer development, ageing and age-related disease. Therefore, understanding the normal processes and mechanisms by which senescent cells are eliminated by the immune system will enable the formulation of conjectures concerning the mechanism responsible for impaired senescent cells elimination in later life. Such an understanding could lead to novel therapeutic strategies that enhance elimination of senescent cells by the immune system to improve tissue repair, cancer therapy and prevent deleterious effects of accumulation of senescent cells.

Thursday, March 3, 2016

This is an illustrative example of the continued exploration of modest life extension via metabolic manipulation in short-lived animals. A lot of effort is spent on sifting through the existing catalog of known and approved drugs for those that might impact life span, something I consider to be a waste of time and effort from the point of view of producing therapies to extend life in humans. It is an important part of purely scientific efforts to map the interaction of metabolism and aging, however:

To identify drugs that delay age-related degeneration, we used the powerful Caenorhabdtitis elegans model system to screen for FDA-approved drugs that can extend the adult lifespan of worms. Here we show that captopril extended mean lifespan. Captopril is an angiotensin-converting enzyme (ACE) inhibitor used to treat high blood pressure in humans. To explore the mechanism of captopril, we analyzed the acn-1 gene that encodes the C. elegans homolog of ACE. Reducing the activity of acn-1 extended the mean life span. Furthermore, reducing the activity of acn-1 delayed age-related degenerative changes and increased stress resistance, indicating that acn-1 influences aging. Captopril could not further extend the lifespan of animals with reduced acn-1, suggesting they function in the same pathway; we propose that captopril inhibits acn-1 to extend lifespan.

To define the relationship with previously characterized longevity pathways, we analyzed mutant animals. The lifespan extension caused by reducing the activity of acn-1 was additive with caloric restriction and mitochondrial insufficiency, and did not require sir-2.1, hsf-1 or rict-1, suggesting that acn-1 functions by a distinct mechanism. The interactions with the insulin/IGF-1 pathway were complex, since the lifespan extensions caused by captopril and reducing acn-1 activity were additive with daf-2 and age-1 but required daf-16. Captopril treatment and reducing acn-1 activity caused similar effects in a wide range of genetic backgrounds, consistent with the model that they act by the same mechanism. These results identify a new drug and a new gene that can extend the lifespan of worms and suggest new therapeutic strategies for addressing age-related degenerative changes.

Thursday, March 3, 2016

There are many ways to extend life in short-lived nematode worms, but most overlap, being different ways to manipulate the same few core mechanisms. Everything in cellular biology connects to everything else, so isn't at all unexpected for there to be a dozen indirect ways to alter levels of any one particular protein, or alter the behavior of any one particular pathway. Much of the present focus in the aging research community involves mapping all of these methods so as to pin down the list of those core mechanisms, the most important ways in which metabolism determines variations in longevity between individuals and species. This actually has very little relevance to the future of human longevity and the development of rejuvenation treatments: those will emerge from efforts to repair the cell and tissue damage known to cause aging, an approach that will produce rejuvenation, not from altering the operation of metabolism to merely slightly slow down aging.

"We found that longevity can be extended by increasing the amount of a protein called arginine kinase-1 (ARGK-1). ARGK-1 maintains ATP availability within cells, and we suspect that increased levels trigger a fuel sensor, regulating energy homeostasis and extending lifespan." The research team identified ARGK-1 by comparing protein levels in normal worms to those in worms lacking S6 kinase (S6K), a genetic change that extends worm lifespan by at least 25%. Reduction of S6K proteins also extends lifespan significantly in several other organisms, including laboratory mice, showing that this pathway that controls aging is evolutionarily conserved. "ARGK-1 caught our attention because levels in S6K mutant worms were more than 30 times higher compared to normal worms. When we created normal worms that overexpressed ARGK-1, they also lived significantly longer, meaning that ARGK-1 on its own can extend life."

ARGK-1 and its mammalian equivalent, creatine kinase, are enzymes that transport energy in the form of phosphoarginine or phosphocreatine to various locations within cells. The research team found that, as in worms, creatine kinase levels are increased in the brains of mice lacking a similar S6K protein. "Our main goal in studying aging is not to find ways to extend human lifespan, but to understand the processes by which our cells and tissues become less functional over time. Such insight might allow us to develop better preventive care that improves overall health at advanced ages, or interventions that can slow or perhaps even prevent the progression of diseases associated with aging. For example, in cancer, some tumors highly activate S6K to feed tumor growth. Further work to understand the relationship between creatine kinase and S6K may lead to new avenues to pursue novel drugs for age-related diseases, including cancer."

Friday, March 4, 2016

Mitochondrially targeted antioxidant compound SkQ1, a plastinquinone, has at this point been moving through the commercial development pipeline for a decade or so. This is par for the course in medicine, sad to say. Engaging with the regulatory system is a slow, slow process, and requires such a large amount of money that organizing the funding itself often requires years of groundwork and initiatives.

SkQ1 has been shown to modestly extend life in laboratory animals, and along the way have also proven to be a useful therapy for a range of inflammatory conditions of the eye. They work by soaking up damaging oxidative molecules where they are produced, in the mitochondria, before they can cause harm to cell structures, particular the nearby mitochondrial DNA. That said, any significant alteration to the net rate of production of oxidative molecules affects the regulation of many cellular activities. A lot of unrelated methods of slowing aging in laboratory species involve either reducing or raising the rate of production of oxidative molecules by mitochondria, for example. So it isn't just a matter of preventing damage, but also of changing cellular behavior. Since it has a demonstrated ability to reduce inflammation, it is probably useful as a treatment for a range of conditions in which inflammation is an important contributing cause.

In any case, it looks like work is progressing past the initial availability of therapies for eye conditions towards formulations of SkQ1 in pill form. A lot of people in the broader longevity advocacy community will be interested in this, but bear in mind that, like all approaches so far shown to slow aging in short-lived animals, it will probably have only much smaller effects in long-lived species such as our own. Reducing the rate of mitochondrial damage caused by oxidative molecules isn't in the same class of expected outcome as repairing that damage or completely preventing its consequences, as is the goal of SENS strategies such as allotopic expression of mitochondrial DNA.

Mitotech S.A., a Luxembourg based clinical stage biotechnology company, announced a successful completion of its pre-clinical program and a start of clinical development for systemic drug Plastomitin based on Mitotech's lead compound SkQ1. SkQ1 is a small molecule engineered specifically for reducing oxidative stress inside mitochondria. Previously, SkQ1 demonstrated efficacy and safety in a double-masked placebo-controlled Phase 2 study of an eye drop formulation - Visomitin - in the U.S.

"This is a very exciting new step for our company. Our strategy assumes parallel development of a variety of formulations for our lead compound SkQ1 targeting a spectrum of age-related disorders. Visomitin had been the most advanced drug in our pipeline and already reached Phase III stage for dry eye indication in the U.S. Ophthalmic field, where we have been pursuing uveitis in addition to dry eye syndrome, remains the forefront area of development for Mitotech. At the same time, this new milestone brings us to clinical level of development for a variety of indications outside ophthalmic field. Mitotech is now in a great position to tackle critical disorders associated with aging such as neurodegenerative and metabolic diseases. Here at Mitotech we feel that we are approaching a major clinical breakthrough that could help many patients around the world."

"SkQ1 has demonstrated efficacy when administered systemically in a whole spectrum of preclinical studies. The very unique mechanism of action of the molecule has proved its benefit in models of rare genetic diseases as well as in models of more common age-related disorders. We see enormous potential in this novel mode of action and our clinical team worked very diligently on getting Plastomitin to its first clinical trial. Mitotech's goal is to progress with this new clinical program as efficiently as we did with the ophthalmic program and to deliver Plastomitin to patients within the next few years."

Friday, March 4, 2016

The cryonics industry offers low-temperature preservation of the body and brain on death, and this is presently the only alternative to the grave and oblivion for those who will age to death prior to the advent of rejuvenation therapies. Preservation of the structures holding the data of the mind provides a chance at life again in a future in which technology has advanced to the point at which restoration of a preserved individual becomes practical. The media these days treats cryonics with a lot more respect than used to be the case, though they still tend to dumb things down by talking about freezing rather than vitrification with cryoprotectants - a very important distinction when talking about tissue preservation. I think that this change in attitudes is in part because the development of vitrification techniques for use in the organ preservation and transplant industry is much more evidently making progress and gathering support in the research community. Since that is an accepted field of research, and meanwhile researchers are demonstrating preservation of fine structure in vitrified brain tissue, it becomes hard for journalists to dismiss cryonics out of hand.

In a nondescript industrial office park in San Leandro, a little city on the outskirts of Oakland, sits the headquarters of a business named Trans Time. The walls in the foyer of the building are filled with posters about anti-aging research. There's a lab with microscopes and beakers that look like they've been around since Trans Time opened in 1974, and a white room with an operating table. In the very back of the office, you'll find a large canister of liquid nitrogen, and a handful of 10-foot-tall metal vats that look like huge coffee Thermoses. Visitors aren't allowed to look inside these vats, but if you could, you'd see that one of them contains three human corpses - or, as the facility refers to them, "patients."

With just three patients frozen in its tanks, Trans Time is a scrappy little cryonics competitor. (The last person to enter one of Trans Time's vats was the company's founder, Paul Segall, a Berkeley Ph.D who co-founded the publicly-traded medical company BioTime. He died of a brain aneurism in 2003.) The two largest cryonics facilities are Alcor, in Arizona, and the Cryonics Institute, in Michigan; that's where you'll find most of the 300 or so people who are currently frozen. There's also KrioRus in Russia, which has 45 people on ice. And there are over 2,000 people worldwide who have signed up to be frozen, but haven't died yet.

Greg Fahy is a cryobiologist at 21st Century Medicine, a scientific institution based in southern California that has received funding from the National Institutes of Health to work on cryonically preserving organs. And he thinks the sci-fi fantasy of bringing frozen bodies back to life may not be as far-fetched as we think. "We're getting pretty good at this. We can load a kidney up with cryoprotectant and save it. We now know we can remove a piece of the brain and preserve it with perfection, and then put it back and it will still operate." Fahy, who has experimented successfully with cryonic preservation in rabbits and rats, thinks it may one day work in humans, too. "There's nothing about brain tissue that prevents it from being cryonically preserved."

In fact, Fahy said, the biggest obstacle to successful cryonic reanimation might be the law, not science. Most cryonics experts agree that cryonic preservation would work best on bodies that aren't yet dead, and haven't begun to decompose. But under current law, cryonics facilities are prohibited from freezing their patients while they're alive. (Doing so would be considered assisted suicide, or possibly murder.) "There may need to be legal changes that need to be made to allow cryonic preservation before deterioration begins."

Cryonics, itself, represents a kind of faith - a faith that scientific progress will continue unabated, and will eventually be able to solve even death itself. Cryonicists believe so strongly in our scientific future that many think that people who bury, cremate or compost their bodies instead of freezing them are, essentially, committing suicide.


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