Fight Aging! Newsletter, May 26th 2014

May 26th 2014

The Fight Aging! Newsletter is a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: both the road to future rejuvenation and 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 medicine, news from the longevity science community, advocacy and fundraising initiatives to help advance rejuvenation biotechnology, links to online resources, and much more.

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  • A Selection of Recent Targeted Cancer Treatment Research
  • The Goal of Using Stem Cells to Repair the Aging Brain
  • Two Interviews with Aubrey de Grey
  • Mice Lacking the Pain Receptor Gene TRPV1 Live Longer
  • A Report from the First International Mini-Symposium on Methionine Restriction and Lifespan
  • Latest Headlines from Fight Aging!
    • More Insight Into GDF-11 and Myostatin From Fly Studies
    • Calorie Restriction Benefits Arrive Very Rapidly
    • Alcor Goes the Extra Mile
    • Losing Your Indifference
    • Syndrome X is a Developmental Disorder that Has Little Relevance to Aging
    • Suggesting the Combined Use of Metformin and Rapamycin
    • Axons Can Be Regrown
    • Interfering in Amyloid Beta Production as an Alzheimer's Therapy
    • Muscle Stem Cell Rejuvenation Restores Strength
    • Meeting in the Middle on Lab Grown Organs


I'm not overly worried about cancer, or at least not in comparison to all of the other things likely to cause me pain, suffering, and death a couple of decades from now. I think that present work on targeted cell killing technologies will lead to a suite of treatments that are robust enough, therapies and infrastructure that will reduce the risks and consequences of cancer to an acceptably low level over the period of time in which we will be availing ourselves of the first generation of rejuvenation treatments. Or at least that will be the case if matters proceed well and growth continues on an accelerating path for those fields of aging and longevity science most likely to produce meaningful results.

The big risk here is the same as for any nascent technological revolution: that the world continues to focus on things that don't really matter all that much, a category which includes a lot of the mainstream aging science, sad to say, and thus the rejuvenation research community fails to grow and fails to realize useful treatments in time for my old age in the 2040s. I think that the odds of this failure coming to pass are much higher than the chances of the cancer community failing to deliver over the same time frame. I will be astounded and unhappy in equal measure to find that cancer has not been wrestled into a state akin to that of tuberculosis by 2040: a minor threat, once a dreadful killer, kept caged by advanced medical technology.

Thus I am not overly worried about cancer; it is a concern in life, just like road safety and general health, but not an overwhelming concern. As is the case for stem cell medicine cancer research is enormously well funded. It is not a field that needs any more help and support than it already has in order to make good progress towards bringing cancer under medical control - though of course this is the case because plenty of people don't agree with me, and are willing to step up and do something about it. Researchers are well on the way to realizing the next generation of treatments that will soon enough replace chemotherapy and radiotherapy, consisting of far more effective targeted approaches that employ nanoparticles, immune cells, bacteria, and viruses to destroy cancer cells with minimal side-effects.

Here are a few representative papers and research results from the cancer community, published recently:

Oncolytic viral therapy: targeting cancer stem cells

Cancer stem cells (CSCs) are defined as rare populations of tumor-initiating cancer cells that are capable of both self-renewal and differentiation. Extensive research is currently underway to develop therapeutics that target CSCs for cancer therapy, due to their critical role in tumorigenesis, as well as their resistance to chemotherapy and radiotherapy.

To this end, oncolytic viruses targeting unique CSC markers, signaling pathways, or the pro-tumor CSC niche offer promising potential as CSCs-destroying agents/therapeutics. We provide a summary of existing knowledge on the biology of CSCs, including their markers and their niche thought to comprise the tumor microenvironment, and then we provide a critical analysis of the potential for targeting CSCs with oncolytic viruses, including herpes simplex virus-1, adenovirus, measles virus, reovirus, and vaccinia virus.

Herpes-loaded stem cells used to kill brain tumors

Cancer-killing or oncolytic viruses have been used in numerous phase 1 and 2 clinical trials for brain tumors but with limited success. In preclinical studies, oncolytic herpes simplex viruses seemed especially promising, as they naturally infect dividing brain cells. However, the therapy hasn't translated as well for human patients. The problem previous researchers couldn't overcome was how to keep the herpes viruses at the tumor site long enough to work.

[Researchers] turned to mesenchymal stem cells (MSCs) - a type of stem cell that gives rise to bone marrow tissue - which have been very attractive drug delivery vehicles because they trigger a minimal immune response and can be utilized to carry oncolytic viruses. [Researchers] loaded the herpes virus into human MSCs and injected the cells into glioblastoma tumors developed in mice. Using multiple imaging markers, it was possible to watch the virus as it passed from the stem cells to the first layer of brain tumor cells and subsequently into all of the tumor cells.

Using imaging proteins to watch in real time how the virus combated the cancer, [researchers] noticed that the gel kept the stem cells alive longer, which allowed the virus to replicate and kill any residual cancer cells that were not cut out during the debulking surgery. This translated into a higher survival rate for mice that received the gel-encapsulated stem cells.

New Method Sneaks Drugs into Cancer Cells Before Triggering Release

Biomedical engineering researchers have developed an anti-cancer drug delivery method that essentially smuggles the drug into a cancer cell before triggering its release. The method can be likened to keeping a cancer-killing bomb and its detonator separate until they are inside a cancer cell, where they then combine to destroy the cell.

The technique uses nanoscale lipid-based capsules, or liposomes, to deliver both the drug and the release mechanism into cancer cells. One set of liposomes contains adenosine-5'-triphosphate (ATP), the so-called "energy molecule." A second set of liposomes contains an anti-cancer drug called doxorubicin (Dox) that is embedded in a complex of DNA molecules. When the DNA molecules come into contact with high levels of ATP, they unfold and release the Dox. The surface of the liposomes is integrated with positively charged lipids or peptides, which act as corkscrews to introduce the liposomes into cancer cells.

In a mouse model, the researchers found that the new technique significantly decreased the size of breast cancer tumors compared to treatment that used Dox without the nanoscale liposomes.


Some aspects of aging cannot be repaired through the use of therapies that manipulate or deliver stem cells. Accumulations of metabolic waste that the body cannot break down occur both inside and in between cells, for example. Growing levels of DNA damage, both nuclear and more importantly mitochondrial, also cannot be addressed with stem cell treatments that look much like today's transplant therapies. This still leaves many secondary consequences of aging that can be partially repaired by inducing temporarily enhanced regeneration in an old individual, however. Joint and heart tissue damage are perhaps the most obvious, but there is a much longer list of benefits to be realized even using comparatively crude stem cell transplants.

Eventually the successors to today's treatments will provide more comprehensive fixes to the issues of aging stem cells. At present they are temporary patches that do little to address the root causes of dysfunction - and so the mechanisms of aging will proceed to eat away what has been shored up at an ever faster rate. But treatments in the foreseeable future will provide wholesale replacement of worn cell populations, such as the age-damaged cells of the immune system, or renewal of specific populations of stem cells to restore tissue maintenance to something closer to youthful levels, organ by organ. There will also be a move beyond cell transplants towards efforts to reprogram or signal existing cells in order to alter their behavior. These treatments will provide a more lasting bulwark against aging, though without other forms of repair therapy to achieve such goals as clearing metabolic waste and repairing DNA damage, this too will be broken down all too quickly.

The stem cell research field is admirably focused on repair of age-related conditions. Much of the future revenue of this field depends on producing effective regeneration in the old, as the aged suffer almost all of the conditions that are most obviously treated with stem cell technologies. Thus the research community must find ways to make these treatments work and work well in aged individuals. The dynamics of the situation forces researchers to get to grips with the nature of aging insofar as it impacts stem cell function.

Here a researcher considers the work that must yet be accomplished in order to produce means of reliably manipulating the stem cells present within an individual's brain. The goals here include spurring greater feats of repair and regeneration, or the creation of a larger stream of new brain cells to make up losses due to age and injury.

Endogenous stem cells for enhancing cognition in the diseased brain

Adult neural progenitor cells or neural stem cells (NSCs) persist in the adult human brain [and] some brain regions display an unexpected capacity for newborn neuron migration and survival. Several milestones need to be achieved prior to considering functional repair [in the brain through use of NSCs]. These include, but may not be limited to:

(1) Understanding the mechanisms leading to NSC quiescence and loss with aging. Several mechanisms are involved in the different regulatory steps of NSC self-renewal and loss. We will emphasize some of the mechanisms leading to NSC loss with aging. Once these mechanisms are identified, we should be able to amplify the pool of NSCs and direct their differentiation.

(2) Identifying the molecules responsible for fate determination of NSCs and their daughter cells to generate glia or neurons of different types, including interneurons and long projection neurons.

(3) Determining the inhibitory molecules that make the adult brain resistant to repair. Some repair has been reported in the cortex of rodents, but it is abortive possibly due to an unfriendly environment.

(4) Finally, although we can genetically manipulate NSCs in rodents, it is a different issue in humans. Delivery systems need to be improved. Each of this point is further discussed below.

Despite the hurdles outlined above and the length of time that will be required for achieving brain repair and cognitive enhancement, we cannot fail to pursue our investigations of the four fields outlined above. Overall, the present energetic study of stem cell biology and brain delivery systems will provide a better understanding of brain development, endogenous responses to injuries, and additional therapeutic approaches for brain repair, and hold great promise for broadening the therapeutic options available for maintaining and restoring cognition following brain injury and during neurodegenerative diseases.


Aubrey de Grey is the co-founder of the SENS Research Foundation and the originator of SENS, the Strategies for Engineered Negligible Senescence. To my eyes SENS is the most important of present initiatives aimed at producing treatments for degenerative aging: de Grey has led the production of a work of synthesis, drawing together important research from widely disparate reaches of the medical research community, produced by researchers often unaware of the relevance of their work to aging or the efforts of scientists in unrelated fields. The sum of this joined research supports (a) the identification of specific forms of cellular and molecular damage as the causes of aging, and (b) sound and detailed research plans for the production of means to repair this damage, and thereby reverse the effects of degenerative aging.

Synthesis is an often overlooked and important activity in the sciences: someone has to survey the diverse strands of progress in a field as complex as medicine, draw the connections that are rarely apparent to researchers at the cutting edge, deeply immersed as they are in advancing their own narrow but deep specialties. It isn't just a matter of joining puzzle pieces, however. Synthesis also means establishing ties between researchers who will benefit from an exchange of knowledge, but would not have become aware of one another without outside intervention. All fields of science go through periods of fragmentation and exploration, accompanied by a rapid expansion in knowledge, but this also tends to create divides of mutual ignorance and lack of communication between specialties. This is only natural: there are only so many hours in the day, and no one person can know everything there is know about what thousands of researchers in hundreds of laboratories are up to. Thus forming the foundations for the next phase of development in medical science requires initiatives that focus on synthesis, networking, and review: building connections and identifying which pieces of the puzzle join together.

Aubrey de Grey is of course only one of the more visible folk involved in the work of the SENS Research Foundation. There are scores of researchers and other people in a broad network involved in creating better odds for the development of rejuvenation therapies in our future, which is not to mention the thousands of donors who have helped to raise millions of dollars to fund the initial stages of research. As in all such initiatives someone has to be the visible spokesperson, to raise awareness and present the goal of defeating aging to a public that is only just starting to think of this as a possibility.

Here are a couple of recent interviews with de Grey; one audio podcast from Radio New Zealand, and a video from the St. Gallen Symposium in Switzerland.

Aubrey de Grey: extending longevity

English author and theoretician in the field of gerontology, and the Chief Science Officer and co-founder of the SENS Research Foundation. Duration:  45′ 58″.

One-on-One: an investigative interview with Aubrey de Grey

Aubrey de Grey (GB), Chief Science Officer & Co-Founder, SENS Research Foundation. Topic Leader: Stephen Sackur (GB) Presenter HARDtalk, BBC Broadcasting House.


All sorts of disparate functions in higher animals have evolved to influence one another. In part this is because evolution produces promiscuous reuse of component parts, so any one given gene or the protein it encodes may have numerous functions and impact numerous different biological systems. Coupled with the fact that there are an awful lot of proteins making up our cellular machinery, this means that any attempt to alter the operation of metabolism so as to reliably and safely slow aging and extend healthy life is a challenging prospect. Researchers have spent a few billion of dollars and more than a decade simply trying to recreate the known and well-researched enhancements to health and longevity produced by calorie restriction. There is no available therapy to show for this work as of yet, and it is clear that there remains a fair way to go to reach even a good, comprehensive, and defensible model of how this one single type of metabolic alteration works. It is a ferociously complex business.

Then there are many other normally hidden linkages between, on the one hand, parts of metabolism that have nothing to do with longevity and, on the other hand, parts that do in fact influence both aging and health. These relationships do not tend to come into play in nature in the same dramatic manner as the metabolic shift brought on by calorie restriction - otherwise they wouldn't be hidden. But when you have a laboratory and modern biotechnology, all sorts of sometimes surprising connections can be uncovered. Take this connection between a component of pain sensing and insulin metabolism, for example:

No Pain, Big Gain

Mice lacking the pain receptor TRPV1 live longer than controls and have more youthful metabolisms. While searching for an explanation for the mutant rodents' longevity, the researchers discovered that the animals responded to glucose extraordinarily efficiently even once they reached advanced age. Young mice with healthy metabolisms rapidly clear glucose from their blood streams, while it tends to linger in older mice with metabolic disorders. The mice without TRPV1 were able to produce spikes in insulin and to clear the glucose throughout their lives, whereas the control mice were less able to ramp up insulin production to clear glucose as they aged.

Curious about how TRPV1 influences insulin production, the researchers switched to another model organism: Caenorhabditis elegans. When C. elegans lost the worm equivalents of TRPV1, the mutant worms lived up to 32 percent longer than did controls.

Through experiments in both C. elegans and mice, the researchers found that overactive TRPV1 reduces longevity through setting off a calcium-signaling cascade. In mice, this eventually leads to over-production of the neuropeptide CGRP in sensory neurons that innervate the pancreas. The presence of CGRP in these neurons suppresses insulin secretion. As a final test, the researchers blocked CGRP in elderly wild-type mice. Following sustained treatment, the animals' metabolic functions began to resemble those of younger mice. [Researchers] hypothesized that TRPV1 is overactive in older mice due to chronic inflammation, which is known to activate the pain receptor and is a hallmark of type 2 diabetes.

TRPV1 Pain Receptors Regulate Longevity and Metabolism by Neuropeptide Signaling

The sensation of pain is associated with increased mortality, but it is unknown whether pain perception can directly affect aging. We find that mice lacking TRPV1 pain receptors are long-lived, displaying a youthful metabolic profile at old age. Loss of TRPV1 inactivates a calcium-signaling cascade that ends in the nuclear exclusion of the CREB-regulated transcriptional coactivator CRTC1 within pain sensory neurons originating from the spinal cord. In long-lived TRPV1 knockout mice, CRTC1 nuclear exclusion decreases production of the neuropeptide CGRP from sensory endings innervating the pancreatic islets, subsequently promoting insulin secretion and metabolic health.

In contrast, CGRP homeostasis is disrupted with age in wild-type mice, resulting in metabolic decline. We show that pharmacologic inactivation of CGRP receptors in old wild-type animals can restore metabolic health. These data suggest that ablation of select pain sensory receptors or the inhibition of CGRP are associated with increased metabolic health and control longevity.

Thus chronic pain isn't just a horrible experience resulting from the damage of aging, but rather in and of itself causes further harm and dysregulation of metabolism. No-one said life is fair, and this is all the more reason to work on ways to effectively treat aging and and its consequences.


Methionine is an essential amino acid. Our metabolism cannot produce it, but is nonetheless an important raw material for the manufacture of proteins, and thus must be obtained in the diet. If you don't obtain enough of it, you die. Fortunately just about any sensible diet, and even most deficient diets, contain far more than you actually need to get by. Very few foodstuffs are lacking in methionine.

If you are the sort who likes undertaking strict and novel diets for the inherent challenge involved, rather than the outcome, then you should give up whatever you are doing right now and give a low methionine diet a try. You will be faced with challenging research to identify appropriate levels of methionine for a human low methionine diet, poor and contradictory nutritional data on the methionine content of various foodstuffs, and a comprehensive avoidance list that includes most of the standard staples and fallback alternatives used in the recipes of any given culinary tradition. I feel quite sorry for those who are forced into such a diet through suffering one of a few rare medical conditions such as homocystinuria, as the challenges inherent in organizing your own low methionine diet almost rise to the level of making the expensive tailored medical diets produced by a variety of big name companies look cost-effective.

Why undertake a low methionine diet if not forced to do so by pressing medical circumstances? For the same reasons one would undertake calorie restriction or intermittent fasting, both of which are far easier propositions: just like these two options, methionine restriction has been shown to extend life and improve health in a range of laboratory species. The evidence for calorie restriction to bring health benefits to human practitioners is compelling, and further bolstered by a mountain of animal studies results accumulated over decades. In the case of methionine restriction there is, so far as I know, only very sparse data for humans, but a good enough set of data from rodent studies to make it interesting. Methionine restriction is likely an important underlying mechanism for the operation of calorie restriction, which makes sense as a lesser intake of food generally means a lesser intake of methionine. Thus anyone advocating that you give methionine restriction a try for health reasons would argue on the basis of studies in mammals that strongly suggest it is a cause of calorie restriction benefits, and then point to the supporting data mountain for calorie restriction.

Caveat emptor, of course. I'm one who has in the past debated whether it is wise to try alternate day fasting given that there is much more data for straight calorie restriction, so you can probably imagine my views on methionine restriction. Being a conservative late adopter in all things has a lot going for it.

In a like fashion the research community is generally very conservative and and slow-moving in most matters. It takes a while, sometimes decades, for research to percolate through the system. Methionine restriction is beginning to be considered more widely among those who work with calorie restriction or fasting, however. So we have the small symposium noted below, for example, as a sign that folk are talking on this topic. Where there is presently discussion and modest scientific meetings there will later be conferences and commercial ventures - and possibly better and more reliable information on whether and how to practice methionine restriction were one inclined to do so:

The First International Mini-Symposium on Methionine Restriction and Lifespan

It has been 20 years since the Orentreich Foundation for the Advancement of Science, under the leadership Dr. Norman Orentreich, first reported that low methionine (Met) ingestion by rats extends lifespan. Since then, several studies have replicated the effects of dietary methionine restricted (MR) in delaying age-related diseases.

We report the abstracts from the First International Mini-Symposium on Methionine Restriction and Lifespan held in Tarrytown, NY, September 2013. The goals were (1) to gather researchers with an interest in MR and lifespan, (2) to exchange knowledge, (3) to generate ideas for future investigations, and (4) to strengthen relationships within this community. The presentations highlighted the importance of research on cysteine, growth hormone (GH), and ATF4 in the paradigm of aging. In addition, the effects of dietary restriction or MR in the kidneys, liver, bones, and the adipose tissue were discussed.

The symposium also emphasized the value of other species, e.g., the naked mole rat, Brandt's bat, and Drosophila, in aging research. Overall, the symposium consolidated scientists with similar research interests and provided opportunities to conduct future collaborative studies.

Among the presentations discussed is one of the only studies on methionine restriction in humans I've seen, preliminary and brief as it was. It is worth noting in passing that in comparison to the mild reduction in methionine here, rodent life span studies on methionine restriction tend to cut down methionine levels in the diet by a much larger proportion.

Previous findings in rodent models that dietary MR increases maximum lifespan and reduces the development of aging-related impairments suggest that MR may have important implications as a preventive or therapeutic strategy in humans. However, to date, there have been few studies aimed at translating these pre-clinical findings to the clinic.

To this end, we conducted a short-term controlled cross-over feeding study of MR in healthy adults. This study consisted of two isocaloric diet groups (control and 86% MR). Our objectives were to determine the feasibility of feeding an MR diet and to assess the effects of MR on relevant blood biomarkers. The study was conducted with 12 healthy adults and consisted of two 3-week experimental feeding periods with a 2-week washout. The MR diet was well-tolerated by all subjects with no negative side-effects reported.

Decreases in plasma levels of Met (22%) and cysteine (15%) were observed in the MR group after 3 weeks. MR significantly decreased plasma total cholesterol (15%), LDL (23%), and uric acid (25%), but had no effects on leptin, adiponectin, IGF-1, or glutathione.

Altogether, these findings demonstrate the feasibility of a MR diet in humans and indicate that MR has significant short-term effects on blood lipids similar to those observed in laboratory animal models. In addition, the lack of effects on blood adipokines and glutathione are consistent with more recent laboratory findings that indicate that restrictions in both Met and Cys may be required for the full range of beneficial effects on adipokines and longevity.


Monday, May 19, 2014

The protein GDF-11 has recently been shown to influence the decline in muscle stem cell function with aging and other aspects of aging in mice. Alterations in circulating levels of GDF-11 can restore stem cell activity in aged individuals, in at least some tissues, though there is the strong possibility that overriding this age-related reaction to rising levels of cellular damage may lead to cancer.

GDF-11 is related to myostatin, a protein shown to guide muscle growth. Loss of myostatin leads to very muscular individuals, and as is the case for for GDF-11 scientists are considering the development of treatments based on manipulating levels of this protein. Here researchers present more context for these overlapping mechanisms based on fly studies:

Using transgenic RNAi screening, we recently discovered several myokines that regulate lifespan and muscle aging in the fruit fly Drosophila melanogaster. Among the myokines regulating the lifespan of Drosophila, we found Myoglianin, a TGF-beta ligand expressed primarily by skeletal muscle and glia. Drosophila Myoglianin is homologous to human GDF11 and Myostatin (GDF8), two highly related TGF-beta ligands that circulate in the bloodstream in mammals.

We found that Drosophila Myostatin (Myoglianin) extends lifespan and delays systemic aging by acting on muscle, adipocytes, and possibly other tissues. These effects were not due to feeding or changes in muscle mass, suggesting that Drosophila may be a convenient system for testing the direct signaling roles of Myostatin without the indirect confounding effects deriving from the increased muscle mass observed in Myostatin knock-out mice. In fact, these mice have increased insulin sensitivity and decreased adiposity due to higher nutrient utilization in muscle (and consequent reduced nutrient availability for other tissues) deriving from the doubling in muscle mass, which is a prominent feature of Myostatin knock-out mice.

In addition to Myostatin, Myoglianin is homologous to the related factor GDF11. A previous study in mice showed that GDF11 levels decline during aging and that this contributes to developing age-related cardiac hypertrophy. The finding that the GDF11 homolog Myoglianin preserves muscle function during aging in Drosophila suggests that GDF11 may also have anti-aging effects on tissues other than the heart. Indeed very recent studies have shown that GDF11 delays skeletal muscle and brain aging in mice, suggesting that GDF11 is an evolutionarily conserved, general regulator of tissue aging.

Monday, May 19, 2014

Researchers still don't have a complete and clear picture as to how calorie restriction extends life and produces considerable health benefits. At present the research consists of a large bucket of metabolic changes with varying confidence levels in their involvement as longevity-assurance mechanisms. Reduction in visceral fat tissue seems important, as does the chain of events that starts with sensing levels of methionine in the diet, and also upregulation of the cellular housekeeping processes of autophagy.

There is plenty of room yet to raise up previously unexamined changes to a greater level of importance, however, or to argue over which of the presently better known mechanisms provide a greater contribution to the end result. I expect this process of discovery and argument to continue: as this paper indicates, calorie restriction changes an enormous number of discrete elements of metabolism, and most of these elements interact with one another in complex ways within the vast network of change and feedback. There is more than enough work here for another generation of researchers.

Dietary restriction (DR) extends longevity and delays the occurrence and progression of age associated diseases in a range of organisms. The ubiquity of these effects suggests there should be conserved common molecular pathways underlying how animals slow aging in response to DR. Such mechanisms that might be elucidated in model organisms may therefore apply to mammals and even perhaps primates including humans

One approach to discover such underlying mechanisms of longevity assurance is to study age-dependent gene expression in DR relative to normal-diet animals. Perhaps unsurprisingly, a great many genes are seen to differ between these groups and it is likely that only a fraction of these actually participate in the mechanisms that directly confer longevity assurance.

The breadth of overall transcript changes in response to diet is illustrated by meta-analysis of publicly available transcriptional studies. [Researchers] compiled 40 DR gene expression cases in mouse and identified 12,214 differentially expressed genes. Fewer analyses of chronic differences between DR and normal food have been conducted with Drosophila. [Researchers] examined the chronic effect of DR with samples taken at six and eight different age points in the control and DR cohorts respectively over the course of their lifespan. This design identified 2,079 genes whose transcript abundance associated with adult diet.

Besides rapidly adjusting transcript profiles to acute changes in diet, diet switches rapidly alter age-specific mortality. When switched from protein to non-protein diets, the age-specific mortality of formally protein-fed adults quickly adopts the mortality rate and trajectory of a continuously non-protein-fed cohort. Remarkably, when flies are shifted from a rich diet to just a relatively restricted diet, within days the cohort adopts the same trajectory of low age-specific of adults continuously maintained on restricted diet (and vice versa for cohorts switched from restricted to rich diets). These observations suggest that the molecular, cellular and physiological changes caused by DR to extend lifespan must occur within a short time frame after adults experience an alternative diet.

Tuesday, May 20, 2014

Cryonics is the low-temperature preservation of your body and brain as soon as possible after death. It is the only option available for people today that offers any sort of a chance at a longer life in the future, as for so long as the structures in the brain that store the data of the mind are preserved then it is possible for future technology to restore an individual to life. That restoration will not be easy and isn't possible today, but we can envisage the sort of nanodevices and repair strategies that would be needed, and a cryopreserved individual has time on his or her side. Despite its potential to save lives, cryonics remains a small and largely non-profit industry consisting of just a few primary providers and a handful of support companies. Few people indeed avail themselves of this option.

Alcor is one of the two long-standing cryonics providers present in the US and the staff there have in the past proven that they will go the extra mile for their members, striving to produce the best outcome possible even when they are presented with impossible circumstances. The last time I made this point, it was to remind people that if you want a good cryopreservation, one that follows on as close to immediately after death as possible, then don't leave things to the last minute and don't make it hard for the organizations involved to deliver.

A-2531, a neurocryopreservation member, was declared legally dead at 10:15am (MST) on Tuesday May 6, 2014 and became Alcor's 124th patient.

Shortly after 9 am local time, Alcor received a call from a member in Alabama claiming to have been shot by an intruder. After immediately calling police and medical services in the area, we stayed on the phone with him as much as he allowed. It soon became apparent that he had not been shot but was intending to shoot himself in the chest and had already taken a large dose of sleeping pills. Clearly deeply distressed emotionally, he called one or two family members to say goodbye, but still wanted Alcor to cryopreserve him. As we soon learned, hearing the police arriving, he cut off our phone call and shot himself before anyone could prevent him.

We immediately contacted an attorney to be ready to file an injunction to try to block the expected autopsy. (This is a powerful reason never to kill yourself, no matter how distressed you are, if you want to be successfully cryopreserved.) With great good fortune, the police and coroner declared the cause of death obvious, took blood samples, and quickly released our member. Two members of Alcor's response team got on a plane the same afternoon, did a field washout, circulated medications, and performed a neuro separation. The patient arrived at Alcor on Wednesday at 2:10 am. After a longer than usual perfusion for a neuro case, perfusion was completed at 7:32am.

Tuesday, May 20, 2014

That living, being alive and active and enjoying the potential that this brings, is good in and of itself is an axiom for those who work in medicine, including those who work towards the tools needed to extend healthy life and rejuvenate the old. If life is not good and valuable, then why bother? Yet if you look around at what does and does not take place in this world of ours, you might be forgiven for thinking that most people do not in fact place as great a value on life as they might. Here is an article on this theme from the Movement for Indefinite Life Extension.

We have become really good at being indifferent to the most widespread forms of death, in order to spare ourselves from stressing out on futilely trying to do something about it. Now that we have the tools and techniques, and the times have changed, we have to change that way of thinking from indifference back toward letting that horror affect us. Horror benefits us in that it is our cue to be driven to action to make sure that the horror can't happen again.

A few days ago I was thinking about a typical farm hand of Medieval times, walking outside to smell the heavy wet grass and earth of a cold wet spring day. Focus on your heartbeat, feel it pulsing. Theirs pulsed like that. They thought of their hearts stopping and of how it couldn't possibly be lost to the dust of history anytime soon. You think that, too. Their hearts are lost to the dust of history. Yours is next. So many tangled groves in forests have had the wind blowing through them for all of these years, without one person, without one spoken word, in a place near a stream, where there was once a mighty, crackling stone fireplace that warmed multiple generations of families across the 6th through 8th centuries. It was a place that hosted countless memories which later tormented the souls of dying, now long-dead grandfathers.

They don't deserve to be dead. They deserve what they earned: the world that is paying exponentially exciting, satiating, and fullfillingly valuable dividends today. This is an incredibly motivating and driving factor in what pushes me to pursue indefinite life extension. People take on a variety of diverse augmentations over time, becoming unique collections of intriguing insight - dynamic power tools for slicing and dicing the elements. We can't afford for these wealths of rare and powerful abilities and resources to be pillaged and killed off. Sometimes it seems as if life-extensionists like me have to explain to people why it's bad to let people be killed before we can get down to business in a worldwide effort to reach the goals that can get this done.

Wednesday, May 21, 2014

Syndrome X patients do not develop physically in childhood, and thus appear to not be aging. However this is an extreme malfunction of developmental programs, not an absence of aging. The operation of their metabolism still generates all of the forms of damage that lead to degenerative aging, but these individuals die young and so none of that is given the chance to rise to the level of displaying the recognizable symptoms of aging.

Some people persist in trying to make the link that doesn't exist, however. This popular science article is a decent coverage of what is presently called Syndrome X and present thoughts on theories of aging. The researcher whose work on Syndrome X is mentioned here has adopted a variant view of aging as a genetic program, and seeks to sequence the few known Syndrome X patients in search of the common genetic cause in the hopes that this will inform considerations of normal aging. I, among others, think that this is a futile quest, though it may produce the path to curing Syndrome X in the future, should it turn out to have a simple root cause in genetic mutation.

Richard Walker has been trying to conquer ageing since he was a 26-year-old free-loving hippie. Walker, now 74, believes that the key to ending ageing may lie in a rare disease that doesn't even have a real name, "Syndrome X". He has identified four girls with this condition, marked by what seems to be a permanent state of infancy, a dramatic developmental arrest. He suspects that the disease is caused by a glitch somewhere in the girls' DNA.

Most scientists say that ageing is not caused by any one culprit but by the breakdown of many systems at once. Our sturdy DNA mechanics become less effective with age, meaning that our genetic code sees a gradual increase in mutations. Telomeres, the sequences of DNA that act as protective caps on the ends of our chromosomes, get shorter every year. Epigenetic messages, which help turn genes on and off, get corrupted with time. Heat shock proteins run down, leading to tangled protein clumps that muck up the smooth workings of a cell. Faced with all of this damage, our cells try to adjust by changing the way they metabolise nutrients and store energy. To ward off cancer, they even know how to shut themselves down. But eventually cells stop dividing and stop communicating with each other, triggering the decline we see from the outside.

Scientists trying to slow the ageing process tend to focus on one of these interconnected pathways at a time. Some researchers have shown, for example, that mice on restricted-calorie diets live longer than normal. Other labs have reported that giving mice rapamycin, a drug that targets an important cell-growth pathway, boosts their lifespan. Still other groups are investigating substances that restore telomeres, DNA repair enzymes and heat shock proteins.

During his thought experiments, Walker wondered whether all of these scientists were fixating on the wrong thing. What if all of these various types of cellular damages were the consequences of ageing, but not the root cause of it? He came up with an alternative theory: that ageing is the unavoidable fallout of our development.

Most researchers agree that finding out the genes behind Syndrome X is a worthwhile scientific endeavour, as these genes will no doubt be relevant to our understanding of development. They're far less convinced, though, that the girls' condition has anything to do with ageing. "It's a tenuous interpretation to think that this is going to be relevant to ageing," says David Gems, a geneticist at University College London.

Wednesday, May 21, 2014

This, I think, is a great example of what emerges as a consequence of the distorting effects of regulation on medical research. Because it costs a ridiculous amount of money and time to push anything new past the regulators of the FDA, there is a great focus on generating very marginal new uses of drugs that have already been approved. Thus instead of forging ahead to build radically improved new technologies, things far better than mere drugs, much of the research community does nothing more than tinker with what is already known. This is a terrible thing to be happening at a time when the research community is finally shedding its inhibitions regarding the treatment of aging, and researchers feel able to speak openly about the goal of extending health human life spans. It is a stupendous waste of potential, and the cost is measured in lives lost.

Rapamycin, an antibiotic and immunosuppressant approved for use about 15 years ago, has drawn extensive interest for its apparent ability - at least in laboratory animal tests - to emulate the ability of dietary restriction in helping animals to live both longer and healthier. A big drawback to long-term use of rapamycin [is] the increase in insulin resistance, observed in both humans and laboratory animals. The new research identified why that is happening. It found that both dietary restriction and rapamycin inhibited lipid synthesis, but only dietary restriction increased the oxidation of those lipids in order to produce energy.

Rapamycin, by contrast, allowed a buildup of fatty acids and eventually an increase in insulin resistance, which in humans can lead to diabetes. However, the drug metformin can address that concern, and is already given to some diabetic patients to increase lipid oxidation. In lab tests, the combined use of rapamycin and metformin prevented the unwanted side effect.

"If proven true, then combined use of metformin and rapamycin for treating aging and age-associated diseases in humans may be possible. This could be an important advance if it helps us find a way to gain the apparent benefits of rapamycin without increasing insulin resistance. It could provide a way not only to increase lifespan but to address some age-related diseases and improve general health. We might find a way for people not only to live longer, but to live better and with a higher quality of life."

Thursday, May 22, 2014

The axons that link neurons in the nervous system can grow to great length, up to several feet long in human limbs for example. Thus it isn't enough just to be able to replace or repair cells in the nervous system when building regenerative treatments, the axons must also be considered. Here researchers demonstrate a first step towards axon regrowth, which is to get it to happen at all. Creating restoration of function is the next step that must be built on this foundation:

Axons in the central nervous system (the CNS, consisting of brain, eyes and spinal cord) cannot regenerate after an injury in higher animals such as mice and humans. Earlier work had shown that axon growth can be blocked by disabling the proteins B-RAF and C-RAF, part of the RAF-MEK growth-signaling pathway involved in neuronal development. This growth-signaling pathway is inactive in adult animals.

To isolate the effects of B-RAF in the nervous system, [researchers] genetically engineered mice so that B-RAF in neurons could be turned on at will. Activation of B-RAF enabled normal growth of sensory axons in mouse embryos that lacked a crucial nerve growth-signaling pathway and would normally not develop proper sensory innervation.

The researchers then tested whether boosting B-RAF in adult mice could help repair injured sensory axons, which are not part of the CNS. In mice with identical neuronal injuries, those with activated B-RAF showed significant axon regrowth. The regenerating axons even reconnected with the spinal cord, seemingly unchecked by the inhibitory cues that normally inhibit regeneration in the adult spinal cord.

Next, the researchers set their sights on the more elusive goal - regeneration inside the adult CNS. In an encouraging step towards fulfilling that dream, the researchers found that B-RAF activation strongly enhances axon regeneration in injured optic nerve. Moreover, when they combined B-RAF activation with another manipulation, the inactivation of the PTEN gene, the combined axon regeneration was even greater than they had expected from a simple additive effect.

Thursday, May 22, 2014

Much of the focus in Alzheimer's research remains on amyloid beta and the processes by which it accumulates in the brain. This researcher is one of a number of attempts over the years to produce a drug candidate that interferes beneficially in these mechanisms:

A molecular compound [restored] learning, memory and appropriate behavior in a mouse model of Alzheimer's disease. The molecule also reduced inflammation in the part of the brain responsible for learning and memory. [This] is the second mouse study that supports the potential therapeutic value of an antisense compound in treating Alzheimer's disease in humans. "Our current findings suggest that the compound, which is called antisense oligonucleotide (OL-1), is a potential treatment for Alzheimer's disease."

OL-1 blocks the translation of RNA, which triggers a process that keeps excess amyloid beta protein from being produced. The specific antisense significantly decreased the overexpression of a substance called amyloid beta protein precursor, which normalized the amount of amyloid beta protein in the body. Excess amyloid beta protein is believed to be partially responsible for the formation of plaque in the brain of patients who have Alzheimer's disease.

Scientists tested OL-1 in a type of mouse that overexpresses a mutant form of the human amyloid beta precursor gene. Like people who have Alzheimer's disease, [the] mice have age-related impairments in learning and memory, elevated levels of amyloid beta protein that stay in the brain and increased inflammation and oxidative damage to the hippocampus - the part of the brain responsible for learning and memory.

Scientists found that learning and memory improved in the genetically engineered mice that received OL-1 compared to the genetically engineered mice that received random antisense. They also tested the effect of administering the drug through the central nervous system, so it crossed the blood brain barrier to enter the brain directly, and of giving it through a vein in the tail, so it circulated through the bloodstream in the body. They found where the drug was injected had little effect on learning and memory.

Friday, May 23, 2014

Much of the work on the aging of stem cells in recent years has focused on muscle stem cells, and has shown that to a large degree the progressive decline in function with age is not due to a loss of stem cells, but rather because these cells become less active and stop doing their jobs. This is probably an evolved reaction to rising levels of cellular damage that serves to reduce the risk of cancer, but which comes at the cost of increasing frailty as tissue maintenance falters.

Researchers are making inroads into understanding the signal mechanisms involved in this process of stem cell decline. Work is already underway on the development of potential treatments based on at least temporarily overriding these signals in the old. Here is another example of relevant research in this field, which uncovers an aspect of aging in stem cells that is inherent to the cells themselves rather than being a property of the surrounding tissue and its protein signals:

The elderly often suffer from progressive muscle weakness and regenerative failure. We demonstrate that muscle regeneration is impaired with aging owing in part to a cell-autonomous functional decline in skeletal muscle stem cells (MuSCs). Two-thirds of MuSCs from aged mice are intrinsically defective relative to MuSCs from young mice, with reduced capacity to repair myofibers and repopulate the stem cell reservoir in vivo following transplantation. This deficiency is correlated with a higher incidence of cells that express senescence markers and is due to elevated activity of the p38α and p38β mitogen-activated kinase pathway.

We show that these limitations cannot be overcome by transplantation into the microenvironment of young recipient muscles. In contrast, subjecting the MuSC population from aged mice to transient inhibition of p38α and p38β in conjunction with culture on soft hydrogel substrates rapidly expands the residual functional MuSC population from aged mice, rejuvenating its potential for regeneration and serial transplantation as well as strengthening of damaged muscles of aged mice. These findings reveal a synergy between biophysical and biochemical cues that provides a paradigm for a localized autologous muscle stem cell therapy for the elderly.

Friday, May 23, 2014

This popular science piece argues that the future of bioartificial organ development will be a process of top down and bottom up tissue engineering attempts eventually meeting somewhere in the middle, and there providing the ability to generate complex replacement organs to order:

Although a body, no less than a car, may eventually need replacement parts, surgeons cannot simply place an order at the Organ Zone. One alternative to waiting for a donor organ is to handcraft one. Doing so is as inconvenient at it sounds. First, you need a scaffold. This, too, can come from a donor, a cadaver even, provided all the cells are removed, leaving only extracellular matrix consisting of collagen or cartilage. To date, this approach has been used to accomplish relatively simple repairs in human patients. For example, scaffolds fashioned from cadaver materials and plastics have been seeded with stem cells to create new windpipes.

While optimism does seem to be in order, this approach to tissue engineering, with its arduous and time-consuming shaping of scaffolds and pipetting of stem cells, has something of a preindustrial, handicraft feel to it. Moreover, it seems inherently resistant to the sort of top-down optimization you might see in an industrial setting. Mass production would seem to be out of the question. But what about mass customization? Mass customization refers to a kind of bottom-up process that relies on computer-aided design (CAD) tools and rapid prototyping platforms such as 3D printers. Since it was learned that more than 90% of bioprinted cells manage to survive the rigors of bottom-up processing, researchers interested in generating 3D replacement organs have been pressing the "print" button. If they succeed, they will create an industry that has the distinction of skipping the mass production phase of industrial development.

That may seem too large a chasm to cross. The other side may be reached, however, partly thanks to insights gleaned from top-down systems. For example, it is already well understood that printing an organ won't be as simple as dropping cells and supporting materials in the right place and calling it a finished product. An organ grows and develops over time amidst a storm of signals and signal responses, and these depend on environmental cues and cellular sensitivities and propensities for self-organization. Exactly how all these interactions can be orchestrated is unclear, but researchers, undaunted, are pressing forward.


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