FIGHT AGING! NEWSLETTER
August 27th 2012
The Fight Aging! Newsletter is a weekly email containing news, opinions, and happenings for people interested in aging science and engineered longevity: making use of diet, lifestyle choices, technology, and proven medical advances to live healthy, longer lives. This newsletter is published under the Creative Commons Attribution 3.0 license. In short, this means that you are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!
- The Concept of "Aging Successfully" Seems Wrongheaded
- Nascent Brainmaking
- A Political Party for the 2045 Initiative
- Alcor and Cryonics in the Popular Press
- Latest Headlines from Fight Aging!
- Identifying Cancer Stem Cells for Melanoma
- Testing Stem Cells From Amniotic Fluid as a Stroke Therapy
- Investigating the Gene Network of Calorie Restriction
- Obesity Correlates With Faster Mental Decline
- SIRT6 Overexpression Extends Mean Lifespan in Male Mice
- A Cautionary Note on Arranging Your Cryopreservation in Advance
- Slowing Stem Cell Aging
- An In-Depth Look at Organovo
- Reviewing the Regulation of Autophagy in Aging
- Failing Neural Plasticity and Age-Related Memory Decline
THE CONCEPT OF "AGING SUCCESSFULLY" SEEMS WRONGHEADED
There is no "successful terminal cancer" movement. So why so much focus on the idea of "successful aging?" This is one of many examples of the way in which the medical community is far more accepting of the suffering caused by aging to death than that caused by other form of progressive disability or medical condition:
"The concept of 'successful aging' is one put forward by a fairly wide-ranging group of people in medicine and research. When you break it down, 'aging successfully' means that a bunch of really horrible things happen to you and your body, and then you die, but at least you weren't suffering as much as those guys over there. This seems wrongheaded on a number of levels. It is the sort of thing that a researcher talks about when they are trying to avoid any mention of lengthening human life through medicine - which was at one time very much required ... This is no longer completely the case, but old habits die hard and there remains a sizable contingent in the research community who refuse to acknowledge that extending life is an ongoing goal. Hence talk of 'successful aging' and 'compression of morbidity' in connection with efforts to eliminate age-related disease or slow the pace at which people decline in old age. Anything other than raising the prospect of extending maximum life span in addition to healthy life span.
This is all somewhat complicated by the fact that no good definition for successful aging exists - and, really, how could it? In trying, you'll end up with something as ridiculous and self-defeating as the first paragraph in this post. You are in effect, and within the bounds of the philosophy of medicine, setting out to define an acceptable level of suffering, pain, and degeneration, rather than proposing to do treat it - which I think becomes ever more evident the more that you think about the whole thing. ... Implicit in this is the acceptance of aging and disability - the underlying assumption that aging must happen, and along with it great suffering. Aging cannot be successful. It is not a success to suffer, degenerate, and die. It isn't success to point out other people who are suffering more than you are. This whole way of thinking about about aging is a wrong, bad path that leads away from what needs to be done, which is to consider aging as a medical issue that should be addressed, just like every other medical issue that causes pain and hardship."
Here is an example of the degree to which tissue engineers have progressed in their understanding of how to grow a brain:
"Yoshiki Sasai, a stem-cell biologist at the RIKEN Center for Developmental Biology in Kobe, Japan, [has] impressed many researchers with his green-fingered talent for coaxing neural stem cells to grow into elaborate structures. As well as the optic cup, he has cultivated the delicate tissue layers of the cerebral cortex and a rudimentary, hormone-making pituitary gland. He is now well on the way to growing a cerebellum - the brain structure that coordinates movement and balance.
"What does one do with the ability to tissue engineer a brain? This will be possible not too many years from now. It's not as obviously useful as the ability to engineer a heart, as the brain can't be replaced outright in the same way - although that said it seems possible, based on present knowledge, for a least a few small portions of the brain to be successfully transplanted without affecting the mind. Not every part of the brain is greatly involved in the data and processing mechanisms that make up the self. But this seems as though it will be far harder than transplanting any other organ elsewhere in the body, and hard enough that parallel lines of research into repairing tissue in situ through stem cells and signaling manipulation may win out from the outset. So the likely primary benefit resulting from the sort of work carried out by Sasai's group will be knowledge: information that can be applied to the development of ways to rebuild damaged brain tissue in place rather than building outside the body and then undergoing a transplant operation."
A POLITICAL PARTY FOR THE 2045 INITIATIVE
The formation of single issue political parties focused on engineered longevity and scientific development to that end seems to be a strategy very much in the air at the moment.
"I note that the Russian community behind the well-backed 2045 initiative are trying their hands at launching a political party to further the cause. There is a website for the Evolution 2045 party concept; at this point it would seem to be chiefly worthwhile as a way to gain some additional insight into the thinking of those steering the 2045 initiative. ... The Initiative 2045 announces the creation of its own political party - 'Evolution 2045' - in order to advocate for a new strategy for human development. This is a Russia-based party, but its goals are international and global. Our ultimate goal is to inspire other countries to follow suit, and compete not in the arms race, but in the race for building a bright future for mankind.
"Single issue political parties are a long-standing and widely used methodology for advancing particular causes in Europe and further East, far more so than across the pond in the US, though they do exist there as well. In most European countries you'll find a range of these organizations, some more successful than others. The Green parties are perhaps the exemplar of the type, formed around a movement and grown to staid success in terms of delivering their message, with the Pirate parties as another, younger and still dynamic example.
"Either way, radical optimism about what can be achieved in the near future - if we just worked at it - is in comparatively short supply in our culture. Visionaries who talk about the path to humanity ascendant are a small minority in comparison to the masses and the talking heads who are blinkered by the present and look little further than the bounds of what is. So more vision and more optimism are very welcome, even if harnessed to a program that isn't my first choice for how to proceed towards engineering greatly extended lives."
ALCOR AND CRYONICS IN THE POPULAR PRESS
Some positive coverage of the cryonics industry to look over:
"The public attitude towards cryonics has shifted greatly over the past ten years, at least as measured by the changing tenor of articles in the popular press. They are more favorable, more respectful, and more accurate on technical details. So greater exposure and publicity over the past decade has brought benefits, and increasing familiarity with the topic has allowed more people to overcome whatever knee-jerk reactions they normally have to all novel ideas. This is a positive trend, perhaps driven as much by the general proliferation of media enabled by the internet as by efforts made by the cryonics community, and will hopefully continue apace.
"The Alcor Life Extension Foundation is the world's leading provider of cryonics, the practice of using ultra-cold temperatures to preserve humans until such a time when medicine is advanced enough to restore good health. The widely-held belief that it involves freezing is actually something of a red herring. As soon as possible after legal death is pronounced, cryoprotectant solution - a sort of antifreeze - is administered to a patient through their circulatory system, entering almost every cell in the body. Known as vitrification, this process avoids ice crystal formation and allows the body to be cooled with virtually no freezing damage, before being placed in liquid nitrogen in a Dewar container and moved to storage indefinitely.
"For a long time cryonics was dismissed by many as science-fiction, an unnatural or even immoral procedure, but while the company make no bones about cryonics being an entirely speculative process, futurist and Alcor chief executive Max More says that the field is gaining legitimacy in the eyes of others. 'People have certainly grown less hostile,' he told Metro. 'In terms of how science looks at cryonics we've definitely seen an improvement over time.' Mr More added that Alcor's teams which intervene at members' deathbeds are also being treated more favourably by doctors. 'Our relationship with hospitals and hospices has also improved; they used to be very adversarial and reluctant to even let us in, now hospital staff are usually fascinated and want to help in any way they can. They even let us position our equipment in the room next to the patient before clinical death, their whole attitude has really turned around.'"
The highlights and headlines from the past week follow below. Remember - if you like this newsletter, the chances are that your friends will find it useful too. Forward it on, or post a copy to your favorite online communities. Encourage the people you know to pitch in and make a difference to the future of health and longevity!
LATEST HEADLINES FROM FIGHT AGING!
IDENTIFYING CANCER STEM CELLS FOR MELANOMA
Friday, August 24, 2012
The cancer stem cell hypothesis continues to show promise as a way to strike at the root of many different forms of cancer: "Cancer stem cells are defined by three abilities: differentiation, self-renewal and their ability to seed a tumor. These stem cells resist chemotherapy and many researchers posit their role in relapse. A [new study] shows that melanoma cells with these abilities are marked by the enzyme ALDH, and imagines new therapies to target high-ALDH cells, potentially weeding the body of these most dangerous cancer creators. ... We've seen ALDH as a stem cell marker in other cancer types, but not in melanoma, and until now its function has been largely unknown. ... [Researchers] transplanted ALDH+ and ALDH- melanoma cells into animal models, showing the ALDH+ cells were much more powerfully tumorigenic. In the same ALDH+ cells, the group then silenced the gene that creates this protein, finding that with ALDH knocked down, melanoma cells died in cultures and lost their ability to form tumors in animal models. In cell cultures, silencing this ALDH gene also sensitized melanoma cells to existing chemotherapies. When the group explored human tumor samples, they found distinct subpopulations of these ALDH+ cells, which made up about 0.1-0.2 percent of patients' primary tumors. In samples of metastatic melanoma - the most aggressive form of the disease - the percentage of ALDH+ cells was greater, even over 10 percent in some tumors, further implying the powerful danger of these cells."
TESTING STEM CELLS FROM AMNIOTIC FLUID AS A STROKE THERAPY
Friday, August 24, 2012
Many different sources of stem cells remain under investigation, such as those derived from amniotic fluid: "We recently reported isolation of viable rat amniotic fluid-derived stem (AFS) cells. Here, we tested the therapeutic benefits of AFS cells in a rodent model of ischemic stroke. Adult male Sprague-Dawley rats received a 60-minute middle cerebral artery occlusion (MCAo). Thirty-five days later, animals exhibiting significant motor deficits received intravenous transplants of rat AFS cells or vehicle. At days 60-63 post-MCAo, significant recovery of motor and cognitive function was seen in stroke animals transplanted with AFS cells compared to vehicle-infused stroke animals. Infarct volume [was] significantly reduced, coupled with significant increments in the cell proliferation marker, Ki67, and the neuronal marker, MAP2, in the dentate gyrus (DG) and the subventricular zone (SVZ) of AFS cell-transplanted stroke animals compared to vehicle-infused stroke animals. ... This study reports the therapeutic potential of AFS cell transplantation in stroke animals, possibly via enhancement of endogenous repair mechanisms."
INVESTIGATING THE GENE NETWORK OF CALORIE RESTRICTION
Thursday, August 23, 2012
Research into the detailed mechanisms of calorie restriction continues apace: "Dietary restriction (DR), limiting nutrient intake from diet without causing malnutrition, delays the aging process and extends lifespan in multiple organisms. The conserved life-extending effect of DR suggests the involvement of fundamental mechanisms, although these remain a subject of debate. To help decipher the life-extending mechanisms of DR, we first compiled a list of genes that if genetically altered disrupt or prevent the life-extending effects of DR. We called these DR-essential genes and identified more than 100 in model organisms such as yeast, worms, flies, and mice. In order for other researchers to benefit from this first curated list of genes essential for DR, we established an online database called GenDR. To dissect the interactions of DR-essential genes and discover the underlying lifespan-extending mechanisms, we then used a variety of network and systems biology approaches to analyze the gene network of DR. We show that DR-essential genes are more conserved at the molecular level and have more molecular interactions than expected by chance. Furthermore, we employed a guilt-by-association method to predict novel DR-essential genes. In budding yeast, we predicted nine genes related to vacuolar functions; we show experimentally that mutations deleting eight of those genes prevent the life-extending effects of DR. Three of these mutants [had] extended lifespan under ad libitum, indicating that the lack of further longevity under DR is not caused by a general compromise of fitness. These results demonstrate how network analyses of DR using GenDR can be used to make phenotypically relevant predictions. ... comparing the influence of gene expression changes during DR on the interactomes of multiple organisms led us to suggest that DR commonly suppresses translation, while stimulating an ancient reproduction-related process."
OBESITY CORRELATES WITH FASTER MENTAL DECLINE
Thursday, August 23, 2012
Here is another of many studies to link being overweight with cognitive decline: "People who are obese and suffer from high blood pressure and other problems linked to heart disease and diabetes may also see a faster decline in their mental abilities, according to a new study ... Yet even obese people without these physical conditions experienced a faster decline in functions such as memory, the researchers noted. This finding belies the concept of being obese and healthy ... Participants came from the long-running Whitehall II study, which began in 1985 and follows British civil servants from middle age onward. For the new findings, researchers followed more than 6,400 people aged 39 to 63 for 10 years. At the start of the study, they recorded patients' risk factors, including weight. During the follow-up decade, participants also took tests on memory, reasoning and overall mental function at three intervals. People with metabolic syndrome who were also obese saw a more rapid decline - 22.5 percent faster - in their mental function than those who weren't obese and didn't suffer from the syndrome. Moreover, those who did not have metabolic syndrome but were obese also saw mental function decline more quickly than participants who were not obese."
SIRT6 OVEREXPRESSION EXTENDS MEAN LIFESPAN IN MALE MICE
Wednesday, August 22, 2012
Some more data to add to the muddy waters of sirtuin research: "Since the discovery that overexpression of yeast Sir2 deacetylase extends lifespan by as much as 30% over a decade ago, much effort has been invested in researching whether this effect is conserved in higher organisms as well. Indeed, in worms and flies, two separate groups found that SIR2 extended lifespan as well, by 50% and 18%, respectively. ... In parallel to the work in worms and flies, researchers were trying to make headway in the role of sirtuins in higher organisms. There are seven mammalian homologs to the yeast Sir2, SIRT1-SIRT7. SIRT1 is the most well-researched and has been shown to regulate metabolism and age-related diseases. However, SIRT1 overexpression did not increase lifespan, although this was said to be due to the relatively weak expression of the transgene. Therefore, a role for sirtuins in regulating lifespan of mammals looked bleak. Despite the controversy surrounding sirtuins and longevity, there has never been any doubt that mammalian sirtuins are important regulators of health and disease. Previous results from our lab have shown SIRT6 to be involved in the calorie restriction response, and demonstrate that SIRT6 overexpression in mice protects against diet-induced obesity and its metabolic consequences. These results, along with data that SIRT6 knockout mice display a premature aging-like phenotype, prompted us to turn towards SIRT6 as a potential regulator of mammalian aging. Over the course of three years, we measured the lifespan of mice overexpressing exogenous SIRT6 (MOSES). This study was performed in two separate lines from distinct founders, to ensure that the random integration of the transgene into the genome did not influence the results. We found that the gene insertion in both lines did not disrupt any neighboring genes, and results were similar in both lines. In this way we overcame the issue of site-specific integration, which was previously shown to be a problem in sirtuin studies. Additionally, we chose to work with a mixed background, to ensure no strain-specific effects. Strikingly, both male MOSES lines had significant mean and median lifespan extension, of 14.5% and 9.9%. Even more interesting, there was no lifespan extension in either female lines examined, attesting to a gender-specific role for SIRT6."
A CAUTIONARY NOTE ON ARRANGING YOUR CRYOPRESERVATION IN ADVANCE
Wednesday, August 22, 2012
In the latest case report from Alcor, there is a cautionary note on the need to solidify the arrangements and financing of cryopreservation before the last minute: "Alcor member A-2628 (he wishes his identity to be kept private) was pronounced legally deceased on July 23, 2012. A whole body member, A-2628 became Alcor's 112th patient. On Friday, July 20th, Alcor was notified through the TeleMed alert system that a 90 year old individual wishing to be cryopreserved was in serious condition in a Las Vegas hospital. This individual had filled out an application for membership in 2009 (and was provisionally assigned the number A-2628) but never followed through with the necessary paperwork and funding. Since he became unable to make cryonics arrangements, this case had to be treated as a third-party arrangement. Because of the greater risk involved, Alcor requires additional conditions to be met before accepting such a case. These conditions are rarely met. These include some past interest in cryonics on the part of the person for whom cryopreservation is sought; lack of opposition by close relatives; finances in place without undue hardship; no long ischemic time; and informed consent of persons making the arrangement. This case was one of the rare ones to proceed, in large part due to the determined efforts of A-2628's granddaughter supported by the family accountant."
SLOWING STEM CELL AGING
Tuesday, August 21, 2012
Via the New Scientist: "Could we stem the tide of ageing by delaying the deterioration of stem cells? A new compound that appears to do just that could help us find ways to protect our organs from age-related wear and tear, experiments in mice suggest. As we age, so do our mesenchymal stem cells (MSCs): their numbers in our bone marrow decline, and those that are left lose the ability to differentiate into the distinct cell types - such as bone, cartilage, fat and possibly muscle cells - that help in the healing process. ... We think this ageing of stem cells may be linked to the onset of some age-related disorders, such as osteoporosis ... Earlier research in mice had suggested that the prion protein expressed by MSCs might play a role in holding back stem cell ageing. Mice lacking the prion protein were less able to regenerate blood cells. [Researchers] have now found that the prion protein performs a similar function in humans - older MSCs from human bone marrow expressed less of the protein than younger ones. In a bid to find a compound that might slow MSC ageing, the team tested numerous molecules known to target prion proteins on dishes of human stem cells. One molecule emerged as a potential candidate - stem cells treated with it produced 300 times the number of cells over 250 days than untreated stem cells. The treated cells kept on dividing for longer. The team then injected treated cells into the thigh bones of mice, and three days later found that they had produced three times as many new cells as they would normally produce. After five weeks, there were 10 times as many cells. The new cells appeared to be of higher quality, too, and readily differentiated into bone and fat cells, as well as those that support the tissue and blood vessels. [Researchers] think the molecule works by helping the prions protect the stem cells from the DNA damage associated with normal ageing."
AN IN-DEPTH LOOK AT ORGANOVO
Tuesday, August 21, 2012
For those following the progress of Organovo, a business-focused review: "In the classical approach to tissue engineering, cells are seeded and grown in a biocompatible matrix designed to direct cell differentiation and function. Scaffoldings play an important role in providing the cell architecture for structure and migration, as well as enabling the diffusion of vital nutrients and expressed product. Unfortunately, there are challenges that exist with the classical approach. Scaffolds, made from both natural and synthetic polymers, must be engineered to degrade at a rate in which the cells within them deposit and build their own extracellular matrix. Scaffold choice, immunogenicity, degradation rate, toxicity of degradation products, host inflammatory responses, fibrous tissue formation due to scaffold degradation, and mechanical mismatch with the surrounding tissue are key issues that may affect the long term behavior of the engineered construct, and directly interfere with its primary biological function. Additionally, scaffolds may elicit adverse host responses and interfere with direct cell-cell interaction. To get around the challenges of classical tissue engineering, Organovo has developed the first 3D bioprinter, called NovoGen MMX. The NovoGen MMX Bioprinter is a novel, fully automated, hardware and software platform developed to fabricate three-dimensional (3D) primary human or other living mammalian cells into tissue, with tremendous cellular viability and biology that is superior to even an animal model. Organovo's NovoGen MMX mechanical extruder enables the fabrication of three-dimensional tissue constructs in a wide variety of geometries (tubular structures, networked sheets, etc...). The speed and precision of this instrument enables the production of small-scale tissue models for drug discovery as well as various drug absorption and toxicology assays. NovoGen MMX works similar to an inkjet printer, in where cells are printed in tiny spheres; essentially 'bio-ink'. The concept of bioprinting relies on the demonstrated principle that groups of individual cells will self-assemble to generate aggregates, through the actions of cell surface proteins that bind to each other and form junctions. Furthermore, if two or more compatible self-assembled aggregates are placed in close proximity, under the proper conditions they will fuse to generate larger, more complex structures."
REVIEWING THE REGULATION OF AUTOPHAGY IN AGING
Monday, August 20, 2012
Autophagy, a collection of processes by which a cell breaks down damaged components to recycle their materials, is important in many mechanisms known to extend life in various laboratory animals. Better maintained cells are better for a longer life: more autophagy is a good thing, but it declines with age, because of a gradual buildup of materials that cannot be recycled and thus clog up the cellular components that perform autophagy - and for other, less well understood reasons. Here is an open access review on some of the controlling mechanisms: "One part of the aging process involves a decline in cellular housekeeping functions disturbing the maintenance of organism homeostasis. The accumulation of damaged and defective components increases cellular stress, for example, oxidative stress, which activates cellular defence mechanisms including NF-κB signaling pathway and innate immunity system, such as inflammasomes. Aging is associated with a low-grade proinflammatory phenotype which further interferes with housekeeping and cellular homeostasis. Recent studies have indicated that autophagy is a crucial cleansing system preventing inflammation but its capacity clearly declines with aging. The NF-κB signaling system and the autophagic degradation pathway have been closely conserved during evolution and emerging studies indicate that these systems have many context-dependent interactions with each other. We will review the recent literature on the control mechanisms of autophagy by NF-κB signaling and particularly we will focus on its context-dependent regulation during the aging process."
FAILING NEURAL PLASTICITY AND AGE-RELATED MEMORY DECLINE
Monday, August 20, 2012
An open access paper: "Cognitive impairment associated with subtle changes in neuron and neuronal network function rather than widespread neuron death is a feature of the normal aging process in humans and animals. Despite its broad evolutionary conservation, the etiology of this aging process is not well understood. However, recent evidence suggests the existence of a link between oxidative stress in the form of progressive membrane lipid peroxidation, declining neuronal electrical excitability and functional decline of the normal aging brain. The current study applies a combination of behavioural and electrophysiological techniques and pharmacological interventions to explore this hypothesis in a gastropod model (Lymnaea stagnalis feeding system) that allows pinpointing the molecular and neurobiological foundations of age-associated long-term memory (LTM) failure at the level of individual identified neurons and synapses. ... Classical appetitive reward-conditioning induced robust LTM in mature animals in the first quartile of their lifespan but failed to do so in animals in the last quartile of their lifespan. LTM failure correlated with reduced electrical excitability of two identified serotonergic modulatory interneurons (CGCs) critical in chemosensory integration by the neural network controlling feeding behaviour. Moreover, while behavioural conditioning induced delayed-onset persistent depolarization of the CGCs known to underlie appetitive LTM formation in this model in the younger animals, it failed to do so in LTM-deficient senescent animals. ... The results identify the CGCs as cellular loci of age-associated appetitive learning and memory impairment in Lymnaea and buttress the hypothesis that lipid peroxidation-dependent depression of intrinsic excitability is a hallmark of normal neuronal aging."