Fight Aging! Newsletter, April 9th 2012

April 9th 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!



- SENS Foundation 2011 Research Report Released
- Volunteers Wanted for the SENS Foundation Academic Initiative
- A Histogram of Results from Life Span Studies
- Spurring Stem Cells to Rebuild Cartilage
- Discussion
- Latest Headlines from Fight Aging!


As a companion to the 2011 annual report, the SENS Foundation released their 2011 research report this past week. It goes into much more depth on the laboratory work and results: the foundations for future rejuvenation biotechnology capable of repairing the damage of aging.

"The subtitle on our logo banner reads 'advancing rejuvenation biotechnologies', and in keeping with the dynamic connotations of that statement, we've spent 2011 engaged in focused, concrete actions toward embodying it. ... We're excited to be a part of this revolution in scientific innovation, grateful to everyone who has supported us through their generous gifts of time and funding, and delighted to have multiple exciting developments to report on the research front. ... There is a lot of material in the report, and I encourage you to read the whole thing - it's very approachable for the layperson, and a good way to obtain a top to bottom view of the Foundation's research strategy at present. That more or less encompasses these questions: what exactly causes aging, and what can be done here and now to make progress towards preventing it and reversing it? For example, here's an excerpt from the GlycoSENS category, research with the potential to reverse the cause of much of the chemical and structural aging of skin, blood vessel walls, and many forms of connective tissue:

"The elasticity of the artery wall, the flexibility of the lens of the eye, and the high tensile strength of the ligaments are examples of tissues that rely on maintaining their proper structure. But chemical reactions with other molecules in the extracellular space occasionally result in a chemical bond (a so-called crosslink) between two nearby proteins that were previously free-moving, impairing their ability to slide across or along each other and thereby impairing function. It is the goal of this project to identify chemicals that can react with these crosslinks and break them without reacting with anything that we don't want to break. ... In 2011, we established a Center of Excellence for GlycoSENS and other rejuvenation research at Cambridge University and hired postdoctoral student Rhian Grainger to design and perform experiments to develop reagents that can detect proteins bearing glucosepane crosslinks, facilitating further studies on its structure, abundance, and cleavage by small molecules. We also established a collaboration with researchers at Yale University, who will lend their expertise in generating advanced glycation end-products and lead efforts in developing agents which may be able to cleave glucosepane."


A portion of the work of the SENS Foundation is directed towards ensuring that the life science community of tomorrow is more focused on longevity science than the community of today. The project of building the SENS vision of rejuvenation biotechnology will stretch over decades, and life science students presently earning their degrees will be the ones to perform the bulk of the work, with careers focused on the defeat of aging:

"Are you studying for a life science or biotechnology degree, teaching students, or otherwise a part of the academic life science community? Do you have an interest in helping to advance longevity science and the development of cures for the diseases of aging? The SENS Foundation Academic Initiative is looking for volunteers to help with their growth in funding and interest: Over the last few months, the SENS Foundation Academic Initiative has witnessed a rapid increase in its membership numbers, and in the interest it receives from students across the United States and the world. In order to properly utilize and expand upon this interest, the Initiative will need new volunteers, new ideas, and new projects. For this reason, the Academic Initiative is seeking additional volunteers to help it fulfill its purpose: specifically, to help the Initiative craft itself into an organization capable of launching a legitimate grassroots youth movement in support of SENS Foundation. To join us in this mission, you can either fill out our brief online volunteer application or email Daniel Kimbel, the Academic Coordinator, at daniel dot kimbel at sens dot org. If you are interested in being involved, please don't hesitate to contact us. We can use volunteers from nearly any background.

"The Initiative is focused on the groundwork necessary to build tomorrow's rejuvenation biotechnology research community: people who will enter the workforce to repair mitochondria, build the ultimate cure for cancer, find ways to safely break down the aggregated proteins and crosslinks that cause age-related degeneration - and more. The defeat of aging through biotechnology is a program that will last for decades and radically transform the medical and life science communities along the way. Working with the SENS Foundation and the Academic Initiative is a way to get in on the ground floor of this grand venture, and build connections that will serve you well in future years. The Foundation stands at the center of a web of medical and biotechnology research, with labs and projects around the world, involving many of the most noteworthy researchers in their fields - this is what the beginning of a great revolution looks like, and the years ahead will see great change and great excitement."


You may find this to be of interest - a graphical illustration of decades of work by scientists noting how to move the needle when it comes to altering life span in diverse species:

"Kingsley G. Morse Jr. is one of the regulars at the Gerontology Research Group mailing list. He maintains a spreadsheet of all the life span studies in various organisms that he has been able to find, and is generally willing to sell that data at white paper rates, should you happen to be interested. He recently posted a histogram assembled from the study results, which I'm sure you'll agree is interesting.

"The history of working to extend life in laboratory animals - and of studying effects on longevity and mortality in humans - is largely a big null result. Other than calorie restriction, the effects of which were first formally cataloged by scientists in the 1930s, all of the excitement shows up in the past twenty years or so. The successes are a tiny fraction of the studies that showed nothing, or showed a result well within the margin of error, or produced results that could not be replicated. In mammals, mostly mice, the bulk of studies that do extend life significantly fall in to the 15% to 30% life extension bracket - on a par with moderate to severe calorie restriction. Only a few methods have been demonstrated to reach beyond that point.

"To a large degree this is because near everything tried to date has been a form of metabolic manipulation - change the operation of metabolism to slow the effective rate at which damage accrues to the organism. I would be surprised to see any great improvement in the length of life lived by laboratory animals until the research community changes strategy to focus on actually repairing and reversing the cellular and molecular damage that causes aging. The difference between slowing aging and repairing aging will be as night and day when it comes to the practical results that can be achieved."


Signs of progress in cartilage engineering achieved by directing existing cells in the body to undertake the work of repair that normally doesn't occur:

"A small molecule dubbed kartogenin encourages stem cells to take on the characteristics of cells that make cartilage, a new study shows. And treatment with kartogenin allowed many mice with arthritis-like cartilage damage in a knee to regain the ability to use the joint without pain. ... The new approach taps into mesenchymal stem cells, which naturally reside in cartilage and give rise to cells that make connective tissue. These include chondrocytes, the only cells in the body that manufacture cartilage. 'In the blue-sky scenario, this would be a locally delivered therapy that would target stem cells already there,' says study coauthor Kristen Johnson, a molecular biologist at the Genomics Institute of the Novartis Research Foundation in San Diego. Johnson and her colleagues screened 22,000 compounds in cartilage and found that one, kartogenin, induced stem cells to take on the characteristics of chondrocytes. The molecule turned on genes that make cartilage components called aggrecan and collagen II. Tests of mice with cartilage damage similar to osteoarthritis showed that kartogenin injections lowered levels of a protein called cartilage oligomeric matrix protein. People with osteoarthritis have an excess of the protein, which is considered a marker of disease severity. Kartogenin also enabled mice with knee injuries to regain weight-bearing capacity on the joint within 42 days."


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!



Friday, April 6, 2012
An interesting experiment, especially when compared with work on brain aging that focuses on levels of cell proliferation: "During the past decade, it has become increasingly clear that consistent changes in the levels of expression of a small cohort of genes accompany the aging of mammalian tissues. In many cases, these changes have been shown to generate features that are characteristic of the senescent phenotype. Previously, a small pilot study indicated that some of these changes might be reversed in rat liver, if the liver cells became malignant and were proliferating. The present study has tested the hypothesis that inducing proliferation in old rat liver can reset the levels of expression of these age-related genes to that observed in young tissue. A microarray approach was used to identify genes that exhibited the greatest changes in their expression during aging. The levels of expression of these markers were then examined in transcriptomes of both proliferating hepatomas from old animals and old rat liver lobes that had regenerated after partial hepatectomy but were again quiescent. We have found evidence that over 20% of the aging-related genes had their levels of expression reset to young levels by stimulating proliferation, even in cells that had undergone a limited number of cell cycles and then become quiescent again. Moreover, our network analysis [may] provide insights into mechanisms involved in longevity and regeneration that are distinct from cancer."

Friday, April 6, 2012
An example of work that lays the foundations for lung tissue engineering, which has been lagging behind advances for other organs: "How do you grow stem cells into lungs? The question has puzzled scientists for years. First you need the right recipe, and it took [researchers] seven years of trial and error and painstaking science to come up with it. ... Some tissues, like muscle and nerves, are relatively easy to grow, but others, including liver, lung, thyroid, and pancreas, have been much more difficult. These troublesome tissues all spring from the endoderm, the innermost layer of an early embryo. The endoderm forms when an embryo is about three weeks old and differentiates into organs as early as five weeks. Somehow, in these two weeks the endoderm transforms into differentiated organs as diverse as the lungs and the stomach. ... [Researchers] decided to create a knock-in reporter gene that would glow green during the 'fate decision' - the moment when the stem cells expressed a gene called Nkx2-1 and thereby took a step toward becoming lungs. This allowed the team to track the cells as they developed, mapping each of the six critical decisions on the path to lung tissue. ... Once [the] team had grown what appeared to be lung cells, they had to make sure they had the recipe right. They took samples of mouse lungs and rinsed them with detergent until they became cell-free lung-shaped scaffolds. They seeded one lung with 15-day-old homegrown lung cells that they had purified from stem cells. As a control, they seeded another lung with undifferentiated embryonic stem cells. Within 10 days after seeding, the lung cells organized themselves and populated the lung, creating a pattern recognizable [as] lung tissue. ... A happy side effect of the discovery was that the scientists also mapped out the road from stem cell to thyroid. [The] thyroid, it turns out, also comes from the endoderm layer, deriving from a progenitor that expresses the same key gene as lung progenitors. [The] work will likely have a huge impact on lung stem cell researchers, who have been waiting for a discovery like this to propel their research on inherited lung disease."

Thursday, April 5, 2012
Progress in the tissue engineering of cell structures for use as research tools, and later as the basis for therapies: "Three-dimensional clusters of pancreatic beta-cells that live much longer and secrete more insulin than single cells grown in the laboratory are valuable new tools for studying pancreatic diseases such as diabetes and for testing novel therapies. This cutting-edge advance is described in [an open access paper] ... Finding a solution for the culturing and final transplantation of pancreatic cells will be an enormous breakthrough for the treatment of diabetes ... Growing pancreatic cells in the laboratory is challenging, in part because to survive and function normally they require cell-cell contact. [Researchers] developed an innovative method that uses photolithography to create microwell cell culture environments that support the formation of 3-D pancreatic beta-cell clusters and control the size of the cell aggregates. They describe the ability to remove these cell clusters from the microwells and encapsulate them in hydrogels for subsequent testing or implantation."

Thursday, April 5, 2012
Via ScienceDaily: "Individuals who suffer from autoimmune diseases also display a tendency to develop atherosclerosis - the condition popularly known as hardening of the arteries. Clinical researchers [have] now discovered a mechanism which helps to explain the connection between the two types of disorder. The link is provided by a specific class of immune cells called plasmacytoid dendritic cells (pDCs). ... Using laboratory mice as an experimental model, the researchers were able to show that pDCs contribute to early steps in the formation of athersclerotic lesions in the blood vessels. Stimulation of pDCs causes them to secrete large amounts of interferons, proteins that strongly stimulate inflammatory processes. The protein that induces the release of interferons is produced by immune cells that accumulate specifically at sites of inflammation, and mice that are unable to produce this protein also have fewer plaques. Stimulation of pDCs in turn leads to an increase in the numbers of macrophages present in plaques. Macrophages normally act as a clean-up crew, removing cell debris and fatty deposits by ingesting and degrading them. However, they can also 'overindulge,' taking up more fat than they can digest. When this happens, they turn into so-called foam cells that promote rather than combat atherosclerosis. In addition, activated, mature pDCs can initiate an immune response against certain molecules found in atherosclerotic lesions, which further exacerbates the whole process. ... The newly discovered involvement of pDCs in the development of atherosclerosis [reveals] why the stimulation of pDC that is characteristic of autoimmune diseases contributes to the progression of atherosclerosis. The findings also suggest new approaches to the treatment of chronic inflammation that could be useful for a whole range of diseases."

Wednesday, April 4, 2012
An introduction to calorie restriction at h+ Magazine: "In the early twentieth century nutrition researchers found that rats maintained on reduced caloric intake showed lower spontaneous tumors compared to rats fed ad libitum (allowed to eat as much as they chose). Although this work did not address caloric restriction (CR) and aging, it suggested that CR might slow the onset of age-associated disease in rodents. ... Numerous follow-up studies demonstrated that a micronutrient adequate CR diet significantly increased the lifespan of many species, largely crossing species boundaries. ... While CR increases the lifespans of most species examined, it also suppresses many of the diseases associated with human aging, thus increasing the 'health-span.' Over short periods, CR lowers blood pressure, heart rate, and glucose levels, and improves memory in older individuals and measures of cognitive performance in animals. Over longer periods CR significantly reduces the risk for many different types of cancer, age-related brain atrophy, heart disease (and atherosclerosis related diseases), autoimmune disease, and adult onset diabetes. CR appears to lessen the risk for, and attenuates or even reverses the symptoms of Alzheimer's and possibly Parkinson's diseases; two major age-related neurodegenerative diseases that cause enormous human suffering. ... Interestingly, CR appears to promote the progression of Amyotrophic Lateral Sclerosis (Lou Gehrig's disease), indicating it does not protect from all human diseases. Aging causes extensive, often organ-specific changes in gene expression patterns. Analysis [has] shown that aging, calorically restricted mice show gene expression patterns resembling those of young animals, compared to ad libitum-fed mice of the same age. CR also lowers cellular oxidative damage by reducing mitochondrial oxygen free radical production, lessens age-related telomere shortening, lowers inflammation, increases DNA damage repair efficiency and lowers damage to DNA and RNA (thus promoting genomic stability), lowers insulin levels while promoting insulin sensitivity, reduces the number of senescent (non-dividing) cells that accumulate with aging, attenuates age-related cellular protein cross-linking, and increases the removal of damaged cellular proteins - a process called 'autophagy' which declines with age and plays a role in resistance to infection, cancer, heart disease, and neurodegeneration. "

Wednesday, April 4, 2012
An open access review paper: "Several studies suggest that an increase in adult neurogenesis has beneficial effects on emotional behavior and cognitive performance including learning and memory. The observation that aging has a negative effect on the proliferation of neural stem cells has prompted several laboratories to investigate new systems to artificially increase neurogenesis in senescent animals as a means to compensate for age-related cognitive decline. ... recent evidences indicate that the relative abundance of stem cells in certain organs does not necessarily correlate with their impact on organ function. Specifically, the mammalian brain is perhaps the organ with the lowest regenerative potential but the one in which the signs of aging are more manifested. Using the words of the renaissance writer Michel de Montaigne, 'age imprints more wrinkles on the mind than it does on the face' indicating that age-related cognitive decline has the highest impact on the quality of life. To which extent this decline is dependent on neural stem and progenitor cells (together referred to as NSCs) is hard to tell but growing evidences indicate that, despite their negligible numbers, the few resident NSCs that are located in specific brain regions, most notably the subgranular zone of the hippocampus, seem to play a major role in cognitive functions such as learning, memory, and emotional behavior by generating, through intermediate progenitors, neurons that are constantly added to the brain circuitry throughout life. ... the available data strongly suggests that aging almost exclusively acts at the level of NSC proliferation. Yet, the many contradicting results and uncertainties on identifying the exact causes of this 'decreased proliferation' [need] to be fully acknowledged in order to give a rigorous and meaningful direction to this relatively new field. ... The fact that NSCs can efficiently respond to physiological and pathological stimuli to increase neurogenesis indicates that stimulation of endogenous NSCs offers a promising alternative to transplantation approaches that until now were intensely investigated."

Tuesday, April 3, 2012
A look at some of the research aimed at reversing the damage caused by heart attacks: "Our ultimate hope is that, during the acute period following myocardial infarction (MI), patients will be able to receive direct injections of factors that transform the existing fibroblast cells in the 'scar' into new myocytes. The resulting increase in muscle mass should help MI survivors to live more normal lives. ... When heart muscle cells become injured and die following an MI, patients have the major problem that these cells have little or no capacity for regeneration. ... Part of the process of remodelling that occurs following the injury is that fibroblast cells migrate to the site and create the scar. ... The process at first can be considered beneficial since without fibroblasts adding structural support damaged hearts would rupture. But later difficulties arise when the fibrotic scar doesn't contract like the muscle it has replaced. Reduced global contractility means the heart has to work much harder, and the extra stress can ultimately lead to heart failure and even death. ... One of the Holy Grails of cardiovascular research has been to replace these lost myocytes and return functionality to the heart. Some of the first approaches to be investigated were the introduction of stem or progenitor cells to the sites of injury. ... But many hurdles have been encountered including getting cells to integrate with neighbouring cells in the heart, and there have been concerns that residual 'rogue' cells could persist with the potential to keep dividing and give rise to tumours. Harnessing the vast reservoir of fibroblasts already present in the heart, we felt, could overcome many of these issues. They've the big advantage they're already present in the organ and closely integrated with neighbouring cells. ... the team were able to identify three [genes] Gata4, Mef2c, and Tbx5 that could convert fibroblasts taken from the hearts of adult mice into new myocytes. ... In the second part of the study, the team injected fibroblasts that already had the three genes inserted directly into the scar tissue of mice. They were able to show the fibroblasts differentiated into cardiomyocyte-like cells. ... The fibroblasts converted into cells with nice patterns of striations, typical of myocytes, and developed units that could generate force. ... In the latest study [they] have been able to take the process one step further by injecting a viral vector encoding the genes for Gata4, Mef2c, and Tbx5 directly into the scar tissue of mice who had just experienced an MI. ... With these studies we've obtained even better results showing that the fibroblasts become more like cardiomyocytes and functionally couple with their neighbours. They could beat in synchrony and improve the function of the heart."

Tuesday, April 3, 2012
Via ScienceDaily: scientists "have shown in animal models that the loss of memory that comes with aging is not necessarily a permanent thing. ... [Researchers] took a close look at memory and memory traces in the brains of both young and old fruit flies. What they found is that like other organisms - from mice to humans - there is a defect that occurs in memory with aging. In the case of the fruit fly, the ability to form memories lasting a few hours (intermediate-term memory) is lost due to age-related impairment of the function of certain neurons. Intriguingly, the scientists found that stimulating those same neurons can reverse these age-related memory defects. ... This study shows that once the appropriate neurons are identified in people, in principle at least, one could potentially develop drugs to hit those neurons and rescue those memories affected by the aging process. In addition, the biochemistry underlying memory formation in fruit flies is remarkably conserved with that in humans so that everything we learn about memory formation in flies is likely applicable to human memory and the disorders of human memory. ... Olfactory memory, which was used by the scientists, is the most widely studied form of memory in fruit flies - basically pairing an odor with a mild electric shock. These tactics produce short-term memories that persist for around a half-hour, intermediate-term memory that lasts a few hours, and long-term memory that persists for days. The team found that in aged animals, the signs of encoded memory were absent after a few hours. In that way, the scientists also learned exactly which neurons in the fly are altered by aging to produce intermediate-term memory impairment. ... the scientists took the work a step further and stimulated these neurons to see if the memory could be rescued. To do this, the scientists placed either cold-activated or heat-activated ion channels in the neurons known to become defective with aging and then used cold or heat to stimulate them. In both cases, the intermediate-term memory was successfully rescued."

Monday, April 2, 2012
Via EurekAlert!: "injecting cardiovascular disease (CVD) patients with vaccines and monoclonal antibodies to combat atherosclerosis could soon change the treatment landscape of heart disease. Both approaches [can] be considered truly ground breaking since for the first time they target the underlying cause of CVD. ... with phase 2a trials on recombinant antibodies currently ongoing, [such] treatments could soon become a clinical reality. ... If all goes well, the first in class of these treatments could be licensed within four to five years ... Established therapies against atherosclerosis almost exclusively focus on risk factor modification - that is reduction of dyslipidaemia, hypertension and hyperglycaemia. ... It was in the early 1990s that identification of antibodies against oxidised low density lipoproteins (LDL) in artery plaques, first gave rise to the concept that CVD might be an autoimmune disease where the immune system attacks oxidised LDL. ... Since it is impractical to develop vaccines based on oxidised LDL (due to difficulty of standardising the particle) [researchers] looked to identify structures within the oxidised LDL that triggered the desired protective response. ... The team were able to identify three [peptides], which when formulated with a carrier and adjuvant, reduced development of atherosclerosis in mice by 60 to 70%. ... Further along the development pathway, and already in clinical trials, is an altogether different immune approach involving injection of antibodies directly targeting oxidised LDL. ... The rationale is that since oxidised LDL plays a major role in the development of atherosclerotic plaques and harmful inflammatory processes, directly targeting oxidised LDL should prevent plaque formation and reduce inflammation ... Preclinical studies show that administration of the BI-204 monoclonal antibody [reduced] the formation of atherosclerotic plaques and plaques already present by 50%. In the phase I study, which took place in 80 healthy volunteers with elevated levels of LDL, BI-204 was found to be safe and well tolerated. Now for the current phase 2a double blind [study], BI-204 is being delivered intravenously to 144 patients with stable coronary artery disease in addition to standard care."

Monday, April 2, 2012
Artificial cells will be useful tools in the medicine of tomorrow: "Daniel Hammer, professor of chemical engineering and biological engineering at the University of Pennsylvania, is building white blood cells in the lab from plastics that can act as artificial cell walls. Think of a gel capsule of your preferred headache medicine but on a much smaller scale and with a programmable molecular brain. These synthetic cells, known as leuko-polymersomes, could one day deliver the latest cancer-killing drugs directly to a tumor or send out a chemical beacon that signals natural white blood cells to come and join the fight against a disease. ... Ultimately I think that we could program these cells to do things that we never thought white blood cells could do ... Instead of boosting immune response, for example, Hammer envisions synthetic cells that could act as inhibitors to the body's defenses, providing relief for people suffering from autoimmune disorders. Hammer has been studying how to turn plastics into cellular structures for more than a decade, but it's just in the past few years that the field has kicked into high gear. His team is learning to mimic the targeting capabilities that let natural white blood cells take the fight to viruses and bacteria - what Hammer describes as a kind of 'molecular zip coding' - and the adhesive properties that let them stand their ground when they arrive. In 2010, Hammer and colleagues from Duke University designed synthetic molecules shaped like the receptors white blood cells use to find and adhere to inflamed tissue. In-vitro tests showed that synthetic cells could seek out inflamed tissue and stick to it once they arrived."



Does somebody know if there is still an opinion of reducing the need for the amount of sleep by way of dopamine enhancing drugs being one of the life extention stratagies still under consideration.

Posted by: Ronald Marullo at April 9th, 2012 2:33 PM

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