Fight Aging! Newsletter, November 14th 2011

November 14th 2011

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!



- More SENS5 Presentation Videos
- A Certain Frustration
- Quantifying the Beneficial Effects of Exercise on the Brain
- Betrayed By Your Own Biology
- Pointing Toward Naked Mole Rat Mitochondria
- Discussion
- Latest Headlines from Fight Aging!


A few more videos from the SENS5 conference on longevity science, held earlier this year. These address cellular senescence in fat tissue and the damage it does, and the prospects for using myostatin-based therapies to engineer muscle regrowth and thus reverse the general decline in muscle mass and strength that occurs with age:


Advocacy for a cause has its ups and downs:

"The best communities involved in advocacy and outreach are balanced somewhere between eagerness ('It's all so obvious, look what we could achieve!') and frustration ('But it's all so obvious - why don't they get it?'). Advocacy is hard despite its simplicity and time-worn, well-understood nature: it is hard because it is slow and incremental toil at the best of times, the human relations equivalent of banging two rocks together to make fire. You talk to people, you persuade people to your way of looking at things over and over and over again, making tiny little gains each time. For longevity science, the people willing to do this work are generally the bright sparks, the early adopters and foresightful folk who see the opportunity to defeat aging, see how plausible it is, and are full of enthusiasm for this goal. They are then run into the meatgrinder of tiny, incremental progress in persuading the world one person at a time. Occasionally this isn't pretty, and hence the frustration. None of us are getting any younger, and while the science is so very obviously heading the right direction to produce working rejuvenation biotechnology, it is doing so very, very slowly. Only a minuscule fraction of the scientific community are working on relevant projects, there is next to no funding, and only a minuscule fraction of the public at large care one way or another. That needs to change, and changing it is slow going."


Exercise is good for your long term health, and researchers can increasingly tell you exactly why this is the case:

"Armed with newer, cheaper, and better biotechnologies, researchers can measure ever more of the detailed effects of good health practices such as regular exercise, calorie restriction, and the like. It is possible now to examine the workings of metabolism in any specific part of the body in very great detail, all the way down to the molecular machinery in our cells, see how it changes with age, and see how those changes differ with different lifestyle choices. ... Healthy brain aging and cognitive function are promoted by exercise. The benefits of exercise are attributed to several mechanisms, many which highlight its neuroprotective role via actions that enhance neurogenesis, neuronal morphology and/or neurotrophin release. However, the brain is also composed of glial and vascular elements, and comparatively less is known regarding the effects of exercise on these components in the aging brain. Here, we show that aerobic exercise at mid-age [also] counters several well-established glial markers of brain aging. Similarly, we show that age-related changes in neurovascular morphology and function were reduced with exercise. ... Thus, our results show that exercise can potentially mitigate progressive age-related changes in several key non-neuronal elements of the brain. Further, we show that these brain processes are still highly responsive to exercise in the midlife age range, consistent with studies showing that cognitive function can benefit from exercise even if initiated at later ages."


The future is a business of odds and probabilities, and that includes the matter of your health and longevity. You can do everything right and still get the short end of the stick through some unhappy accident - but that's no excuse to make things worse for yourself by not doing your best to swing the odds in your favor:

"you have the power to shape that statistical landscape through good lifestyle choices and strategies such as helping to fund research into rejuvenation biotechnology and signing up with a cryonics provider - but nothing is a certainty. You can shift your chances, shift your life expectancy (itself a statistical measure), but you can't entirely remove happenstance and sheer bad luck. You are far better off by making and following good plans, but bad end results are still possible. For example, even someone who signs up to be cryopreserved and does a good job of managing the organization of his own cryosuspension at the end of life can still be cut short by bad luck:

"Suspended Animation (SA) went to the hospital and began to prepare for a probable cryonics case. Through medical imaging on October 30, physicians determined the individual's brain damage [due to a massive intracerebral hemorrhagic stroke] was so extensive they declared him brain-dead. After the family decided to withdraw life support, SA performed field stabilization and attempted washout; however their success was limited due to the compromised blood flow of the brain. SA completed a neuroseparation before shipping the anatomical donation on dry ice to Alcor.

"It's important to recognize that, despite best reasonable efforts, the possibility remains that we are going to be betrayed by our own biology in the end. The quote above is an unfortunate example of the type, in which the patient suffered a brain-damaging end of life incident that will greatly reduce the possibility of a good cryopreservation - and that despite high quality support from medical staff and everyone else involved in organizing the response. ... So the best preparation in the world can be sabotaged by the body breaking down in exactly the wrong way at the end of life. All we can do is strive to minimize the risks."


More genetic research on long-lived naked mole rats points toward the mitochondria and factors affecting oxidative damage of the mitochondria as important factors in aging:

"Naked mole rats are of interest to researchers because they can live nine times as long as comparable rodent species: this implies that they are a good place to look for determinants of longevity and important mechanisms of aging. You can go far in biology by comparing similar species that nonetheless exhibit sharply defined differences in your area of interest. The naked mole rat genome was sequenced and published this year, but research into the genetics of aging in the species that predates the availability of the full genome is still arriving at the presses.

"Using a combination of 2nd-generation sequencing platforms, [we] were able to compare gene expression between wild-derived mice and naked mole-rats without using a naked mole-rat reference genome. ... Within over-expressed genes in the naked mole-rat, genes associated with oxidoreduction were strongly overrepresented as well as genes associated with mitochondria and more specifically mitochondrial matrix. Consistent with the free radical theory of ageing, the over-expression of genes related to oxidoreduction could protect the naked mole-rat from reactive oxygen species. [With caveats, and] in view of the hypothesis that mitochondria play a major role in mammalian ageing, these results point towards a putative role for oxidoreduction and mitochondrial alterations in the long lifespan of the naked mole-rat."

You might look at the membrane pacemaker theory of longevity for more background on why mitochondria are likely important here:


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, November 11, 2011
Via EurekAlert!: researchers "created super strong, marathon mice and nematodes by reducing the function of a natural inhibitor, suggesting treatments for age-related or genetically caused muscle degeneration are within reach. It turns out that a tiny inhibitor may be responsible for how strong and powerful our muscles can be. ... By acting on a receptor (NCoR1), [researchers] were able to modulate the transcription of certain genes, creating a strain of mighty mice whose muscles were twice a strong as those of normal mice. ... By genetically manipulating the offspring of [mice and nematodes], the researchers were able to suppress the NCoR1 corepressor, which normally acts to inhibit the buildup of muscle tissues. ... In the absence of the inhibitor, the muscle tissue developed much more effectively. The mice with the mutation became true marathoners, capable of running faster and longer before showing any signs of fatigue. In fact, they were able to cover almost twice the distance run by mice that hadn't received the treatment. They also exhibited better cold tolerance. Unlike previous experiments with so-called super mice, this study addresses the way energy is burned in the muscle and the way the muscle is built. Examination under a microscope confirmed that the muscle fibers of the modified mice are denser, the muscles are more massive, and the cells in the tissue contain higher numbers of mitochondria - cellular organelles that deliver energy to the muscles. Similar results were also observed in nematode worms, allowing the scientists to conclude that their results could be applicable to a large range of living creatures."

Friday, November 11, 2011
Michael Rae is the co-author of Ending Aging, a research assistant at the SENS Foundation, and a long-standing figure of note in the calorie restriction community: "I would say that one exciting recent development is that, with an increase in our research budget this year (based on performance last year and a more optimistic financial outlook from many of our donors), we've recently approved funding for several quite important and exciting research projects. One is a project whose ultimate aim is to tissue engineer a new thymus. The thymus is a gland located near the breast bone, where T-cells (an important immune cell) mature. The thymus shrinks with age, and the tissues on the outer layer of the organ where T-cells mature lose their architectural integrity, leading to a progressive failure to produce new T-cells to fight novel infections. The thymus engineering project, which is underway with SENS Foundation support at the Wake Forest University Institute for Regenerative Medicine by Dr. John Jackson and colleagues, is to use a trick that you may have heard of having been used to make a new rat heart using the tissue scaffolding of another's. ... The fifth SENS Conference was, indeed, quite amazing! Unlike the previous conference, this time much more of the work being presented had already been published; it was none the less remarkable to see just how much had been accomplished in the last year, from restoring cognitive function in a mouse model of Alzheimer's disease using a drug that boosted up the ability of their brains' lysosomes ('garbage disposal systems' as it were) to break down the sticky beta-amyloid protein [to] a just-begun study on a very bold and ambitious way [to] restore the loss of cells and degraded circuitry of the aging neocortex (the area of the brain where, arguably, our highest, most 'human' cognitive activity occurs)."

Thursday, November 10, 2011
A good demonstration of the state of the art of tissue engineering: "Last spring, a research team at Japan's RIKEN Center for Developmental Biology created retina-like structures from cultured mouse embryonic stem cells. This week, the same group reports that it's achieved an even more complicated feat - synthesizing a stem-cell-derived pituitary gland. The pituitary gland is a small organ at the base of the brain that produces many important hormones and is a key part of the body's endocrine system. It's especially crucial during early development, so the ability to simulate its formation in the lab could help researchers better understand how these developmental processes work. ... The experiment wouldn't have been possible without a three-dimensional cell culture. The pituitary gland is an independent organ, but it can't develop without chemical signals from the hypothalamus, the brain region that sits just above it. With a three-dimensional culture, the researchers could grow both types of tissue together, allowing the stem cells to self-assemble into a mouse pituitary. ... Using this method, we could mimic the early mouse development more smoothly, since the embryo develops in 3-D in vivo. ... Fluorescence staining showed that the cultured pituitary tissue expressed the appropriate biomarkers and secreted the right hormones. The researchers went a step further and tested the functionality of their synthesized organs by transplanting them into mice with pituitary deficits. The transplants were a success, restoring levels of glucocorticoid hormones in the blood and reversing behavioral symptoms, such as lethargy."

Thursday, November 10, 2011
Tengion is one of the research groups attempting to tissue engineer replacement sections of intestine: "Tengion has demonstrated that smooth muscle cells seeded on its biological scaffolding and then implanted in rodents exhibit functional regeneration of both the inner lining of epithelial cells and the surrounding layers of small intestine smooth muscle cells in as little as eight weeks post-implantation. ... The regeneration of small intestine from smooth muscle cells using our technology platform represents an important step forward in the development of functional, regenerated organs. Our goal is to translate preclinical data and proof of concept findings into clinical programs that could represent a broad range of medical treatment possibilities for patients in need of new bladders, kidneys and other organs. ... In this preclinical study, patch and tubular constructs were implanted in rodent small intestines and histologically evaluated for evidence of regeneration of the neo-mucosa and muscle layers. In as little as eight weeks post-implantation, laminarly organized neo-mucosa and muscle layer bundles were demonstrated, supporting the approach of using autologous smooth muscle cells and biomaterial combination products to spur regeneration of the small intestine. Patients with short bowel syndrome have typically undergone extensive small intestine resectioning and may become dependent on parenteral nutrition, a costly treatment associated with multiple complications, and could potentially benefit from a regenerative medicine approach."

Wednesday, November 9, 2011
A good example of the next generation of targeted cancer therapies is outlined at the Technology Review: "scientists at the National Cancer Institute have developed a possible solution that involves pairing cancer-specific antibodies with a heat-sensitive fluorescent dye. The dye is nontoxic on its own, but when it comes into contact with near-infrared light, it heats up and essentially burns a small hole in the cell membrane it has attached to, killing the cell. To target the tumor cells, the researchers used antibodies that bind to proteins that are overexpressed in cancer cells. ... Normal cells may have a hundred copies of these antibodies, but cancer cells have millions of copies. That's a big difference. ... The result is that only cancer cells are vulnerable to the light-activated cascade. ... The researchers tested the new treatment in mice and found that it reduced tumor growth and prolonged survival. There are a few kinks to work out before the system can be adapted for humans, though. For instance, the researchers couldn't test the treatment's effect on large tumors, since killing off too many cells at once caused cardiovascular problems in the mice. Finding the right cancer-cell markers to pair with the dye may also prove difficult. For example, HER-2, one of the proteins targeted in the study, is only expressed in 40 percent of breast-cancer cells in humans. Still, the lack of toxicity associated with the treatment is a huge advantage,"

Wednesday, November 9, 2011
A human interest piece on research into the genetics and biochemistry of centenarians amongst the Ashkenazi Jewish population: "Irving Kahn is about to celebrate his 106th birthday. He still goes to work every day. Scientists are studying him and several hundred other Ashkenazim to find out what keeps them going. And going. And going. ... The world's oldest stockbroker, he first went to work on Wall Street in 1928. ... Still, a man who at 105 - he'll be 106 on December 19 - has never had a life-threatening disease, who takes no cholesterol or blood-pressure medications and can give himself a clean shave each morning (not to mention a 'serious sponge bath with vigorous rubbing all around'), invites certain questions. Is there something about his habits that predisposed a long and healthy life? (He smoked for years.) Is there something about his attitude? (He thinks maybe.) Is there something about his genes? (He thinks not.) And here he cuts me off. He's not interested in his longevity. But scientists are. ... Pharmaceutical companies and the National Institutes of Health are throwing money into longevity research. Major medical centers have built programs to satisfy the demand for data and, eventually, drugs. Irving himself agreed to have his blood taken and answer questions for the granddaddy of these studies, the Longevity Genes Project at Albert Einstein College of Medicine in the Bronx, which seeks to determine whether people who live healthily into their tenth or eleventh decade have something in common - and if so, whether it can be made available to everyone else."

Tuesday, November 8, 2011
Yet another reason to try to minimize chronic inflammation, such as that generated by excess fat tissue: researchers "have shown that the development of osteoarthritis is in great part driven by low-grade inflammatory processes. This is at odds with the prevailing view attributing the condition to a lifetime of wear and tear on long-suffering joints. ... It's a paradigm change. People in the field predominantly view osteoarthritis as a matter of simple wear and tear, like tires gradually wearing out on a car. [It] also is commonly associated with blow-outs [such] as a tear in the meniscus - a cartilage-rich, crescent-shaped pad that serves as a shock-absorber in joints - or some other traumatic damage to a joint. ... [The] findings offer hope that by targeting the inflammatory processes that occur early on in the development of osteoarthritis - well before it progresses to the point where symptoms appear - the condition might someday be preventable. ... initial damage to the joint sets in motion a chain of molecular events that escalates into an attack upon the damaged joint by one of the body's key defense systems against bacterial and viral infections, the so-called complement system. This sequence of events involves activation of a chain reaction called the 'complement cascade,' and begins early in the development of osteoarthritis. ... An early clue regarding the complement system's key role in osteoarthritis came when [researchers] compared the levels of large numbers of proteins present in the joint fluid taken from osteoarthritis patients with levels present in fluid from healthy individuals. They found that the patients' tissues had a relative overabundance of proteins that act as accelerators in the complement cascade, along with a dearth of proteins that act as brakes."

Tuesday, November 8, 2011
Here's a long and detailed post from the SENS Foundation on the recent demonstration of the benefits of senescent cell destruction: "studies involving the use of putative 'premature aging' models must be interpreted with caution ... In the case of this new report, however, while caution is still merited, the nature of the intervention used makes the study relatively free of such complications. The investigators did not simply modulate or normalize the very thing that the mutation (in this case, to the mitotic checkpoint component BubR1) itself disrupts, as in other widely-publicized studies involving putative 'accelerated aging'. Rather, the defective checkpoint system was left to proceed, and one of its downstream consequences, which was still under normal regulation - and one known to be directly induced by the normal degenerative aging process - was reversed at the structural level, by clearing out the p16Ink4a-positive senescent cells that had accumulated to an abnormal degree in their tissues. This left some aspects of the abnormal 'progeroid' phenotype in these organisms (the cardiovascular defects) intact, but illustrated the dysfunctional consequences of having tissues riddles with such cells. While still of abnormal origin, there is no strong reason to think that the ongoing effects of a rising burden of such cells would not be similar - and thus, that the effects of ablating such cells are uninformative about the effects of a similar intervention in 'normally' aging bodies. ... How might the results of this intervention be translated for human rejuvenation therapies? ... SENS Foundation is currently funding work by Dr. Kevin Perrot in Campisi's laboratory, screening compounds for their effectiveness in eliminating cells exhibiting the classical senescence-associated secretory phenotype."

Monday, November 7, 2011
News of more incremental progress towards a cell transplant therapy to treat Parkinson's: "Parkinson's disease takes hold as cells that produce dopamine die off in part of the brain called the substantia nigra. This causes tremors, rigidity and slowness of movement, though patients may also experience tiredness, pain, depression and constipation, which worsen as the disease progresses. ... Brain cells that die off in Parkinson's disease have been grown from stem cells and grafted into monkeys' brains in a major step towards new treatments for the condition. US researchers say they have overcome previous difficulties in coaxing human embryonic stem cells to become the neurons killed by the disease. Tests showed the cells survive and function normally in animals and reverse movement problems caused by Parkinson's in monkeys. The breakthrough raises the prospect of transplanting freshly grown dopamine-producing cells into human patients to treat the disease. ... Previously we did not fully understand the particular signals needed to tell stem cells how to differentiate into the right type of cells. The cells we produced in the past would produce some dopamine but in fact were not quite the right type of cell, so there were limited improvements in the animals. Now we know how to do it right, which is promising for future clinical use."

Monday, November 7, 2011
Here's a better overview of recent research that demonstrates the benefits of destroying senescent cells: "Baker exploited the fact that many senescent cells rely on a protein called p16-Ink4a. He created a genetic circuit that reacts to the presence of p16-Ink4a by manufacturing an executioner: a protein called caspase-8 that kills its host cell. Caspase-8 is like a pair of scissors - it comes in two halves that only work when they unite. Baker could link the two halves together using a specific drug. By sneaking the drug into a mouse's food, he activated the executioners, which only killed off the cells that have lots of p16-Ink4a. Only the senescent ones get the chop. Baker tested out this system in a special strain of genetically engineered mice that age very quickly. It worked. The senescent cells disappeared, and that substantially delayed the onset of muscle loss, cataracts, and fat loss. Typically, around half of these mice show signs of muscle loss by five months of age. Without their senescent cells, only a quarter of them showed the same signs at ten months. Their muscle fibres were larger, and they ran further on treadmills. Even old mice, whose bodies had started to decline, showed improvements. ... There's been a question of whether senescent cells are important, since they're only a small proportion of cells. Our work indicates that a small number of these cells can have a big impact."



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