FIGHT AGING! NEWSLETTER
September 26th 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 Conference Material
- Peering at the Proteasome
- Sirtuins Come to a Dead End?
- Latest Headlines from Fight Aging!
MORE SENS5 CONFERENCE MATERIAL
A modest collection of further notes and videos from SENS5 can be found in the following Fight Aging! posts:
Dr. Laura Niklasson from Yale University is working on lung engineering. Human lung is an extremely complicated organ. There's 23 generations of branching of airways, they are up to 200 microns in diameter. 70 square meters for gas exchange. More than 100 million air sacks all together. Engineered lung must have right mechanical properties, autologous cells, adequate surface area for gas exchange and adequate barrier to prevent flooding of airways with blood constituents after implantation. ... Scientists implanted engineered half lung in a rat. It was 95% as efficient as a native lung in terms of gas exchange. But in several hours they got thrombosis. Also they saw a little bit of blood cells in airways, so the barrier was not perfect. After being improved this technique can be used to engineering human lungs. ... John Jackson gave a beautiful overview of thymic involution and told us about the ongoing experiments in the Wake Forest Institute for Regenerative Medicine on thymus engineering. ... I personally found the talk by Dr. Charles Greer the most fascinating one. Aparently, there is a subsytem in our brain that is constantly regenerating. The rate and quality of this regeneration process doesn't decline with age. It's the olfactory system. Sensory neurons in olfactory system die every 6-8 weeks. Neurogenesis is constant. New neurons come from the subventricular zone. It's like a river of migrating neurons to olfactory bulb."
PEERING AT THE PROTEASOME
The proteasome is one of the recycling mechanisms that toils to keep the interior of our cells free from broken and unwanted proteins. This sort of activity is known to be an important determinant of the pace of aging and length of life span in a variety of activities: aging is damage, and the more broken parts left to afflict the operation of your cellular machinery, the worse off you are.
"You might have noticed recent investigations into exactly how embryos generated by an old collection of cells - people like you and I - turn out to be made of young cells. After all, every other clump of cells we generate is also old. ... The researchers involved in this latest research into embryonic development think that the proteasome is the root of this profound embryonic damage repair process. ... the level of protein damage was relatively high in the embryo's unspecified cells, but then it decreased dramatically. A few days after the onset of cell differentiation, the protein damage level had gone down by 80-90 percent. We think this is a result of the damaged material being broken down. ... If we're lucky there's a potent life-extending therapy in there somewhere, but of course the odds are good that the process by which the early embryo repairs most of its damage is tightly bound to the embryonic nature of its cellular machinery and will be somewhere between very challenging and next to impossible to safely apply to organized, differentiated structures of adult cells. The difference between 'very challenging' and 'next to impossible' is probably about twenty years of technological development in this era - but we shall see. This seems worth watching."
SIRTUINS COME TO A DEAD END?
You might have noticed the recent press coverage of sirtuin research; it is looking ever more likely that sirtuins, while being one of the first identified components of biochemistry altered by calorie restriction, are not in fact a useful point of manipulation.
"Sirtuins are most likely a dead end, or more charitably a stepping stone for researchers seeking after the mechanisms that link natural variations in metabolism to natural variations in life span, especially those induced by the practice of calorie restriction. It was one of the earliest identified pieces of the puzzle, but possibly not a useful piece in the final analysis. This has become increasingly likely as an outcome over the years as meaningful results failed to emerge from drug development based on the manipulation of sirtuins. But this happens all the time: it's larger than usual news in the scientific community only, I think, because very large sums of money have moved into this line of research over the past years, and it's one of the earliest threads that might have led to drugs that modestly slowed aging.
"The idea that sirtuins promote longevity appeals to scientists because of experiments that were started in yeast and repeated in two other standard laboratory organisms, the roundworm and the fruit fly. It is these foundation experiments that have now come under attack by David Gems and Linda Partridge, researchers on aging at University College London. In an article published Wednesday in the journal Nature, they and colleagues have re-examined experiments in which roundworms and flies, genetically manipulated to produce more sirtuin than normal, were reported to live longer. Both experiments were flawed, they say, because the worms and flies used as a control were not genetically identical to the test organisms. The London researchers report that they have repeated the experiments with proper controls and found that extra sirtuin does not, after all, make the worms or flies live longer."
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!
TOWARDS A BETTER UNDERSTANDING OF NERVE REPAIR
Friday, September 23, 2011
Via ScienceDaily: researchers "have identified more than 70 genes that play a role in regenerating nerves after injury, providing biomedical researchers with a valuable set of genetic leads for use in developing therapies to repair spinal cord injuries and other common kinds of nerve damage such as stroke. ... the scientists detail their discoveries after an exhaustive two-year investigation of 654 genes suspected to be involved in regulating the growth of axons - the thread-like extensions of nerve cells that transmit electrical impulses to other nerve cells. ... We don't know much about how axons re-grow after they're damaged. When you have an injury to your spinal cord or you have a stroke you cause a lot of damage to your axons. And in your brain or spinal cord, regeneration is very inefficient. That's why spinal cord injuries are basically untreatable. ... While scientists in recent decades have gained a good understanding of how nerve cells, or neurons, develop their connections in the developing embryo, much less is known about how adult animals and humans repair - or fail to repair - those connections when axons are damaged. ... Of particular interest [are] the six genes that appear to repress the growth of axons. ... The discovery of these inhibitors is probably the most exciting finding [because] identifying and eliminating the inhibiting factors to the re-growth of axons could be just as essential as the biochemical pathways that promote axon re-growth in repairing spinal cord injuries and other kinds of nerve damage."
MORE ON THE STATE OF SIRTUIN RESEARCH
Friday, September 23, 2011
From In the Pipeline: "I'd say that the whole sirtuin story has split into two huge arguments: (1) arguments about the sirtuin genes and enzymes themselves, and (2) arguments about the compounds used to investigate them, starting with resveratrol and going through the various sirtuin activators reported by Sirtris, both before and after their (costly) acquisition by GlaxoSmithKline. That division gets a bit blurry, since it's often those compounds that have been used to try to unravel the roles of the sirtuin enzymes, but there are ways to separate the controversies. I've followed the twists and turns of argument #2, and it has had plenty of those. It's not safe to summarize, but if I had to, I'd say that the closest thing to a current consensus is that (1) resveratrol is a completely unsuitable molecule as an example of a clean sirtuin activator, (2) the earlier literature on sirtuin activation assays is now superseded, because of some fundamental problems with the assay techniques, and (3) agreement has not been reached on what compounds are suitable sirtuin activators, and what their effects are in vivo. It's a mess, in other words. But what about argument #1, the more fundamental one about what sirtuins are in the first place? That's what these latest results address, and boy, do they ever not clear things up. There has been persistent talk in the field that the original model-organism life extension effects were difficult to reproduce, and now two groups (those of David Gems and Linda Partridge) at University College, London (whose labs I most likely walked past last week) have re-examined these. They find, on close inspection, that they cannot reproduce them. ... It's important to keep in mind that these aren't the first results of this kind. Others had reported problems with sirtuin effects on lifespan (or sirtuin ties to caloric restriction effects) in yeast, and as mentioned, this had been the stuff of talk in the field for some time. But now it's all out on the table, a direct challenge."
OUR BIOLOGY ALREADY ACCOMPLISHES REJUVENATION
Thursday, September 22, 2011
No-one should be surprised by the plausibility of rejuvenation biotechnology, as old people create young children, and only a tiny hint of the damage that makes people old seeps through that process. So we know that there exist ways for cells and larger structures to extremely effectively manage their level of damage - and some of the explorers in stem cell science have already recreated these processes outside their normal context. Here is a further exploration of what happens when old animals create young animals: "Although the body is constantly replacing cells and cell constituents, damage and imperfections accumulate over time. Cleanup efforts are saved for when it really matters. ... I have a daughter. She is made of my cells yet has much less cellular damage than my cells. Why didn't she inherit my cells including the damaged proteins? That's the process I'm interested in. ... A few days after conception, the cells in the embryo all look the same - they are unspecified stem cells that can develop into any bodily cell type. As the process of cell specification (differentiation) begins, they go from being able to keep dividing infinitely to being able to do so only a limited number of times. This is when they start cleansing themselves. ... Quite unexpectedly we found that the level of protein damage was relatively high in the embryo's unspecified cells, but then it decreased dramatically. A few days after the onset of cell differentiation, the protein damage level had gone down by 80-90 percent. We think this is a result of the damaged material being broken down. ... In the past, researchers have believed that the body keeps cells involved in reproduction isolated and protected from damage. Now it has been shown that these types of cells go through a rejuvenation process that rids them of the inherited damage." Can this process be isolated and applied safely to ordinary cells elsewhere in the body? Time will tell, but it's a worthy goal to aim for given its demonstrated effectiveness.
THE POTENTIAL TO GROW IMMUNE CELLS TO ORDER
Thursday, September 22, 2011
One possible form of future immune therapy involves growing vast numbers of tailored immune cells, far more than would ever naturally be present in the body, and then infusing them to sweep away the target problem - cancer being an early target for this sort of approach. Here is some groundwork for these future therapies: "Adult stem cells from mice converted to antigen-specific T cells - the immune cells that fight cancer tumor cells - show promise in cancer immunotherapy and may lead to a simpler, more efficient way to use the body's immune system to fight cancer ... Tumors grow because patients lack the kind of antigen-specific T cells needed to kill the cancer. An approach called adoptive T cell immunotherapy generates the T cells outside the body, which are then used inside the body to target cancer cells. ... It is complex and expensive to expand T cell lines in the lab, so researchers have been searching for ways to simplify the process. [They] found a way to use induced pluripotent stem (iPS) cells, which are adult cells that are genetically changed to be stem cells. ... Any cell can become a stem cell. It's a very good approach to generating the antigen-specific T cells and creates an unlimited source of cells for adoptive immunotherapy. ... By inserting DNA, researchers change the mouse iPS cells into immune cells and inject them into mice with tumors. After 50 days, 100 percent of the mice in the study were still alive, compared to 55 percent of control mice, which received tumor-reactive immune cells isolated from donors."
Wednesday, September 21, 2011
A general interest article on supercentenarians from the Sacramento Bee: "Avice Nelson Clarke paused in her recollections of her long-ago childhood in England to make a remarkable understatement. 'I've seen lots of life already,' she said. At 111, with memories spanning the horse-and-buggy age, the Space Age and the digital age, she is on the outside edge of the nation's trend toward increasing longevity. The oldest old - supercentenarians, as aging experts refer to them - remain rare: Clarke is one of four Sacramento-region residents who reported their ages as 110 or older in the 2010 U.S. census. ... The census recorded a total of 46 Californians in the supercentenarian category. Another 27 people in the Sacramento region reported their ages as 105 to 109, census figures show. While the number of centenarians has boomed in recent decades 96,000 across the country in 2010, according to the Social Security Administration, up from 37,000 only 20 years ago the nation's population of people 110 and older has remained fairly stable. ... The world's verified oldest person ever, Jeanne Calment, died in France in 1997, age 122 years and 164 days. ... Despite the world's aging population, no one's come close to that since then. That speaks to the limits of the human life span. ... Through blood tests and gene sequencing of the oldest old, scientists want to discover the secret of their extraordinary longevity ... How have they managed to live so long? We think their longevity is inherited. They have virtually nothing else in common. Some are smokers, and some never smoked. Some are drinkers, and some never drank. They don't have the same diets. But they have long-lived parents and siblings. It must be in the DNA. ... The key age is the early 80s for men and 90 for women. If you can get to that age without dementia or major heart disease or stroke, it's the idea of getting over the hump into healthy aging. ... Even so, 40 percent of the oldest old [survive] illnesses that prove fatal to others. ... Maybe they have some kind of functional reserve. The people who live the longest seem better able to deal with illness. They have a propensity to remain independent much longer than the rest of us."
RESTORING THE REGENERATIVE POWER OF OLD STEM CELLS
Wednesday, September 21, 2011
A possible road to rejuvenating some portions of the declining mechanisms of tissue regeneration in the old: "The regenerative power of tissues and organs declines as we age. The modern day stem cell hypothesis of aging suggests that living organisms are as old as are its tissue specific or adult stem cells. Therefore, an understanding of the molecules and processes that enable human adult stem cells to initiate self-renewal and to divide, proliferate and then differentiate in order to rejuvenate damaged tissue might be the key to regenerative medicine and an eventual cure for many age-related diseases. ... We demonstrated that we were able to reverse the process of aging for human adult stem cells by intervening with the activity of non-protein coding RNAs originated from genomic regions once dismissed as non-functional 'genomic junk' ... adult stem cells undergo age-related damage. And when this happens, the body can't replace damaged tissue as well as it once could, leading to a host of diseases and conditions. ... The team began by hypothesizing that DNA damage in the genome of adult stem cells would look very different from age-related damage occurring in regular body cells. ... They compared freshly isolated human adult stem cells from young individuals, which can self-renew, to cells from the same individuals that were subjected to prolonged passaging in culture. This accelerated model of adult stem cell aging exhausts the regenerative capacity of the adult stem cells. Researchers looked at the changes in genomic sites that accumulate DNA damage in both groups. ... We found the majority of DNA damage and associated chromatin changes that occurred with adult stem cell aging were due to parts of the genome known as retrotransposons ... By suppressing the accumulation of toxic transcripts from retrotransposons, we were able to reverse the process of human adult stem cell aging in culture." The next step would be to look at this process in old animals, and see what happens when it is reversed.
EXERCISE BOOSTS MITOCHONDRIA IN THE BRAIN AS WELL AS IN MUSCLES
Tuesday, September 20, 2011
Yet another benefit of regular exercise: "Researchers have long known that regular exercise increases the number of organelles called mitochondria in muscle cells. Since mitochondria are responsible for generating energy, this numerical boost is thought to underlie many of the positive physical effects of exercise, such as increased strength or endurance. Exercise also has a number of positive mental effects, such as relieving depression and improving memory. However, the mechanism behind these mental effects has been unclear. In a new study in mice, [researchers] have discovered that regular exercise also increases mitochondrial numbers in brain cells, a potential cause for exercise's beneficial mental effects. ... The researchers assigned mice to either an exercise group, which ran on an inclined treadmill six days a week for an hour, or to a sedentary group, which was exposed to the same sounds and handling as the exercise group but remained in their cages during the exercise period. ... Confirming previous studies, the results showed that mice in the exercise group had increased mitochondria in their muscle tissue compared to mice in the sedentary group. However, the researchers also found that the exercising mice also showed several positive markers of mitochondria increase in the brain ... The study authors note that this increase in brain mitochondria may play a role in boosting exercise endurance by making the brain more resistant to fatigue, which can affect physical performance. They also suggest that this boost in brain mitochondria could have clinical implications for mental disorders, making exercise a potential treatment for psychiatric disorders, genetic disorders, and neurodegenerative diseases."
NEURONS FROM BONE MARROW
Tuesday, September 20, 2011
Via EurekAlert!: "The ability to produce neuroprotectors, proteins that protect the human brain against neurodegenerative disorders such as Parkinson's and ALS, is the holy grail of brain research. A technology developed at Tel Aviv University does just that, and it's now out of the lab and in hospitals to begin clinical trials with patients suffering from amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease. ... the technology is now a patent-pending process that takes stem cells from a patient's own bone marrow and causes them to differentiate into astrocyte-like cells, which are responsible for the well-being of the brain's neurons. The cells release neurotrophic factors, or neuroprotectants, which have been shown to play a key role in reducing the progress of ALS, a debilitating disease characterized by the progressive degeneration of motor neurons, resulting in paralysis of a patient's limbs and organ function. ... In the mouse model, we were able to show that the bone marrow derived stem cells prevent degeneration in the brain following injection of selective neurotoxins. ... Researchers also demonstrated that transplantation of these cells increased the survival rate in the mouse model of ALS and significantly delayed the progress of motor dysfunction. ... The technology was licensed to BrainStorm Cell Therapeutics that has developed it into a clinical grade product called NurOwn, which is now being used in a clinical trial at Jerusalem's Hadassah Medical Center. BrainStorm Cell Therapeutics has recently struck an agreement to expand clinical trials to Massachusetts General Hospital in collaboration with the University of Massachusetts Medical School."
AEROBIC CAPACITY PREDICTS LIFESPAN IN MICE
Monday, September 19, 2011
Another study that points to the value of regular exercise: "Low aerobic exercise capacity is a powerful predictor of premature morbidity and mortality for healthy adults as well as those with cardiovascular disease. For aged populations, poor performance on treadmill or extended walking tests indicates closer proximity to future health declines. Together, these findings suggest a fundamental connection between aerobic capacity and longevity. ... Through artificial selective breeding, we developed an animal model system to prospectively test the association between aerobic exercise capacity and survivability (aerobic hypothesis). ... Laboratory rats of widely diverse genetic backgrounds [were] selectively bred for low or high intrinsic (inborn) treadmill running capacity. Cohorts of male and female rats from generations 14, 15, and 17 of selection were followed for survivability and assessed for age-related declines in cardiovascular fitness including maximal oxygen uptake (VO(2max)), myocardial function, endurance performance, and change in body mass. Median lifespan for low exercise capacity rats was 28% to 45% shorter than high capacity rats. VO(2max), measured across adulthood was a reliable predictor of lifespan. During progression from adult to old age, left ventricular myocardial and cardiomyocyte morphology, contractility, and intracellular Ca(2+) handling in both systole and diastole, as well as mean blood pressure, were more compromised in rats bred for low aerobic capacity. Physical activity levels, energy expenditure (Vo(2)), and lean body mass were all better sustained with age in rats bred for high aerobic capacity."
LINKING AGING, TELOMERE LENGTH, AND CALORIE RESTRICTION
Monday, September 19, 2011
Researchers establish a link between calorie restriction, aging, and telomere length in yeast, but one which poses more questions than it answers: "Dietary restriction promotes longevity in many species, ranging from yeast to primates, and delays aging-related pathologies including cancer in rodent models. There is considerable interest in understanding how nutrient limitation mediates these beneficial effects. Much of what we have learned about the genetics of aging comes from studying isogenic model organisms, where the effects of single gene changes can be examined independently of other genetic alterations. In order to explore a broader spectrum of genetic variation and to gain insight into aging-related phenotypes as polygenic traits, we analyzed the chronological lifespan of 122 S. cerevisiae strains derived from a cross between laboratory and vineyard yeast strains. The major genetic locus controlling chronological lifespan was found to be identical to a previously mapped locus that controls telomere length. Identification of the responsible polymorphism in BUL2, a gene involved in controlling amino acid permeases, allowed us to establish a previously unrecognized link among cellular amino acid intake, chronological aging, and telomere maintenance. While human epidemiological studies have linked shortened telomeres with increased mortality, it is unclear how these processes are connected. Our results suggest that, in yeast, reduced amino acid uptake and consequent reduced nutrient signaling extend chronological lifespan but reduce telomere length."