Fight Aging! Newsletter, July 16th 2012

July 16th 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!



- New Organ 100 Launched
- The World of Aging Science Must Up-end and Change Itself
- An Australian Cryonics Provider
- Discussion
- Latest Headlines from Fight Aging!
    - Trehalose, Calorie Restriction, and Longevity in Yeast
    - Mitochondrial Haplotypes Correlate With Dementia Risk
    - Discussing Rapamycin
    - PGC-1alpha Versus Huntington's Disease
    - Alzheimer's Disease Considered as Synaptic Imbalance
    - Investigating the Mechanisms of Rheumatoid Arthritis
    - Investigating Precursor Ogliomers in Alzheimer's Disease
    - An Epigenetic Contribution to Osteoarthritis
    - Exercise Beneficial in Elderly
    - No Difference in Reprogrammed Cells From Old and Young Mice


The Methuselah Foundation launched the New Organ 100 this past week, a social fundraising initiative for the New Organ Prize, which aims to greatly speed up tissue engineering of whole organs:

"Today, 3,000 people will die from organ failure, many due to the lack of replacement organs. In the U.S. alone, over 100,000 are stuck on a waiting list, and many more can't even get on a list. We need a revolution in medicine, and we need it as soon as possible. Regenerative medicine is coming of aging. Significant breakthroughs are beginning to happen, but the funding to move the science and technology forward remains woefully inadequate.

"The Methuselah Foundation is announcing today the New Organ 100 to kickstart a visible, popular movement with a singular purpose: make regenerative medicine famous to achieve whole organ manufacturing within 10 years. We invite you to be among the initial 100 New Organizers, the seeds of the movement who each make the same pledge: give $10 a month toward raising the New Organ Prize, and ask 10 friends and family to do the same.

"The goal of the New Organ Prize is simple: to stimulate progress while demonstrating the rising demand for greater R&D funding. 100% of gifts go toward growing the prize. Every gift is matched by donors to support the New Organ Fund, which funds our operations and investments in startups advancing critical technologies, such as Organovo's 3D bioprinter and Silverstone Solutions' kidney-matching software."


If we want real results, meaning greatly extended healthy life spans, to arrive in our lifetimes, then things must change:

"It is unfortunate that popular culture, that ongoing conversation of countless threads that lies at the center of our diverse society, is so focused on drugs and pills as the sum of all medicine - anything that is consumed, and so especially when it comes to influencing the pace of aging. It is a terribly wrong, horribly damaging viewpoint, but one that is relentless propagated by the loudest voices, coincidentally also those who gain the most in the short term by creating a culture of customers for their products. When the world thinks of medicine for aging in terms of pills and potions, it shuts the door on support for real rejuvenation biotechnology, such as the detailed plans for development advocated by the SENS Foundation and others.

"Part of the process of building the true medicine of rejuvenation - which will look like gene therapies, tailored cell alterations, engineered enzymes to strip away harmful metabolic side-products, and so on - is obtaining the support and at least superficial understanding of the public at large. That is still very much lacking, and some fraction of the blame for that can be pinned on the short-sighted idiots of the "anti-aging" marketplace who propagate lies and myths about aging and what can be done about it in order to sell products that do next to nothing. They have spent so much time and effort on this over the past decades that they have shaped the visions of popular culture to follow their message - and that harms us all by stripping away possible support for meaningful research and development, and making it harder to create that support.

"The vast majority of commentary on aging, science, longevity, and what can be done about it is garbage at worst, and interesting but ultimately irrelevant to the future of our lives at best. Into the latter half falls work on calorie restriction mimetics such as metformin and rapamycin. They simply don't do enough to worth sinking billions of dollars into further research and development - though of course that research and development will happen anyway, regardless of my opinions on the matter. There are far better paths ahead than tinkering with compounds and genes that have modest effects, on a par with calorie restriction, and potentially serious side-effects to go along with that.

"If results are what matter - and I think they are the only measure worth considering given the pace of death caused by aging - then world of aging and longevity research should focus on the SENS vision of targeted, deliberate repair of specific forms of damage, and move on from the tired old model of patching the end results of damage by trying a lot of compounds to find some that sort of do something beneficial. Nor should research spend their time on the comparatively new approach of trying to slow down the pace at which damage accumulates - again by trying a bunch of compounds to find some that sort of do something beneficial.

"There are now far more effective paths forward for the treatment of aging than the approaches undertaken in past decades when biotechnology and the state of knowledge was too poor to do better. The world of aging science must up-end, change, become quite different. The SENS Foundation and the network of research groups working on related matters are doing the right thing. Big Pharma, the calorie restriction mimetic developers, the people searching for longevity genes or gene therapies to slow aging - they are heading down a side-path that will do little beyond generating new knowledge. Our lives will not be greatly lengthened by their efforts, as we will be old by the time that they produce therapies with modest effects on human life span by slowing down the pace at which damage accumulates. Ways to slow aging are of little value to those already aged. Our healthy lives will be significantly extended only by the successful development of methods of rejuvenation - of damage repair, ways to actually reverse the toll of aging on cells and systems."

Conveniently, the path to building these technologies is laid out in some detail:


It looks like an Australian group are close to establishing a cryonics provider in that country:

"Provision of cryonics services, the low-temperature preservation of the mind's structure on death, is a 40-year-old concern. It is presently the only chance at a longer life available to the vast numbers of people who will age to death prior to the advent of rejuvenation biotechnology of the sort envisaged at the SENS Foundation. In a better world than the one we presently live in, cryonics would already be a world-wide and massive industry, preserving tens of millions of people every year - saving them from oblivion, and giving a chance at a long and interesting future in an age with the technology to restore a preserved person to active life. Sadly this is far from the case. The long term success of providers outside the US has yet to be achieved, for example, as has the sort of growth needed to turn this into a truly robust and competitive industry.

"But there are signs of progress, such as the establishment and continued existence of Russian cryonics provider Kriorus, and more spin-off technology development ventures like 21st Century Medicine. Another group worthy of notice is Stasis Systems Australia:

"Not-for-profit company Stasis Systems Australia is celebrating a key milestone of 10 investors, each paying $50,000 for the privilege of having their body stored when they die. Now the company is looking for a suitable location to build their super-cool facility, possibly in South Australia or New South Wales.

"Co-founder Mark Milton said he had been talking to both SA Health and the NSW Health Department and had received a sympathetic and supportive hearing. More than 250 people have been cryonically preserved around the world, and close to 2000 more have signed contracts with overseas providers, he said."


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, July 13, 2012
You might recall that a few years ago, researchers extended life in nematode worms by feeding them trehalose. Here, scientists link normal abundances of trehalose in yeast cells with the longevity induced by calorie restriction: "Our recent investigation of how a lifespan-extending caloric restriction (CR) diet alters the metabolic history of chronologically aging yeast suggested that their longevity is programmed by the level of metabolic capacity - including trehalose biosynthesis and degradation - that yeast cells developed prior to entry into quiescence. To investigate whether trehalose homeostasis in chronologically aging yeast may play a role in longevity extension by CR, in this study we examined how single-gene-deletion mutations affecting trehalose biosynthesis and degradation impact (1) the age-related dynamics of changes in trehalose concentration; (2) yeast chronological lifespan under CR conditions; (3) the chronology of oxidative protein damage, intracellular ROS level and protein aggregation; and (4) the timeline of thermal inactivation of a protein in heat-shocked yeast cells and its subsequent reactivation in yeast returned to low temperature. Our data imply that CR extends yeast chronological lifespan in part by altering a pattern of age-related changes in trehalose concentration. We outline a model for molecular mechanisms underlying the essential role of trehalose in defining yeast longevity by modulating protein folding, misfolding, unfolding, refolding, oxidative damage, solubility, and aggregation throughout lifespan." Trehelose stimulates autophagy in higher animals, the all-important set of mechanisms that recycle damaged cell components, so one would expect it to be beneficial there as well.

Friday, July 13, 2012
Some mitochondrial DNA lineages are objectively better than others, as demonstrated by correlations with longevity in humans. Here is a correlation with dementia risk, which might be superficially explained by a greater ability to power fuel-hungry neurons, or greater resistance to mitochondrial damage over time: "Mitochondrial dysfunction is a prominent hallmark of Alzheimer's disease (AD). Mitochondrial DNA (mtDNA) damage may be a major cause of abnormal reactive oxidative species production in AD or increase neuronal susceptibility to oxidative injury during aging. The purpose of this study was to assess the influence of mtDNA sequence variation on clinically significant cognitive impairment and dementia risk in the population-based Health, Aging, and Body Composition (Health ABC) Study. We first investigated the role of common mtDNA haplogroups and individual variants on dementia risk and 8-year change on the Modified Mini-Mental State Examination (3MS) and Digit Symbol Substitution Test (DSST) among 1,631 participants of European genetic ancestry. Participants were free of dementia at baseline and incidence was determined in 273 cases from hospital and medication records over 10-12 follow-up years. Participants from haplogroup T had a statistically significant increased risk of developing dementia and haplogroup J participants experienced a statistically significant 8-year decline in 3MS, both compared with common haplogroup H. [Other variants were] associated with a significant decline in DSST score [or] 3MS score."

Thursday, July 12, 2012
A piece by author David Stipp gives an overview of the past few years of research into the effects of rapamycin: "The first strong evidence that a drug could slow aging in mammals came out in 2009 when scientists reported that chronically feeding doses of rapamycin to mice significantly extended their average and maximum lifespans. Yet rapamycin, a drug used to help prevent rejection of transplanted organs, causes multiple side effects in people, including elevated triglycerides and cholesterol, increasing the risk of heart disease; moderate immune suppression, perhaps increasing infection risks; and low blood platelet levels, which raises the specter of dangerous bleeding. In recent years another especially surprising and troubling side effect has come to the fore: Chronically taking large doses of rapamycin induces 'insulin insensitivity' in both rodents and humans, leading to rising blood sugar and potentially to type 2 diabetes. How do we reconcile such adverse effects with the drug's unprecedented ability to boost healthy aging and longevity, at least in mice? Some telling insights on this burning issue were recently published in two reports on rapamycin's effect on insulin and blood sugar: a mouse study that revealed a probable mechanism behind the effect and a theory paper suggesting that the purported diabetes risk has been overblown."

Thursday, July 12, 2012
Via ScienceDaily: researchers "have identified two key regulatory proteins critical to clearing away misfolded proteins that accumulate and cause the progressive, deadly neurodegeneration of Huntington's disease (HD). ... It's a lead we can vigorously pursue, not just for Huntington's disease, but also for similar neurodegenerative conditions like Parkinson's disease and maybe even Alzheimer's disease. ... In HD, an inherited mutation in the huntingtin (htt) gene results in misfolded htt proteins accumulating in certain central nervous system cells. ... [Researchers] focused on a protein called PGC-1alpha, which helps regulate the creation and operation of mitochondria, the tiny organelles that generate the fuel required for every cell to function. ... It's all about energy. Neurons have a constant, high demand for it. They're always on the edge for maintaining adequate levels of energy production. PGC-1alpha regulates the function of transcription factors that promote the creation of mitochondria and allow them to run at full capacity. ... the mutant form of the htt gene interfered with normal levels and functioning of PGC-1alpha, [and] elevated levels of PGC-1alpha in a mouse model of HD virtually eliminated the problematic misfolded proteins. ... PGC-1alpha influenced expression of another protein vital to autophagy - the process in which healthy cells degrade and recycle old, unneeded or dangerous parts and products, including oxidative, damaging molecules generated by metabolism. For neurons, which must last a lifetime, the self-renewal is essential to survival. ... Mitochondria get beat up and need to be recycled. PGC-1alpha drives this pathway through another protein called transcription factor EB or TFEB. ... If you can induce the bioenergetics and protein quality control pathways of nervous system cells to function properly, by activating the PGC-1alpha pathway and promoting greater TFEB function, you stand a good chance of maintaining neural function for an extended period of time."

Wednesday, July 11, 2012
From Maria Konovalenko: "I met Dr. Bredesen during the Buck Advisory Council meeting at the Buck Institute for Research on Aging in Novato, California on May 21. [The] Advisory Council consists of influential individuals who can contribute to Buck Institute's mission of advancing aging research. A very interesting crowd. ... Dale Bredesen opened the mini conference with his report on Alzheimer's research. The majority of scientists envision this horrible degenerative process as accumulation of toxic molecules, namely amyloid beta and tau proteins. Amyloid beta forms plaques between the cells and tau protein tangles inside the cells. These toxic proteins disrupt the functions of our neurons. ... So, Dr. Bredesen views Alzheimer's disease differently - as an imbalance between synaptic maintenance and synaptic reorganization. The thing is that for our brain to function properly we need to form connections between our neurons, and also we need to break down those connections that we no longer need. According to Dale Bredesen, this balance disrupts, it shifts towards synaptic reorganization, we loose our memory, face the horrors of loosing our consciousness and eventually we die. ... So how can we preserve this balance? Dr. Bredesen's lab studies the underlying mechanisms of neurodegeneration. There were able to find out that one of the things that contributes to the balance shift is the change in APP cleavage. APP is amyloid precursor protein. It is concentrated in synapses of our neurons. APP can break down into either two, or four parts. When it breaks down into 2 parts those proteins are sAPP alfa and CTF alfa. This is a 'good' combination. However, during aging amyloid precursor protein cleavage shifts towards the 'bad' combination, which is sAPP beta, Amyloid beta, Jcasp and C31. This is the shift in balance that leads to the onset of disease. The shift can be restored. The mouse strain that has one mutation that leads to not having APP to break down to Jcasp and C31 proteins leads to restoring memory in mice. But the most exciting thing is that Dr. Bredesen is testing a drug that shifts the APP cleavage balance back to normal."

Wednesday, July 11, 2012
Researchers examine possible molecular mechanisms for rheumatoid arthritis in a paper published earlier in the year: "Rheumatoid arthritis (RA) is a systemic autoimmune inflammatory and destructive joint disorder that affects tens of millions of people worldwide. Normal healthy joints maintain a balance between the synthesis of extracellular matrix (ECM) molecules and the proteolytic degradation of damaged ones. In the case of RA, this balance is shifted toward matrix destruction due to increased production of cleavage enzymes and the presence of (autoimmune) immunoglobulins resulting from an inflammation induced immune response. Herein we demonstrate that a polyclonal antibody against the proteoglycan biglycan (BG) causes tissue destruction that may be analogous to that of RA affected tissues. The effect of the antibody is more potent than harsh chemical and/or enzymatic treatments designed to mimic arthritis-like fibril de-polymerization. ... The specific antigen that causes the RA immune response has not yet been identified, although possible candidates have been proposed, including collagen types I and II, and proteoglycans (PG's) such as biglycan. We speculate that the initiation of RA associated tissue destruction in vivo may involve a similar non-enzymatic decomposition of collagen fibrils via the immunoglobulins themselves that we observe here ex vivo."

Tuesday, July 10, 2012
The focus of research on Alzheimer's disease begins to shift away from amyloid plaques: "Cell death in the brain causes one to grow forgetful, confused and, eventually, catatonic. Recently approved drugs provide mild relief for symptoms but there is no consensus on the underlying mechanism of the disease. ... We don't know what the problem is in terms of toxicity. This makes the disease difficult to cure. ... Accumulations of amyloid plaques have long been associated with the disease and were presumed to be its cause. These long knotty fibrils, formed from misfolded protein fragments, are almost always found in the brains of diseased patients. Because of their ubiquity, amyloid fibrils were considered a potential source of the toxicity that causes cell death in the brain. However, the quantity of fibrils does not correspond with the degree of dementia and other symptoms. New findings support a hypothesis that fibrils are a by-product of the disease rather than the toxic agent itself. This paradigm shift changes the focus of inquiry to smaller, intermediate molecules that form and dissipate quickly. These molecules are difficult to perceive in brain tissue. ... For decades, it was believed that fibrils were a toxic species, but increasingly researchers are looking at small, soluble precursor forms of the fibrils, known as oligomers. ... These oligomers may be toxic by inserting themselves into membranes and causing a damage to the membrane. The membrane is critical for the cell viability."

Tuesday, July 10, 2012
An example of the study of epigenetics starting to deliver targets for therapy: "scientists used human tissue samples to discover that those with osteoarthritis have a signature epigenetic change (DNA methylation) responsible for switching on and off a gene that produces a destructive enzyme called MMP13. This enzyme is known to play a role in the destruction of joint cartilage, making MMP13 and the epigenetic changes that lead to its increased levels, prime targets for osteoarthritis drug development. ... To make the discovery, [researchers] compared the extent to which DNA methylation was different in cartilage from patients suffering from osteoarthritis and healthy people of similar age. They found that at one small position, the gene for MMP13 had less DNA methylation in diseased patients. Then they confirmed that reduced methylation of this gene increases levels of the destructive enzyme MMP13. ... We've already seen how epigenetics has advanced our approach to cancer. Now we're seeing it with other diseases ... This study not only lays the groundwork for a new understanding of osteoarthritis, but also shows that the old 'either/or' nature v. nurture argument is outdated: epigenetics teaches us that nature (the daily wear and tear of joints) regulates nurture (the genes in our cartilage) to cause arthritis."

Monday, July 9, 2012
Here is yet another study showing that exercise in the elderly produces benefits large enough to power a massive drug industry were they caused by a pill - yet most people fail to take advantage of the free advantages bestowed by regular exercise: "Aging and physical inactivity are 2 factors that favour the development of cardiovascular disease, metabolic syndrome, obesity, and diabetes. In contrast, adopting a habitual moderate exercise routine may be a nonpharmacological treatment alternative for neuroendocrine aging disorders. We aimed to assess the effects of moderate exercise training on the metabolic profiles of elderly people with sedentary lifestyles. Fourteen sedentary, healthy, elderly male volunteers participated in a moderate training regimen for 60 min/day, 3 days/week for 24 weeks at a work rate equivalent to their ventilatory aerobic threshold. ... Blood samples for analysis were collected at 3 intervals: at baseline (1 week before training began), and 3 and 6 months after training. The training promoted increased aerobic capacity (relative VO2, and time and velocity to VO2max) and reduced serum α-MSH after 3 months of training when compared with the baseline data. In addition, serum thyroid hormone (T3 and T4) was reduced after 6 months of training compared with baseline levels. Our results demonstrate that a moderate exercise training protocol improves the metabolic profile of older people, and metabolic adaptation is dependent on time." You will recall that lower thyroid hormone levels are associated with longevity in humans.

Monday, July 9, 2012
In the last couple of years there have been promising indicators to suggest that age is no barrier to producing useful cells for therapy from a patient. Here is another: "Advanced age is associated with decreased stem cell activity. However, the effect of aging on the differentiation capacity of induced pluripotent stem (iPS) cells into cardiovascular cells has not been fully clarified. We investigated whether iPS cells derived from young and old mice are equally capable of differentiating into vascular progenitor cells, and whether these cells regulate vascular responses in vivo. iPS cells from mouse embryonic fibroblasts (young) or 21 month-old mouse bone marrow (old) were used. Fetal liver kinase-1 positive (Flk-1+) cells, as a vascular progenitor marker, were induced after 3 to 4 days of culture from iPS cells derived from young and old mice. ... purified Flk-1+ cells were directly injected into ischemic hindlimbs of nude mice. Revascularization of the ischemic hindlimb was significantly accelerated in mice transplanted with Flk-1+ cells derived from iPS cells from either young or old mice, as compared to control mice ... The degree of revascularization was similar in the two groups of ischemic mice injected with iPS cell-derived Flk-1+ cells from young or old mice. [The] properties of iPS cells derived from old mice are essentially the same as those of iPS cells from young mice, suggesting the functionality of generated iPS cells themselves to be unaffected by aging." It should be noted that while old cells seem to work just as well, the aged environment of the patient's body does present an obstacle to the benefits of cell therapies.



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