Fight Aging! Newsletter, March 19th 2012
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March 19th 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!



- Brain Preservation Foundation Technology Prize Update
- SENS5 Videos: Cryonics and Data Infrastructure
- Attempting to Address the Popular Myth of Antioxidants
- An Introduction to the Stem Cell Niche
- Discussion
- Latest Headlines from Fight Aging!


You are only irrevocably dead and gone when the structure of your brain, the structure that encodes the data of your mind, is destroyed. Alongside work on rejuvenation biotechnology to defeat aging, work on ways to preserve the mind form some of the most important of any human endeavors presently underway. Preservation of the mind, such as through cryonics, offers the only chance at a longer life in the future available to those who will age to death prior to the advent of medical technologies that can reverse aging. Here is an update from the Brain Preservation Foundation:

"The nonprofit Brain Preservation Foundation (BPF) hereby officially announces a cash prize for the first individual or team to rigorously demonstrate a surgical technique capable of inexpensively and completely preserving an entire human brain for long-term (greater than 100 years) storage with such fidelity that the structure of every neuronal process and every synaptic connection remains intact and traceable using today's electron microscopic (EM) imaging techniques. ... The two current competitors for the BPF technology prize, cryonics spin-off technology company 21st Century Medicine and collaborating scientists in the Max Planck Institute and other research centers, recently put out updates on their progress. You can see images of preserved brain tissue at the BPF website, created with the quite different technologies used by the two teams."


A couple more videos from last year's SENS5 conference have been posted.

"A billion people will die between now and the earliest plausible date for the first package of rough and ready but working rejuvenation therapies - say twenty years from now. Another few decades will pass for the technology to work its way out to global availability at low cost, and the deaths by aging will continue in less fortunate regions while this happens. Even after aging is completely conquered, there will be an ongoing toll of death due to accidents and whatever passes for disease in the age of medical nanotechnology. Death isn't going away completely for we biological folk, no matter how well we do in the field of medicine in the foreseeable future: medicine can't wave away falling rocks.

"Thus will always be a role for what we might term post-mortem critical care: technologies and services to preserve the fine structure of the brain and the mind it contains following death, and keep them preserved until such time as that patient can be restored to life. At present the only post-mortem critical care option is cryonics, with what looks like a fair few years to wait for technology to advance to the point of restoration, and thus an unknown chance of eventual success for any individual - but a significantly greater chance than is offered by the grave, of course. In contrast, in a future in which the technology to restore a preserved person exists, cryonics and other preservation technologies like plastination will occupy a more dynamic position in the medical toolkit, and patients might expect to wait in a preserved state only for transport to the nearest major population center."

"This is an era of data in the sciences - endless, vast stores of data, with more pouring in constantly from new studies. In most fields the infrastructure to manage that data is still under construction; in the life sciences, for example, the rapid advance of bioinformatics and biotechnology in general has outpaced the strategies for data management. The data infrastructure is lacking, even as it is being built up rapidly. This has consequences on the efficiency of research and the speed of progress, but researchers are not blind to this present state of affairs.

"Here, for example, Maria Konovalenko of the Science for Life Extension Foundation presents at last year's SENS5 conference, calling for better and more systematic management of data in longevity research initiatives - which is effectively a form of advocacy for lowering the cost of exchange of information between research groups."


Common knowledge among the public at large is like a large ship - it takes a very long time indeed for it to react to a new scientific consensus and change direction:

"The industry that provides antioxidant supplements to the world has tremendous inertia: enormous income and a very loud voice, and thus little incentive to react to advances in scientific knowledge that might reduce that revenue stream if acted upon. So despite the scientific consensus that ingested antioxidants are not in fact wonderful for your health, and may even be modestly harmful over the long term, the larger players in the industry continue onward as though it's still 1992 outside their offices.

"On the other side of the fence, the public at large keeps buying the products as though it's still 1992, just as blithely ignoring what the scientific community has to say on the matter. Everyone wants that silver bullet to be available now rather than tomorrow, and wants it badly enough to buy lead painted up to a nice sheen if that's all there is. All in all it's a good reminder that any institutional knowledge or common wisdom is likely to be a decade or two out of date - it takes time for information to percolate, even in this age of instant electronic overcommunication. There is seemingly so much that everyone has to say, day in and day out, and yet the important data still takes years to get from point A to point B."


The niche in which stem cells live is arguably more important in the aging of tissues than the stem cells themselves. But what exactly is it, and why does it matter so much? Here is an introduction:

"Stem cell populations in the body live in stem cell niches, each different type of stem cell with its own niche. The niche supplies the necessary environment and many of the cues that direct stem cell activity, and this is why changes in the niche are possibly more important than changes in stem cells themselves when it comes to the decline of stem cell activity with aging. That decline causes a sort of corrosion of your tissues as stem cells increasingly fail to keep up with maintenance and repair - but the evidence to date suggests that those stem cells are generally still capable of doing their jobs, provided they are given their marching orders.

"Ideas about stem cells, and how they behave, have been undergoing a lot of change in recent years, thanks to developments in visualizing, monitoring, and manipulating cells and tissues. ... the detailed mechanisms underlying niche function are extremely varied. Niches may be composed of cells, or cells together with extracellular structures such as the extracellular matrix (ECM). They may be sources of secreted or cell surface factors [that] control stem cell renewal, maintenance, or survival. They may consist of just a single cell type, or a whole host of interacting cells. They may derive from cells outside the stem cell's lineage, or they may derive primarily from the stem cell's own descendents. In general, there seems to be much more consensus about the fact that stem cells invariably need niches than about the specific mechanisms by which niches do their jobs.

"Why should a stem cell need a special environment? This is a pertinent question, given that none of the elementary processes that stem cells rely upon - growing, dividing, differentiating - are unique to stem cells."


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, March 16, 2012
Damaged mitochondria cause problems because their electron transport chains, the core mechanism by which they generate power for the cell, stop working the right way. That leads to a situation in which sub-par mitochondria in a cell are not recycled despite being damaged, and since they replicate like bacteria the bad mitochondria take over the cell. It goes downhill from there, and this whole process is one of the fundamental causes of aging. Ways of addressing this situation include repairing the mitochondria directly or working around their damage by creating replacements for the damaged parts of mitochondrial protein machinery elsewhere in the cell. Here is another line of research that looks at trying to minimize the consequences of that damaged machinery by providing substitute components, but with a different focus: "Mitochondrial dysfunction (primary or secondary) is detrimental to intermediary metabolism. Therapeutic strategies to treat/prevent mitochondrial dysfunction could be valuable for managing metabolic and age-related disorders. Here, we review strategies proposed to treat mitochondrial impairment. We then concentrate on redox-active agents, with mild-redox potential, who shuttle electrons among specific cytosolic or mitochondrial redox-centers. We propose that specific redox agents with mild redox potential improve mitochondrial function because they can readily donate or accept electrons in biological systems, thus they enhance metabolic activity and prevent reactive oxygen species (ROS) production. These agents are likely to lack toxic effects because they lack the risk of inhibiting electron transfer in redox centers. ... This view has been demonstrated by testing the effect of several redox active agents on cellular senescence. Methylene blue (MB) appears to readily cycle between the oxidized and reduced forms using specific mitochondrial and cytosolic redox centers. MB is most effective in delaying cell senescence and enhancing mitochondrial function in vivo and in vitro. Mild-redox agents can alter the biochemical activity of specific mitochondrial components, which then in response alters the expression of nuclear and mitochondrial genes. We present the concept of mitochondrial electron-carrier bypass as a potential result of mild-redox agents, a method to prevent ROS production, improve mitochondrial function, and delay cellular aging. Thus, mild-redox agents may prevent/delay mitochondria-driven disorders."

Friday, March 16, 2012
Just as physical exercise is beneficial, so too is exercising the mind. This open access paper examines structured mental exercise as a basis for therapy that might do at least some good for neurodegenerative disease patients: "Non-pharmacological intervention of memory difficulties in healthy older adults, as well as those with brain damage and neurodegenerative disorders, has gained much attention in recent years. The two main reasons that explain this growing interest in memory rehabilitation are the limited efficacy of current drug therapies and the plasticity of the human central nervous system and the discovery that during aging, the connections in the brain are not fixed but retain the capacity to change with learning. Moreover, several studies have reported enhanced cognitive performance in patients with neurological disease, following non-invasive brain stimulation [i.e., repetitive transcranial magnetic stimulation and transcranial direct current stimulation to specific cortical areas]. The present review provides an overview of memory rehabilitation in individuals with mild cognitive impairment and in patients with Alzheimer's disease with particular regard to cognitive rehabilitation interventions focused on memory and non-invasive brain stimulation. Reviewed data suggest that in patients with memory deficits, memory intervention therapy could lead to performance improvements in memory, nevertheless further studies need to be conducted in order to establish the real value of this approach."

Thursday, March 15, 2012
Less fat tissue is unambiguously good for you over the long term, and one side effect of calorie restriction is the loss of excess fat tissue - but that is only a side effect. More interesting stuff is going on at the level of cells and their mechanisms: "Caloric restriction (CR) slows the aging process and extends longevity, but the exact underlying mechanisms remain debatable. It has recently been suggested that the beneficial action of CR may be mediated in part by adipose tissue remodeling. Mammals have two types of adipose tissue: white adipose tissue (WAT) and brown adipose tissue (BAT). In this study, proteome analysis [was] performed on both WAT and BAT from nine month old male rats fed ad libitum or subjected to CR for six months. Our findings suggest that CR activates mitochondrial energy metabolism and fatty acid biosynthesis in WAT. It is likely that in CR animals WAT functions as an energy transducer from glucose to energy-dense lipid. In contrast, in BAT CR either had no effect on, or down-regulated, the mitochondrial electron transport chain, but enhanced fatty acid biosynthesis. This suggests that in CR animals BAT may change its function from an energy consuming system to an energy reservoir system. Based on our findings, we conclude that WAT and BAT cooperate to use energy effectively via a differential response of mitochondrial function to CR." It is worth noting that there are other signs that the biochemistry of fat tissue, and its effects on health, can be dramatically altered - see the research on fat in GHRKO mice, for example.

Thursday, March 15, 2012
One of the underlying mechanisms by which the advanced glycation endproducts (AGEs) that build up with age cause harm is through hammering on the receptor for AGEs, or RAGE. Some Alzheimer's researchers are looking into targeting RAGE in order to remove the contribution of AGEs to that condition, and it is possible that the results of their work may have more general application to AGEs in aging - though the best possible strategy would be to remove the AGEs rather than work around them: "Researchers have taken another crack at a promising approach to stopping Alzheimer's disease that encountered a major hurdle last year. ... scientists have developed a compound that targets a molecular actor known as RAGE, which plays a central role in mucking up the brain tissue of people with the disease. Scientists [synthesized] a compound that stops RAGE in mice - reversing amyloid deposits, restoring healthy blood flow in the brain, squelching inflammation, and making old, sick mice smarter. But the scientists caution that the work has a long way to go before it's considered as a possible treatment in people. ... A phase 2 study in 399 people of another compound designed to stop RAGE - which stands for Receptor for Advanced Glycation Endproducts - was halted prematurely in November when scientists had questions about the compound's safety at high doses, and after early results indicated that the compound was not helping patients with Alzheimer's disease. ... The benefits of blocking RAGE are even greater than has been realized. RAGE is central to many mechanisms that wreak havoc in the brains of people with Alzheimer's disease. It turns out that when you inhibit RAGE, you block molecules central to creating inflammation in the brain, and that is a major problem with Alzheimer's disease."

Wednesday, March 14, 2012
Here is a study claiming a noticeable impact on mortality rates from eating red meat. Weight is considered to some degree via body mass index, but I have to wonder if this only reflects a modest association of red meat consumption with other, less healthy lifestyle choices rather than an actual red-meat-based mechanism - as an obvious candidate mechanism for that isn't also present in all meat consumption isn't springing to mind: researchers "found that red meat consumption is associated with an increased risk of total, cardiovascular, and cancer mortality. The results also showed that substituting other healthy protein sources, such as fish, poultry, nuts, and legumes, was associated with a lower risk of mortality. ... [Researchers] observed 37,698 men from the Health Professionals Follow-up Study for up to 22 years and 83,644 women in the Nurses' Health Study for up to 28 years who were free of cardiovascular disease (CVD) and cancer at baseline. Diets were assessed through questionnaires every four years. ... One daily serving of unprocessed red meat (about the size of a deck of cards) was associated with a 13% increased risk of mortality, and one daily serving of processed red meat (one hot dog or two slices of bacon) was associated with a 20% increased risk. ... These analyses took into account chronic disease risk factors such as age, body mass index, physical activity, family history of heart disease, or major cancers. ... Replacing one serving of total red meat with one serving of a healthy protein source was associated with a lower mortality risk: 7% for fish, 14% for poultry, 19% for nuts, 10% for legumes, 10% for low-fat dairy products, and 14% for whole grains. The researchers estimated that 9.3% of deaths in men and 7.6% in women could have been prevented at the end of the follow-up if all the participants had consumed less than 0.5 servings per day of red meat."

Wednesday, March 14, 2012
Via ScienceDaily: researchers "have made early retina structures containing proliferating neuroretinal progenitor cells using induced pluripotent stem (iPS) cells derived from human blood. And in another advance, the retina structures showed the capacity to form layers of cells - as the retina does in normal human development - and these cells possessed the machinery that could allow them to communicate information. ... Put together, these findings suggest that it is possible to assemble human retinal cells into more complex retinal tissues, all starting from a routine patient blood sample. Many applications of laboratory-built human retinal tissues can be envisioned, including using them to test drugs and study degenerative diseases of the retina such as retinitis pigmentosa, a prominent cause of blindness in children and young adults. One day, it may also be possible replace multiple layers of the retina in order to help patients with more widespread retinal damage. ... We don't know how far this technology will take us, but the fact that we are able to grow a rudimentary retina structure from a patient's blood cells is encouraging, not only because it confirms our earlier work using human skin cells, but also because blood as a starting source is convenient to obtain."

Tuesday, March 13, 2012
Studies of correlations between longevity, mortality, and specific single nucleotide polymorphisms (SNPs) in humans are becoming more common, but as this one demonstrates they reinforce just how complicated the genetics of metabolism and longevity are. There are many, many correlations with small effects, the majority of which are different in different human populations: "Here we explore association with human longevity of common genetic variation in three major candidate pathways: GH/IGF-1/insulin signaling, DNA damage signaling and repair and pro/antioxidants by investigating 1273 tagging SNPs in 148 genes composing these pathways. In a case-control study of 1089 oldest-old (age 92-93) and 736 middle-aged Danes we found 1 pro/antioxidant SNP, 5 GH/IGF-1/INS SNPs, and 5 DNA repair SNPs to be associated with longevity after correction for multiple testing. In a longitudinal study with 11years of follow-up on survival in the oldest-old Danes we found 2 pro/antioxidant SNPs, 1 GH/IGF-1/INS SNP and 3 DNA repair SNPs to be associated with mortality in late life after correction for multiple testing. ... No formal replications were observed when investigating the 11 SNPs from the case-control study in 1613 oldest-old (age 95-110) and 1104 middle-aged Germans. ... In conclusion, the present candidate gene based association study, the largest to date applying a pathway approach, not only points to potential new longevity loci, but also underlines the difficulties of replicating association findings in independent study populations and thus the difficulties in identifying universal longevity polymorphisms."

Tuesday, March 13, 2012
A therapy that can robustly correct any mitochondrial DNA mutation throughout the body can be turned into a way to rejuvenate the stochastic damage of aging that occurs to the thirteen important mitochondrial genes not replicated in the cell nucleus. If asked to wager, based on the evidence I'd suggest that mitochondrial damage is the largest individual contribution to aging, which is why it's important to see progress on fixing it or making it irrelevant. So this, I think, is a development worth watching: "Researchers [have] identified, for the first time, a generic way to correct mutations in human mitochondrial DNA by targeting corrective RNAs ... I think this is a finding that could change the field. We've been looking to do this for a long time and we had a very reasoned approach, but some key steps were missing. Now we have developed this method and the next step is to show that what we can do in human cell lines with mutant mitochondria can translate into animal models and, ultimately, into humans. ... Gene therapy is often used to express proteins that can treat the cause of a variety of diseases. In this case, [researchers] developed a strategy to target and import specific RNA molecules encoded in the nucleus into the mitochondria and, once there, to express proteins needed to repair mitochondrial gene mutations. First, the research team had to figure out a way to stabilize the reparative RNA so that it was transported out of the nucleus and then localized to the mitochondrial outer membrane. This was accomplished by engineering an export sequence to direct the RNA to the mitochondrion. Once the RNA was in the vicinity of the transport machinery on the mitochondrial surface, then a second transport sequence was required to direct the RNA into the targeted organelle. With these two modifications, a broad spectrum of RNAs were targeted to and imported into the mitochondria, where they functioned to repair defects in mitochondrial respiration and energy production in two different cell line models of human mitochondrial disease. ... This study indicates that a wide range of RNAs can be targeted to mitochondria by appending a targeting sequence with or without a mitochondrial localization sequence, to provide an exciting, general approach for overcoming mitochondrial genetic disorders."

Monday, March 12, 2012
Heat shock proteins (HSPs) are important in cellular housekeeping, the processes of removing and repairing damage - and given how important these processes are to longevity, it's no surprise that we see associations between HSP levels and longevity. Researchers have been investigating how to build therapies based on boosting HSPs in recent years, but here is a different point of view: research to show that insulin resistance reduces HSP levels, which may be another one of the ways in which being fat and sedentary enough to become insulin resistant harms your health: "Heat shock protein (HSP)70 decreases with age. Often aging is associated with coincident insulin resistance and higher blood glucose levels, which also associate with lower HSP70. We aimed to understand how these factors interrelate through a series of experiments using vervet monkeys (Chlorocebus aethiops sabaeous). Monkeys fed low-fat diets showed no association of muscle HSP70 with age, but levels were highly heritable. Insulin resistance was induced in vervet monkeys with high-fat diets, and muscle biopsies were taken after 0.3 or 6 years. HSP70 levels were significantly greater after 0.3 years but were significantly lower following 6 years of high-fat diet. Associations with glucose also switched from being positive to strikingly negative with increasing insulin resistance. In conclusion, a low-fat diet may preserve tissue HSP70 and health with aging, whereas high-fat diets, insulin resistance, and genetic factors may be more important than age for determining HSP70 levels." Which is good news for those folk who make an effort to maintain health and fitness into old age, as insulin resistance and weight gain are avoidable consequences of lifestyle for the vast majority of people.

Monday, March 12, 2012
Mice with the myostatin gene removed grow more muscle, and researchers have been looking into therapies for muscle wasting based on this mechanism for a number of years. Here is another confirmation that myostatin is involved in age-related changes in muscle mass and strength via its effect on stem cells: "Human aging is accompanied by a progressive loss of muscle mass (sarcopenia). We tested the hypothesis that older males (OMs, 70±4 yr, n=9) would have a blunted myogenic response to a physiological stimulus compared to younger controls (21±3 yr, n=9). Subjects completed an acute bout of intense unilateral muscle loading. Young healthy males matched for body mass and activity level served as the control group. Muscle biopsies and blood were obtained before and at 3, 24, and 48 h after muscle loading. The muscle stem cell response was analyzed ... OMs had 35% fewer basal stem cells and a type II fiber-specific impairment in stem cell content and proliferation. Myogenic determination factor staining and cell cycle analysis illustrated a severely blunted progression through the myogenic program. Myostatin protein and mRNA were 2-fold higher in OMs. Stem cell-specific myostatin levels were not different at baseline; however, there were 67% more myostatin-positive type II-associated stem cells in OMs at 24 h. These data illustrate an age-related impairment of stem cell function in a fiber type-specific manner. The greater colocalization of myostatin with stem cells provides a mechanism for the impaired myogenic capacity of aged muscle."


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