Fight Aging! Newsletter, January 21st 2013

January 21st 2013

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!



- Posters: Aging is a Curable Disease
- People Are Not Good at Being Rational, and That Costs a Great Many Lives
- For How Long Can a Desirable Goal Remain Cheap Without Being Aggressively Pursued?
- Discussion
- Latest Headlines from Fight Aging!
    - Sarcopenia Correlates With Increased Mortality
    - Luminescent Marking of Cellular Senescence
    - Plastination Will Have Its Challenges, Just Like Cryonics
    - More on Sestrins and Longevity
    - Reducing Amyloid Beta Levels in a Mouse Model of Alzheimer's
    - Solvents Increase Life in Nematode Worms
    - Adenine in the Diet Blocks Calorie Restriction Benefits in Flies
    - β-blockers Modestly Extend Mean Life Span in Flies and Mice
    - ROS Production Necessary for Tadpole Tail Regrowth
    - An Estimate of the Worldwide Cost of Dementia


The Russian end of the longevity science advocacy community seems to include a majority of its graphic design folk; certainly they've published a range of attractive, glossy materials in past years. Via Maria Konovalenko here are a couple more items to add to the stack - click through for the full size PDF posters.


This is an old story for regular readers, but I'll restate it anyway: people are dying of aging at a rate of something more than a hundred thousand lives a day. It is a mark of our inventive ongoing engagement with ways and means of death that despite this vast toll, aging still only manages to kill two thirds of us - and that in this era of comparatively advanced medicine, comparative peace, and comparative risk aversion.

Biotechnology is today's revolutionary industry in the making. Costs are falling, capabilities increasing just as dramatically as happened for computers two decades ago. We could be well on the way to removing aging as a cause of death at this point. A detailed plan is in hand, the way forward to achieve the goal of rejuvenation biotechnology is as clear as life science research ever gets, and the cost of an initial demonstration of rejuvenation in mice is ten years and a sum of money that's a rounding error in comparison what is spent on developing new and better ways to kill people.

Here's the thing, though, the point that's enough to make bitter old folk of us all: we're not actually well on the way to removing aging as a cause of death. We could be, but we're not - we're only just getting started at a time when we could be far further ahead, and we're moving slowly when we could be moving far faster. The hard-won funding and solid research programs for SENS and related initiatives are a trickle where a river is needed. You have to start at the start, of course, and every flood of effort started with a few drops back at the beginning. Nonetheless the flood does not yet exist, despite every reason for it to do so: a hundred thousand lives a day, the suffering of hundreds of millions more, and yet it's hard to get anyone to care enough to even think much about the topic, let alone do anything to help stop it from happening.

Where is rationality in all this? It's that the world is an asylum, run by the inmates, that makes people bitter before their time. To a first approximation those with resources build wars and circuses, and sometimes throw a crust to to the few who work on making the human condition better than it was yesterday. Those without resources heartily support this strategy, even while they owe pretty much every affordable comfort to work accomplished by a few centuries of researchers and developers - the tiny crust-fed minorities of their time.


The costs of life science research are falling rapidly. What was expensive is now cheap: a few bright graduate studies and a small lab can accomplish in six months what would have required an entire institution and the better part of a decade in 1990. This means that, setting aside the incredible burden of regulation, prototyping a major new medical procedure or taking a therapy from theory to working result in laboratory animals has become cheap in comparison to many endeavors. It can cost considerably less to build a focused therapy given a strategy to work with than to construct the laboratory building in which the researchers work, for example - though it is true that the building will not take as long to assemble.

Degenerative aging in particular does not lack for a plan that can lead to effective therapies: the Strategies for Engineered Negligible Senescence (SENS). The likely cost of following through from where we are now to demonstrating the collection of seven to ten different therapies needed to rejuvenate old mice is a billion dollars and a decade or two in which to spend it well. Today funding for these various lines of research runs at a bare few million a year, and a great deal of work and advocacy was required to reach that far.

A billion dollars at a rate of fifty to a hundred million a year is a large sum of money in one sense, but smaller than countless organized projects that take place in the wealthier regions of the world. How much longer can the earnest pursuit of rejuvenation continue to be within the easy grasp of an alliance of any dozen of the world's twelve hundred billionaires and yet not funded to any great level? If shared between such a group, the individual costs wouldn't come close to what these figures invest in order to achieve far less beneficial end goals.

For how long can a brass ring remain hanging unclaimed? The opportunity to build the basis for human rejuvenation biotechnology exists, yet there is no massively funded effort underway to reach that goal. For how long can this state of affairs continue?


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, January 18, 2013
As might be expected, older people with a greater loss of muscle mass and strength - the condition known as sarcopenia - also tend to exhibit a higher risk of death: "Sarcopenia has been indicated as a reliable marker of frailty and poor prognosis among the oldest individuals. We evaluated the impact of sarcopenia on the risk of all-cause death in a population of frail older persons living in community. We analysed data from the Aging and Longevity Study, a prospective cohort study that collected data on all subjects aged 80 years and older residing in the Sirente geographic area (n = 364). The present analysis was conducted among those subjects who were between 80 and 85 years of age at the time of the baseline assessment (n = 197). The main outcome measure was all-cause mortality over 7-year follow-up. According to the European Working Group on Sarcopenia in Older People (EWGSOP) criteria, the diagnosis of sarcopenia required the documentation of low muscle mass and the documentation of either low muscle strength or low physical performance. [Using] the EWGSOP-suggested criteria, 43 subjects with sarcopenia (21.8%) were identified. During the 7-year follow-up, 29 (67.4%) participants died among subjects with sarcopenia compared with 63 subjects (41.2%) without sarcopenia. After adjusting for potential confounders including age, gender, education, activities of daily living (ADL) impairment, body mass index, hypertension, congestive heart failure, chronic obstructive pulmonary disease, number of diseases, TNF-α, participants with sarcopenia had a higher risk of death for all causes compared with non-sarcopenic subjects."

Friday, January 18, 2013
Here is news of a research tool for those developing ways to target and destroy senescent cells. A successful method should minimize the contribution of cellular senescence to degenerative aging and thus extend healthy life - this is one of the necessary biotechnologies for human rejuvenation that is closest to actual implementation: "Researchers have long known that the gene, p16INK4a (p16), plays a role in aging and cancer suppression by activating an important tumor defense mechanism called 'cellular senescence'. The [team] has developed a strain of mice that turns on a gene from fireflies when the normal p16 gene is activated. In cells undergoing senescence, the p16 gene is switched on, activating the firefly gene and causing the affected tissue to glow. Throughout the entire lifespan of these mice, the researchers followed p16 activation by simply tracking the brightness of each animal. They found that old mice are brighter than young mice, and that sites of cancer formation become extremely bright, allowing for the early identification of developing cancers. "With these mice, we can visualize in real-time the activation of cellular senescence, which prevents cancer but causes aging. We can literally see the earliest molecular stages of cancer and aging in living mice." The researchers used these mice to make several unexpected discoveries. First, the group was able to track the accumulation of senescent cells in aging mice by assessing how brightly each mouse glowed. Surprisingly, the brightest animals were no more likely to die from spontaneous cancer than dimmer animals of the same age. That is, the number of senescent cells in the mouse did not predict its risk of dying. Another surprise came from the disparities in p16 levels among the mice. The authors studied a large group of genetically identical animals that were all housed in the same way and fed the same diet. However, despite identical genetic and environmental conditions, the brightness of individual mice at any given age was highly variable, suggesting that factors beyond genetics and diet influence aging."

Thursday, January 17, 2013
Plastination seems to have the potential to become a viable alternative to cryonics as a long-term storage method for the brains of those who die before the advent of rejuvenation biotechnology. If the fine structure that encodes the data of the mind is preserved, then these individuals can wait indefinitely for the arrival of molecular nanotechnology needed to restore them to life. Cryonics has been around for decades, and has had its challenges, while plastination remains a comparatively new idea - and thus we should expect there to be hurdles to overcome. One of my concerns with room temperature storage of plastinated individuals is the potential for bacteria and bugs than might like to consume the fixative compounds, something that isn't a concern in low-temperature storage. Here is another: " I have always been interested in chemical fixation as a (low cost) alternative for cryonics. In fact, years before all the talk about the "connectome" and "plastination" I spent considerable time exchanging messages with Michael Perry at Alcor about the technical and practical feasibility of chemical brain preservation. But no matter how open minded I tried to be about this approach, I kept running into the same challenges over and over again. The challenge that has concerned me the most is whether a delayed start of chemical brain fixation will produce incomplete distribution of the chemical fixative in the brain because of ischemia-induced perfusion impairment. Thinking about the technical problem of "no-reflow" is not the first thing on the mind of someone who first hears about the idea of using chemical fixatives to preserve the brain. In my case, this concern was not just "theoretical." In my lab I have spent many years looking at the effects of cerebral ischemia on cryopreservation and chemical fixation. Last year we decided to broaden our investigations to delayed chemical fixation and we have not been pleased at what we have observed so far. After 1.5 years of room temperature storage the delayed aldehyde fixed brains are falling apart and continue to decompose. In small animals one might imagine that such perfusion impairment could be overcome by immersing the brains in the fixative instead but human brains are simply too large. By the time that the fixative would have reached the core of the brain, extensive autolysis will have occurred."

Thursday, January 17, 2013
Sestrins have been linked to life span in flies, and here researchers look at the analogs in nematode worms. I've yet to notice similar work for mice, however: "Aging is a process of gradual functional decline leading to death. Reactive oxygen species (ROS) contribute to oxidative stress and cell damage that lead to aging but also serve as signaling molecules. Sestrins are evolutionarily conserved in all multicellular organisms and are required for regenerating hyperoxidized forms of peroxiredoxins and ROS clearance. However, whether sestrins regulate longevity in metazoans is still unclear. Here, we demonstrated that SESN-1, the only sestrin ortholog in Caenorhabditis elegans, is a positive regulator of lifespan. sesn-1 gene mutant worms had significantly shorter lifespans compared to wild-type animals, and overexpression of sesn-1 prolonged lifespan. Moreover, sesn-1 was found to a play key role in defense against several life stressors, including heat, hydrogen peroxide and the heavy metal copper; and sesn-1 mutants expressed higher levels of ROS and showed a decline in body muscle function. [These] results suggest that SESN-1 is required for normal lifespan and its function in muscle cells prevents muscle degeneration over a lifetime."

Wednesday, January 16, 2013
This is one of a number of approaches in recent years that has significantly reduced the levels of amyloid beta in the brain in the mouse version of Alzheimer's disease used for research. As for the others, it remains to be seen whether it is a suitable basis for a human therapy. Even if so, like much of the approach of modern medicine for age-related conditions, it isn't addressing causes, only trying to patch over consequences: "One of the main characteristics of Alzheimer's disease is the production in the brain of a toxic molecule known as amyloid beta. Microglial cells, the nervous system's defenders, are unable to eliminate this substance, which forms deposits called senile plaques. [Researchers] identified a molecule that stimulates the activity of the brain's immune cells. The molecule, known as MPL (monophosphoryl lipid A), has been used extensively as a vaccine adjuvant [for] many years, and its safety is well established. In mice with Alzheimer's symptoms, weekly injections of MPL over a twelve-week period eliminated up to 80% of senile plaques. In addition, tests measuring the mice's ability to learn new tasks showed significant improvement in cognitive function over the same period. The researchers see two potential uses for MPL. It could be administered by intramuscular injection to people with Alzheimer's disease to slow the progression of the illness. It could also be incorporated into a vaccine designed to stimulate the production of antibodies against amyloid beta. "The vaccine could be given to people who already have the disease to stimulate their natural immunity. It could also be administered as a preventive measure to people with risk factors for Alzheimer's disease.""

Wednesday, January 16, 2013
This result is reminiscent of the demonstration that ethanol produces significant life extension in nematodes - and similarly, one wonders whether it will be confirmed, and if so why it wasn't noted a long time ago. If it is accurate, it casts doubt on a range of life span studies that used the solvents in question. "Lifespan extension through pharmacological intervention may provide valuable tools to understanding the mechanisms of aging and could uncover new therapeutic approaches for the treatment of age-related disease. Although the nematode C. elegans is well known as a particularly suitable model for genetic manipulations, it has been recently used in a number of pharmacological studies searching for compounds with anti-aging activity. These compound screens are regularly performed in amphipathic solvents like dimethyl sulfoxide (DMSO), the solvent of choice for high-throughput drug screening experiments performed throughout the world. In this work, we report that exposing C. elegans to DMSO in liquid extends lifespan up to 20%. Interestingly, another popular amphipathic solvent, dimethyl formamide (DMF), produces a robust 50% increase in lifespan. These compounds work through a mechanism independent of insulin-like signaling and dietary restriction (DR). Additionally, the mechanism does not involve an increased resistance to free radicals or heat shock suggesting that stress resistance does not play a major role in the lifespan extension elicited by these compounds. Interestingly, we found that DMSO and DMF are able to decrease the paralysis associated with amyloid-β(3-42) aggregation, suggesting a role of protein homeostasis for the mechanism elicited by these molecules to increase lifespan."

Tuesday, January 15, 2013
Work continues on finding the mechanisms for longevity induced through calorie restriction. This latest paper seems to be as interesting a step forward in this regard as the establishment of dietary methionine levels as a principle trigger for the health and longevity benefits obtained via calorie restriction. That said, I'd like to see this work repeated in mice before giving it too much weight: "A common thread among conserved life span regulators lies within intertwined roles in metabolism and energy homeostasis. We show that heterozygous mutations of AMP biosynthetic enzymes extend Drosophila life span. The life span benefit of these mutations depends upon increased AMP:ATP and ADP:ATP ratios and adenosine monophosphate-activated protein kinase (AMPK). Transgenic expression of AMPK in adult fat body or adult muscle, key metabolic tissues, extended life span, while AMPK RNAi reduced life span. Supplementing adenine, a substrate for AMP biosynthesis, to the diet of long-lived AMP biosynthesis mutants reversed life span extension. Remarkably, this simple change in diet also blocked the prolongevity effects of dietary restriction. These data establish AMP biosynthesis, adenosine nucleotide ratios, and AMPK as determinants of adult life span; provide a mechanistic link between cellular anabolism and energy sensing pathways; and indicate that dietary adenine manipulations might alter metabolism to influence animal life span."

Tuesday, January 15, 2013
It is good to see more researchers controlling for calorie restriction effects as a matter of course in their studies on health and life span: "Chronic treatment with β-adrenergic receptor (βAR) agonists increases mortality and morbidity while βAR antagonists (β-blockers) decrease all-cause mortality for those at risk of cardiac disease. Levels of sympathetic nervous system βAR agonists and βAR activity increase with age, and this increase may hasten the development of age-related mortality. Here, we show that β-blockers extend the life span of healthy metazoans. The β-blockers metoprolol and nebivolol, administered in food daily beginning at 12 months of age, significantly increase the mean and median life span of isocalorically fed, male C3B6F1 mice, by 10 and 6.4 %, respectively. Neither drug affected the weight or food intake of the mice, indicating that induced CR is not responsible for these effects, and that energy absorption and utilization are not altered by the drugs. Both β-blockers were investigated to control for their idiosyncratic, off-target effects. Metoprolol and nebivolol extended Drosophila life span, without affecting food intake or locomotion. Thus, βAR antagonists are capable of directly extending the life span of two widely divergent metazoans, suggesting that these effects are phylogenetically highly conserved. Thus, long-term use of β-blockers, which are generally well-tolerated, may enhance the longevity of healthy humans."

Monday, January 14, 2013
Many lower animals are capable of great feats of regeneration, and researchers are working to understand the mechanisms by which this occurs. There is the possibility that the ability to regenerate lost body parts is something that lies dormant in mammals, rather than being completely lost. Finding out whether or not this is the case requires a far better understanding of regeneration than presently exists. Here, researchers investigate the biochemistry of tail regeneration in tadpoles: "It is generally appreciated that frogs and salamanders have remarkable regenerative capacities, in contrast to mammals, including humans. For example, if a tadpole loses its tail a new one will regenerate within a week. In an earlier study, [researchers] identified which genes were activated during tail regeneration. Unexpectedly, that study showed that several genes that are involved in metabolism are activated, in particular those that are linked to the production of reactive oxygen species (ROS) - chemically reactive molecules containing oxygen. [The researchers] were able to show that a marked increase in H2O2 occurs following tail amputation and interestingly, they showed that the H2O2 levels remained elevated during the entire tail regeneration process, which lasts several days. To assess how vital the presence of ROS are in the regeneration process, [the scientists] limited ROS production using two methods. The first was by using chemicals, including an antioxidant, and the second was by removing a gene responsible for ROS production. In both cases the regeneration process was inhibited and the tadpole tail did not grow back. "When we decreased ROS levels, tissue growth and regeneration failed to occur. Our research suggests that ROS are essential to initiate and sustain the regeneration response. We also found that ROS production is essential to activate Wnt signalling, which has been implicated in essentially every studied regeneration system, including those found in humans.""

Monday, January 14, 2013
A research paper here puts forward an estimate for the cost of treating dementia - though the true economic burden must also consider opportunity costs: what might have been accomplished by patients had they not become disabled. Dementia is but one of the many degenerative conditions of aging, of course, and all of the others have their costs as well. The overall cost of aging is staggering, and, sadly, rarely considered. If it was, we might see more effort put towards developing the means to repair and reverse the causes of aging. "The basic design of this study was a societal, prevalence-based, gross cost-of-illness study in which costs were aggregated to World Health Organization regions and World Bank income groupings. The total estimated worldwide costs of dementia were US$604 billion in 2010. About 70% of the costs occurred in western Europe and North America. In such high-income regions, costs of informal care and the direct costs of social care contribute similar proportions of total costs, whereas the direct medical costs were much lower. In low- and middle-income countries, informal care accounts for the majority of total costs; direct social care costs are negligible. Worldwide costs of dementia are enormous and distributed inequitably. There is considerable potential for cost increases in coming years as the diagnosis and treatment gap is reduced. There is also likely to be a trend in low- and middle-income countries for social care costs to shift from the informal to the formal sector, with important implications for future aggregated costs and the financing of long-term care. Only by investing now in research and the development of cost-effective approaches to early diagnosis and care can future societal costs be anticipated and managed."


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