Fight Aging! Newsletter, September 17th 2012

September 17th 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!



- An Update on Progress in LysoSENS Research
- If Today's Young People Die of Aging, It Will Be By Choice
- Destruction of Senescent Cells May Not Be Sufficient
- Discussion
- Latest Headlines from Fight Aging!
    - Vote for SENS Foundation at Chase Community Giving
    - Spurring Regeneration of Axons in Spinal Injury
    - Struggling With the Separation of Aging and Disease
    - Reversing Deafness Caused by Nerve Cell Damage
    - How to Interpret Life Expectancy Numbers
    - Prostate Cancer Stem Cells Identified
    - Growing Ears to Order
    - Investigating the Mechanisms of Atherosclerosis
    - The Impact of Advancing Age on Muscle


While receiving far less funding than it deserves, the LysoSENS research program is making progress - largely thanks to the support of the community, as funds for this research are almost entirely derived from charitable and philanthropic donations:

"LysoSENS is the oldest extant research program of the SENS Foundation, started back when the SENS program ran under the auspices of the Methuselah Foundation. In brief, LysoSENS is the development of a means of biomedical remediation. A whole range of harmful metabolic byproducts build up in human tissue with age, and we lack the means to break them down, or break them down fast enough. Some of these compounds simply cause harm, while others actually progressively impair the ability of cells to remove any unwanted chemicals, leading to what is known as the garbage catastrophe in aging - cells overwhelmed with broken protein machinery and waste products.

"To do something about this issue we need ways to break down these waste products, such as those that make up lipofuscin, a mix of compounds that bloat and degrade the cellular recycling machinery known as lysosomes. Lipofuscin is implicated in a range of age-related diseases (as well as a class of genetic conditions known as lysosomal storage diseases). The LysoSENS project aims to discover bacterial enzymes capable of breaking down lipofuscin constituents and other important damaging compounds, and which can safely be introduced to human tissue. Researchers will then build a therapy to deliver these enzymes to where they are needed in our cells.

"We have long known that such enzymes must exist, because places such as graveyards and battlefields do not exhibit a buildup of lipofuscin - something is eating it all. So the LysoSENS project started out by sifting through bacteria in soil samples, testing to see which of the bacterial species in the samples could consume harmful compounds such as 7-ketocholesterol, and then isolating the responsible enzymes.

"This has been going on for a few years now, of course, and progress has been made - even at the all-too-low levels of funding available for this work. At this stage in the project a number of candidate enzymes that break down 7-ketocholesterol have been identified, and researchers are now putting them through their paces in cell cultures. One enzyme at least is worthy of a published paper:

"7-Ketocholesterol (7KC) is a cytotoxic oxysterol that plays a role in many age-related degenerative diseases. 7KC formation and accumulation often occurs in the lysosome, which hinders enzymatic transformations that reduce its toxicity and increase the sensitivity to lysosomal membrane permeabilization.

"We assayed the potential to mitigate 7KC cytotoxicity and enhance cell viability by overexpressing 7KC-active enzymes in human fibroblasts. One of the enzymes tested, a cholesterol oxidase engineered for lysosomal targeting, significantly increased cell viability in the short term upon treatment with up to 50 µM 7KC relative to controls. These results suggest targeting the lysosome for optimal treatment of oxysterol-mediated cytotoxicity, and support the use of introducing novel catalytic function into the lysosome for therapeutic and research applications.

"The success of the approach employed by the team at Rice makes this enzyme, Chromobacterium sp. DS1 cholesterol oxidase, an important step toward a true rejuvenation biotechnology - a therapy that can target and repair damage that underlies the diseases and disabilities of the aging process. SENS Foundation is pleased to continue backing Dr. Mathieu's research, so that further work can move us closer to making such treatments a reality."


The future is what we choose to make of it:

"It is possible that folk in middle age today, myself included, won't be able to take advantage of rejuvenation biotechnologies - if, for example, development continues to be funded poorly, broader public support for the reversal of aging fails to emerge, or the first thirty year cycle of research, development, and commercialization fails to produce meaningful results. As Aubrey de Grey notes, minimal levels of funding seem to be the most obvious and plausible blocking issue for the foreseeable future. The young have few such worries: they have time to wait out failed business cycles, slow-moving research, public opposition, and an economic collapse between now and when they would absolutely need rejuvenation therapies. A good fraction of the children born in the past few years will live a thousand years in youthful health and vigor, thanks to an upward, accelerating curve in biotechnology.

"So from my perspective it is indeed the case that the only way today's young folk will die of aging is if they choose to do so - such as by failing to support the goal of engineered longevity because they believe that people should age and die, or because they haven't given much thought to living a life any different from that of their parents and grandparents, or because they choose to remain ignorant of medicine and its future. Those are all choices in the broadest sense, and possibly stupid, though it's worth considering that actual stupidity and mere lack of attention given to a particular topic look much the same from a distance.

"Few of us pay more than a tiny amount of attention to anything beyond our specialties, but this is one of those rare eras in which a great deal hinges on paying attention to a specific field. The future of biotechnology has to potential to reshape and greatly extend all of our lives, and remaining ignorant or on the sidelines only adds to the chance that the necessary advances will arrive too late for us."


Senescent cells accumulate in our tissues with age, and cause harm. The obvious way to deal with this is to destroy them and allow them to be replaced by the normal processes of regeneration and tissue maintenance - but this may not be sufficient:

"Senescent cells build up in our tissues with age. These cells have become damaged or passed the Hayflick limit and thus fallen out of the normal cell cycle of division. They should either self-destruct or be destroyed by the immune system, and until that happens they secrete all sorts of undesirable signaling compounds that tend to harm surrounding tissues. The more senescent cells you have, the more harm they cause - and the growth in their numbers with passing years is one of the root contributing causes of aging.

"Given this outline, plans for dealing with the problem tend to involve identifying and destroying senescent cells - removing the cells from the picture is fairly clearly the way to go. The destroying part is pretty easy (there is no shortage of methods to kill cells) but the identification part is still a challenge, despite considerable progress from the cancer research community in building ways to target specific cell populations via aspects of their surface chemistry or other characteristics. At this point the state of the art demonstration of improved health in mice through destruction of senescent cells requires a combination approach of gene engineering and a targeted therapy, which isn't terribly practical as the basis for a human therapy.

"Progress will be made nonetheless, and a near-future brace of therapies that remove the contribution of senescent cells to aging seems to be very plausible at this point. Yet this all assumes that senescent cells can be wiped out on an ongoing basis without consequence: a fair enough assumption for most tissues, made up of cells that are replaced and replenished on an ongoing basis. Recent research suggests, however, that cells that are far less readily replaced or are normally not replaced at all in the life span of an individual also turn senescent with age - such as those in the brain.

"So if this research holds up we can't just rampage through the body and destroy everything that looks like a senescent cell. More discrimination is needed, which in turn means more complex therapies and a greater understanding of differences in biochemistry between the cell populations of interest. More to the point, we will also need some method of reversing this senescence-like state in the brain and nervous system cells that we want to keep around. Will a general repair of all of the known forms of cellular damage be sufficient for that? Is neural dysfunction absolutely a consequence of the damage modes described by the Strategies for Engineered Negligible Senescence? It seems unlikely that we'll get a solid answer to that question until SENS version 1.0 is implemented in mice, but the initial expectation would be that yes, it is."


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, September 14, 2012
SENS Foundation manages a program of research, development, and advocacy for rejuvenation biotechnology - building the foundation for therapies that will reverse aging in the old by repairing the cellular and biochemical damage that causes it. At present the Chase Community Giving event at Facebook is winding to a close on the 19th of this month, with $10,000 grants provided to those charities given the most votes by the community. So if you have a Facebook account, take a few moments to head on over to the SENS Foundation page and add your vote. Similar past events have demonstrated that there are more than enough SENS supporters out there to win any charitable popularity measure like this; so vote before the 19th and pass it on to your friends.

Friday, September 14, 2012
Researchers continue to make progress in induced nerve regeneration: "researchers were able to regenerate 'an astonishing degree' of axonal growth at the site of severe spinal cord injury in rats. Their research revealed that early stage neurons have the ability to survive and extend axons to form new, functional neuronal relays across an injury site in the adult central nervous system (CNS). The study also proved that at least some types of adult CNS axons can overcome a normally inhibitory growth environment to grow over long distances. Importantly, stem cells across species exhibit these properties. ... The scientists embedded neural stem cells in a matrix of fibrin [mixed] with growth factors to form a gel. The gel was then applied to the injury site in rats with completely severed spinal cords. ... Using this method, after six weeks, the number of axons emerging from the injury site exceeded by 200-fold what had ever been seen before. The axons also grew 10 times the length of axons in any previous study and, importantly, the regeneration of these axons resulted in significant functional improvement. ... The grafting procedure resulted in significant functional improvement: On a 21-point walking scale, without treatment, the rats score was only 1.5; following the stem cell therapy, it rose to 7 - a score reflecting the animals' ability to move all joints of affected legs. Results were then replicated using two human stem cell lines, one already in human trials for ALS. ... We obtained the exact results using human cells as we had in the rat cells."

Thursday, September 13, 2012
There is a school of thought that declares the average pace of degenerative aging as "normal" and states that any faster degenerations should be broken out and called "disease." This is somewhat manageable at the level of taxonomy, where you are only cataloging and describing the various ways in which bodily parts and systems break down, but as a system of thought it falls down badly once you have the ability to look under the hood to see what is going in our biochemistry. All of aging and age-related disease descend from the same collection of damage-causing processes, which like rust in a metal construction can lead to any number of different forms of ultimate structural failure - but all stemming from the same root causes. So trying to draw a dividing line between aging and disease produces issues and unnecessary additional work, especially if the researcher is trying to treat only "disease" but let "aging" progress, as you can see from the opening paragraphs in this paper: "Aging of the musculoskeletal system starts early and is detrimental to multiple functions of the whole organism, since it leads to disability and degenerative diseases. The age-related musculoskeletal changes are important in medical risk assessment and care because they influence the responses to treatment and outcomes of therapy. ... There are two major problems that one faces while trying to disentangle the biological complexity of the musculoskeletal aging: (a) it is a systemic, rather than 'compartmental,' problem, which should be dealt with accordingly, (b) the aging per se is neither well defined nor reliably measurable. A unique challenge of studying any age-related process is a need of distinguishing between the 'norm' and 'pathology,' which are interwoven in the aging. When another dimension is added, namely genetics underlying the system's functioning, even less is known about this aspect, and attempts to decipher genetic relationships between the system's components are few. ... To disentangle the aging-related pathology from the homeostasis particular for aging steady-state, is a challenging task. Despite the multiple definitions of the aging process were proposed, there is no single agreed upon and reliable measurement, therefore underlying molecular mechanism of aging is still not fully understood. The definition of aging is complicated by the occurrence of various diseases that modify body functions and tissue structures; these disease-related changes that are common in older persons are often hard to delineate from the aging process per se."

Thursday, September 13, 2012
Researchers here use stem cells to partially reverse of a form of deafness in laboratory animals: "Deafness is a condition with a high prevalence worldwide, produced primarily by the loss of the sensory hair cells and their associated spiral ganglion neurons (SGNs). Of all the forms of deafness, auditory neuropathy is of particular concern. This condition, defined primarily by damage to the SGNs with relative preservation of the hair cells, is responsible for a substantial proportion of patients with hearing impairment. Although the loss of hair cells can be circumvented partially by a cochlear implant, no routine treatment is available for sensory neuron loss, as poor innervation limits the prospective performance of an implant. Using stem cells to recover the damaged sensory circuitry is a potential therapeutic strategy. Here we present a protocol to induce differentiation from human embryonic stem cells (hESCs) using signals involved in the initial specification of the otic placode. We obtained two types of otic progenitors able to differentiate in vitro into hair-cell-like cells and auditory neurons that display expected electrophysiological properties. Moreover, when transplanted into an auditory neuropathy model, otic neuroprogenitors engraft, differentiate and significantly improve auditory-evoked response thresholds. These results should stimulate further research into the development of a cell-based therapy for deafness."

Wednesday, September 12, 2012
Here is a good discussion on some common errors in the use of life expectancy data - such as mistaking period life expectancy (a statistical measure of health and medical technology) for cohort life expectancy (how long people actually live). It doesn't touch on the great uncertainty in predictions of future longevity due to the rapid pace of development in biotechnology, but is still an interesting read: "The US Government estimated its population had a life expectancy of 78.5 years in 2009. If you type 'life expectancy' into Google, it will spit back the World Bank estimate of 78.2 years in 2010. You've likely read numbers close to these in textbooks and articles. But what do these numbers actually mean? You might guess from the first that someone born in the United States in 2009 could be expected to live about 78.5 years. This is not the case! It actually measures how long someone would be expected to live if every year of their life was spent in 2009. In other words, there is no accounting for progress that decreases mortality rates. And that's on purpose. It is what is known as a 'period life expectancy'. Period life expectancies are used to track the general health of a population. With them you can easily compare one country to another. You can also monitor general population health over time. But the number you want if you'd like to know how long people will actually live is known as a 'cohort life expectancy'. It measures how long someone born in a particular year (a cohort) can be expected to live. It is also not in the US Government yearly mortality report for 2009. The reason is that we won't know it until everyone born in 2009 is dead! That will hopefully take a long long time."

Wednesday, September 12, 2012
Another form of cancer turns out to have a core of stem cells that can be targeted: "the research team generated cellular models of drug resistance by treating prostate tumor cell lines with increasing doses of the common chemotherapy drugs, including docetaxel. They identified a cell population expressing markers of embryonic development. In addition, these cells displayed cancer stem cell functions, including the capacity to initiate tumor cell growth. Next, the team evaluated human tissue samples of prostate cancer and found that patients with more aggressive or metastatic tumors had more of these cancer 'stem' cells. ... The study also defines a new therapeutic strategy for patients with prostate cancer, consisting of a combination of standard chemotherapy and two pharmacological agents that inhibit key signaling pathways associated with embryonic development and cell differentiation. Results showed that chemotherapy eliminated differentiated tumor cells, whereas the signaling pathway inhibitors selectively depleted the cancer stem cell population. Some of these inhibitors are already in clinical trials, and some are FDA-approved. ... By targeting these newly identified cancer 'stem' cells, we are attacking the foundation of tumor growth, rather than treating the symptoms of it."

Tuesday, September 11, 2012
Researchers are making progress in growing replacement ears, using a mix of old and new methods in tissue engineering and reconstructive surgery: "Using a computer model of a patient's remaining ear, scientists craft a titanium framework covered in collagen, the stuff that gives skin elasticity and strength. They take a snip of cartilage from inside the nose or between the ribs and seed the scaffold with these cells. This is incubated for about two weeks in a lab dish to grow more cartilage. When it's ready to implant, a skin graft is taken from the patient to cover the cartilage and the ear is stitched into place. Scientists in her lab have maintained lab-grown sheep ears [for] 20 weeks, proving it can be done successfully and last long-term. They also have grown anatomically correct human ears from cells. These have been implanted on the backs of lab rats to keep them nourished and allow further research. ... Now they are ready to seek approval from the Food and Drug Administration to implant these into patients - probably in about a year."

Tuesday, September 11, 2012
News of an advance in the understanding of atherosclerosis: "Researchers [are] one step closer to understanding why plaque bursts in coronary arteries and causes heart attacks. The clue might be something called microRNA-145. MicroRNAs are short chains of bossy molecules that scientists are increasingly coming to realize control a wide variety of biological processes. ... most heart attacks occur when plaques rupture like a broken eggshell and release their contents into the artery. Researchers are therefore looking for ways to reduce the size of plaques and make them more stable. One of the key questions is what causes the outer layer of the plaque to finally burst - a layer of smooth muscle cells known as the fibrous cap. These cells undergo 'phenotypic transformation' in response to various stressful environments and cardiovascular risk factors, making them more likely to rupture and cause heart attacks. MicroRNA-145 is one of the factors that appear to play a critical role in preventing the transformation of vascular smooth muscle cells into rupture-prone cells. In atherosclerosis-prone animals, microRNA-145-based gene therapy reduced the plaque size by approximately 50 per cent and increased the collagen content of the plaque and fibrous cap area by 40 to 50 per cent, indicating that this therapy can reduce plaque buildup and also make it less prone to rupture, the inciting event of heart attacks. The researchers also found that in human atherosclerotic plaques, the amount of microRNA-145 was reduced compared to normal arteries that were free of plaque, providing supporting human insights to the animal study."

Monday, September 10, 2012
Our muscles decline with age for reasons that seem likely to soon be treatable. Finding ways to retain muscle mass and strength would hopefully allow older people to continue to be active and exercising, thus removing this contribution to the frailty that leads into a downward spiral of health in late life: "Changing demographics make it ever more important to understand the modifiable risk factors for disability and loss of independence with advancing age. For more than two decades there has been increasing interest in the role of sarcopenia, the age-related loss of muscle or lean mass, in curtailing active and healthy aging. There is now evidence to suggest that lack of strength, or dynapenia, is a more constant factor in compromised wellbeing in old age and it is apparent that the decline in muscle mass and the decline in strength can take quite different trajectories. ... An understanding of the impact of aging on skeletal muscle will require attention to both the changes in muscle size and the changes in muscle quality. ... Cross-sectional studies comparing young (18-45years) and old (older than 65years) samples show dramatic variation based on the technique used and population studied. The median of values of rate of loss reported across studies is 0.47% per year in men and 0.37% per year in women. Longitudinal studies show that in people aged 75years, muscle mass is lost at a rate of 0.64-0.70% per year in women and 0.80-00.98% per year in men. Strength is lost more rapidly. Longitudinal studies show that at age 75years, strength is lost at a rate of 3-4% per year in men and 2.5-3% per year in women. Studies that assessed changes in mass and strength in the same sample report a loss of strength 2-5 times faster than loss of mass. Loss of strength is a more consistent risk for disability and death than is loss of muscle mass."



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