Fight Aging! Newsletter, September 10th 2012

September 10th 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!



- Discussion
- Considering a Negative Result for Primate Calorie Restriction
- Personal Survival and Swimming Against the Cultural Currents
- Fat Tissue: Where Did it All Go Wrong?
- Latest Headlines from Fight Aging!
    - Nanog Reverses Some Aspects of Stem Cell Aging
    - Longevity in Mammals as an Ancient Phenomenon
    - A Chart of Changing Mortality Rates and Life Expectancy
    - Jnk3 as a Potential Target for Alzheimer's Therapy
    - On α-synuclein and Neurodegeneration
    - Reproductive Tissues Influence Life Span
    - Manipulation of Osteopontin Can Reverse Declining Muscle Regeneration
    - Stem Cell Transplant Restores Feeling After Spinal Injury
    - On Extending Life in Mice Via Telomerase Expression
    - Bioscience and Pushing the Limits of Lifespan


The latest data from one of the primate studies of calorie restriction, health, and longevity, should be considered in context:

"As I'm sure you noticed, the latest data from one of the two long-running primate studies of calorie restriction is being presented in the press as a negative result: no extension of mean life span in the rhesus monkeys in that study. This contrasts with another study that may or may not presently show a modest extension of primate life span with calorie restriction, depending on how you feel about the way in which the researchers are interpreting their data.

"The press are largely running with 'calorie restriction doesn't work,' but that's because the mainstream media is shallow, either reprinting a superficial summary or at best treating each new research result in isolation rather than considering it in the context of the field as a whole. Doing the job properly, employing actual knowledge and analysis, takes more time and doesn't sell any more papers - so why bother? This is why the media should chiefly be used as a flagging mechanism; if you see discussion of a topic, note that it happened and then do your own research and analysis.

"In science, each new set of data and consequent analysis should be added to the existing array for a given topic. Progressing towards a greater understanding is an incremental affair, especially given than a large proportion of studies and data are flawed in some way ... So what should we take away from the results of the two ongoing primate studies of life span and health under calorie restriction? After two decades one shows a modest boost to life span, the other no increase, and both show health benefits resulting from calorie restriction - though to different degrees. The control groups are fed differently, one allowed to eat as much as they like, the other on a set diet that has more calories than the restricted group. The composition of the diets in the two studies are also different. Even the genetic heritage of the rhesus monkeys involved is different enough for scientists to consider it significant, given the many but tenuous relationships to longevity found in the human genome over the past decade.

"When looking beyond these studies to the broader context of data derived from a range of human studies and countless studies in mice, we see that calorie restriction absolutely, definitely has a large positive impact on health and longevity in shorter-lived mammals, and a large positive impact on measures of health in humans.

"The first important point to consider is that these studies add to the weight of data and theory suggesting the effect of calorie restriction on the life span of longer-lived primates is small. Consider that any study is going produce results somewhere statistical map of what is possible and plausible: if two studies both show no extension or only a modest extension of life, then there would have to be a good reason to continue to believe that a large extension of life is possible. This concurs with the present scientific consensus and reasonable expectations: if calorie restriction could produce a 40% extension of maximum human life span, as it does in mice, then we'd have known about it since the age of antiquity. Our history is rife with cloistered groups that practiced austere lifestyles, after all, and many of them existed in periods of comparative wealth wherein suitable levels of nutrition were readily available.

"A second important point is that this latest primate data in no way detracts from the health benefits produced by calorie restriction and demonstrated in numerous human studies. These research results are impressive: if calorie restriction were a drug, people would be falling over themselves to get a hold of it, as it leads to benefits that go far beyond anything that medical science can presently offer a basically healthy individual.

"The future of calorie restriction research at the level of investigation and understanding - as opposed to attempts to build calorie restriction mimetic drugs - will, I suspect, involve a great deal of thought on how to reconcile significant beneficial effects on measures of health and disease risk with an apparently small beneficial effect on life span. That isn't an intuitive outcome given the view of aging as an accumulation of damage, and the straightforward relationship between better health measures and greater life span extension in shorter-lived mammals like mice or rats. What is does indicate is that some of the differences in metabolism between mammals species are very significant when it comes to life span: one hypothesis is that some of the beneficial metabolic changes brought about in mice by calorie restriction are essentially already running by default in your average human, and account for our present longevity in comparison to similarly sized mammals.

"So from the perspective of a dispassionate observer of metabolic science, calorie restriction continues to offer a tremendous and ever-deepening opportunity to really dig into the operation and evolution of mammalian biochemistry. From the perspective of those of us who want to live very much longer than our predecessors, calorie restriction has to be nothing more than a common sense health practice, akin to flossing and exercise, but not something that we hang unrealistic hopes on. Real progress in living longer must come from medical science, from efforts to build rejuvenation biotechnologies that can repair the damage that causes aging. Absent advances in longevity medicine we will age and die just like our ancestors, no matter what we eat; taking care of our health is, like supporting research initiatives in longevity science, one more optimization to help us live long enough to see the deployment of therapies to treat and reverse aging."


Its fair to say that at this time most people don't put in much thought or effort when it comes to living a longer, healthier life. The mainstream of our culture is somewhere between indifferent and hostile to this goal. But research of biotechnologies that can achieve reversal of aging in the old requires widespread support in order to grow to become a powerful, rapidly moving field like stem cell medicine or cancer research. So we are currently swimming against the current, in an uphill struggle to persuade and raise funding for building therapies for aging - and that won't be the first time this happens in a matter crucial to personal survival:

"[The] additional cost in time and resources imposed [on longevity science] by the nature of our present culture is an existential threat. It threatens to kill us by ensuring that the development of effective ways to reverse aging in the old arrive too late. Given that progress in this field of science and technology is a matter of persuading funding sources and raising money to accomplish known goals, it could be argued that this is a fight to change the prevailing culture rather than a matter of research. If we want to live, it's a fight we have to win - or at least convince a few tens of millions to become supporters of longevity science in the same way that most people are supporters of cancer research.

"But let us look to the future, at what I see as a loosely analogous cultural battle that will start to arrive at around the same time as the means to reverse aging - one that will also present an existential threat to personal survival.

"Consider that at some point in the next few decades it will become possible to simulate and then emulate a human brain. That will enable related technological achievements as reverse engineering of memory, a wide range of brain-machine interfaces, and strong artificial intelligence. It will be possible to copy and alter an individual's mind: we are at root just data and operations on that data. It will be possible for a mind to run on computing hardware rather than in our present biology, for minds to be copied from a biological brain, and for arbitrary alterations of memory to be made near-immediately. This opens up all of the possibilities that have occupied science fiction writers for the past couple of decades: forking individuals, merging in memories from other forks, making backups, extending a human mind through commodity processing modules that provide skills or personality shards, and so on and so forth.

"There is already a population of folk who would cheerfully take on any or all of these options. I believe that this population will only grow: the economic advantages for someone who can edit, backup, and fork their own mind are enormous - let alone the ability to consistently take advantage of a marketplace of commodity products such as skills, personalities, or other fragments of the mind.

"But you'll notice I used what I regard as a malformed phrase there: 'someone who can edit, backup, and fork their own mind.' There are several sorts of people in the world; the first sort adhere to some form of pattern theory of identity, defining the self as a pattern, wherever that pattern may exists. Thus for these folk it makes sense to say that 'my backup is me', or 'my fork is me.' The second sort, and I am in this camp, associate identity with the continuity of a slowly changing arrangement of mass and energy: I am this lump of flesh here, the one slowly shedding and rebuilding its cells and cellular components as it progresses. If you copy my mind and run it in software, that copy is not me. So in my view you cannot assign a single identity to forks and backups: every copy is an individual, large changes to the mind are equivalent to death, and it makes no sense to say something like 'someone who can edit, backup, and fork their own mind.'

A copy of you is not you, but there is worse to consider: if the hardware that supports a running brain simulation is anything like present day computers, that copy isn't even particularly continuous. It is more like an ongoing set of individuals, each instantiated for a few milliseconds or less and then destroyed, to be replaced by yet another copy. If self is data associated with particular processing structures, such as an arrangement of neurons and their connections, then by comparison a simulation is absolute different: inside a modern computer or virtual machine that same data would be destroyed, changed, and copied at arbitrary times between physical structures - it is the illusion of a continuous entity, not the reality.

That should inspire a certain sense of horror among folk in the continuity of identity camp, not just because it is an ugly thing to think about, but because it will almost certainly happen to many, many, many people before this century ends - and it will largely be by their own choice, or worse, inflicted upon them by the choice of the original from whom the copy was made.

This is not even to think about the smaller third group of people who are fine with large, arbitrary changes to their state of mind: rewriting memories, changing the processing algorithms of the self, and so on. At the logical end of that road lie hives of software derived from human minds in which identity has given way to ever-changing assemblies of modules for specific tasks, things that transiently appear to be people but which are a different sort of entity altogether - one that has nothing we'd recognize as continuity of identity. Yet it would probably be very efficient and economically competitive.

The existential threat here is that the economically better path to artificial minds, the one that involves lots of copying and next to no concern for continuity of identity, will be the one that dominates research and development. If successful and embedded in the cultural mainstream, it may squeeze out other roads that would lead to more robust agelessness for we biological humans - or more expensive and less efficient ways to build artificial brains that do have a continuity of structure and identity, such as a collection of artificial neurons that perform the same functions as natural ones.

This would be a terrible, terrible tragedy: a culture whose tides are in favor of virtual, copied, altered, backed up and restored minds is to my eyes little different from the present culture that accepts and encourages death by aging. In both cases, personal survival requires research and development that goes against the mainstream, and thus proceeds more slowly.

Sadly, given the inclinations of today's futurists - and, more importantly, the economic incentives involved - I see this future as far more likely than the alternatives. Given a way to copy, backup, and alter their own minds, people will use it and justify its use to themselves by adopting philosophies that state they are not in fact killing themselves over and again. I'd argue that they should be free to do so if they choose, just the same as I'd argue that anyone today should be free to determine the end of his or her life. Nonetheless, I suspect that this form of future culture may pose a sizable set of hurdles for those folk who emerge fresh from the decades in which the first early victories over degenerative aging take place."


In this post, an interesting open access paper on the evolutionary origins of our present challenges with fat tissue.

"Accumulation of excess body fat is easy to accomplish in a wealthy society, and it has very unpleasant consequences over the long term. The more time you spend carrying additional visceral fat tissue, the higher your risk of suffering all of the common age-related diseases in later life, the greater your expected medical bills, and the shorter your life expectancy. This is all well understood and widely ignored: the urges to eat and laze are strong in the average human.

"The way in which our bodies grasp at nutrients and aggressively store any excess as fat tissue didn't evolve because it is harmful, however. It evolved because it provides an advantage to survival and propagation of the species - at least it did while we occupied an evolutionary niche characterized by unreliable access to food. When we leave that niche for one with reliably abundant nutrition, these metabolic mechanisms become a maladjustment. We have succeeded ourselves out of the obvious and ugly scenarios of famine and into the more subtle scenarios of self-sabotage. Change in our environment is now self-directed and far faster than evolution can keep up with: we are the masters of our own destiny, and what goes on in our heads becomes more important than many other factors when it comes to health, longevity, and our environment."


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 7, 2012
It's been a while since nanog was discussed here; it's one of the genes associated with early efforts to reprogram somatic cells into stem cells and seems to be important in the activity of embryonic stem cells. Here researchers are investigating the reversal of stem cell aging: "Although the therapeutic potential of mesenchymal stem cells (MSC) is widely accepted, loss of cell function due to donor aging or culture senescence are major limiting factors hampering their clinical application. Our laboratory recently showed that MSC originating from older donors suffer from limited proliferative capacity and significantly reduced myogenic differentiation potential. This is a major concern, as the patients most likely to suffer from cardiovascular disease are elderly. Here we tested the hypothesis that a single pluripotency associated transcription factor, namely Nanog, may reverse the proliferation and differentiation potential of BM-MSC from adult donors. Microarray analysis showed that [expressing Nanog] markedly upregulated genes involved in cell cycle, DNA replication and DNA damage repair and enhanced the proliferation rate and clonogenic capacity of [adult] BM-MSC. Notably, Nanog reversed the myogenic differentiation potential and restored the contractile function of [adult] BM-MSC to a similar level as that of neonatal BM-MSC. ... Overall, our results suggest that Nanog may be used to overcome the effects of organismal aging on BM-MSC, thereby increasing the potential of MSC from aged donors for cellular therapy and tissue regeneration."

Friday, September 7, 2012
An interesting view on the evolutionary depths of longevity in mammals, achieved through analysis of presently available genomes: "It is widely assumed that our mammalian ancestors, which lived in the Cretaceous era, were tiny animals that survived massive asteroid impacts in shelters, and evolved into modern forms after dinosaurs went extinct, 65 Mya. The small size of most Mesozoic mammalian fossils essentially supports this view. Paleontology, however, is not conclusive regarding the ancestry of extant mammals, because Cretaceous and Paleocene fossils are not easily linked to modern lineages. Here we use full-genome data to estimate the longevity and body mass of early placental mammals. Analysing 36 fully-sequenced mammalian genomes, we reconstruct two aspects of the ancestral genome dynamics ... Linking these molecular evolutionary processes to life history traits in modern species, we estimate that early placental mammals had a life-span above 25 years, and a body mass above one kilogram. This is similar to current primates, cetartiodactyls or carnivores, but markedly different from mice or shrews, challenging the dominant view about mammalian origin and evolution. Our results imply that long-lived mammals existed in the Cretaceous era, and were the most successful in evolution, opening new perspectives about the conditions for survival to the Cretaceous-Tertiary crisis."

Thursday, September 6, 2012
This chart from the Scientific American clearly illustrates the progress in tackling heart disease over the past few decades, a factor that is driving a steady rise in life expectancy at older ages. Mortality rates for this range of conditions are falling quite dramatically: "A baby born in the U.S. this year is likely to live to blow out 78 birthday candles - a far longer average life span than someone born even in the 1960s. Heart disease is still the biggest killer but it, along with fatal infectious diseases and infant mortality have all fallen to much lower levels in the past half century. Researchers are now hard at work tackling the growing afflictions, such as nervous system diseases and Alzheimer's, which are far more likely to attack the ever more senescent population. ... Researchers are exploring two main approaches to extending healthy human life span. One camp believes we should focus on curing disease and replacing damaged body parts via stem cell therapies. Another camp believes we must slow the aging process on the cellular and molecular levels." If you include the SENS approach to repair of the causes of aging under "curing disease and replacing damaged body parts", then this describes the most important issue of our time in the life sciences: will the research community take an effective path or not in the treatment of aging? This will determine how long we all live.

Thursday, September 6, 2012
Via ScienceDaily: "Scientists have found that eliminating an enzyme from mice with symptoms of Alzheimer's disease leads to a 90 percent reduction in the compounds responsible for formation of the plaques linked to Alzheimer's disease. ... The key to reducing A-beta peptides was the elimination of an enzyme called jnk3. This enzyme stimulates a protein that produces A-beta peptides, suggesting that when jnk3 activities are high, A-beta peptide production increases - increasing chances for their accumulation and formation into plaques. The researchers also observed that jnk3 activities in brain tissue from Alzheimer's disease patients were increased by 30 to 40 percent when compared to normal human brain tissue. Jnk3 activity typically remains low in the brain, but increases when physiological abnormalities arise. ... [Researchers] deleted jnk3 genetically from Alzheimer's disease model mice carrying the mutations that are found among early-onset Alzheimer's disease patients. In six months, the deletion of the enzyme had lowered A-beta peptide production by 90 percent, which persisted over time, with a 70 percent reduction seen at 12 months in these mice. When the researchers saw that elimination of jnk3 dramatically lowered A-beta peptides in the mice, they also looked for effects on cognitive function at 12 months. The deletion of jnk3 improved cognitive function significantly, reaching 80 percent of normal, while cognitive function in disease model mice was 40 percent of normal. The number of brain cells, or neurons, in the Alzheimer's disease mice was also increased with jnk3 deletion, reaching 86 percent of the value in normal mice, while the neuron numbers were only 74 percent in Alzheimer's model mice."

Wednesday, September 5, 2012α-synuclein-and-neurodegeneration.php
In recent years a build up of α-synuclein has been shown to be important in some neurodegenerative conditions: "The discovery of α-synuclein has had profound implications concerning our understanding of Parkinson's disease (PD) and other neurodegenerative disorders characterized by α-synuclein accumulation. In fact, as compared with pre-α-synuclein times, a "new" PD can now be described as a whole-body disease in which a progressive spreading of α-synuclein pathology underlies a wide spectrum of motor as well as nonmotor clinical manifestations. Not only is α-synuclein accumulation a pathological hallmark of human α-synucleinopathies but increased protein levels are sufficient to trigger neurodegenerative processes. α-Synuclein elevations could also be a mechanism by which disease risk factors (e.g., aging) increase neuronal vulnerability to degeneration. An important corollary to the role of enhanced α-synuclein in PD pathogenesis is the possibility of developing α-synuclein-based biomarkers and new therapeutics aimed at suppressing α-synuclein expression. The use of in vitro and in vivo experimental models, including transgenic mice overexpressing α-synuclein and animals with viral vector-mediated α-synuclein transduction, has helped clarify pathogenetic mechanisms and therapeutic strategies involving α-synuclein. These models are not devoid of significant limitations, however. Therefore, further pursuit of new clues on the cause and treatment of PD in this post-α-synuclein era would benefit substantially from the development of improved research paradigms of α-synuclein elevation."

Wednesday, September 5, 2012
A review paper: "Aging and reproduction are two defining features of our life. Historically, research has focused on the well-documented decline in reproductive capacity that accompanies old age, especially with increasing maternal age in humans. However, recent experiments in model organisms such as worms, flies and mice have shown that a dialogue in the opposite direction may be widely prevalent, and that signals from reproductive tissues have a significant effect on the rate of aging of organisms. This pathway has been described in considerable detail in the nematode Caenorhabditis elegans. Molecular genetic studies suggest that signals from the germline control a network of transcriptional regulators that function in the intestine to influence longevity. This network includes conserved, longevity-promoting Forkhead Box (FOX)-family transcription factors such as DAF-16/FOXO and PHA-4/FOXA, nuclear hormone receptors (NHRs) as well as a transcription elongation factor, TCER-1/TCERG1. Genomic and targeted molecular analyses have revealed that these transcription factors modulate autophagy, lipid metabolism and possibly other cellular processes to increase the length of the animal's life."

Tuesday, September 4, 2012
Muscle mass and strength decline with age, and researchers continue to explore the mechanisms by which this happens: "Skeletal muscle regeneration following injury is accompanied by rapid infiltration of macrophages, which play a positive role in muscle repair. Increased chronic inflammation inhibits the regeneration of dystrophic muscle, but the properties of inflammatory cells are not well understood in the context of normal muscle aging. This work uncovers pronounced age-specific changes in the expression of osteopontin (OPN) in CD11b+ macrophages present in the injured old muscle as well as in the blood serum of old injured mice and in the basement membrane surrounding old injured muscle fibers. Furthermore, young CD11b+ macrophages enhance regenerative capacity of old muscle stem cells even when old myofibers and old sera are present; and neutralization of OPN similarly rejuvenates the myogenic responses of old satellite cells in vitro and notably, in vivo. This study highlights potential mechanisms by which age related inflammatory responses become counter-productive for muscle regeneration and suggests new strategies for enhancing muscle repair in the old."

Tuesday, September 4, 2012
Via the New Scientist: "For the first time, people with broken spines have recovered feeling in previously paralysed areas after receiving injections of neural stem cells. Three people with paralysis received injections of 20 million neural stem cells directly into the injured region of their spinal cord. The cells, acquired from donated fetal brain tissue, were injected between four and eight months after the injuries happened. The patients also received a temporary course of immunosuppressive drugs to limit rejection of the cells. None of the three felt any sensation below their nipples before the treatment. Six months after therapy, two of them had sensations of touch and heat between their chest and belly button. The third patient has not seen any change. ... The fact we've seen responses to light touch, heat and electrical impulses so far down in two of the patients is very unexpected. They're really close to normal in those areas now in their sensitivity. ... The sensory gains, first detected at three months post-transplant, have now persisted and evolved at six months after transplantation. We clearly need to collect much more data to demonstrate efficacy, but our results so far provide a strong rationale to persevere with the clinical development of our stem cells for spinal injury. ... We need to keep monitoring these patients to see if feeling continues to affect lower segments of their bodies. These are results after only six months, and we will follow these patients for many years. ... There could be several reasons why the stem cells improve sensitivity ... They might help to restore myelin insulation to damaged nerves, improving the communication of signals to and from the brain. Or they could be enhancing the function of existing nerves, replacing them entirely or reducing the inflammation that hampers repair."

Monday, September 3, 2012
Suitable genetic engineering of telomerase can extend life in mice, but it isn't a straightforward process, and it is unclear as to how this would translate to humans given the complex relationship between telomere biology and aging on the one hand and the differences between humans and mice on the other: "The absence of telomerase [and consequent] telomere shortening in somatic cells plays a controversial role in mammalian aging. On the one hand, genetic knockout of telomerase function in mice has little noticeable effect on the aging of first-generation mutants. Serious phenotypic consequences are seen only in the fourth through sixth generations of such mutants when premature aging-associated phenotypes appear. This is because the normal length of mouse telomeres is sufficient for several mouse life spans, including all of the cell divisions associated with development. On the other hand, ectopic expression of the catalytic subunit of telomerase (telomerase reverse transcriptase, TERT) in epithelial cells has been reported to extend life span by up to 40% in mice engineered to be cancer-resistant. Unfortunately, ectopic expression of TERT in wild-type mice or mutations in human TERT increase cancer risk. There is evidence that active telomerase [and consequently] long telomeres protect cells from the metabolic and mitochondrial compromise that occurs when shortened telomeres induce p53 ... Ironically, shortened telomeres also result in increased cancer rates, probably due to increased genomic instability. Consistent with a homeostatic mechanism is the observation that telomerase reactivation has been shown to partially reverse tissue degeneration in aged telomerase-deficient mice (fourth generation). There is a paradox here: Mouse chromosomes possess enough reserve telomere length to fuel cell divisions for up to six organismal generations, yet mice apparently have at least a subset of cells in which dysfunction is linked to shorter telomeres and/or the absence of telomerase within a single life span. This paradox relates to the critical question of whether sufficient clinical benefit could result from ectopic telomerase expression in human aging and in diseases associated with shortened telomeres ... Of course, one potentially important difference is that humans have significantly shorter telomeres than mice."

Monday, September 3, 2012
A short article on longevity science than manages to miss most of the interesting work presently taking place by focusing on the mainstream of metabolic manipulation to slow aging and researchers who talk about compression of morbidity without extending life: "As scientists make new breakthroughs in understanding the mechanics of aging, the upper limits of aging might be changing for Homo sapiens. Already, life expectancy has increased dramatically since the late nineteenth century, when it was 40 for males and 42 for females at birth, and age 58 and 59 respectively if they survived to age 10 (infant mortality was much higher in 1890). Life expectancy is expected to keep rising to perhaps age 100 sometime in the 22nd century, according to the United Nations. This comes from better hygiene and nutrition, and also from bio-med breakthroughs that range from antibiotics to targeted therapies for cancer and robotic surgery. Is it possible that new waves of discoveries might take us on a path of even more dramatic increases in life extension? Until recently, mainstream scientists would have answered with an emphatic no, suggesting that this was a fantasy offered up by alchemists, charlatans, and pseudo-scientists. Two trends have shifted this point of view. The first is a realization that aging is one of the greatest risk factors for many diseases, and therefore needs to be seriously addressed by biomedical researchers. Not with a primary endpoint of radically prolonging life, which remains controversial, but as a major element of conventional research into understanding and combating cancer, diabetes, heart disease, and other chronic diseases of the elderly. The second trend is that scientists have succeeded in upping the lifespan of many animals, sometimes dramatically, discoveries that have launched wide-ranging research into the mechanics of aging. The big question is: Can these processes be replicated in humans?"



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