Fight Aging! Newsletter, December 23rd 2013

December 23rd 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!

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  • 3 to 1 Matching of SENS Research Donations Until Year End
  • Longevity Induces Virtue
  • Extending Life by Manipulating Metabolism Only Produces Dramatic Results in Short-Lived Species
  • December 2013 Issue of Rejuvenation Research
  • Increasing NAD to Reduce HIF-1 Reverses Age-Related Inflammation and Insulin Resistance in Muscle Tissue
  • A Brace of Papers from the Longevity Genetics Community
  • Latest Headlines from Fight Aging!
    • Targeting Tau With Antibodies in Alzheimer's Disease
    • A Look at the Damage Done By 7-ketocholesterol
    • Generating Functional Kidney Tissue From Stem Cells
    • Healthcare Costs Increase With Excess Weight
    • Blocking miR-712 to Treat Atherosclerosis
    • Considering the Data on Mitochondrial DNA Damage in Aging
    • Towards Printed Retinal Tissue
    • Natural Human Longevity is Accompanied by Increased Healthspan
    • Proposing a Microvascular Theory of Aging
    • Life Extension in Mice Via p66Shc Refuted


For the past month, Fight Aging!, Jason Hope, and the Methuselah Foundation have been matching up to $15,000 of donations to the SENS Research Foundation. This matching offer ends on 12/31/2013. Every $1 you donate is matched by $3, with the funds going to expand work on the foundations of tomorrow's rejuvenation therapies, treatments capable of preventing and reversing all aging-related disease and disability. Generous donors have contributed thousands of dollars in the past few weeks, and we're nearly at the goal with just one week left. So make your tax-deductible donation at the SENS Research Foundation website:


When you have more to lose, you behave in a more civilized fashion. This is a fair theory to explain why - despite the industrialization of war and nationalism - violence has in fact decreased over recorded history, even over the past century. We have on balance become much wealthier, and that includes a wealth of healthy years in comparison to our ancestors. This alters the balance of risk and reward in favor of trade, cooperation, patience, peace, and long-term over short-term gains.

Can we expect this trend to continue? I don't see why not. We are nowhere near the point at which a near-certainty of future longevity stretches ahead for so far that it is pointless to plan: there are still retirement funds and a structure of life that focuses relentlessly on a beginning, an industrious middle, and an end. Talk to me again when centuries are on the table, and we'll see how people approach things then from the perspective of foresight and organization.

Here is an article that argues for the benefits of longevity from the point of view of civics and the practical philosophy of living one's live as best one can - with an look at what lies beneath everyday to decisions to be humane and cultivated:

Life Extension and Risk Aversion

A major benefit of longer lifespans is the cultivation of a wide array of virtues. Prudence and forethought are among the salutary attributes that the lengthening of human life expectancies - hopefully to the point of eliminating any fixed upper bound - would bring about. Living longer renders people more hesitant to risk their lives, for the simple reason that they have many more years to lose than their less technologically endowed ancestors.

‚ÄčThis is not science fiction or mere speculation; we see it already. In the Western world, average life expectancies increased from the twenties and thirties in the Middle Ages to the early thirties circa 1800 to the late forties circa 1900 to the late seventies and early eighties in our time. As Steven Pinker writes in his magnum opus, The Better Angels of Our Nature, the overall trend in the Western world (in spite of temporary spikes of conflict, such as the World Wars) has been toward greater peace and increased reluctance of individuals to throw their lives away in armed struggles for geopolitical gain. Long-term declines in crime rates, automobile fatalities, and even smoking have accompanied (and contributed to) rises in life expectancy. Economic growth and improvements in the technologies of production help as well. If a person has not only life but material comfort to lose, this amplifies the reluctance to undertake physical risks even further.

When life is long and good, humans move up on the hierarchy of needs. Not starving today ceases to be a worry, as does not getting murdered tomorrow. The true creativity of human faculties can then be directed toward addressing the grand, far more interesting and technologically demanding, challenges of our existence on this Earth.

The less likely a failure is to rob one of opportunities forever, the more likely humans will be to pursue the method of iterative learning and to discover new insights and improved techniques through a beneficent trial-and-error process, whose worst downsides will have been curtailed through technology and ethics. Life extension will lead us to avoid and eliminate the risks that should not exist, while enabling us to safely pursue the risks that could benefit us if approached properly.

Of the virtues brought by greater longevity, greater prosperity and more rapid progress will do the most to shape our future for the better. We are a young species in the grand scheme of things, and there is much left to accomplish. Given success in rejuvenation biotechnology development of the sort undertaken by the SENS Research Foundation many of us alive today will live on to see a golden future in which we expand from this world to form a society of ageless trillions, wealthy beyond measure, and blessed with a near complete understanding of physics, chemistry, and biology. In the long term all that matters is knowledge and technology: everything else is fleeting, including our lives if we don't move rapidly enough towards practical rejuvenation treatments.


I'm sure that you noticed recent research results demonstrating a five-fold increase in life span in nematode worms. That's actually only half as long as the present record for that species, but both approaches involved tinkering with genes associated with insulin-like signaling, one of the better studied areas of intersection between metabolism, genetics, and aging. The press picks up on this sort of thing and uses it to wave around wild comparisons with hypothetical 500-year human life spans; wild comparisons in the headline attract attention regardless of merit, and the press is in the attention business, not the truth, sense, and accuracy business. There isn't any merit of course: one thing that is pretty clear from the data of the past couple of decades is that ways of manipulating metabolism to slow aging only have dramatic outcomes in very short-lived species.

A good example is manipulation of growth hormone metabolism, such as by removing the growth hormone gene, or interfering with gene expression of growth hormone, or by blocking or removing growth hormone receptor. In mice the best of these methods extends life by 60-70%. There is, however, an analogous natural mutation in the human growth hormone receptor that leads to Laron dwarfism. Those with the condition do not appear to live any longer than the rest of us, but may be resistant to some age-related disease. That is quite a climb-down in comparison to the results in mice.

But we can see the same sort of trend when comparing effects in worms with effects in mice: the best of the methods of slowing aging explored to date produce much greater results in nematodes, which of course normally live for a fraction of a mouse life span.

This should all make sense if considered from the perspective of evolution. Why would species evolve the ability to extend life in response to circumstances, or evolve a toolkit that allows for easier subsequent evolution of altered life span, or evolve a general adaptability of life span? The usual answer stems from consideration of the metabolic response to calorie restriction: for a short-lived species surviving a famine to reproduce later requires a great lengthening of life. For a long-lived species that survival doesn't require any lengthening of life, but it does require other types of short-term resistance to privation. So the evolutionary pressures that emerge from environmental changes that proceed on a timescale of seasons are very different for short-lived species, but they are sufficiently ubiquitous across all of evolutionary time to have very deep roots in our ancestry.

The evidence to date obtained from myriad ways of slowing aging in mice, flies, and worms suggest that we shouldn't be terribly excited by even a tenfold extension of healthy life through present genetic engineering or similar approaches when it occurs in very short-lived animals. There is no good reason at this time to expect any of these strategies to achieve results of great consequence in humans. Researchers may find therapies that improve upon present-day marginal treatments for age-related conditions, but that is about it - a very poor showing in the grand scheme of things.

The future of human life extension is very different from this work: it will be based on direct repair of damage rather than altering metabolism to slow the accumulation of damage. Aging is damage, and removing that damage should constitute a reversal of aging. However, we have at this point very little data to use to understand how damage repair will differ in its outcome between short-lived and long-lived species. It wouldn't be unreasonable to expect partial repair - such as, say, partial clearance of AGEs or replacement of mitochondrial DNA or removal of some fraction of senescent cells - to have more of an effect on mouse life span than on human life span. But more data is needed: clearly it is the case that ongoing perfect damage repair should have exactly the same effect in mice and people, the result being agelessness and indefinite healthy life span.


The latest issue of Rejuvenation Research is out this month. In the editorial, Aubrey de Grey of the SENS Research Foundation returns once more to a topic that puzzles many of us: the pervasive public disinterest when it comes to medical research to enable longer lives accompanies by extended health and youth.

Selling Anti-Aging Research: The Perils of Mixed Messages

A truth universally acknowledged within gerontology, as within any scientific discipline, is that the funding necessary for research in a given field is forthcoming from public sources only to the extent that the goals of such research are favored by the general public. As such, it has been a persistent source of frustration that biogerontology research remains rather far from the holy grail of delivering truly effective medical intervention, and thus that decision-makers over governmental research funding tend to deprioritize such research.

I strongly believe, based on my own quite extensive interaction with people from all walks of life who (for example) attend my talks, that the "Tithonus error" (that postponing aging would extend ill-health rather than health span) underpins most of the public's ambivalence concerning our field, despite gerontologists' vocal attempts to correct it. But be that as it may, the facts are these: fully 56% of the US public are unenthusiastic about living longer.

Maybe it's mostly the Tithonus error, but I must not overstate that case: in my experience, even those who are disabused of that misconception are uncannily prone to fall back on some other objection to such work (whether it be overpopulation, boredom, immortal dictators, whatever).

Over the decade I've been writing on this topic, I haven't come up with any better ideas on how to address this issue than to keep on bootstrapping and persuading: growing the number of supporters, writing more material, spreading knowledge, raising funds to further the production of research results that will help to persuade more people. It's a grind, but sooner or later the old, wrong ideas will suddenly wither away in the face of a significant number of people willing to call them out. All advocacy goes this way: when a cause seems to emerge from nowhere in the course of a few years, you can be certain that advocates were plugging away for the prior ten or twenty years, laying the groundwork, building arguments and support, and persuading a critical mass of people to join in, slowly but surely.

We've seen significant progress in attitudes to longevity science and extended lives over the years since the Methuselah Foundation and SENS Research Foundation have been in existence. But I still wish I had a better magic argument to open the eyes of those who hold to their disinterest in living longer. I don't think it exists, however: it really isn't a matter of facts. We have plenty of those, and they all support longer lives and the medical research needed to create greater human longevity. It is the stubborn resistance to even acknowledge the message of the research community that proves frustrating: for some years now researchers have been straightforwardly presenting healthy life extension as a plausible result of near future research - and yet all too few people care to listen.


There has been a fair amount of research into the effects of manipulating hypoxia-inducible factor 1 (HIF-1) in lower animals, mostly nematode worms I believe. Interestingly this is one of the few manipulations in which either reducing or increasing levels of the protein in question can increase longevity. This is a sign that there is probably significant complexity involved in this outcome, such as in relationships with other mechanisms or that the effects of changes are tied to specific tissues in the body or locations within cells.

Researchers are today announcing - and, I think, overhyping - new research into a way to manipulate HIF-1 that is apparently an offshoot of past and ongoing research into sirtuins and aging. When considering the source of the work, the overhyping is perhaps less of a surprise than it might otherwise be: this is a group with a very large sunk cost behind them and little to show for it. Deep pockets nonetheless still back continued efforts, and they have a lot of experience with the press. This is a formula that leads to breathless press materials touting rejuvenation. The people who are really, actually working on rejuvenation are more restrained these days.

So let's start by noting that I disagree with the title of the article quoted below. I think that (a) these researchers have found an interesting set of interactions to help explain why manipulation of HIF-1 can affect longevity, and (b) the changing levels of that and various related proteins with advancing age are responses to accumulated cellular damage. Perhaps the most relevant damage is mitochondrial, given that cycling of NAD is involved in the chain of unpleasant results that unfold when mitochondrial DNA becomes damaged, or perhaps it is something else.

So to my eyes what they focus on isn't a cause, it's a consequence. The fastest way to see what causes what at this point is to work on repairing the known forms of damage rather than tracing back all of the myriad complexity of relationships and feedback loops in the cell - a task that would take substantially longer than just building means of biological repair for our cells and other small-scale structures.

A New - and Reversible - Cause of Aging

Ana Gomes, a postdoctoral scientist in the Sinclair lab, had been studying mice in which [the] SIRT1 gene had been removed. While they accurately predicted that these mice would show signs of aging, including mitochondrial dysfunction, the researchers were surprised to find that most mitochondrial proteins coming from the cell's nucleus were at normal levels; only those encoded by the mitochondrial genome were reduced.

As Gomes and her colleagues investigated potential causes for this, they discovered an intricate cascade of events that begins with a chemical called NAD and concludes with a key molecule that shuttles information and coordinates activities between the cell's nuclear genome and the mitochondrial genome. Cells stay healthy as long as coordination between the genomes remains fluid. SIRT1's role is intermediary, akin to a security guard; it assures that a meddlesome molecule called HIF-1 does not interfere with communication.

For reasons still unclear, as we age, levels of the initial chemical NAD decline. Without sufficient NAD, SIRT1 loses its ability to keep tabs on HIF-1. Levels of HIF-1 escalate and begin wreaking havoc on the otherwise smooth cross-genome communication. Over time, the research team found, this loss of communication reduces the cell's ability to make energy, and signs of aging and disease become apparent.

While the breakdown of this process causes a rapid decline in mitochondrial function, other signs of aging take longer to occur. Gomes found that by administering an endogenous compound that cells transform into NAD, she could repair the broken network and rapidly restore communication and mitochondrial function. If the compound was given early enough - prior to excessive mutation accumulation - within days, some aspects of the aging process could be reversed.

Examining muscle from two-year-old mice that had been given the NAD-producing compound for just one week, the researchers looked for indicators of insulin resistance, inflammation and muscle wasting. In all three instances, tissue from the mice resembled that of six-month-old mice. In human years, this would be like a 60-year-old converting to a 20-year-old in these specific areas.


You'll find quite a few papers on longevity and genetics in the preprint queue of Current Vascular Phamacology at the moment. This is a portion of the output of that part of the research community focused on developing a full understanding of the molecular biology of how aging progresses and varies between individuals and species. Biology is fantastically complex, and obtaining that full understanding will be a much, much more challenging endeavor than merely successfully treating or reversing aging.

Treating and even curing aging are goals that might be achieved without a full understanding of exactly how aging progresses. Consider this: you don't need anything even close to a full molecular model of the progression of rust to greatly extend the life of metal equipment through scrubbing and protective coating. Exactly the same argument about knowledge and action can be applied to biology and medicine. Knowing what the damage is and having a complete understanding of how that damage progresses to cause the visible symptoms of aging are two very different things, the latter much more complex than the former, and only the former actually needed to produce useful therapies.

Nonetheless, most of the present work and funding in the aging science community is focused on developing an understanding of how degenerative aging progresses, not on damage repair and treatment of aging. So most of the output of the research community looks much along the lines of these first few papers I'm going to point out today.

The Challenges in Moving from Ageing to Successful Longevity

During the last decades survival has significantly improved and centenarians are becoming a fast-growing group of the population. Genetic factors contribute to the variation of human life span by around 25%, which is believed to be more profound after 85 years of age. It is likely that multiple factors influence life span and we need answers to questions such as: 1) What does it take to reach 100?, 2) Do centenarians have better health during their lifespan compared with contemporaries who died at a younger age?, 3) Do centenarians have protective modifications of body composition, fat distribution and energy expenditure, maintain high physical and cognitive function, and sustained engagement in social and productive activities?, 4) Do centenarians have genes which contribute to longevity?, 5) Do centenarians benefit from epigenetic phenomena?, 6). Is it possible to influence the transgenerational epigenetic inheritance (epigenetic memory) which leads to longevity?, 7) Is the influence of nutrigenomics important for longevity?, 8) Do centenarians benefit more from drug treatment, particularly in primary prevention?, and, 9) Are there any potential goals for drug research?

Genes Of Human Longevity: An Endless Quest?

Human longevity is a complex trait which genetics, epigenetics, environmental and stochasticity differently contribute to. To disentangle the complexity, our studies on genetics of longevity were, at the beginning, mainly focused on the extreme phenotypes, i.e. centenarians who escaped the major age-related diseases compared with cross sectional cohorts.

In association studies on candidate genes many SNPs, positively or negatively correlated with longevity have been identified. On the other hand, the identification of longevity-related genes does not explain the mechanisms of healthy aging and longevity, but it opens a huge amount of questions on epigenetic contribution, gene regulation and the interactions with essential genomes, i.e. mitochondrial DNA and microbiota.

Centenarian Offspring: a model for Understanding Longevity

A main objective of current medical research is the improving of life quality of elderly people as priority of the continuous increase of ageing population. Accordingly, the research interest is focused on understanding the biological mechanisms involved in determining the positive ageing phenotype, i.e. the centenarian phenotype.

Centenarians have been used as an optimal model for successful ageing. However, it is characterized by several limitations, i.e. the selection of appropriate controls for centenarians and the use itself of the centenarians as a suitable model for healthy ageing. Thus, the interest has been centered on centenarian offspring, healthy elderly people. They may represent a model for understanding exceptional longevity for the following reasons: to exhibit a protective genetic background, cardiovascular and immunological profile as well as a reduced rate of cognitive decline than age-matched people without centenarian relatives.

Phenotypes and Genotypes of High Density Lipoprotein Cholesterol in Exceptional Longevity

A change in the lipoprotein profile is a metabolic hallmark of aging and has been the target for modern medical developments. Although pharmaceutical interventions aimed at lipid lowering substantially decrease the risk of cardiovascular disease, they have much less impact on mortality and longevity. Moreover, they have not affected death from other age-related diseases.

In this review we focus on high density lipoprotein (HDL) cholesterol, the levels of which are either elevated or do not decrease as would be expected with aging in centenarians, and which are associated with lower prevalence of numerous age-related diseases; thereby, suggesting a potential HDL-mediated mechanism for extended survival. We also provide an update on the progress of identifying longevity-mediating lipid genes, describe approaches to discover longevity genes, and discuss possible limitations. Implicating lipid genes in exceptional longevity may lead to drug therapies that prevent several age-related diseases, with such efforts already on the way.

It has to be said, however, that some areas of research are close enough to the development of actual rejuvenation treatments - those addressing at least some of the root cause damage of aging rather than downstream consequences - that even the scientific mainstream is coming around to the idea. The impact of cellular senescence on aging is one such field, as several obvious and existing applications of medical technology may aid in removal of the senescent cells that accumulate with age, and early work in mice confirms that such treatments should prove helpful:

Cellular Senescence in Ageing, Age-Related Disease and Longevity

Cellular senescence is the state of permanent inhibition of cell proliferation. There is mounting evidence that senescent cells contribute to ageing and age-related disease by generating a low grade inflammation state (senescence-associated secretory phenotype-SASP). Even though cellular senescence is a barrier for cancer it can, paradoxically, stimulate development of cancer via proinflammatory cytokines. There is evidence that senescent vascular cells, both endothelial and smooth muscle cells, participate in atherosclerosis and senescent preadipocytes and adipocytes have been shown to lead to insulin resistance.

Thus, modulation of cellular senescence is considered as a potential pro-longevity strategy. It can be achieved in several ways like: elimination of selected senescent cells, epigenetic reprogramming of senescent cells, preventing cellular senescence or influencing the secretory phenotype. Some pharmacological interventions have already been shown to have promising activity in this field.


Monday, December 16, 2013

Researchers here apply an immune therapy approach to clearing out misfolded or otherwise damaged tau proteins implicated in the pathology of Alzheimer's disease:

Tau aggregation occurs in neurodegenerative diseases including Alzheimer's disease and many other disorders collectively termed tauopathies. Trans-cellular propagation of tau pathology, mediated by extracellular tau aggregates, may underlie pathogenesis of these conditions.

P301S tau transgenic mice express mutant human tau protein and develop progressive tau pathology. Using a cell-based biosensor assay, we screened anti-tau monoclonal antibodies for their ability to block seeding activity present in P301S brain lysates. We infused three effective antibodies or controls into the lateral ventricle of P301S mice for 3 months.

The antibodies markedly reduced hyperphosphorylated, aggregated, and insoluble tau. They also blocked development of tau seeding activity detected in brain lysates using the biosensor assay, reduced microglial activation, and improved cognitive deficits. These data imply a central role for extracellular tau aggregates in the development of pathology. They also suggest that immunotherapy specifically designed to block trans-cellular aggregate propagation will be a productive treatment strategy.

Monday, December 16, 2013

One important component of aging is an inability of the body to break down some metabolic waste products that accumulate slowly over life. Small amounts are largely harmless, but by old age these accumulations become large enough and prevalent enough to cause disease. Atherosclerosis, for example, is associated with the buildup of oxidized cholesterols known as oxysterols, such as 7-ketocholesterol.

The SENS approach to removing this contribution to aging is medical bioremediation: find enzymes in wild bacteria species that can be adapted for use in human tissues to safely break down the problem waste products. Research has been ongoing at a low level of funding for a few years now, with 7-ketocholesterol as one of the early targets.

Here, researchers examine in more detail just how 7-ketocholesterol causes harm:

The damage of barrier tissues, such as the vascular endothelium and intestinal epithelium, may lead to disturbances of local immune homeostasis. The aim of the study was to assess and compare the effect of oxidized cholesterols (7-ketocholesterol and 25-hydroxycholesterol) on the barrier properties of human primary aortic endothelium (HAEC) and intestinal epithelium cells.

7-ketocholesterol [caused] extensive damage to the endothelial monolayer, while 25-hydroxycholesterol caused partial damage and did not affect the epithelial monolayer. 7-ketocholesterol, but not 25-hydroxycholesterol, increased endothelial cell apoptosis and decreased the viability of endothelial cells.

Oxidized cholesterols destroy the HAEC, but not the epithelial barrier, via cell apoptosis dependent on the site of oxidation. Damage to the endothelium by oxidized cholesterol may disrupt local homeostasis and provide open access to inner parts of the vascular wall for lipids, other peripheral blood-derived agents, and immune cells, leading to inflammation and atherogenesis.

Tuesday, December 17, 2013

Researchers continue to make progress in producing small amounts of functional organ tissue from stem cells. This is an early step on the way to creating whole organs from a patient's own cells, but producing larger amounts of tissue is still limited by the need for engineered blood vessel networks - something that is proving to be a challenge. Here, researchers show off progress in producing small but functional kidney structures:

[Scientists] have grown the world's first kidney from stem cells - a tiny organ which could eventually help to reduce the wait for transplants. The breakthrough, published in the journal Nature Cell Biology, followed years of research and involved the transformation of human skin cells into an organoid - a functioning "mini-kidney" with a width of only a few millimetres.

Scientists are hoping to increase the size of future kidneys and believe the resulting organs will boost research and allow cheaper, faster testing of drugs. Within the next three to five years, the artificial organs could be used to allow doctors to repair damaged kidneys within the body, rather than letting diseases develop before proceeding with a transplant.

The process for developing the kidney was "like a scientific approach to cooking". The scientists methodically examined which genes were switched on and off during kidney development and then manipulated the skin cells into embryonic stem cells which could "self-organise" and form complex human structures. "The [researchers] spent years looking at what happens if you turn this gene off and this one on," he said. "You can eventually coax these stem cells through a journey - they [the cells] go through various stages and then think about being a kidney cell and eventually pop together to form a little piece of kidney."

Tuesday, December 17, 2013

Past studies have shown that carrying around excess fat tissue harms you in all sorts of ways. One indirect way to measure the level of that harm is to look at medical costs - and indeed researchers have shown that lifetime medical costs increase when you are overweight, even though your life expectancy is reduced. Here is more of the same:

Health care costs increase in parallel with body mass measurements, even beginning at a recommended healthy weight. The researchers found that costs associated with medical and drug claims rose gradually with each unit increase in body mass index (BMI). Notably, these increases began above a BMI of 19, which falls in the lower range of the healthy BMI category. "Our findings suggest that excess fat is detrimental at any level."

Using health insurance claims data for 17,703 Duke employees participating in annual health appraisals from 2001 to 2011, the researchers related costs of doctors' visits and use of prescription drugs to employees' BMIs. Measuring costs related to doctors' visits and prescriptions, the researchers observed that the prevalence of obesity-related diseases increased gradually across all BMI levels. In addition to diabetes and hypertension - the two diseases most commonly associated with being overweight or obese - the rates of nearly a dozen other disease categories also grew with increases in BMI. Cardiovascular disease was associated with the largest dollar increase per unit increase in BMI.

The average annual health care costs for a person with a BMI of 19 was found to be $2,368; this grew to $4,880 for a person with a BMI of 45 or greater. Women in the study had higher overall medical costs across all BMI categories, but men saw a sharper increase in medical costs the higher their BMIs rose.

Wednesday, December 18, 2013

This work is characteristic of much of modern medical development in that it does nothing to address underlying root causes of an age-related condition, but rather finds a way to partially patch over this one end result at a fairly late point in the chain of consequences.

[Researchers] have developed a potential treatment for atherosclerosis that targets a master controller of the process. In a twist, the master controller comes from a source that scientists had thought was leftover garbage. It is a micro RNA molecule, which comes from an unused template that remains after punching out ribosomes - workhorse protein factories found in all cells.

The treatment works by stopping the inflammatory effects of disturbed blood flow on cells that line blood vessels. In animal models of atherosclerosis, a drug that blocks the micro RNA can stop arteries from becoming blocked, despite the ongoing stress of high-fat diet. The micro RNA appears to function similarly in human cells. "We've known that aerobic exercise provides protection against atherosclerosis, partly by improving patterns of blood flow. Now we're achieving some insight into how. Healthy flow tunes down the production of bad actors like this micro RNA. Targeting it could form the basis for a therapeutic approach that could be translated with relative ease compared to other drugs."

Micro RNAs were recently discovered to be able to travel from cell to cell, and thus could orchestrate processes such as atherosclerosis. Out of all the micro RNAs the researchers examined, one in particular, called miR-712, was the micro RNA most strongly induced by disturbed blood flow in the atherosclerosis model system. In response to disturbed or unhealthy blood flow, endothelial cells produce miR-712, the researchers found. miR-712 in turn inhibits a gene called TIMP3, which under healthy flow conditions restrains inflammation in endothelial cells.

Wednesday, December 18, 2013

These researchers are concerned about the state of data for mitochondrial DNA damage in aging, suggesting that the research community doesn't in fact have enough data to demonstrate that work in mice is fully relevant to the human molecular biology of aging in this case:

A significant body of work, accumulated over the years, strongly suggests that damage in mitochondrial DNA (mtDNA) contributes to aging in humans. Contradictory results, however, are reported in the literature, with some studies failing to provide support to this hypothesis. With the purpose of further understanding the aging process, several models, among which mouse models, have been frequently used. Although important affinities are recognized between humans and mice, differences on what concerns physiological properties, disease pathogenesis as well as life-history exist between the two; the extent to which such differences limit the translation, from mice to humans, of insights on the association between mtDNA damage and aging remains to be established.

In this paper we revise the studies that analyze the association between patterns of mtDNA damage and aging, investigating putative alterations in mtDNA copy number as well as accumulation of deletions and of point mutations. Reports from the literature do not allow the establishment of a clear association between mtDNA copy number and age, either in humans or in mice. Further analysis, using a wide spectrum of tissues and a high number of individuals would be necessary to elucidate this pattern.

Likewise humans, mice demonstrated a clear pattern of age-dependent and tissue-specific accumulation of mtDNA deletions. Deletions increase with age, and the highest amount of deletions has been observed in brain tissues both in humans and mice. On the other hand, mtDNA point mutations accumulation has been clearly associated with age in humans, but not in mice. Although further studies, using the same methodologies and targeting a larger number of samples would be mandatory to draw definitive conclusions, the revision of the available data raises concerns on the ability of mouse models to mimic the mtDNA damage patterns of humans, a fact with implications not only for the study of the aging process, but also for investigations of other processes in which mtDNA dysfunction is a hallmark, such as neurodegeneration.

Thursday, December 19, 2013

Researchers are working on tissue printing for structures in the retina, and this is an early proof of principle:

A group of researchers [have] used inkjet printing technology to successfully print cells taken from the eye for the very first time. The breakthrough [could] lead to the production of artificial tissue grafts made from the variety of cells found in the human retina and may aid in the search to cure blindness. At the moment the results are preliminary and provide proof-of-principle that an inkjet printer can be used to print two types of cells from the retina of adult rats - ganglion cells and glial cells. This is the first time the technology has been used successfully to print mature central nervous system cells and the results showed that printed cells remained healthy and retained their ability to survive and grow in culture.

"The loss of nerve cells in the retina is a feature of many blinding eye diseases. The retina is an exquisitely organised structure where the precise arrangement of cells in relation to one another is critical for effective visual function. Our study has shown, for the first time, that cells derived from the mature central nervous system, the eye, can be printed using a piezoelectric inkjet printer. Although our results are preliminary and much more work is still required, the aim is to develop this technology for use in retinal repair in the future."

Thursday, December 19, 2013

There has been an increasing level of research into natural variations in human longevity in recent years, largely focused on genetics and metabolism in long-lived families and populations. This produces a fair amount of epidemiological data too, which allows for this sort of analysis to be conducted:

Hypothesizing that members of families enriched for longevity delay morbidity compared to population controls and approximate the health-span of centenarians, we compared the health-spans of older generation subjects of the Long Life Family Study (LLFS) to controls without family history of longevity and to centenarians of the New England Centenarian Study (NECS).

We estimated hazard ratios, the ages at which specific percentiles of subjects had onsets of diseases, and the gain of years of disease-free survival in the different cohorts compared to referent controls. Compared to controls, LLFS subjects had lower hazards for cancer, cardiovascular disease, severe dementia, diabetes, hypertension, osteoporosis, and stroke.

The age at which 20% of the LLFS siblings and probands had one or more age-related diseases was approximately 10 years later than NECS controls. While female NECS controls generally delayed the onset of age-related diseases compared with males controls, these gender differences became much less in the older generation of the LLFS and disappeared amongst the centenarians of the NECS. The analyses demonstrate extended health-span in the older subjects of the LLFS and suggest that this aging cohort provides an important resource to discover genetic and environmental factors that promote prolonged health-span in addition to longer life-span.

Friday, December 20, 2013

It seems that everyone has their own theory of aging these days, something that might be taken as a sign of increased interest in the field:

One of the main features of human aging is the loss of adult stem cell homeostasis. Organs that are very dependent on adult stem cells show increased susceptibility to aging, particularly organs that present a vascular stem cell niche. Reduced regenerative capacity in tissues correlates with reduced stem cell function, which parallels a loss of microvascular density (rarefraction) and plasticity. Moreover, the age-related loss of microvascular plasticity and rarefaction has significance beyond metabolic support for tissues because stem cell niches are regulated co-ordinately with the vascular cells. In addition, microvascular rarefaction is related to increased inflammatory signals that may negatively regulate the stem cell population. Thus, the processes of microvascular rarefaction, adult stem cell dysfunction, and inflammation underlie the cycle of physiological decline that we call aging.

Observations from new mouse models and humans are discussed here to support the vascular aging theory. We develop a novel theory to explain the complexity of aging in mammals and perhaps in other organisms. The connection between vascular endothelial tissue and organismal aging provides a potential evolutionary conserved mechanism that is an ideal target for the development of therapies to prevent or delay age-related processes in humans.

Friday, December 20, 2013

There are many years of studies showing that p66Shc deficiency in mice produces resistance to a number of age related conditions, lowered inflammation, and extended life. Here, however, researchers undertake a more rigorous study and rule out life extension. This is a not infrequent event in the genetics of longevity: a result goes unchallenged for the better part of a decade only to be later refuted when more funding arrives due to increased interest.

The signaling molecule p66Shc is often described as a longevity protein. This conclusion is based on a single life span study that used a small number of mice. The purpose of the present studies was to measure life span in a sufficient number of mice to determine if longevity is altered in mice with decreased Shc levels (ShcKO). Studies were completed at UC Davis and the European Institute of Oncology (EIO).

At UC Davis, male C57BL/6J wild type and Shc knockout (ShcKO) mice were fed 5% or 40% calorie-restricted (CR) diets. In the 5% CR group, there was no difference in survival curves between genotypes. There was also no difference between genotypes in prevalence of neoplasms or other measures of end-of-life pathology. At 40% calorie restriction group, 70th percentile survival was increased in ShcKO, while there were no differences between genotypes in median or subsequent life span measures.

At EIO, there was no increase in life span in ShcKO male or female mice on C57BL/6J, 129Sv, or hybrid C57BL/6J-129Sv backgrounds. These studies indicate that p66Shc is not a longevity protein. However, additional studies are needed to determine the extent to which Shc proteins may influence the onset and severity of specific age-related diseases.


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