Fight Aging! Newsletter, November 3rd 2014

November 3rd 2014

Herein find a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress on the road to bringing aging under medical control, the prevention of age-related disease, and present understanding of what works and what doesn't when it comes to extending healthy life. Expect to see summaries of recent advances in medicine, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more.

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  • The Most-Cited Near Future Directions in Aging Research
  • A Profound Lack of Ambition When it Comes to Longer Lives
  • Impact of Lifelong Cytomegalovirus Infection on Aging
  • The Role of Immune Cells in Enhanced Regeneration of Organs
  • Recent Metastasis Research
  • Latest Headlines from Fight Aging!
    • Decellularization in Blood Vessel Transplants
    • An Interesting View of Mitochondrial Damage and Disease
    • Boosting FoxO1 to Treat Pulmonary Hypertension
    • Challenges in Using Old Tissue and Cells in Treatments
    • mTOR Signaling and Menopause
    • Cross-Links Stiffen the Extracellular Matrix With Age
    • Tissue Engineering of Small Stomachs for Research
    • Primary Age-Related Tauopathy
    • Dementia as a Consequence of Many Small, Unnoticed Strokes
    • Achieving Immortality by Ending Aging


Citations in an academic paper have some similarities to links in the web, or at least in the case where those links are a result of human choice and consideration. Considered in the abstract, a citation is a vote of attention rather than an opinion on the contents of the cited paper. To find out what the author actually thinks you'd have to read and understand the paper, something that is largely beyond today's expert systems software. If you want to systematically analyse academic sentiment in a field, however, even one as comparatively small as aging research, software is nonetheless what you will be using. There are too many people making too many citations to go about this in any other way.

The group of researchers quoted below took a hybrid approach to the challenge of a more rigorous determination of the consensus position of what comes next for aging research. They used the web of citations to find a handful of the most cited papers - a very simple piece of automated analysis - and then processed the contents of those papers with the Mark I Human Brain. This is the present best of both worlds: take advantage of the tasks that computers find easy and the tasks that we humans find easy and merge the work somewhere in the middle. The processing cycles of graduate students, much like those of modern computers, are cheap and widely available these days.

If you make a habit of following my litany of complaints about the state of the field of aging research then the results of this analysis of the mainstream focus will come with few surprises attached. It is all about gently slowing aging through manipulation of metabolism, establishing greater knowledge of the fine details of metabolic changes with aging, use of stem cells, telomere biology, and and some items relating to present day treatment strategies for the most common age-related conditions, such as type 2 diabetes and heart disease. The class of aging research I favor, repairing the cellular damage that causes aging after the SENS model, is still barely gaining a foothold as a coherent strategy in the bigger picture. That is the only path towards true rejuvenation of the old and prevention of age-related disease, however, as present approaches are merely going to make the old slightly less impacted by the processes of damage accumulation that are eating them alive.

Of modern medical research, stem cell research, cancer research, and probably immunology are about the only fields with sizable factions that are heading more or less in the right direction, working on classes of treatment that might actually be considered damage repair. That's two and half distinct damage processes out of seven and a half or so that make up aging, depending on who is counting. A lot more has to be accomplished yet.

Aging and energetics' 'Top 40' future research opportunities 2010-2013

Energetics can be defined as the study of the causes, mechanisms, and consequences of the acquisition, storage, and utilization of metabolizable energy by biological organisms. The United States - indeed the world - is currently undergoing a crisis of excess energy storage, sometimes called the obesity epidemic. A consistent finding from ecology, basic laboratory science, and epidemiologic research is that aspects of energetics, including the perceived and actual availability of food, the ingestion of food, the composition of the food consumed, the amount of body energy accreted and expended, affect disease and disability, senescence, mortality rate, and longevity.

To identify research priorities and opportunities in the domain of aging and energetics as advocated in the 40 most cited papers related to aging and energetics in the last 4 years. The investigators conducted a search for papers on aging and energetics in Scopus, ranked the resulting papers by number of times they were cited, and selected the ten most-cited papers in each of the four years that include 2010 to 2013, inclusive.

Ten research categories were identified from the 40 papers. These included: (1) Calorie restriction (CR) longevity response, (2) role of mTOR (mechanistic target of Rapamycin) and related factors in lifespan extension, (3) nutrient effects beyond energy (especially resveratrol, omega-3 fatty acids, and selected amino acids), 4) autophagy and increased longevity and health, (5) aging-associated predictors of chronic disease, (6) use and effects of mesenchymal stem cells (MSCs), (7) telomeres relative to aging and energetics, (8) accretion and effects of body fat, (9) the aging heart, and (10) mitochondria, reactive oxygen species, and cellular energetics.

The paper is open access and contains a very readable overview of each of these areas. It is worth a look as a matter of interest. This is after all a fair cross-section of the work being funded today, to a first approximation, and which must largely be supplanted in the near future by damage repair approaches if we are to see significant gains in health human life span and meaningful treatments for age-related degeneration in the old within our lifetimes.


We live in an age of rapidly advancing biotechnology, and research communities are on the verge of developing actual, real, working rejuvenation treatments. Given the funding there are lines of research under way today that might take the ills of aging and turn them back. Yet most people really don't care all that much, and are even troubled by the idea that they might be able to live for decades longer in good health. Those who do spend time thinking on it are largely bedeviled by a profound lack of ambition, and spend their time talking about dietary modifications, lifestyle choices, and supplements mined from the natural world that cannot possibly achieve any meaningful difference in human life span.

A few years here and there, sure. Anyone can do that - just eat less. But adding decades to life can only come from future advances in medicine that are a radical departure from the present methods of treating age-related conditions. Rejuvenation will arise from repair of the root causes of aging, removing wastes and broken molecules within and around cells. This needs new gene therapies, new classes of drug that can interact with metabolic wastes that have gone largely neglected to date, and much more.

For those of us aware of what might be possible were much greater effort focused on repair of the cellular and molecular damage of aging, infographics such as the one linked below are somewhat depressing. Researchers could be figuring out how to revert the molecular damage in cells that causes age-related frailty and disease, with the goal of entirely eliminating these causes of pain and suffering from the human condition, but the public at large are hesitant to step beyond recommendations on whether or not to drink coffee or exercise a little more. Their boundaries of the possible are so narrow as to exclude any meaningful change through medical science. It is almost as though they don't want success:

A Handy Guide to Longer Living Through Science!

The grail of longevity research remains that elusive drug, food, personality trait or lifestyle change that will prolong robust, healthy life. It's not here yet.

You'll see analogous sentiments in the economic arena, a fear of change and an underlying echo of the belief that financial traditions and edifices are in some way more important than human life. Longevity is cast as bad news for no reason other than things must change, and bad decisions and bad entitlements will have to be unwound:

Americans Are Living Longer Than Ever. And That May Kill Your Pension

For the first time, both boys and girls born today can expect to see at least 90 years of age, according to revised mortality tables published on Monday by the Society of Actuaries. Middle age and old age have also stretched out. Half a century ago reaching age 65 meant automatic retirement and imminent infirmity. Today, millions of 65-year-olds aren't just in the workforce - they are reinventing themselves and looking for new pursuits, knowing they have many good years ahead. What is good news for humanity, though, sends tremors through the pension world. Every few extra years of life expectancy come with a price tag. Already, many private and public pension funds are woefully underfunded - and the new tables essentially mean they are even further behind.

All this noted, a great deal of progress in advocacy has in fact occurred in the past decade. Nonsense and low expectations are not universal, and discussion of rejuvenation and radical life extension is more commonplace than it was. The research community is in the early stages of a great tectonic shift in research strategy, moving from treating only the manifestations of aging to treating the underlying processes - and accepting that the goal is extension of healthy life spans, not just treating diseases. So some people are willing to look for more and call out those who are short-sighted, trapped in parochial visions of what is possible and plausible:

Why I Want to Live Past 75

The best thing about Ezekiel Emanuel's "Why I Hope To Die at 75" is that it calls attention to the most consequential development of our time, the aging of the American and global population. His argument is colorful and contrarian, but also based on 20th century assumptions. And, it is as misguided as it is unimaginative. For Emanuel's thesis to make sense, we must accept that "the miracle of longevity," which has been brought about by innovation, invention and human imagination, has run out of gas. In other words, his argument presupposes that what has enabled longevity has run its course and we're done making progress.

Let's recognize Dr. Emanuel's piece for what it is - a sweeping declaration of 21st century impossibility framed by what was achieved in the 20th century. It's a static view of the human condition, which is his basic mistake. Rather, human imagination that will fuel invention and innovation can continue to propel us to a healthier and more active life as we live to be 100 as a matter of course.


I don't normally point out funding press materials, preferring to focus on the other end of the research process, but this one, drawn to my attention by the Healthspan Campaign newsletter, contains a good overview of the current state of knowledge regarding the persistent herpesvirus called cytomegalovirus (CMV) and its role in immune aging. CMV is actually just about as innocuous and prevalent as herpesviruses get: most people are infected by the time they reach old age, and near all of them suffered no obvious and immediate consequences of that infection. Given the readership demographics here, I'd give even odds that you have CMV lurking in your tissues as you read this.

No obvious consequences is not the same as no consequences: the results of CMV infection are very real, just slow to appear. Like other herpesviruses, CMV can remain latent in the body and cannot be permanently cleared by the efforts of the immune system. One thesis on how it contributes to degeneration of the immune system is that ever more of the immune system's limited cohort of cells become specialized to attack CMV, with no resulting gain in that unending fight, leaving ever fewer cells able to tackle all of the other necessary tasks. In effect this is a sort of progressive misconfiguration of a programmable system, and a problem that might in the near future be addressed by selectively destroying these specialized cells. Some experiments conducted in recent years strongly suggest that this will spur the generation of replacement immune cells, and consequently a restoration of some lost functionality in the immune system.

This is a pretty compelling hypothesis given the evidence to date, but as for so much of everything that involves the immune system it is yet to be proven beyond a doubt. As for many of these sorts of things my preferred approach to investigation would be to fix the damage, here meaning removal of the CMV-specialized memory T cells, such as by adopting one of the targeted cell destruction technologies in the late stages of development in the cancer research community, and see what happens afterwards in tissue and animal studies. That of course is not the way things are done in the mainstream of research, where the tendency is to be much more conservative in adopting hypotheses for experimentation, and the first focus is on developing as complete an understanding as possible before building potential treatments. That may all lead to the same place in the end, or it may not - we shall see.

Impact of Lifelong Cytomegalovirus Infection on Aging and the Immune System Focus of UA Research

A virus that infects us when we're young and then hides in our cells throughout our lives without causing symptoms may weaken the ability of our immune system to defend against influenza, West Nile or other viruses as we age. "It is critically important to understand the causes and consequences of lifelong CMV infection for immunity and aging. CMV is present in 70 to 90 percent of people over 65, which by 2050 will translate into 70 million people in the United States and more than 1 billion people in the world." CMV has been associated with impaired immunity, increased morbidity due to cardiovascular diseases, and reduced lifespan and health span - the length of life spent in good health.

"Our research group recently showed that infection with only CMV, and no other acute or persistent viruses, causes defects in immune responsiveness to other infections and causes alterations in the naïve T cell receptor repertoire and impaired effector T cell responses. But the precise mechanism by which CMV affects naïve T cell responses remains incompletely understood. Our study seeks to define the cost, if any, of persistent CMV infection on immune function as we age and to begin to define ways to intervene against the negative effects of CMV in aging."

The adverse impact of lifelong CMV infection on the aging of T cells - a type of white blood cell essential to the functioning of the immune system - and the development of new immune responses could be due to a number of factors. "Improved control of CMV and/or reduction of CMV-specific [memory T cell] accumulation could be beneficial for immune defense, such as immune responsiveness to vaccination. But it is also possible that the virus actually helps the immune system in the younger age, while impairing it in older adults. The immune system works hard to keep the dormant CMV in check. We hypothesize that efficient CMV control will correlate with strong and successful responses to vaccination in humans and that individuals who use vast resources to control CMV will be less likely to respond well to vaccination."


Immune cells play an important role in regeneration, though this is yet another aspect of the immune system as a whole that is understood in outline but the all-important details remain a big blank space in the middle of the map. The interactions between the immune system and the rest of our biochemistry are very complex, to say the least, and cataloging them will no doubt keep hundreds of researchers busy for a few decades yet. There are many good reasons to dig into these details, and one of them is that immune cells and their behavior may have a lot to do with the very large differences in regenerative capabilities observed both between species and between embryonic and adult regeneration in the same species. It is quite possible that enhanced regeneration of organs in mammals might be obtained through nothing more than manipulation of immune cells, though it remains to be seen just how far this approach can take us.

Salamanders and zebrafish are both studied for their ability to regenerate entire organs, such as the heart and limbs. In both cases, the immune cells called macrophages have been shown to play a necessary role in this exceptional regeneration. Without them, lost tissue scars as it does in mammals rather than regenerating to form new replacement tissue structures. Some mammals have demonstrated enhanced regeneration with similarities to salamander regeneration, however, such as the genetically engineered MRL mice that lack the p21 gene. Given the connections between the immune system and tissue regrowth it is tempting to speculate on whether enhanced regeneration in the MRL mouse lineage has anything to do with p21's immune regulation roles. Sadly there is still too little data here to do more than speculate.

Below you'll find a more recent study that demonstrates immune cells to be responsible for a portion of the differences between mammalian embryonic and adult heart tissue regeneration. As you might be aware, the heart doesn't regenerate well at all in adults, but it's a whole different story in embryos. That's true for a range of tissues, in fact, but this work just covers the heart:

Heart's own immune cells can help it heal

The heart holds its own pool of immune cells capable of helping it heal after injury. Most of the time when the heart is injured, these beneficial immune cells are supplanted by immune cells from the bone marrow, which are spurred to converge in the heart and cause inflammation that leads to further damage. In both cases, these immune cells are called macrophages, whether they reside in the heart or arrive from the bone marrow. Although they share a name, where they originate appears to determine whether they are helpful are harmful to an injured heart. In a mouse model of heart failure, blocking the bone marrow's macrophages from entering the heart protects the organ's beneficial pool of macrophages, allowing them to remain in the heart, where they promote regeneration and recovery.

Researchers have known for a long time that the neonatal mouse heart can recover well from injury, and in some cases can even regenerate. If you cut off the lower tip of the neonatal mouse heart, it can grow back. But if you do the same thing to an adult mouse heart, it forms scar tissue. This disparity in healing capacity was long a mystery because the same immune cells appeared responsible for both repair and damage. Until recently, it was impossible to distinguish the helpful macrophages that reside in the heart from the harmful ones that arrive from the bone marrow.

The investigators found that the helpful macrophages originate in the embryonic heart and harmful macrophages originate in the bone marrow and could be distinguished by whether they express a protein on their surface called CCR2. Macrophages without CCR2 originate in the heart; those with CCR2 come from the bone marrow, the research showed. [The researchers] asked whether a compound that inhibits the CCR2 protein would block the bone marrow's macrophages from entering the heart. "When we did that, we found that the macrophages from the bone marrow did not come in. And the macrophages native to the heart remained. We saw reduced inflammation in these injured adult hearts, less oxidative damage and improved repair. We also saw new blood vessel growth. By blocking the CCR2 signaling, we were able to keep the resident macrophages around and promote repair. We have identified similar immune cell subtypes that are present in the human heart. We need to find out more about their roles in heart failure in patients and understand more about how macrophages that reside in the heart promote repair."


Most cancers kill through metastasis. It isn't the initial malignant tumor but rather the spread of its cells throughout the body to seed more growths that outpaces today's medical toolkit. Absent metastasis, most cancers would be far more controllable and far less deadly, and even last generation treatments like chemotherapy could be made more localized and less taxing on the patient. Thus while a way to block metastasis in a majority of cancers is not a cure, it is a worthwhile stepping stone to aim for. Many of the same considerations come into play as for research aimed at destroying cancer cells: are there common mechanisms involved in the dispersal of malignant cancer cells into the blood system; do these migrating cells have any common surface molecules or other distinguishing traits; how plausible is it to interfere in their activities without impacting normal tissues; and so forth.

Cancer research is well funded in comparison to other fields of medical science. While there is a lot of dead wood and waste, as is always the case given the large amounts of public funding, the field as a whole is heading in the right direction towards a robust suite of next generation treatments. For those of us not expecting a high chance of dealing with cancer for another couple of decades at least, the odds are good that we will have a comparatively smooth ride of it. It will be expensive and unpleasant in comparison to, say, avoiding cancer entirely, but targeted immunotherapies with few side effects and that work to produce cures in near every patient will be the order of the day. Metastatic cells will be sabotaged one way or another - either interrupted in their attempts to escape the primary tumor or chased down by targeted cell killers in the bloodstream. All in all it will be a far cry from today's late detection of cancer, standard treatments of radiotherapy and chemotherapy, and the poor odds faced by many patients.

These two items give a decent view into the sort of investigations into metastasis taking place today. Greater understanding and better tools are emerging as researchers search for ways to intervene in the underlying processes driving metastasis so as to prevent cancers from spreading:

Decoding the emergence of metastatic cancer stem cells

Researchers have mapped how information flows through the genetic circuits that cause cancer cells to become metastatic. The research reveals a common pattern in the decision-making that allows cancer cells to both migrate and form new tumors. Researchers say the commonality may open the door to new drugs that interfere with the genetic switches that cancer must flip to form both cancer stem cells and circulating tumor cells - two of the main players in cancer metastasis. "Though some of the circuits for metastasis have been mapped, this is the first study to examine how cancer uses two of those circuits, in concert, to produce not just cancer stem cells, but also dangerous packs of hybrid stem-like-cells that travel in groups to colonize other parts of the body."

The switch that many cancer cells use to become metastatic is the circuit that governs the epithelial-to-mesenchymal transition, or EMT. The EMT, an important feature in embryonic development and wound healing, allows cells to revert back along their developmental path and take on certain stem-like features that allow them to form new tissues and repair tissue damage. [Researchers examined] the interaction between the three-way EMT switch and a second, well-documented genetic switch that gives rise to cancer stem cells (CSCs). The research showed that the CSC circuit also operates as a three-way switch. In addition, the study found "significant correspondence" between the operation of the two switches, which suggests a mechanism that would confer "stemness" on hybrid E-M cancer cells that are known to travel in packs called circulating tumor cells (CTCs).

The coupling between the two switches shows that two seemingly independent and distinct cellular programs - one that drives migration and a second that drives adaptation and tumorigenesis - are linked. "The existence of a link suggests that we may be able to simultaneously target both processes with innovative new therapies."

Viewing Cancer on the Move: New Device Yields Close-up Look at Metastasis

[Researchers] reported on successful tests that captured video of human breast cancer cells as they burrowed through reconstituted body tissue material and made their way into an artificial blood vessel. "There's still so much we don't know about exactly how tumor cells migrate through the body, partly because, even using our best imaging technology, we haven't been able to see precisely how these individual cells move into blood vessels. Our new tool gives us a clearer, close-up look at this process."

Researchers were able to record video of the movement of individual cancer cells as they crawled through a three-dimensional collagen matrix. This material resembles the human tissue that surrounds tumors when cancer cells break away and try to relocate elsewhere in the body. This process is called invasion. [The researchers] also collected video of single cancer cells prying and pushing their way through the wall of an artificial vessel lined with human endothelial cells, the same kind that line human blood vessels. By entering the bloodstream through this process, called intravasion, cancer cells are able to hitch a ride to other parts of the body and begin to form deadly new tumors.

"Cancer cells would have a tough time leaving the original tumor site if it weren't for their ability to enter our bloodstream and gain access to distant sites. So it's actually the entry of cancer cells into the bloodstream that allows the cancer to spread very quickly." Knowing more about this process could unearth a key to thwarting metastasis.


Monday, October 27, 2014

Given a donor blood vessel, researchers can strip it of its cells to leave just the extracellular matrix structure. This can then be repopulated with a patient's own cells, making it possible to transplant the blood vessel without risk of rejection. This is one of a number of applications of decellularization demonstrated in human trials in recent years:

Our study is a proof-of-concept clinical report of the successful recellularisation of two decellularised human blood vessels with autologous whole peripheral blood, which were subsequently used for a bypass procedure in two patients with portal vein thrombosis without the need for immunosuppression. The work is important conceptually because it provides early evidence for generating clinically useful personalized blood vessels using a simple blood sample from the patient.

Vascular diseases are increasing health problems affecting more than 25 million individuals in westernized societies. Such patients could benefit from transplantation of tissue-engineered vascular grafts using autologous cells. One challenge that has limited this development is the need for cell isolation, and risks associated with ex vivo expanded stem cells. Here we demonstrate a novel approach to generate transplantable vascular grafts using decellularized allogeneic vascular scaffolds, repopulated with peripheral whole blood (PWB) in vitro in a bioreactor. For clinical validation, two autologous PWB tissue-engineered vein conduits were prepared and successfully used for by-pass procedures in two pediatric patients. These results provide a proof of principle for the generation of transplantable vascular grafts using a simple autologous blood sample, making it clinically feasible globally.

In the present and other currently ongoing studies we have successfully recellularized veins using blood from individuals and patients in the age range of 4-55 years. However, it is reported that the numbers of circulating stem/precursor cells is decreased in patients with diabetes and end-stage renal diseases. So it remains to be tested whether this method would work in such patients. We did not detect any HLA antibodies after transplantation indicating satisfactory decellularization of the blood vessels. Both patients have been transplanted on compassionate grounds and therefore optimization of the technique has been on a "patient to patient" basis. We are currently seeking permits to carry out a clinical trial, which will include a larger number of patients to determine the efficacy of grafting tissue-engineered veins as vascular replacement therapy.

Monday, October 27, 2014

Mitochondria are the bacteria-like power plants of the cell, thousands to each cell, and each mitochondrion bearing its own DNA separate from that in the cell nucleus. Damage to this DNA is important in aging, and in a variety of diseases. Mitochondrial disease and mitochondrial contributions to degenerative aging are two very different things, however, for all that they both involve damage to mitochondrial DNA. In mitochondrial disease most of a patient's mitochondria have the same form of mutational damage, inherited from the mother or generated very early in embryonic growth. In aging the damage is random between cells, but there are certain forms of mutational damage that become amplified because they make a damaged mitochondrion more likely to survive and replicate in comparison to its undamaged peers.

Here is an interesting, albeit minority view on mitochondrial damage and how cells respond to it. It is of more relevance to mitochondrial disease, but there are aspects of it that might be informative with respect to cells in old tissues overtaken by damaged, dysfunctional mitochondria:

The new research shows that small changes in the ratio of mutant to normal mitochondrial DNA within the thousands of mitochondrial DNAs inside each cell can cause abrupt changes in the expression of numerous genes within the nuclear DNA. "By showing that subtle changes in the cellular proportion of the same mitochondrial DNA mutation can result in a wide range of different clinical manifestations, these findings challenge the traditional model that a single mutation causes a single disease. The research offers key insights into understanding the underlying cause of metabolic and neurodegenerative disorders such as diabetes, Alzheimer, Parkinson and Huntington disease, as well as human aging. The discrete changes in nuclear gene expression in response to small increases in mitochondrial DNA mutant level are analogous to the phase changes that result from adding heat to ice. As heat is added, the ice abruptly turns to water and with more heat, the water turns abruptly to steam."

[Researchers investigated] levels of a pathogenic mutation in one particular base of mitochondrial DNA. Researchers already knew that if 10 to 30 percent of a person's mitochondrial DNA has this mutation, a person has diabetes, and sometimes autism. Individuals with an mtDNA mutation level of 50 to 90 percent have other multisystem diseases, particularly MELAS syndrome, a severe condition which involves brain and muscle impairments. Above the 90 percent level, patients die in infancy. In the current study, conducted in cultured human cells, [the researchers] analyzed cells with different levels of this pathogenic mtDNA mutation to determine the effects on the gene expression of the cell. The researchers measured variations in cellular structure and function, nuclear gene expression, and production of different proteins.

The gene expression profile - the pattern of gene activity seen at the level at which mtDNA mutations trigger brain disorders - parallels the profiles found in Alzheimer, Parkinson and Huntington diseases. "The findings in this study provide strong support for the concept that common metabolic diseases such as diabetes and obesity, heart and muscle diseases, and neurodegenerative diseases have underpinnings in energy deficiencies from malfunctioning mitochondria. Thus this concept brings together a cluster of diseases previously considered to be separate from one another."

Tuesday, October 28, 2014

Researchers here uncover an interesting role for one of the forkhead box (FOX) proteins, and the potential basis for a treatment for pulmonary hypertension:

An estimated 100 million people worldwide suffer from pulmonary hypertension. The disease is characterised by progressive narrowing of the pulmonary arteries. The reduced diameter of the vessels leads to poor perfusion. The right ventricle tries to compensate by increasing its pumping action. This, in turn, increases the blood pressure in the pulmonary arteries. In the course of time, chronic overload damages the heart. The result is cardiac insufficiency, also known as congestive heart failure. Several forms of treatment developed in recent years aim mainly to alleviate the symptoms and relieve strain on the heart. Pulmonary hypertension, however, is still incurable, not least of all due to insufficient knowledge of what causes the disease at the molecular level.

[Scientists] have now achieved a major advance. In transcription factor FoxO1 they have identified a key molecule that plays a decisive role in the regulation of cell division in vascular wall cells and the lifespan of the cells. "The vessel walls of pulmonary arteries are constantly being renewed. A complex interplay of many factors normally ensures that the ratio between dividing and dying cells is balanced." The researchers found an important clue about the central role of FoxO1 in tissue samples from pulmonary hypertension patients: "In these patients, FoxO1 is not sufficiently active, so that the activity of various genes is not properly controlled. If we switch off FoxO1 by means of genetic or pharmacological intervention, the vascular wall cells divide more frequently." Consequently, pulmonary hypertension develops.

Reduced FoxO1 activity is therefore an important factor in the development of pulmonary hypertension. In further experiments it was found that certain growth factors and chemical messengers are responsible for reduced FoxO1 activity. Accordingly, pathological cell division in pulmonary vessel walls normalized when the researchers boosted FoxO1 activity. "Rats suffering from pulmonary hypertension were essentially cured." Based on these positive findings, the scientists are optimistic that the study findings can be used to develop a novel therapeutic approach.

Tuesday, October 28, 2014

Cell therapies and tissue engineering benefit from being able to use a patient's own cells as a starting point. If the patient is old, as is the case for most potential uses of regenerative medicine, cells are tissues are damaged and dysfunctional. To what degree is this an issue in the construction of treatments? It is clearly killing the patient by degrees, but one of the more promising signs for the near future of stem cell treatments in recent years has been that old stem cells appear to be capable of youthful action given the right cues. The cellular and molecular damage of aging is there, however, and other uses for a patient's own tissues are indeed impacted. This is why the stem cell research field is on a trajectory to understand and reverse aspects of aging in old tissues; they have to do this in order to ensure that the majority of possible treatments will work effectively:

Adipose tissue-derived microvascular fragments are promising vascularisation units for applications in the field of tissue engineering. Elderly patients are the major future target population of such applications due to an increasing human life expectancy. Therefore, we herein investigated the effect of aging on the fragments' vascularisation capacity. Microvascular fragments were isolated from epididymal fat pads of adult (8 months) and aged (16 months) C57BL/6 donor mice. These fragments were seeded onto porous polyurethane scaffolds, which were implanted into dorsal skinfold chambers to study their vascularisation.

Scaffolds seeded with fragments from aged donors exhibited a significantly lower functional microvessel density and intravascular blood flow velocity. This was associated with an impaired vessel maturation, as indicated by vessel wall irregularities, constantly elevated diameters and a lower fraction of CD31/α-smooth muscle actin double positive microvessels in the implants' border and centre zones. Additional in vitro analyses revealed that microvascular fragments from adult and aged donors do not differ in their stem cell content as well as in their release of angiogenic growth factors, survival and proliferative activity under hypoxic conditions. However, fragments from aged donors exhibit a significantly lower number of matrix metalloproteinase 9-positive perivascular cells. Taken together, these findings demonstrate that aging is a crucial determinant for the vascularisation capacity of isolated microvascular fragments.

Wednesday, October 29, 2014

Researchers are digging in to some of the proximate mechanisms that lead to menopause, and making some progress by the looks of it. This is a good example of the general approach to aging taken by the research community: start at the end stage manifestation of dysfunction, such as menopause, and work backwards through layers of metabolic changes in search of causes. These changes are reactions to cellular and molecular damage that is fairly well described at this time. Researchers have a good catalog of the fundamental differences between old tissues and young tissues, but for most outcomes in aging there is no good understanding in detail of exactly how this damage spirals out to produce the observed late stage results.

So how to go about filling this gap in understanding? Instead of trying to fix the damage and working forwards to see the results, researchers follow a strategy of working backwards from the end stages. The final state of knowledge will be the same, but this approach is far less likely to produce meaningful treatments: applications of partial knowledge of the late stages of disease leads to efforts to manipulate the operation of a complex system in order that it runs less poorly when damaged. It is patching a failing machine, hard, expensive and doomed to failure. Compare that with treatments that remove the damage: much simpler, and more likely to be effective. If your engine rusts, you remove the rust every now and again, not rebuild the engine to work slightly better while rusting into uselessness.

Some women can have successful pregnancies at the age of 50, whereas other are unable to get pregnant when they are 30. Researchers are not yet able to fully explain such differences. One factor is that the onset of menopause is influenced by the point at which the uterus runs out of eggs to release. A recent [study] sheds light on the mystery of the biological clock that governs fertility. Just as newborn infants require nurturance in order to survive, eggs in the uterus need nourishment and support from the granulosa cells of the primary follicle. According to the latest [discovery] a signaling pathway in these cells plays a key role in enabling immature eggs to survive.

The mTOR signaling pathway in the granulosa cells is necessary for activating expression of the kit ligand growth factor, which subsequently binds to the c-kit receptors of eggs and determines their fate. "This mechanism permits the granulosa cells to decide when eggs will begin to grow and when they will die. In that sense, they serve as a kind of biological clock that monitors the onset of menopause." Researchers believe that the discovery will point the way to interventions that stimulate the growth of eggs that have been unable to mature.

Wednesday, October 29, 2014

One of the root causes of degenerative aging is the accumulation of sugary metabolic wastes known as advanced glycation end-products that are in some cases very hard to for our evolved biochemistry to break down. Some types can form cross-links, gluing together important proteins such as those making up the supporting extracellular matrix scaffold. The properties of elastic tissues such as skin and blood vessel walls derive from the particular structure of the extracellular matrix, and cross-links degrade that structure, preventing it from functioning correctly. Their presence contributes to blood vessel stiffening with age and all the problems that result from that, for example, but there are plenty of other affected tissues.

The SENS approach to this contributing cause of aging is to build the necessary tools to work with the most common cross-link compound in human tissues, glucosepane. It is hoped that other research groups will pick up the work once they no longer have to start by building the very fundamental tools for the job. As things stand few research institutions are willing to start from scratch when there are so many other lines of research presently available that do not need a complete tool infrastructure built before anything can be accomplished.

Advanced age is associated with increases in muscle passive stiffness, but the contributors to the changes remain unclear. Our purpose was to determine the relative contributions of muscle fibers and extracellular matrix (ECM) to muscle passive stiffness in both adult and old animals. Passive mechanical properties were determined for isolated individual muscle fibers and bundles of muscle fibers that included their associated ECM, obtained from tibialis anterior muscles of adult (8-12 mo old) and old (28-30 mo old) mice. Maximum tangent moduli of individual muscle fibers from adult and old muscles were not different at any sarcomere length tested. In contrast, the moduli of bundles of fibers from old mice was more than twofold greater than that of fiber bundles from adult muscles at sarcomere lengths of more than 2.5 μm.

Because ECM mechanical behavior is determined by the composition and arrangement of its molecular constituents, we also examined the effect of aging on ECM collagen characteristics. With aging, muscle ECM hydroxyproline content increased twofold and advanced glycation end-product protein adducts increased threefold, whereas collagen fibril orientation and total ECM area were not different between muscles from adult and old mice. Taken together, these findings indicate that the ECM of tibialis anterior muscles from old mice has a higher modulus than the ECM of adult muscles, likely driven by an accumulation of densely packed extensively crosslinked collagen.

While looking at this research it is worth bearing in mind that short lived rodents have a different cross-link biochemistry in comparison to we long-lived humans. Early attempts to develop cross-link-breaking drugs floundered on this issue: promising results in rats didn't translate to human medicine at all. The overall picture of how this degeneration proceeds and why it happens is very similar, so there is much that can be learned, but the types of cross-link are different in ways that matter greatly for the development of treatments.

Thursday, October 30, 2014

The first stage of success in tissue engineering of any specific organ is to produce small sections of tissue that are close enough to the real thing to be used in research. Given a methodology to reliably produce these tissue sections from the starting point of a cell sample, they can be used in drug testing, to investigate the detail mechanisms of genetic diseases and aging, and similar applications. It is also possible that even small amounts of tissue can be the basis for some treatments, as patches for localized injuries that are resistant to regeneration:

Three-dimensional "mini-stomachs" have been created from human stem cells. The tiny organs measure about 3 millimeters in diameter and can be used as models for the infections that are often precursors to peptic ulcers and stomach cancer. "This represents the first in vitro model of the human stomach, and it's not a cute little term - they really do look like 'mini stomachs.'"

When the researchers first tried to grow these tissues, they did so using embryonic stem cells - cells that originate from a human embryo. The growth process, from start to finish, took about a month, [and] the end product was a small organ that contained human stomach tissue made of at least eight different cell types. But before the researchers could celebrate, they had to make sure the technique could be deployed using cells from adults as well, a critical step in ensuring that the technique can be tailored to fit a specific patient. It worked in those cells too.

[The researchers] have started exploring whether this tissue could be used to patch ulcers in mice. Stomach ulcers are essentially defects in the lining of the organs; in severe cases, they can be "patched" to avoid pain and internal bleeding. Right now, patching ulcers involves growing gastric tissues from a sample removed during a biopsy. [But] growing tissues from stem cells would allow researchers to bypass that step altogether, because they could start with cells taken from a patient's blood. "I think if our animal trials go well we could certainly scale up and start patching ulcers within the next ten years."

Thursday, October 30, 2014

Alzheimer's disease is the name given to the end state of rising amyloid levels in the brain: it is the stage at which the patient has a lot of amyloid and is severely impacted by it. But we will all suffer increased levels of amyloid to some degree, and we will all be negatively affected by it to some degree. This is similarly the case for the other protein aggregate involved in Alzheimer's disease, tau, that precipitates into tangles in brain tissue. Rising levels are a shared manifestation of aging, it is just that some people arrive at the pathological level much earlier. One of the objectives of repair based treatments that fix damaged clearance mechanisms or remove protein aggregates from tissues is to make this difference irrelevant - everyone should undergo the therapies every so often, and then no-one would have to worry about a future involving degeneration of the mind:

We recommend a new term, "primary age-related tauopathy" (PART), to describe a pathology that is commonly observed in the brains of aged individuals. Many autopsy studies have reported brains with neurofibrillary tangles (NFTs) that are indistinguishable from those of Alzheimer's disease (AD), in the absence of (Aβ) plaques. For these "NFT+/Aβ-" brains, for which formal criteria for AD neuropathologic changes are not met, the NFTs are mostly restricted to structures in the medial temporal lobe, basal forebrain, brainstem, and olfactory areas (bulb and cortex).

Symptoms in persons with PART usually range from normal to amnestic cognitive changes, with only a minority exhibiting profound impairment. Because cognitive impairment is often mild, existing clinicopathologic designations, such as "tangle-only dementia" and "tangle-predominant senile dementia", are imprecise and not appropriate for most subjects. PART is almost universally detectable at autopsy among elderly individuals, yet this pathological process cannot be specifically identified pre-mortem at the present time.

Improved biomarkers and tau imaging may enable diagnosis of PART in clinical settings in the future. Indeed, recent studies have identified a common biomarker profile consisting of temporal lobe atrophy and tauopathy without evidence of Aβ accumulation. For both researchers and clinicians, a revised nomenclature will raise awareness of this extremely common pathologic change while providing a conceptual foundation for future studies.

Friday, October 31, 2014

Dementia can result from age-related damage to the white matter in the brain, known as leukoaraiosis or white matter hyperintensities. Here researchers look at the source of this damage:

Approximately 50 per cent of older individuals have evident white matter damage on their medical imaging scans. For most patients, these changes are harmless but when this damage is severe, it can cause impairment. Previous studies have already established that the more white matter disease there is in the brain, the more likely patients are to have symptoms of dementia such as cognitive impairment or changes in behaviour. What was not understood is why this white matter disease develops - the traditional assumption was that it might be the result of the natural aging process.

The researchers conducted an intensive study to observe the development of this white matter disease over a short period of time, rather than on an annual basis - the interval at which previous studies have performed repeat brain imaging. The study involved 5 patients with white matter disease undergoing detailed MRI scanning of their brains every week for 16 consecutive weeks. The weekly MRI scans revealed new tiny spots arising in the brain's white matter that were, based on their MRI appearance, characteristic of small new strokes (cerebral infarcts). The lesions had no symptoms but, with time, came to resemble the existing white matter disease in the subjects' brains. In the study's random sampling, the majority of subjects had this phenomenon: Tiny strokes occurring without symptoms, and developing into the kind of white matter disease that causes dementia.

"The findings suggest that the tiny, silent strokes are likely much more common than physicians previously appreciated, and these strokes are likely a cause of the age-related white matter disease that can lead to dementia. We don't yet know whether these small strokes are responsible only some or most of the white matter disease seen in older patients. But in those where it is the cause, the detection of white matter disease on brain imaging should trigger physicians to treat patients aggressively when managing stroke risk factors such as high blood pressure, diabetes, high cholesterol, cigarette smoking and lack of exercise not only to prevent further strokes, but also to reduce the development of cognitive impairment over time."

Friday, October 31, 2014

Some people do seem to like to jump straight to talking about immortality as soon as the topic of extending human life comes up. Immortality here is meant in the sense of complete resistance to aging through medical technology capable of repairing the cellular and molecular damage that causes degenerative aging and all its symptoms and conditions. Near perfect repair is a long way out into the future - we'll get there by degrees, with prototype rejuvenation treatments that are steadily expanded and improved step by step over decades or centuries. Each new advance will allow us to live long enough to benefit from the next. We don't even have the prototypes yet, however, and most of the research community is not heading in the right direction to produce them. So there is a lot to be done yet in order to produce any meaningful benefits for those who are old and suffering, and that includes persuading the surprisingly large majority who think that aging and all the pain and death it causes should be left untouched:

The dream to live forever has captivated mankind since the beginning. We see this in religion, literature, art, and present day pop-culture in a myriad of ways. But all along, the possibility that we'd actually achieve such a thing never quite seemed real. Now science, through a variety of medical and technological advances the likes of which seem as far fetched as immortality itself, is close to turning that dream into a reality. This hour we talk with experts who are on the cutting edge of this research about the science and implications of ending aging.

What exactly is aging anyway? A natural process which is best, albeit unfortunately, left to itself? Or should we think of it more like a fatal disease - something to be cured at all costs like cancer or Ebola? And why not think of it as such? The fact is that aging kills more people and causes more suffering than all other sources combined. Does not the Hippocratic oath therefore compel medical experts to find its cure if they can? Or should the guiding principle, do no harm, more appropriately be applied to those who'll suffer the consequences if we were to actually end aging?

Whether you love life or simply fear death, chances are you've imagined what it would be like to live forever. What would you do with all that time? How would the world around you change? And speaking of the world around you, could it even sustain an immortal population? With densely packed mega-cities and resource shortages plaguing us already, how would society manage the extra burdens incurred by radical life extension? Some believe that longer life spans would lead to increased productivity and innovation; enough so to hedge against the burdens it would create. Others see longer life spans as a sure fire way to make an already challenging resource management problem even worse.


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