FIGHT AGING! NEWSLETTER
April 7th 2014
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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- A Few Papers in Regenerative Medicine and Tissue Engineering
- Long Term Calorie Restriction Very Beneficial in Primates
- The Rejuvenation Research Journal is Open Access
- What Can Rheumatoid Arthritis Teach Us About Normal Aging of the Immune System?
- Video: Aubrey de Grey at TEDxSalford
- Latest Headlines from Fight Aging!
- How to Help in the Fight Against Aging
- Genetics and Epigenetics of Aging and Longevity
- Working With Very Small Embryonic-Like Stem Cells
- Associating Arterial Stiffness and β-Amyloid Progression
- A Start on Manipulating the Mechanisms of Nerve Regrowth
- A Good Example of Failing to Control for Calorie Intake
- The State of Cancer Immunotherapy
- Cardiac Risks in Youth Associate With Worse Cognitive Function in Later Life
- Neuropeptide Y Required for Calorie Restriction Benefits
- A Novel Longevity-Associated Genetic Locus in Humans
A FEW PAPERS IN REGENERATIVE MEDICINE AND TISSUE ENGINEERING
Regenerative medicine and tissue engineering are fields that emerge from the growing ability to control cells and cellular behavior. Complete control over cells will one day be the basis for the vast majority of all medicine dealing with natural, unmodified humans. Little is left beyond that arena aside from the removal of metabolic waste products that cells are not equipped to destroy. However, this is a narrow view of the future. Long before complete cellular control is achieved researchers will already be modifying cells and their components: building better and more reliable machinery, augmenting or replacing the evolved components of a cell and a body one by one. So at the same time as fields emerging from cellular control take over near-all medicine, they themselves will be transformed and made obsolete by the growing ability to replace our evolved biology with something better.
But this dynamic will play out a way down the line. It is interesting to look ahead, and also to keep an eye on areas in which replacements for evolved cellular components could happen comparatively soon, such as in the development of artificial mitochondria. If you are interested in the impact on your future health and life, it is control over - and the ability to repair - our present biology that is the most important line of research and development. That is work that has the best chance of extending healthy life spans soon enough to matter to you and I.
There is a lot going on in the energetic fields of cell research, and it is fortunate that the interests of the researchers involved are largely aligned with those of life extension supporters. Most of the medical conditions that would benefit the most from cell therapies are age-related, and thus researchers have a strong incentive to figure out how to make their work effective in old tissues. This will require them to provide solutions for a number of the aspects of degenerative aging, such as the changes in signaling protein levels that reduce stem cell activity, the dysfunction of the aged immune system, and so forth. With that in mind, here is a random selection of recent work in regenerative medicine and tissue engineering.
Self-healing engineered muscle grown in the laboratory
Every muscle has satellite cells on reserve, ready to activate upon injury and begin the regeneration process. The key to the team's success was successfully creating the microenvironments - called niches - where these stem cells await their call to duty. "Simply implanting satellite cells or less-developed muscle doesn't work as well. The well-developed muscle we made provides niches for satellite cells to live in, and, when needed, to restore the robust musculature and its function."
To put their muscle to the test, the engineers ran it through a gauntlet of trials in the laboratory. By stimulating it with electric pulses, they measured its contractile strength, showing that it was more than 10 times stronger than any previous engineered muscles. They damaged it with a toxin found in snake venom to prove that the satellite cells could activate, multiply and successfully heal the injured muscle fibers.
New Penn-Designed Gel Allows for Targeted Therapy After Heart Attack
We used a microdialysis technique to show that, after a heart attack, local enzyme levels go way up, but when the inhibitor molecules are delivered via the gel, we see the activity level of this enzyme go down. Over the next 28 days, we also used imaging techniques to show thicker cardiac walls and less expansion and dilation of the ventricle. And, as a result, we see better performance in the heart using clinical measurements like ejection fraction, the amount of the blood the heart is pumping.
While most groups working in this field are attempting to develop myocardial regenerative therapies, our team is focused on the biomechanical stabilization of the heart after heart attack. Most researchers working towards regenerative therapies often overlook an important fact, namely, that the overwhelming majority of patients who suffer heart attack initially have adequate heart function. We strongly believe that optimizing the function of the surviving heart muscle after heart attack will be a more realistic and effective strategy than trying to regenerate the muscle that is lost.
New human trial shows stem cells are effective for failing hearts
The study is the largest placebo-controlled double-blind randomized trial to treat patients with chronic ischemic heart failure by injecting a type of stem cell known as mesenchymal stromal cells directly into the heart muscle. The study included 59 patients with chronic ischemic heart disease and severe heart failure.
Six months after treatment, patients who received stem cell injections had improved heart pump function compared to patients receiving a placebo. Treated patients showed an 8.2-milliliter decrease in the study's primary endpoint, end systolic volume, which indicates the lowest volume of blood in the heart during the pumping cycle and is a key measure of the heart's ability to pump effectively. The placebo group showed an increase of 6 milliliters in end systolic volume.
LONG TERM CALORIE RESTRICTION VERY BENEFICIAL IN PRIMATES
Calorie restriction improves health and extends life in nearly all shorter-lived species examined to date. In mice life span can be extended by 40% or more this way, but theorists don't expect an outcome of the same magnitude to take place in human calorie restriction practitioners. Firstly, our ancestors would certainly have noticed such a large effect at some point in the past few thousand years, and at the very least in the past few hundred. Secondly, longevity resulting from calorie restriction is thought to have evolved to enable greater resistance to seasonal shortages of food. A season is a short time for a human, but a long time for a mouse - and thus only the mouse has the evolutionary pressure to develop a very plastic life span in response to food availability.
Nonetheless, the calorie restriction response evolved very early on in the tree of life, and the short term effects in mice and humans are surprisingly similar. In human studies from recent years the practice of calorie restriction is shown to produce very favorable changes to metabolism and health, far greater and better than can be achieved with any present drug or medical technology. It's the same situation as exists for exercise: if either were a drug it would outsell every pharmaceutical created to date. But trying telling people they should exercise more and eat less and see how far you get.
Short-term studies are one thing, but studying calorie restriction over the long term in long-lived species is a big investment. A pair of primate studies that record the effects of calorie restriction on health and life span started decades ago and are still underway. One runs under the auspices of the NIA, the other at the University of Wisconsin-Madison. You may recall that the NIA researchers published results back in 2012 that suggested calorie restriction does not in fact have any significant effect on primate longevity. Some of the research community have in turn pointed out that the NIA study has potential issues, but I won't rehash all of that here as it is covered in the article quoted below. You might look back at these posts for background:
- Considering a Negative Result for Primate Calorie Restriction
- No Extension of Average Lifespan in Primate Study of Calorie Restriction
The latest results from the Wisconsin-Madison study have now been published, and they are more positive and more in line with what we'd expect based on short term response to calorie restriction in primates, humans included.
Monkey Caloric Restriction Study Shows Big Benefit; Contradicts Earlier Study
The latest results from a 25-year study of diet and aging in monkeys shows a significant reduction in mortality and in age-associated diseases among those with calorie-restricted diets. The study of 76 rhesus monkeys was performed at the Wisconsin National Primate Research Center in Madison. When they were 7 to 14 years of age, the monkeys began eating a diet reduced in calories by 30 percent. The comparison monkeys, which ate as much as they wanted, had an increased risk of disease 2.9 times that of the calorie-restricted group, and a threefold increased risk of death.
Still, the effects of caloric restriction on primates have been debated. An influential 2012 report on 120 monkeys being studied at the National Institute of Aging (NIA) reported no differences in survival for caloric restriction animals and a trend toward improved health that did not reach statistical significance.
The discrepancy may be a result of how the feeding was implemented in control animals in the NIA study. "In Wisconsin, we started with adults. We knew how much food they wanted to eat, and we based our experimental diet on a 30 percent reduction in calories from that point." In contrast, the NIA monkeys were fed according to a standardized food intake chart designed by the National Academy of Science. The Wisconsin researchers concluded that the NIA controls were actually on caloric restriction as well. "At all the time points that have been published by NIA, their control monkeys weigh less than ours, and in most cases, significantly so."
Twenty monkeys entered the NIA study as mature adults, 10 in the test group and 10 in the control group, and five of these (four test monkeys and one control monkey) lived at least 40 years. "Heretofore, there was never a monkey that we are aware of that was reported to live beyond 40 years. Hence, the conclusion that caloric restriction is ineffective in their study does not make sense to me and my colleagues."
This should all be filed away under basic good health practices. Yet calorie restriction, including attempts to recreate its effects on metabolism through drugs and targeted manipulation of gene expression, is the not the path to greatly extended longevity. It is among the best of presently available paths to raising your odds of having a better old age, which is good in and of itself, but you can't calorie restrict yourself to a decent chance of living to see 100. A good 99% of the people with the best diets and lifestyles die without seeing a century of life. The only thing that will make a significant difference to your prospects of great and healthy longevity is faster progress towards rejuvenation treatments - ways to prevent and reverse the course of aging. They don't exist yet, but they could in the decades ahead. Here and now that means fundraising and advocacy: pushing SENS and similar repair-based approaches to treating aging into the research mainstream.
THE REJUVENATION RESEARCH JOURNAL IS OPEN ACCESS
The Rejuvenation Research journal is completely open access as of when I looked it over today. I believe that to be a fairly recent change, so those of you without subscriptions might want to wander through the archives in search of interesting reading. In particular you might find the editorials by Aubrey de Grey to be well worth reading, and looking over those articles should provide great deal of insight into the state of aging research and the related noteworthy tensions and debates within the scientific community. Below is quoted the most recent editorial (in PDF format only, I'm afraid to say), followed by a couple of others that you may also find worthwhile:
The Real End of Ageism (PDF)
The "isms" are not so easily consigned to history, as anyone who belongs to any of the respective groups knows all too well. But ageism has a particular distinction: the group most guilty of it is precisely those affected by it, i.e. the elderly themselves.
Really? How can I make such a claim? Surely the elderly are vocal in defence of their rights to be treated as equals with the young? In many ways they certainly are. But bizarrely, when it comes to their health everything is different. They tend to the view that medical care should be prioritized for those who have not yet enjoyed a good innings. If you haven't encountered this yourself and don't believe me, try it: talk about it to a few retirees and you're in for a shock.
Let's look under the hood a bit. Why would the elderly take this view? It turns out to be very easy to explain. In a world in which aging is truly inevitable, forever, there is a pretty solid ethical basis for the idea that equitable distribution of aggregate quality of life among all people translates into working harder to maintain or restore the health of the young than the old, simply because they have more to gain before the inevitable final curtain falls. And that's exactly the premise that the elderly are non-randomly more likely than the young to adopt, since they've had that much longer having it drilled into them by the rest of humanity. They've lost the ability to aim high.
So I come to my call to action. Throughout history, humanity has only acted energetically against discrimination when those who are suffering it led the way. Therefore, we need to change this attitude on the part of the elderly, and fast, if we are to maximize humanity's cognizance of the horror of aging and its urge to defeat it as soon as science allows. We need to make the aged less ageist. And the only way we can do it is by educating them that aging is within striking distance of being brought under comprehensive medical control: the same sort of control that they are familiar with - but their parents, or at least their grandparents, were not - in respect of the diseases, such as tuberculosis and diphtheria, that back then claimed over one third of all babies before the age of one.
Selling Anti-Aging Research: The Perils of Mixed Messages
In practice, researchers do make estimates of probabilities of success all the time - in choosing what projects to work on, in evaluating each other's work during peer review, etc. So the issue here is actually not the assessment itself, but the publicizing of the assessment. Researchers in aging are acutely aware of the intense hope with which their work is followed by the wider world, and are paralyzed by fear of over-selling and under-delivering, which (they presume) would result in their being painted as no better than the purveyors of miracle anti-aging cures of time immemorial.
To me, it is that attitude which is reprehensible. Whether or not it is true [that] the loss of reputation arising from such over-selling (if it turned out so to be) would be so awful as to outweigh the funding considerations, that dilemma is between two purely selfish motives - money now and notoriety-driven shortage of money later, or less money now but reputation untarnished. What my colleagues should, in fact, be asking themselves is how they can best repay society for its decision to give them their chosen life of freedom from the private-sector rat race. (I will not digress into whether the academic rat race is any better.) I submit that the answer is clear: Researchers should say what they actually think. At present, it is customary for researchers to dangle the carrot of success in our research without mentioning time frames, thus conveniently protecting themselves from any chance of being seen as overoptimistic, but also failing to engender the public enthusiasm so vital for allowing the necessary research to actually happen. This cannot be allowed to continue.
Late-Onset, Preventative, Combination Treatments: The Triple Challenge Facing the Most Promising Anti-Aging Research Paradigm
There is no doubt whatsoever that therapies that significantly delayed the onset of age-related ill-health would be by far the most cost-effective category of medicine in history, whether that cost is measured in dollars or in human suffering. It is thus a paradox that so little effort is expended by governments or the private sector in the quest to develop such therapies, as compared to the vast amount spent on the very modestly effective treatments for age-related diseases and disability that we have today or on the equally modest prospective improvements on those treatments that disease-specific researchers aim to develop. I do not claim originality for this observation.
I believe that the main reason for this ostensibly misguided caution is that biogerontologists simply do not have good evidence that such a quest would even modestly succeed, even with a dramatic rise in the funds allocated to it. Though they are quite good at convincing themselves and each other of the promise of hypothetical "magic bullet" interventions - the most popular within the field being drugs that would mimic calorie restriction (CR) - they essentially never convince anyone with purse strings to hand. In my view, this is not because they lack marketing eloquence or motivation, but because the hard facts do not inspire objective confidence that successes seen thus far in the laboratory will ever, even in principle, translate to the clinic. The recent negative results in primate calorie restriction have surely rendered this problem even more intractable.
WHAT CAN RHEUMATOID ARTHRITIS TEACH US ABOUT NORMAL AGING OF THE IMMUNE SYSTEM?
Rheumatoid arthritis is characteristically a disease of young women, as I was once told by an old man in the medical profession. That is a little of an exaggeration, but autoimmune diseases are not age-related by and large. Can they teach us anything about aging, however?
With this question in mind, you might think of accelerated aging conditions such as progeria, conditions that are not in fact accelerated aging, despite appearances, but rather a single form of damage run amok due to genetic mutation. In the case of progeria, this damage involves malformed lamin proteins, something that does seem to occur in a very minor way in normal aging. Researchers are still digging in to what might be learned there - it remains elusive as to whether this is in any way important, or a cause or a consequence, in normal aging.
Another example is the study of type 2 diabetes. This is a condition often used as a proxy for aging in animal studies, as the effect on some measures of health is to speed up the normal decline. But that doesn't mean it is accelerated aging any more than is progeria. Aging is cellular and molecular damage and the consequences of that damage. There are lots of ways to induce damage in an organism, but that doesn't mean that the type of damage you are looking at has any great relevance to aging. Some do, some don't, and some have only a very narrow relevance in some cases. It all depends on the details.
Back to rheumatoid arthritis, as there are researchers who argue that some of its effects can be categorized as an accelerated aging of the immune system. A fair fraction of the frailty of age stems from vulnerability to infections and a growing inability of the immune system to clear out senescent and potentially cancerous cells. As long-term readers will know by now, the immune system malfunctions with age for reasons that are at least partially structural, falling into a state of chronic inflammation coupled with increasing ineffectiveness. The question for today is whether the forms of damage and malfunction exhibited in rheumatoid arthritis are at all relevant to the normal progression of immune aging: the result looks like accelerated aging at the high level, in terms of reduced function and changes in various measures, but is there actually any overlap in the type of causative damage involved?
Some opinions on the subject follow in an open access paper, but it's worth remembering that rheumatoid arthritis might be one of the least understood of the common autoimmune conditions. Despite a great deal of work, researchers haven't yet resolved its causes or more than a fraction of the mechanisms involved in driving the condition. It may even be several quite distinct conditions lumped under this one heading, all with a similar outcome but deriving from different origins. It's a complex field, one with plenty of room for debate in the absence of a full picture that joins all of the puzzle pieces together.
Targets of Immune Regeneration in Rheumatoid Arthritis
Many of the aging-related morbidities, including cancer, cardiovascular disease, neurodegenerative disease, and infectious susceptibility, are linked to a decline in immune competence with a concomitant rise in proinflammatory immunity, placing the process of immune aging at the center of aging biology. Immune aging affects individuals older than 50 years and is accelerated in patients with the autoimmune disease rheumatoid arthritis.
Immune aging results in a marked decline in protective immune responses and a parallel increase in tissue inflammatory responses. By studying immune cells in patients with rheumatoid arthritis, several of the molecular underpinnings of the immune aging process have been delineated, such as the loss of telomeres and inefficiencies in the repair of damaged DNA. Aging T cells display a series of abnormalities, including the unopposed up-regulation of cytoplasmic phosphatases and the loss of glycolytic competence, that alter their response to stimulating signals and undermine their longevity.
Understanding the connection between accelerated immune aging and autoimmunity remains an area of active research. With increasing knowledge of the molecular pathways that cause immunosenescence, therapeutic interventions can be designed to slow or halt the seemingly inevitable deterioration of protective immunity with aging.
Research into the effects of HIV infection and AIDS on the immune system is another area with a similar relationship to normal immune aging, I should mention. There are those who think that at least some shared mechanisms are at work in both cases.
VIDEO: AUBREY DE GREY AT TEDXSALFORD
As I'm sure you all know by now, we'd be languishing a lot further away from the goal of human rejuvenation if not for Aubrey de Grey and the network of people within and without the research community who have joined in to help push longevity science towards respectability and plausibility. Today a great deal more funding is going towards lines of work that contribute materially to halting and reversing degenerative aging than was the case a decade ago. For that we can thank the efforts of de Grey, the Methuselah Foundation staff, the SENS Research Foundation staff, numerous allied researchers, and thousands of volunteers and donors. This work and support has helped create a great change in the research and funding environment, and made radical life extension something that is discussed seriously in far more communities.
Yet there is still a great deal of work to be done. The great change in society and attitudes towards aging has only just started; most people still accept aging and death as set in stone, and even oppose efforts to treat aging as the medical condition it is. The next stage ahead is one in which the average fellow in the street has the same perception of aging as he does of cancer, and supports efforts to do something about it just as strongly. Only then will truly massive funding for the defeat of aging arrive from the traditional sources. Until then, we continue to bootstrap support and funding, year by year.
Aubrey de Grey is a prolific speaker, and gives many presentations in any given year. I'm pointing out this recently uploaded video of a presentation given by de Grey last year because one of the slides caught my eye. It provides the following information on yearly budgets for research institutions:
Even though 90% of US deaths and at least 80% of US medical costs are caused by aging:
National Institutes of Health budget ($M): ~30,000
National Institute of Aging budget: ~1,000
Division of Aging Biology budget: ~150
Spent on translational research (max): ~10
SENS Research Foundation budget: ~5
There is something to think about. On the one hand this is a reminder of just how far removed funding priorities are from the sensible goal of dealing with aging. On the other hand, you can see that this is a field of research in which small foundations funded by philanthropy can make a large difference to the current rate of progress, given that very little funding goes to the most promising programs. When looking at these numbers it is also worth noting that public funds, for which it is comparatively easy to obtain good data, are thought to make up a little over a third of overall medical research. It is very unclear as to the breakdown of private medical research funding when it comes to work relevant to aging, however. Perhaps it is similar, perhaps not.
A true maverick, Aubrey de Grey challenges the most basic assumption underlying the human condition - that aging is inevitable. He argues instead that aging is a disease - one that can be cured if it's approached as "an engineering problem." His plan calls for identifying all the components that cause human tissue to age, and designing remedies for each of them - forestalling disease and eventually pushing back death.
He has developed a possibly comprehensive plan for such repair, termed Strategies for Engineered Negligible Senescence (SENS), which breaks the aging problem down into seven major classes of damage and identifies detailed approaches to addressing each one. A key aspect of SENS is that it can potentially extend healthy lifespan without limit, even though these repair only needs to approach perfection rapidly enough to keep the overall level of damage below pathogenic levels. With his astonishingly long beard, wiry frame and penchant for bold and cutting proclamations, de Grey is a magnet for controversy. A computer scientist, self-taught biogerontologist and researcher, he has co-authored journal articles with some of the most respected scientists in the field.
LATEST HEADLINES FROM FIGHT AGING!
HOW TO HELP IN THE FIGHT AGAINST AGING
Monday, March 31, 2014
Researcher João Pedro de Magalhães has a good page of suggestions on how to help efforts to produce treatments for - and ultimately defeat - degenerative aging. As of about a decade ago, the bottom line is largely a matter of funding provided to the right lines of research, those associated with SENS, the strategies for engineered negligible senescence. But there is always a need for the next generation of researchers, and those who can help raise funds and persuade new supporters to join the community:
Research on aging, like scientific and medical research in general, depends on having researchers with adequate funding to carry out innovative science. One obvious way to contribute to gerontology is to become a researcher or at least a professional in a research institution. Even if you do not wish to have a career in science or are at an early stage of your career but wish to contribute to research, most labs welcome volunteers and interns. No matter your level of experience and skills, there are always ways in which can help.
Not everyone is cut to do research, however. Many people interested in aging that contact me, in fact, already have careers in completely different areas. But even if you cannot become a researcher there are many other ways you can help. Provided you have the means, of course, another straightforward way to help is by funding research on aging via charitable donations or venture capital investments. A word on how scientific funding works may be in order...
While government funding exists to support scientific research, including research on aging, this is largely inadequate. The problem is not only that funding is not sufficient to allow progress at a sufficient pace, but government funding is often misdirected. (And I acknowledge this having received substantial government funding to support my lab, so this is not just a case of sour grapes.) The problem with government funding is that, because of the way funding is typically allocated via peer-review, it is a conservative process which rewards incremental advances but discourages out-of-the-box, innovative projects. Therefore, while projects that follow-up on established paradigms, such as caloric restriction, have a chance of being funded, radical projects like those inspired by SENS have no chance. (This is not to say we should cut funding from caloric restriction and provide funding for SENS, but merely illustrates the point that high-risk, high-reward projects have little or no chance of receiving government funding.)
Given the above problems with science funding, the current situation is one in which progress is being impeded by the lack of funding (and money is very tight at the moment) and the imperfect allocation of existing resources. So if you have the means to donate to the science of aging then this is extremely valuable to researchers. Of course few people have the wealth to create a foundation, but even small contributions to labs or initiatives related to aging research are valuable as they allow researchers to explore ideas that would not be supported by traditional funding sources.
GENETICS AND EPIGENETICS OF AGING AND LONGEVITY
Monday, March 31, 2014
Clearly we are going to be hearing a lot about the genetics and epigenetics of aging in the years ahead. The price of biotechnologies in this field has fallen, sequencing and analysis is cheap, and interest in intervening in the aging process is growing. Sadly, and as I've outlined in past posts, I don't see this as a path towards greatly extending the healthy human life span. Researchers will learn a great deal about how aging progresses, and produce benefits for other areas of medicine, but work on genetic analysis and alteration of epigenetic patterns can only be a hard and complicated path to slowing aging through manipulation of the operation of metabolism. As an end goal that is of very limited benefit to those of us who will be old before it arrives.
Here is an open access review from researchers involved in one of the current commercial ventures focusing on the genetics and epigenetics of aging:
During aging, vital bodily functions such as regeneration and reproduction slowly decline. As a result, the organism loses its ability to maintain homeostasis and becomes more susceptible to stress, diseases, and injuries. A loss of essential body functions leads to age-associated pathologies, which ultimately cause death.
Evolutionary theories of aging predict the existence of certain genes that provide selective advantage early in life with adverse effect on lifespan later in life (antagonistic pleiotropy theory) or longevity insurance genes (disposable soma theory). Indeed, the study of human and animal genetics is gradually identifying new genes that increase lifespan when overexpressed or mutated: gerontogenes. Furthermore, genetic and epigenetic mechanisms are being identified that have a positive effect on longevity.
The gerontogenes are classified as lifespan regulators, mediators, effectors, housekeeping genes, genes involved in mitochondrial function, and genes regulating cellular senescence and apoptosis. In this review we demonstrate that the majority of the genes as well as genetic and epigenetic mechanisms that are involved in regulation of longevity are highly interconnected and related to stress response.
WORKING WITH VERY SMALL EMBRYONIC-LIKE STEM CELLS
Tuesday, April 1, 2014
The existence of very small embryonic-like cells (VSELs) is debated, as while several groups have claimed to isolate them from adult tissues over the past few years, others have failed to replicate this work. There have been some suggestions that these cells might be created in response to specific stresses - which may or may not be present in a researcher's approach to isolating them - rather than lying dormant in all adult tissues. This is important because if VSELs can be reliably obtained from tissues such as skin they will provide a ready, low-cost source of pluripotent cells for research and therapeutic use.
Here is an open access paper published by another group of researchers who are investigating VSELs and their potential utility for future therapies:
The purpose of this study was to determine the lineage progression of human and murine very small embryonic-like (HuVSEL or MuVSEL) cells in vitro and in vivo. VSEL cells represent a rare population in the bone marrow (less than 0.02% of nucleated cells). VSEL cells have been identified in most tissues that have been examined, including blood and other solid organs. VSEL cells have scant cytoplasm and, as the name suggests, have morphologic characteristics indicative of an immature state of differentiation, including dispersed chromatin. In addition, VSEL cells express genes that are expressed by embryonic stem cells, including Oct4, nanog, and stage-specific embryonic antigen SSEA-1. Thus, VSEL cells may give rise to derivatives of all three germ layers. VSEL cells may therefore be prime candidates for cells with the capacity to regenerate many different structures.
In vitro, HuVSEL and MuVSEL cells differentiated into cells of all three embryonic germ layers. HuVSEL cells produced robust mineralized tissue of human origin. Immunohistochemistry demonstrated that the HuVSEL cells gave rise to neurons, adipocytes, chondrocytes, and osteoblasts. MuVSEL cells were also able to differentiate into similar lineages. First round serial transplants of MuVSEL cells demonstrated that 60% of the cells maintained their VSEL cell phenotype while other cells differentiated into multiple tissues at 3 months. Secondary transplants did not identify donor VSEL cells, suggesting limited self renewal but did demonstrate VSEL cell derivatives in situ for up to 1 year. At no point were teratomas identified.
These studies show that VSEL cells produce multiple cellular structures in vivo and in vitro and lay the foundation for future cell-based regenerative therapies for bone, neural, and connective tissue disorders.
ASSOCIATING ARTERIAL STIFFNESS AND β-AMYLOID PROGRESSION
Tuesday, April 1, 2014
Researchers here show an association between blood vessel stiffening and the deposition of β-amyloid in people who have not yet developed Alzheimer's disease. In general we should not be surprised to see associations between different measurable aspects of aging, as aging is a global phenomenon resulting from a small number of root causes. Thus many of the outcomes proceed in parallel to one another.
Here, however, the causes of stiffness and rising levels of amyloid formation are - so far as we know at present - two somewhat independent groups of processes. So the fact that they associate suggests that vascular dysfunction contributes to Alzheimer's disease, a relationship already suspected from a range of other evidence. Certainly the degeneration of blood vessels with aging is the cause of other forms of dementia.
Deposition of Aβ was determined in a longitudinal observational study of aging by positron emission tomography twice 2 years apart in 81 nondemented individuals 83 years and older. Arterial stiffness was measured with a noninvasive and automated waveform analyzer. Pulse wave velocity (PWV) was measured. The change in Aβ deposition over 2 years was calculated with repeat Aβ-positron emission tomography.
The proportion of Aβ-positive individuals increased from 48% at baseline to 75% at follow-up. Brachial-ankle PWV was significantly higher among Aβ-positive participants at baseline and follow-up. Femoral-ankle PWV was only higher among Aβ-positive participants at follow-up. Measures of central stiffness and blood pressure were not associated with Aβ status at baseline or follow-up, but central stiffness was associated with a change in Aβ deposition over time.
This study showed that Aβ deposition increases with age in nondemented individuals and that arterial stiffness is strongly associated with the progressive deposition of Aβ in the brain, especially in this age group. The association between Aβ deposition changes over time and generalized arterial stiffness indicated a relationship between the severity of subclinical vascular disease and progressive cerebral Aβ deposition.
A START ON MANIPULATING THE MECHANISMS OF NERVE REGROWTH
Wednesday, April 2, 2014
Researchers are making inroads into understanding and manipulating mechanisms of nerve regrowth so as to improve the outcome following injury:
The researchers were interested in understanding how axons in the peripheral nervous system (PNS) make a vigorous effort to grow back when they are damaged, whereas central nervous system (CNS) axons mount little or no effort. If damage occurs in the peripheral nervous system, which controls areas outside of the brain and spinal cord, about 30% of the nerves grow back and there is often recovery of movement and function. The researchers wanted to explore whether it was possible to generate a similar response in the CNS.
To investigate the differences between how the two systems respond to damage, the researchers looked at mouse models and cells in culture. They compared the responses to PNS damage and CNS damage in a type of neuron called a dorsal root ganglion, which connects to both the CNS and the PNS.
When nerves are damaged in the PNS, the damaged nerves send 'retrograde' signals back to the cell body to switch on an epigenetic program to initiate nerve growth. Very little was previously known about the mechanism which allows this 'switching on' to occur. The researchers identified the sequence of chemical events that lead to the 'switching on' of the program to initiate nerve regrowth and pinpointed the protein PCAF as being central to the process. Furthermore when they injected PCAF into mice with damage to their central nervous system, there was a significant increase in the number of nerve fibres that grew back.
A GOOD EXAMPLE OF FAILING TO CONTROL FOR CALORIE INTAKE
Wednesday, April 2, 2014
Calorie restriction has a such a large impact on health that you almost have to disregard any study of health and longevity in laboratory animals that fails to control for it. Even mild differences in levels of calorie intake can swamp out the effects actually being studied. In humans calorie restriction doesn't have the same dramatic effect on longevity as it does in mice - we'd have noticed by now - but it does produce a dramatic improvement in measures of health. So it is probably past time that we look with suspicion on any study that fails to account for levels of calorie intake.
This work seems like a good example of the type, as the researchers examined dietary habits that most likely correlate strongly with overall calorie intake, but did not control for calorie intake in the analysis:
Study participants were adults aged 35 years or over within the Health Survey for England (HSE). Since 2001, HSE participants have been asked about fruit and vegetable consumption on the previous day. Cox regression was used to estimate hazard ratios for an association between fruit and vegetable consumption and all-cause, cancer and cardiovascular mortality, adjusting for age, sex, social class, education, body mass index, alcohol consumption and physical activity.
We found a strong inverse relationship between fruit and vegetable consumption and all-cause mortality which was stronger when deaths within a year of baseline were excluded and when fully adjusting for physical activity. Seriously ill individuals may eat less due to illness-induced anorexia, or perhaps those with chronic illness receive more health advice and may therefore consume more fruit and vegetables. By excluding deaths within a year of baseline, we attempted to address reverse causality.
Fruit and vegetable consumption was significantly associated with reductions in cancer and cardiovascular disease mortality, with increasing benefits being seen with up to more than seven portions of fruit and vegetables daily for the latter. Consumption of vegetables appeared to be significantly better than similar quantities of fruit. When different types of fruit and vegetable were examined separately, increased consumption of portions of vegetables, salad, fresh and dried fruit showed significant associations with lower mortality. However, frozen/canned fruit consumption was apparently associated with a higher risk of mortality.
THE STATE OF CANCER IMMUNOTHERAPY
Thursday, April 3, 2014
A popular science article on the current state of progress towards therapies for cancer based on mobilizing the immune system to attack cancer cells:
More than a century ago, American bone surgeon William Coley came across the case of Fred Stein, whose aggressive cheek sarcoma had disappeared after he suffered a Streptococcus pyogenes infection following surgery to remove part of the large tumor. Seven years later, Coley tracked Stein down and found him alive, with no evidence of cancer. Amazed, Coley speculated that the immune response to the bacterial infection had played an integral role in fighting the disease, and the doctor went on to inoculate more than 10 other patients suffering from inoperable tumors with Streptococcus bacteria. Sure enough, several of those who survived the infection - and one who did not - experienced tumor reduction.
Coley subsequently developed and tested the effect of injecting dead bacteria into tumors, hoping to stimulate an immune response without risking fatal infection, and found that he was able to cause complete regression of cancer in some patients with sarcoma, a type of malignant tumor often arising from bone, muscle, or fat. Unfortunately, with the increasing use of radiation treatments and the advent of systemic chemotherapy, much of Coley's work was abandoned by the time he died in 1936.
Today, however, the use of immune modulation to treat cancer is finally receiving its due. Unlike chemotherapy and radiation treatments, which directly attack cancer cells, immunotherapy agents augment the body's normal immune machinery, increasing its ability to fight tumors. This strategy involves either introducing compounds that directly stimulate the immune cells to work harder, or introducing synthetic proteins that mimic the components of the normal immune response, thereby increasing the body's entire immune reaction. With a handful of therapies already on the market, and dozens more showing promise in all stages of clinical development, these treatments are poised to forever change the way that we approach cancer management.
CARDIAC RISKS IN YOUTH ASSOCIATE WITH WORSE COGNITIVE FUNCTION IN LATER LIFE
Thursday, April 3, 2014
The publicity materials for this study discuss cardiac risks such as high blood pressure and blood glucose in youth without mentioning how they usually come about. The most common path towards suffering these danger signs in earlier life is to let yourself become fat and sedentary. Both of these line items are independently associated with greater ill-health and medical expenditure in later life:
Young adults with such cardiac risk factors as high blood pressure and elevated glucose levels have significantly worse cognitive function in middle age, according to a new study by dementia researchers. The findings bolster the view that diseases like Alzheimer's develop over an individual's lifespan and may be set in motion early in life. And they offer hope that young adults may be able to lower their risk of developing dementia through diet and exercise, or even by taking medications.
"These cardiovascular risk factors are all quite modifiable. We already know that reducing these risk factors in midlife can decrease the risk of dementia in old age. If it turns out that the damage begins before middle age, we may need to expand our focus and work on reducing heart disease risks in earlier stages of life."
The study examines data from more than 3,300 18- to 30-year-olds in the Coronary Artery Risk Development in Young Adults (CARDIA) study, which began enrolling thousands of participants nationwide in 1985 to understand how heart disease develops in black and white adults. Cardiac risk factors were measured every two to five years for 25 years, at which point those in the study underwent tests to measure their executive function, cognitive processing speed and verbal memory. Those whose blood pressure and glucose exceeded recommended levels during the 25-year study performed worse on all three tests, while high cholesterol was associated only with poor verbal memory.
The authors cited a number of mechanisms by which elevated blood pressure and glucose could diminish cognition in middle age, such as by reducing blood supply to the brain, causing changes in brain structure and increasing inflammation and oxidative stress, which can damage neurons. Another possibility is that these risk factors may interfere with the clearance of amyloid proteins associated with Alzheimer's disease.
NEUROPEPTIDE Y REQUIRED FOR CALORIE RESTRICTION BENEFITS
Friday, April 4, 2014
Researchers uncover proteins necessary to the benefits of calorie restriction by the use of genetic engineering to create lineages of laboratory animals that each lack a specific protein of interest, and then observing the results of calorie restriction for each lineage. Unlike most such efforts, in this case some of the mechanisms thought important to calorie restriction still function even without neuropeptide Y, the protein in question, but nonetheless life is not extended.
Since calorie restriction changes near everything in metabolism along the way to extending life, it has been difficult to identify which of these myriad changes are required or which contribute the greatest benefit. This work may prove useful to winnow the list of responses to calorie restriction in order to find those most important to health and longevity.
Knowledge of genes essential for the life-extending effect of dietary restriction (DR) in mammals is incomplete. In this study, we found that neuropeptide Y (Npy), which mediates physiological adaptations to energy deficits, is an essential link between DR and longevity in mice. The lifespan-prolonging effect of lifelong 30% DR was attenuated in Npy-null mice, as was the effect on the occurrence of spontaneous tumors and oxidative stress responses in comparison to wild-type mice.
In contrast, the physiological processes activated during adaptation to DR, including inhibition of anabolic signaling molecules (insulin and insulin-like growth factor-1), modulation of adipokine and corticosterone levels, and preferential fatty acid oxidation, were unaffected by the absence of Npy. This study clearly showed that Npy is a neuropeptide that links DR to longevity in mammals. However, Npy is not required for many of the physiological adaptations to DR.
Among the neuroendocrine changes induced by DR, inhibition of anabolic signaling molecules, including insulin, GH/IGF-1, and mTOR, and upregulation of adiponectin were found to extend lifespan in rodents without restricted food intake. Thus, the effects of DR were attributed to these molecules or related signaling pathways based on the observed physiological adaptations. However, in the present study, the salutary effects of DR were significantly reduced in Npy-/- mice, even though they showed normal physiological adaptions to DR. Therefore, these neuroendocrine adaptations to DR may not be essential for longevity or cancer and stress resistance.
A NOVEL LONGEVITY-ASSOCIATED GENETIC LOCUS IN HUMANS
Friday, April 4, 2014
Finding genetic correlations with longevity in humans is challenging. All results found to date produce only small statistical effects, and very few indeed can be replicated between different study populations. This suggests that genetic contributions to longevity are diffuse and highly variable. Any single difference contributes very little, and that contribution is contingent on many other differences, such that any given regional population will have a very different map of genetic variations to longevity differences.
Here is a rare example of a more robust association between a genetic locus and longevity, and you'll note that as for other results the statistical effect on mortality is small. The paper is open access, but the full text is PDF only.
The genetic contribution to the variation in human lifespan is approximately 25%. Despite the large number of identified disease-susceptibility loci, it is not known which loci influence population mortality. We performed a genome-wide association meta-analysis of 7729 long-lived individuals of European descent (older than 85 years) and 16121 younger controls (younger than 65 years) followed by replication in an additional set of 13060 long-lived individuals and 61156 controls. In addition, we performed a subset analysis in cases older than 90 years.
We observed genome-wide significant association with longevity, as reflected by survival to ages beyond 90 years, at a novel locus, rs2149954, on chromosome 5q33.3. We also confirmed association of rs4420638 on chromosome 19q13.32, representing the TOMM40/APOE/APOC1 locus. In a prospective meta-analysis the minor allele of rs2149954 (T) on chromosome 5q33.3 associates with increased survival with a hazard ratio of 0.95. This allele has previously been reported to associate with low blood pressure in middle age. Interestingly, the minor allele (T) associates with decreased cardiovascular mortality risk, independent of blood pressure.
We report on the first GWAS-identified longevity locus on chromosome 5q33.3 influencing survival in the general European population. The minor allele of this locus associates with low blood pressure in middle age, although the contribution of this allele to survival may be less dependent on blood pressure. Hence, the pleiotropic mechanisms by which this intragenic variation contributes to lifespan regulation have to be elucidated.