Is Parkinson's an Autoimmune Disease?
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This is an interesting view on the later stages Parkinson's disease that seems fairly orthogonal to the present mainstream focus on α-synuclein and its removal:

The cause of neuronal death in Parkinson's disease is still unknown, but a new study proposes that neurons may be mistaken for foreign invaders and killed by the person's own immune system. "This is a new, and likely controversial, idea in Parkinson's disease; but if true, it could lead to new ways to prevent neuronal death in Parkinson's that resemble treatments for autoimmune diseases."

For decades, neurobiologists have thought that neurons are protected from attacks from the immune system, in part, because they do not display antigens on their cell surfaces. "That idea made sense because, except in rare circumstances, our brains cannot make new neurons to replenish ones killed by the immune system. But, unexpectedly, we found that some types of neurons can display antigens."

Cells display antigens with special proteins called MHCs. Using postmortem brain tissue donated to the Columbia Brain Bank by healthy donors [researchers] first noticed - to their surprise - that MHC-1 proteins were present in two types of neurons. These two types of neurons - one of which is dopamine neurons in a brain region called the substantia nigra - degenerate during Parkinson's disease.

[The researchers] conducted in vitro experiments with mouse neurons and human neurons created from embryonic stem cells. The studies showed that under certain circumstances - including conditions known to occur in Parkinson's - the neurons use MHC-1 to display antigens. Among the different types of neurons tested, the two types affected in Parkinson's were far more responsive than other neurons to signals that triggered antigen display. The researchers then confirmed that T cells recognized and attacked neurons displaying specific antigens.

"Right now, we've showed that certain neurons display antigens and that T cells can recognize these antigens and kill neurons, but we still need to determine whether this is actually happening in people. We need to show that there are certain T cells in Parkinson's patients that can attack their neurons. This idea may explain the final step. We don't know if preventing the death of neurons at this point will leave people with sick cells and no change in their symptoms, or not."

Link: http://newsroom.cumc.columbia.edu/blog/2014/04/17/parkinsons-autoimmune-disease/

Turning Cells into Programmable Medical Devices
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Targeted delivery of drugs and proteins to modify metabolism and cell behavior may in the future be accomplished by engineered cells. Cells already do a great many useful things, so why reinvent the wheel when there is existing machinery that can be adapted to new purposes? This is a line of research with the potential to radically change the face of medicine and our own biology, leading to a future in which most of us have large numbers of enhanced and altered cells in every organ, monitoring and reacting to local conditions in order to help maintain the body against the processes of aging and disease far more effectively than our present evolved mechanisms can manage.

A synthetic biology team has created a new technology for modifying human cells to create programmable therapeutics that could travel the body and selectively target cancer and other sites of disease. "The project addressed a key gap in the synthetic biology toolbox. There was no way to engineer cells in a manner that allowed them to sense key pieces of information about their environment, which could indicate whether the engineered cell is in healthy tissue or sitting next to a tumor."

The end result is a protein biosensor that sits on the surface of a cell and can be programmed to sense specific external factors. For example, the engineered cell could detect big, soluble protein molecules that indicate that it's next to a tumor. When the biosensor detects such a factor, it sends a signal into the engineered cell's nucleus to activate a gene expression program, such as the production of tumor-killing proteins or chemicals. Since this toxic program would be activated only near tumor cells, such an approach could minimize side effects as well as improve therapeutic benefits.

Called a Modular Extracellular Sensor Architecture (MESA), the biosensor platform is completely self-contained so that several different biosensors can be present in a single cell without interfering with one another, allowing bioengineers to build increasingly sophisticated functional programs. The platform is also highly modular, enabling the biosensors to be customized to recognize factors of relevance to various patients' needs. "By linking the output of these biosensors to genetic programs, one can build in a certain logical command, such as 'turn the output gene on when you sense this factor but not that factor.' In that way, you could program a cell-based therapy to specify which cells it should kill."

Link: http://www.mccormick.northwestern.edu/news/articles/2014/04/building-smart-cell-based-therapies.html

A Midlife Crisis for the Mitochondrial Free Radical Theory of Aging
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Here is an open access paper that covers some of the challenges that have faced the interpretation of just how and why it is that mitochondria have an important role in the aging process. The mitochondrial free radical theory of aging has been broadly considered, in several forms, but as for just about every theory of aging early models turned out to be too simple and straightforward. The reality on the ground is more complex, which is why you'll find a mass of data that supports this theory and another mass of data that contradicts it:

Since its inception more than four decades ago, the Mitochondrial Free Radical Theory of Aging (MFRTA) has served as a touchstone for research into the biology of aging. The MFRTA suggests that oxidative damage to cellular macromolecules caused by reactive oxygen species (ROS) originating from mitochondria accumulates in cells over an animal's lifespan and eventually leads to the dysfunction and failure that characterizes aging.

A central prediction of the theory is that the ability to ameliorate or slow this process should be associated with a slowed rate of aging and thus increased lifespan. A vast pool of data bearing on this idea has now been published. ROS production, ROS neutralization and macromolecule repair have all been extensively studied in the context of longevity. We review experimental evidence from comparisons between naturally long- or short-lived animal species, from calorie restricted animals, and from genetically modified animals and weigh the strength of results supporting the MFRTA.

Viewed as a whole, the data accumulated from these studies have too often failed to support the theory. Excellent, well controlled studies from the past decade in particular have isolated ROS as an experimental variable and have shown no relationship between its production or neutralization and aging or longevity. Instead, a role for mitochondrial ROS as intracellular messengers involved in the regulation of some basic cellular processes, such as proliferation, differentiation and death, has emerged. If mitochondrial ROS are involved in the aging process, it seems very likely it will be via highly specific and regulated cellular processes and not through indiscriminate oxidative damage to macromolecules.

Link: http://dx.doi.org/10.1186/2046-2395-3-4

Public Views on the Future of Technology
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A few things are of interest in this survey, with one being that a majority of people don't like specific instances of societal change resulting from technological advances if asked about them, which isn't much of a surprise given human nature. Another is that extended human longevity shows up as a desired goal for a larger minority than has been the case in the past - I would expect to see growth in this number when measured, given the events of the past few years. This being a survey there is little distinction made between the fantastical drawn from science fiction and the plausible drawn from science, which is unfortunate, but it is still worth a look.

The American public anticipates that the coming half-century will be a period of profound scientific change, as inventions that were once confined to the realm of science fiction come into common usage. This is among the main findings of a new national survey by The Pew Research Center, which asked Americans about a wide range of potential scientific developments - from near-term advances like robotics and bioengineering, to more "futuristic" possibilities like teleportation or space colonization.

Asked to describe in their own words the futuristic inventions they themselves would like to own, the public offered three common themes: 1) travel improvements like flying cars and bikes, or even personal space crafts; 2) time travel; and 3) health improvements that extend human longevity or cure major diseases. One in ten Americans (9%) list the ability to travel through time as the futuristic invention they would like to have, and an identical 9% would want something that improved their health, increased their lifespan, or cured major diseases.

At the same time, many Americans seem to feel happy with the technological inventions available to them in the here and now - 11% answered this question by saying that there are no futuristic inventions that they would like to own, or that they are "not interested in futuristic inventions." And 28% weren't sure what sort of futuristic invention they might like to own.

A substantial majority of Americans (81%) believe that within the next 50 years people needing an organ transplant will have new organs custom made for them in a lab. Belief that this development will occur is especially high among men, those under age 50, those who have attended college, and those with relatively high household incomes. But although expectations for this development are especially high within these groups, three-quarters or more of every major demographic group feels that custom organs are likely to become a reality in the next half-century.

Link: http://www.pewinternet.org/2014/04/17/us-views-of-technology-and-the-future/

A Canine Longitudinal Aging Study Proposed
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As noted below researchers are making an effort to establish the basis for a comprehensive study of aging in longer-lived species. Most present work on aging in mammals takes place in mice and rats, and while there are many similarities between mice and humans there are also sometimes unexpected differences in the biochemistry of aging between short-lived and long-lived species. For example that the important types of advanced glycation end-product (AGE), which produce cross-links that accumulate in tissues over a life span to cause damage and dysfunction, turned out to be very different in rodents and humans sabotaged some of the first serious efforts to produce AGE-breaker drugs to slow or reverse this contribution to the aging process.

Scientists aim to bridge the gap between lab research and aging's complexities in real life using the power of dogs. [They] are joining interdisciplinary collaborators from across the country to form the Canine Longevity Consortium - the first research network to study canine aging. It will lay the groundwork for a nationwide Canine Longitudinal Aging Study (CLAS), using dogs as a powerful new model system that researchers can study to find how genetic and environmental factors influence aging and what interventions might mitigate age-related diseases.

"Dogs offer tremendous potential as a model system for human aging. They share many genetic characteristics with humans that let us combine traditional demographic and epidemiological approaches with new techniques like comparative genomics. Unlike any other model system for aging, dogs share our environment and, increasingly, our health care options. Once developed, a canine model holds enormous promise, and we expect it to have a significant impact on aging research."

[Researchers] aim to craft the CLAS to see how an individual dog's aging trajectory is shaped by genes and the environment, gain detailed understanding of when and why dogs die, and find treatments to combat age-related illness. The researchers will start with pilot projects to choose the best breeds for the study and to determine how best to collect, analyze and share the large-scale data it will produce. The team will conduct an epidemiological analysis of genetic and environmental factors influencing canine lifespan, high-resolution mapping of canine longevity, and a yearlong epidemiological analysis of age and cause of death in all dogs seen within a select group of three private veterinary clinics.

Link: http://www.news.cornell.edu/stories/2014/04/aging-research-goes-dogs

A Decellularized Oesophagus Demonstrated in Rats
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Researchers here make use of the process of decellularization to match a donor organ to the recipient. In the ideal procedure, donor cells are removed and the remaining extracellular matrix of the organ is repopulated with the recipient's cells, thereby eliminating most issues of transplant rejection. The use of a donor matrix bypasses the present inability to construct a sufficiently complex scaffold for most tissues, complete with cues and guides for blood vessel formation and other structures within tissue:

A tissue-engineered oesophageal scaffold could be very useful for the treatment of pediatric and adult patients with benign or malignant diseases such as carcinomas, trauma or congenital malformations. Here we decellularize rat oesophagi inside a perfusion bioreactor to create biocompatible biological rat scaffolds that mimic native architecture, resist mechanical stress and induce angiogenesis.

Seeded allogeneic mesenchymal stromal cells spontaneously differentiate (proven by gene-, protein and functional evaluations) into epithelial- and muscle-like cells. The reseeded scaffolds are used to orthotopically replace the entire cervical oesophagus in immunocompetent rats.

All animals survive the 14-day study period, with patent and functional grafts, and gain significantly more weight than sham-operated animals. Explanted grafts show regeneration of all the major cell and tissue components of the oesophagus including functional epithelium, muscle fibres, nerves and vasculature. We consider the presented tissue-engineered oesophageal scaffolds a significant step towards the clinical application of bioengineered oesophagi.

Link: http://dx.doi.org/10.1038/ncomms4562

More Evidence of the Inverse Relationship Between Dementia and Cancer Mortality
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It is perhaps unexpected that incidence of dementia and incidence of cancer seem to have a robust inverse relationship, one that has shown up in multiple different study populations. In general we think of aging as a global phenomenon in the body keyed to rising levels of damage in all tissues: if you are farther down the road than your peers for whatever reason then you would expect a higher risk of all of the potential failure modes in the complex systems of your body.

In one sense, yes, this is true. But in some people risk of cancer rises significantly more rapidly than risk of dementia, and in others vice versa. As this study shows the differentiation in risk starts early in the progression of age-related cognitive decline:

Older people who are starting to have memory and thinking problems, but do not yet have dementia may have a lower risk of dying from cancer than people who have no memory and thinking problems. "Studies have shown that people with Alzheimer's disease are less likely to develop cancer, but we don't know the reason for that link. One possibility is that cancer is underdiagnosed in people with dementia, possibly because they are less likely to mention their symptoms or caregivers and doctors are focused on the problems caused by dementia. The current study helps us discount that theory."

The study involved 2,627 people age 65 and older in Spain who did not have dementia at the start of the study. They took tests of memory and thinking skills at the start of the study and again three years later, and were followed for an average of almost 13 years. The participants were divided into three groups: those whose scores on the thinking tests were declining the fastest, those whose scores improved on the tests, and those in the middle.

During the study, 1,003 of the participants died, including 339 deaths, or 34 percent, among those with the fastest decline in thinking skills and 664 deaths, or 66 percent, among those in the other two groups. A total of 21 percent of those in the group with the fastest decline died of cancer, according to their death certificates, compared to 29 percent of those in the other two groups. People in the fastest declining group were still 30 percent less likely to die of cancer when the results were adjusted to control for factors such as smoking, diabetes and heart disease, among others.

Link: http://www.eurekalert.org/pub_releases/2014-04/aaon-opw040314.php

The Fragile Elderly Hip
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Here is an open access review that looks at what is known of the proximate mechanisms that cause increasing fragility of bone with advancing age. These are not the root causes, but it remains to be determined how exactly the laundry list of primary differences between old tissues and young tissues produces the results discussed below. Arguably it is faster and more efficient to investigate by doing; work to reverse these primary changes in tissue samples and animals and see what happens. That is a lot easier than trying to understand the full scope of the complexity of aging, and has a much greater chance of producing meaningful therapies to halt the advance of aging in the near term:

Every hip fracture begins with a microscopic crack, which enlarges explosively over microseconds. Most hip fractures in the elderly occur on falling from standing height, usually sideways or backwards. The typically moderate level of trauma very rarely causes fracture in younger people. Here, this paradox is traced to the decline of multiple protective mechanisms at many length scales from nanometres to that of the whole femur.

With normal ageing, the femoral neck asymmetrically and progressively loses bone tissue precisely where the cortex is already thinnest and is also compressed in a sideways fall. At the microscopic scale of the basic remodelling unit (BMU) that renews bone tissue, increased numbers of actively remodelling BMUs associated with the reduced mechanical loading in a typically inactive old age augments the numbers of mechanical flaws in the structure potentially capable of initiating cracking.

Menopause and over-deep osteoclastic resorption are associated with incomplete BMU refilling leading to excessive porosity, cortical thinning and disconnection of trabeculae. In the femoral cortex, replacement of damaged bone or bone containing dead osteocytes is inefficient, impeding the homeostatic mechanisms that match strength to habitual mechanical usage. In consequence the participation of healthy osteocytes in crack-impeding mechanisms is impaired.

Observational studies demonstrate that protective crack deflection in the elderly is reduced. At the most microscopic levels attention now centres on the role of tissue ageing, which may alter the relationship between mineral and matrix that optimises the inhibition of crack progression and on the role of osteocyte ageing and death that impedes tissue maintenance and repair.

Link: http://www.thebonejournal.com/article/S8756-3282(14)00002-7/fulltext

Learning to Reverse Aspects of Cell Aging By Observing the Embryo
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Adults are old, but children are young: at some point in the early development of an embryo, a collection of presently poorly cataloged processes erase the changes of aging present in the adult cells that created it. It is probably the case that there is little in this that can be applied directly to making us live longer, as the sort of radical restructuring of cells that takes place in the developing embryo would be fatal to the much more complex adult organism. We couldn't apply this to ourselves for all the same reasons that we can't constantly renew ourselves like the tiny creatures called hydra. Our nervous system, mind, and other complex and finely balanced processes depend on the present detailed structure of our long-lived cells, and that structure would be erased.

However, as the authors of this paper point out, there is potentially much to be learned from the embryo that could be of benefit for stem cell treatments. In this case the research community absolutely wants to be able to reverse the damage of aging in induced pluripotent stem cells (IPSCs) generated from an old patient. To a certain extent this already happens, but greater control and effectiveness is desired:

Stem cells are defined not only by their differentiation potential but also by their capacity for unlimited self-replication. The need for prolonged self-replication requires adequate telomere length and telomere maintenance, which can limit the powerful new methods available for generating induced pluripotent cells. IPSCs lacking sufficient telomere length fail to [pass] the most stringent tests of pluripotency, and cannot be maintained in culture over long periods. This might have contributed, in part, to the variable quality of iPSCs during early efforts [and] may ultimately limit the future application of iPSCs in regenerative medicine. To correct this, present efforts in the field of iPSCs have strived to improve the quality of iPSC generated by focusing on telomere dynamics during the process of reprogramming.

Telomeres protect and cap linear chromosome ends, yet these genomic buffers erode over an organism's lifespan. Short telomeres have been associated with many age-related conditions in humans, and genetic mutations resulting in short telomeres in humans manifest as syndromes of precocious aging. In women, telomere length limits a fertilized egg's capacity to develop into a healthy embryo. Thus, telomere length must be reset with each subsequent generation. Although telomerase is purportedly responsible for restoring telomere DNA, recent studies have elucidated the role of alternative telomeres lengthening (ALT) mechanisms in the reprogramming of early embryos and stem cells.

Telomere length in the oocyte is markedly shorter than somatic cells. In contrast, sperm are of the few cell types documented to elongate telomeres over the human lifespan, presumably due to the effects of telomerase activity in spermatogonia throughout the life of the male. Following fertilization and activation of the egg, embryonic cells undergo dramatic telomere lengthening. Notably, telomerase activity remains undetectable in these cells. This effect remains robust in telomerase knock-out mice, suggesting an ALT-dependent mechanism at play in preimplantation mammalian development. Moreover, the lengthening takes place in parthenogenetically activated eggs, which lack sperm input during activation, suggesting that the capacity for telomere length reprogramming resides in the oocyte.

Link: http://dx.doi.org/10.1155/2014/925121

TRF2 as a Potential Biomarker of Cellular Senescence
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The accumulation of senescent cells with age is one of the causes of degenerative aging, as senescent cells behave badly, emitting proteins that harm surrounding tissues. Finding a way to clearly identify senescent cells is a necessary step on the path to a targeted treatment that can destroy them, using engineered immune cells, nanoparticles, viruses, or any of the other approaches to selective cell destruction that are presently under development. Much of the work towards this end is focused on p16, which seems promising but may or may not in the end prove to be discriminating enough. Here researchers are exploring a different marker of senescence:

While TRF2 is found at telomeres, where it plays an essential role in maintaining telomere integrity, little is known about the cellular localization of methylated TRF2. In this report, we have shown that methylated TRF2 is associated with the nuclear matrix and that this localization is largely free of human telomeres. We show that methylated TRF2 drastically alters its nuclear staining as normal human primary fibroblast cells approach and enter replicative senescence. This altered nuclear staining, which is found to be overwhelmingly associated with misshapen nuclei and abnormal nuclear matrix folds, can be suppressed by hTERT and it is barely detectable in transformed and cancer cell lines.

We find that dysfunctional telomeres and DNA damage, both of which are potent inducers of cellular senescence, promote the altered nuclear staining of methylated TRF2, which is dependent upon the ATM-mediated DNA damage response. Collectively, these results suggest that the altered nuclear staining of methylated TRF2 may represent ATM-mediated nuclear structural alteration associated with cellular senescence. Our data further imply that methylated TRF2 can serve as a potential biomarker for cellular senescence.

Link: http://www.impactaging.com/papers/v6/n4/full/100650.html

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