Fight Aging! Newsletter, December 15th 2014

December 15th 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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  • Fight Aging! SENS Fundraiser Update: In the Home Stretch, Just a Few Thousand To Go
  • The Present Undesirable Inconsistency of Genetic Studies
  • Markers for Senescence in Cells
  • And if the Research Community Does in Fact Find a Viable Treatment for Obesity?
  • Reviewing Age-Related Macular Degeneration
  • Latest Headlines from Fight Aging!
    • Restoring Lost Golgi Function Reduces Amyloid Beta in Alzheimer's Disease
    • Working on Bone Tissue Engineering
    • Paul Allen's Next $100 Million in Life Science Funding
    • A View of Comparative Biology in Medical Research
    • A View of Stochastic DNA Damage in Aging
    • Infectious Agents and Inflammation in Neurodegeneration
    • Regenerating the Meniscus
    • Treating a Cloudy Cornea with Stem Cells
    • Senescent Cells Promote Wound Healing
    • A Look at the Current State of Cancer Immunotherapy


As I'm sure you're all aware, back in October Fight Aging! launched a matching fundraiser in support of the work of the SENS Research Foundation. Together Christophe and Dominique Cornuejols, Dennis Towne, Håkon Karlsen, Jason Hope, Methuselah Foundation, Michael Achey, Michael Cooper, and Fight Aging! established a sizable matching fund and challenged the community to donate tens of thousands more by the end of the year, with all of this going to expand ongoing rejuvenation research programs. The SENS Research Foundation coordinates scientific efforts essential for the near future production of therapies capable of repairing the cellular and molecular damage that causes aging. The Foundation staff also advocate in and beyond the research community, organize noted conferences such as this year's Rejuvenation Biotechnology 2014, and help to build the next generation of enthusiastic scientists, people who see treatments for aging as the hot new thing in cutting edge biotechnology.

The Foundation takes a very careful, strategic view on research, and focuses funding on fields needed for tomorrow's rejuvenation toolkit but which are at present stalled, ignored, or poorly funded - such as work on mitochondrial DNA repair and removal of various forms of harmful metabolic waste, such as those that clog up and damage lysosomes with age. Early stage research in most areas of biotechnology is becoming quite cheap these days, and a lot can be done with a few hundred thousand dollars, a few smart young scientists, and an established academic laboratory with space to spare. Certainly it is possible to unjam fields that are stuck because no-one wants to invest the time to build the basic tools needed for any meaningful work to take place, as is the case for breaking down glucosepane cross-links in human tissues, or where present relevant research is largely intended for use with comparatively rare genetic diseases, and thus is funded below the levels needed to ensure reliable progress, as is the case for some of the work relevant to working around the contribution of mitochondrial DNA damage to aging.

Which is all to say that grassroots efforts at the level of our Fight Aging! SENS fundraiser are meaningful and important. We light the way and attract later, wealthier donors, and further do actually help to ensure that good research is accomplished with our funds. I'm pleased to say that the community has shown considerable generosity and support, especially in the last week since Giving Tuesday and an offer by Aubrey de Grey to further match donations that day. At present with three weeks to go more than 500 people have pitched in and we are just a few thousands short of our goal. Thank you to all who have helped!

So if you have friends who are on the fence, or even friends who have never heard of the SENS Research Foundation and efforts in the scientific community to bring an end to pain, suffering, and disease in aging, then now is a good time to reach out.


Common genetic variants contribute to individual differences in longevity when considered statistically across thousands of individuals and decades of their lives. But even statistically common genetic variations are not particularly important until later life. For all but a few unlucky individuals with rare genetic conditions, the difference between comparative health and comparative frailty at the end of middle age is a matter of lifestyle choices and environment, not genes. After that, however, genetics becomes increasingly important as an influence. It is important to realize that, again, this is only when considered statistically. For every centenarian with a given genetic variation there are scores of other individuals with that very same variant who died at much younger ages. Odds of survival that are improved from 1% to, say, 1.5% remain terrible odds.

The dominant theme emerging from research into the genetics of longevity within our species is that individual variants have very small effects. Further, most statistical associations between specific genetic differences and human longevity are not replicated when studies are repeated with different populations. This tends to be true even for different study populations in the same region - see a recent investigation of associations between FOXO3A and longevity for a good example of this outcome. So in addition to being small, effects are very complicated and highly variable between even very similar genetic lineages. At present there are really only two good associations discovered to date, variants of APOE and FOXO3A, and even these are hard to extract from the data at times.

The situation is somewhat better when it comes studies of age-related conditions and genetics. There are a wide range of robust associations for various conditions in which certain genetic variants seem to imply a lower resistance to specific disease processes that occur in everyone. Investigating the biochemistry of a disease tends to turn up candidate genetic variants in the process of obtaining a better understanding of what exactly is going wrong. You might look at what is known of genetic associations with Parkinson's disease for a good example of how this tends to work out in practice.

To further complicate things, most work in biology and medicine doesn't start with humans, and this is especially true of longevity science. People, mice, flies, worms, and even yeast are all part of the same evolutionary tree and share a surprising number of genes and mechanisms relating to the intersection of metabolism and longevity - which is where you'll most likely find the engines driving natural variations between individuals, as well as the fine details of the ongoing progressive global systems failure that is aging. This common evolutionary heritage is why researchers can obtain insights into human aging and metabolic processes from yeast and flies, and if that can be done it is certainly a whole lot cheaper than trying the same wait and see studies in people.

This doesn't mean that any of this is straightforward, however. People are not mice, and considerably progress in finding longevity-associated genes and single gene mutations that reliably extend life in rodents has not yet led to any similar advances in a coherent mapping of the human genetics of longevity. This short note on the topic is from the lead at one of the groups involved in sequencing the bowhead whale genome in search of explanations for its lengthy life span, thought to be in excess of two centuries:

Why genes extending lifespan in model organisms have not been consistently associated with human longevity and what it means to translation research

A recent paper reports the largest genome-wide association study of human longevity to date. While impressive, there is a remarkable lack of association of genes known to considerably extend lifespan in rodents with human longevity, both in this latest study and in genetic association studies in general. Here, I discuss several possible explanations, such as intrinsic limitations in longevity association studies and the complex genetic architecture of longevity.

Yet one hypothesis is that the lack of correlation between longevity-associated genes in model organisms and genes associated with human longevity is, at least partly, due to intrinsic limitations and biases in animal studies. In particular, most studies in model organisms are conducted in strains of limited genetic diversity which are then not applicable to human populations. This has important implications and, together with other recent results demonstrating strain-specific longevity effects in rodents due to caloric restriction, it questions our capacity to translate the exciting findings from the genetics of aging to human therapies.

Of the 51 gene manipulations extending lifespan in mice, how many would still extend lifespan in genetically heterogeneous mice and by how much? How many would be detrimental? When considering potential applications of the genetics of aging one should keep in mind that these have not been replicated in humans and that even in model organisms these are derived from a very small selection of clones that do not represent the whole species.

For me this is one more item to add to the great mountain of evidence telling us that manipulation of genetics and the operation of metabolism so as to slow aging simply isn't the right path forward. It is too hard, too slow, an attempt to alter an enormously complex and poorly understood system in non-trivial ways, and has too poor an outcome even if successful in comparison to other strategies. Slowing aging can't help the old, and it would be a real shame if all of the effort and investment of the next few decades leads only to therapies that do little for the young and nothing for those of us who helped to bring them about.

To move rapidly towards treatments for aging we should look at cataloging the differences between young tissues and old tissues, determine which of those differences are fundamental and primary, not caused by any of the others, and build the means to revert those differences. The state of knowledge about aging is far further advanced towards that goal than towards a goal of safe metabolic re-engineering.


Cells are complex machines that have many carefully regulated states. One of those states is senescence, in which the cell permanently exits the cell cycle, stops dividing, and begins to secrete a variety of molecules that, among other things, degrade surrounding extracellular matrix structures and encourage nearby cells to also become senescent or change their behavior in other ways. This senescent state seems to be a tool that originally evolved to help manage embryonic growth: senescent cells are found in embryos in places that suggest they are managing shape or tissue transitions during development.

Evolution promiscuously reuses everything that emerges in biology, and at some point cellular senescence became a reaction to damage likely to cause cancer. Toxins, stress, and the various forms of cellular and molecular damage of aging can provoke cells into more readily becoming senescent, either directly or through changes in the signaling environment in tissues. Cancers result from damage to nuclear DNA, producing cells capable of unfettered replication. Senescence is a form of defense that removes potentially cancerous cells from consideration, or at least to some degree. Cancers and cellular senescence are two aspects of our biology in the midst of a long-running evolutionary struggle: the story of the lengthening of human life span in comparison to other primates is one of a moving balance between death by cancer and death by failing tissue function. Many of the most important mechanisms in aging, cellular senescence included, can be viewed in that context. However, too much cellular senescence actually promotes some forms and aspects of cancer precisely because of the various molecules secreted by these cells. There is a tipping point between cancer suppression and cancer promotion determined by the changes in the cellular environment caused by the presence of senescent cells. It is a complex situation.

Senescent cells sometimes destroy themselves through programmed cell death mechanisms that serve to remove damaged cells from circulation before they cause issues, and are sometimes destroyed by the immune system. Those that linger stick around for the long term, however, accumulating in ever increasing numbers. To make things worse, as the immune system declines with aging it does an increasingly poor job of removing these cells, so even as the pace of creation accelerates due to age-damaged tissues, the policing mechanisms are in decline. A sizable percentage of adult skin cells are senescent by the time old age rolls around, for example.

In an ideal world, the perfect situation for adult cellular senescence would be if all these cells in fact destroyed themselves fairly promptly, say within a few days. That is a long way removed from the present situation, but it is something that near future medicine could achieve. The cancer research community is developing all sorts of ways to precisely target cells based on their particular biochemical differences, usually and most easily based on differences in surface chemistry, the molecules presented on the exterior of the cell membrane. Many cancers are distinctive enough to target in this way, and so an industry of research and development has for years been working on the use of altered viruses, designer nanoparticles, and the like, that can find and bind to particular combinations of cell surface chemistry, and once there deliver some form of traditional cancer therapy in the tiny dosage needed to destroy a single cell. Manufacturing tens of millions of such devices for each dose of a therapy promises a very effective next generation of treatments that nonetheless have few side-effects - a world removed from the present standards of chemotherapy and radiation therapy.

Turning these prototype cancer therapies into senescent cell clearance treatments is a very plausible path forward. The roadblock in the way is the need for a good, reliable marker to determine which cells are senescent and which are not. Some of the most interesting work on senescent cell clearance has focused on p16 as a marker for cellular senescence, but this is not as discerning as would be liked despite the successes achieved to date in mice. A couple of other lines of research have looked promising in recent years, such as using lysosomal hydrolases or TRF2 as markers. We are still waiting on a research group to pull this all together, but meaningful removal of senescent cells remains probably the closest item in the rejuvenation toolkit to actual realization.

Here is recent news in which the research team seem fairly confident they have a good marker for senesence in the form of a combination of proteins. They have tried a couple of different cell lines by the sound of it, but I'd want to see more diverse tissues tested; there is no necessary reason to expect cellular senescence to generate usefully similar surface chemistry in all of the most common cell types in the body, though it would be pleasant if that did turn out to be the case. That said, despite the lack of funding for senescent cell clearance with the explicit goal of treating aging it seems there is still some progress, as illustrated by the fact that these cancer researchers are aware enough of efforts in that direction to talk about it at all:

Study offers future hope for tackling signs of aging

"What we have found is a series of novel markers - a way to detect senescent cells. What is more, we have shown that they can be used to predict increased survival in certain types of cancer. Until now, good protocols to help spot these cells have been sadly lacking. Our research has described new markers located on the surface of the old cells. This makes these markers particularly useful to quickly identify these cells in laboratory and human samples using a range of techniques."

As a first clinical application of these markers, the researchers observed that they were present in high numbers in samples from different types of cancer and that this correlated with a better prognosis of the disease. This was particularly evident in breast cancer. "These markers could be useful tools not only to study senescent cells in the lab but also they could be developed into diagnostics to help predict survival in cancer patients. Moreover, they could also be used in the future to define strategies to selectively eliminate the old cells from the tissues and thus reduce their effects on promoting ageing in healthy subjects."

Characterization of novel markers of senescence and their prognostic potential in cancer

Cellular senescence is a terminal differentiation state that has been proposed to have a role in both tumour suppression and ageing. This view is supported by the fact that accumulation of senescent cells can be observed in response to oncogenic stress as well as a result of normal organismal ageing. Thus, identifying senescent cells in in vivo and in vitro has an important diagnostic and therapeutic potential.

The molecular pathways involved in triggering and/or maintaining the senescent phenotype are not fully understood. As a consequence, the markers currently utilized to detect senescent cells are limited and lack specificity. In order to address this issue, we screened for plasma membrane-associated proteins that are preferentially expressed in senescent cells. We identified 107 proteins that could be potential markers of senescence and validated 10 of them (DEP1, NTAL, EBP50, STX4, VAMP3, ARMX3, B2MG, LANCL1, VPS26A and PLD3). We demonstrated that a combination of these proteins can be used to specifically recognize senescent cells in culture and in tissue samples and we developed a straightforward fluorescence-activated cell sorting-based detection approach using two of them (DEP1 and B2MG).

Of note, we found that expression of several of these markers correlated with increased survival in different tumours, especially in breast cancer. Thus, our results could facilitate the study of senescence, define potential new effectors and modulators of this cellular mechanism and provide potential diagnostic and prognostic tools to be used clinically.


Research into treatments for the direct consequences of obesity may be, like much of aging research at the moment, the cover story set up by metabolic researchers in order to raise funds from a system that demands some connection, however tenuous, to the end goal of building treatments. In fact the principal goal of these scientific groups is to catalog and completely understand the massive complexity of cellular metabolism. Making use of that knowledge for any purpose other than to speed up other areas of the cataloging process is a distant second concern. A lot of modern medical research makes much more sense if viewed through this lens, though I can't vouch for the accuracy of its cynicism. It is generally true that knowledge is the primary goal of science, while it is more typically the engineering disciplines whose members work on building new applications of that knowledge. The line between scientist and engineer - between researcher and clinician - was always blurry and indistinct, however, and remains so today.

We live in a world in which wealth has been generated to such an extent that our natural urges, evolved for scarcity, now guide us to harm ourselves. Food, transport, and comfort are so cheap in wealthier regions of the world that simply failing to care and plan for diet and health will turn a thin individual into a considerably overweight individual in a matter of a handful of years. In some parts of Asia the transition from rural subsistence poverty to a society of such wealth happened in a single lifetime, bringing the demographics of disease and longevity into line with the US and Western Europe in that short span of years. Thus there are a lot of overweight individuals nowadays: we are a lot wealthier today even than fifty years ago in measures that matter, such as cost of calories and transportation. As a result a lot more money flows into medical services related to the health consequences of being overweight, and - follow the money - a large amount of funding exists for work on medical means to address these conditions. This is largely centered around work on treating type 2 diabetes, but it is also true that there is a greater level of funding for numerous other conditions much more commonly suffered by those who are overweight.

There is far less funding for the strategy of simple self control and just eating less, but that's what you get in an age of comfort. People want to be told they are fine, there is nothing they did wrong, and that the research community is working on zero-effort, write-a-check methods for making everything right in the world. People don't want to be told to adjust their expectations and diet while simultaneously exercising their willpower, even if that approach can reverse being overweight and reverse type 2 diabetes to boot. A lot of wishful thinking sloshes around in this ecosystem.

The inevitable consequence of giving a lot of researchers a lot of money to do something about obesity, even if they are principally focused on building the Grand Map of Metabolism, is that someone, somewhere, might actually come up with a treatment that works. I can assure you that there is a lot more funding out there for work on obesity and type 2 diabetes, conditions that the vast majority of patients choose to suffer - and worse, choose on a daily basis to continue to suffer - than for meaningful research into treating aging. Does success make it all worthwhile in comparison to other things those resources might have purchased in the research community? That is a question without an answer.

The best hypothetical treatment for obesity is probably one that does absolutely nothing other than make the patient eat less. That seems to be the case in the research noted below, so one has to wonder to what degree the rest of the panoply of effects they describe are relevant to the end result:

Another success on the path to cure adult-onset diabetes, obesity

A new treatment for adult-onset diabetes and obesity developed by researchers has essentially cured lab animals of obesity, diabetes and associated lipid abnormalities through improved glucose sensitivity, reduced appetite and enhanced calorie burning. In preclinical trials, the new peptide - a molecular integration of three gastrointestinal hormones - lowered blood sugar levels and reduced body fat beyond all existing drugs.

These preclinical results advance the clinical work the team announced last year that a peptide combining the properties of two endocrine hormones, GLP-1 and GIP, was an effective treatment for adult-onset diabetes. This new molecule includes a third hormone activity, glucagon. "A number of metabolic control centers are influenced simultaneously, namely in the pancreas, liver, fat depots and brain. The benefits of the previously reported individual co-agonists have been integrated to a single molecule of triple action that provides unprecedented efficacy to lower body weight and control metabolism."

The triple hormone specifically and equally targets three receptors of GLP-1, GIP and glucagon. GLP-1 and GIP predominantly contribute to enhancing insulin action and reducing blood glucose. GLP-1 also curbs appetite, while glucagon primarily increases the long-term rate at which calories are burned and improves liver function.

A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents

We report the discovery of a new monomeric peptide that reduces body weight and diabetic complications in rodent models of obesity by acting as an agonist at three key metabolically-related peptide hormone receptors: glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon receptors. Such balanced unimolecular triple agonism proved superior to any existing dual coagonists and best-in-class monoagonists to reduce body weight, enhance glycemic control and reverse hepatic steatosis in relevant rodent models. We demonstrate that these individual constituent activities harmonize to govern the overall metabolic efficacy, which predominantly results from synergistic glucagon action to increase energy expenditure, GLP-1 action to reduce caloric intake and improve glucose control, and GIP action to potentiate the incretin effect and buffer against the diabetogenic effect of inherent glucagon activity.


AMD, age-related macular degeneration, results in progressive retinal damage and consequent blindness in the central portion of the visual field. Like many age-related conditions at root it is caused by damage and failures in tissues that happen to everyone, but in some people this rises more rapidly to levels sufficient to cause noticeable pathology. Lifestyle choices with a negative impact on circulation and chronic inflammation, such as lack of exercise, obesity, and smoking, all raise the risk of suffering this form of degenerative blindness. But if everyone lived long enough, we'd all get it eventually: absent treatments for aging, missing out on any specific age-related disease at the present time is really just a matter of being nailed by something else first.

Of course we'd like to do better than rolling the dice and taking bets on what kills us first. We want the means to repair the slowly accumulating forms of cellular and molecular damage that cause aging - to miss out on all of the consequences of aging and continue living in good health and youthful vigor. This will be a new strategy in medicine, one that at present has only recently gained acceptance in the mainstream research community. Working to treat aging itself is a departure for the scientific community, which up until now in has focused on trying to patch over the consequences of aging, the many varied age-related diseases such as AMD, one by one. This end stage of aging is a complex forest of dysfunction and failing, flailing biological systems struggling to cope, and progress in any sort of meaningful treatment has been correspondingly expensive and the benefits marginal.

Aging has simple roots, however, just a few forms of cellular dysfunction and hardy waste products that result from the normal operation of our metabolism. Like rust in an intricate metal structure, the end result of simple damage accumulating in a system as complicated as human biology is by necessity very complex. Damage spirals out in chains of cause and effect, as systems that rely upon one another progressively fail in their function. There is a little of genetics and a lot of lifestyle choice in the risks of any particular age-related condition versus another, but mostly it is dumb luck: small random events in your biology snowball into large differences over time. Why focus on trying to manipulate and manage the complicated end results when you could focus on removing the simpler causes? It is well past time for this change in medical strategy.

AMD is a poster child for some attempts to repair the causes of aging because there is a fairly direct link between retinal cell death and one form of hardy, lingering metabolic waste product generated in the normal course of being alive:

Age-related macular degeneration is the leading cause of blindness in people over the age of 65. It is caused or exacerbated by the accumulation of A2E (a toxic byproduct of vitamin A metabolism) in the cells in the retina of the eye. A2E is resistant to breakdown in the lysosome, and therefore accumulates in the lysosomes of retinal pigment epithelial cells throughout life, until the cells become disabled and vision begins to fade. Enzymes that could break down A2E would thus lead to a regenerative cure for age-related macular degeneration.

Direct links are good because it makes for a more straightforward test case and proof of principle. The evidence to date strongly suggests that repair, in this case breaking down waste products, will cause benefits. So there is less likelihood of research efforts becoming bogged down in questions of interpretation or tracing cause and effect through several or more layers of poorly understood biological mechanisms. This is important when there is as little funding for rejuvenation research like this as is presently the case: work must be efficient and lead as directly as possible to solid proof for the repair approach as a research strategy.

Here is an interesting review of what is known of the mechanisms of AMD as well as the present mainstream approaches to treatment - a list that does not at this time include the approach of breaking down metabolic waste products like A2E known to contribute to the condition. It is a small illustration of the larger point that aiming at repair of root causes is a whole new paradigm for the research community, and one that is only just starting to gain greater acceptance. It is still the case that the overwhelming majority of research on age-related disease that you see today is not informed by that viewpoint on strategy and goals:

Present and Possible Therapies for Age-Related Macular Degeneration

AMD is an umbrella term that encompasses two pathologically overlapping, yet distinct, processes: geographic atrophy (GA) (dry) AMD and neovascular (wet) AMD. Clinically, the presentation of AMD differs depending upon the development of neovascular or GA AMD. Unfortunately, both GA and neovascular AMD orchestrate a progressive and unremitting sequential loss of central vision within the affected eye(s) cumulating to blindness.

Our current understanding behind the pathogenesis of AMD stipulates that there is no predominant aetiological factor dictating the development of AMD. Rather, there is a multifactorial element to AMD, whereby interactions between several facets intertwine and coordinate a cascade of sequential steps that provide the appropriate environment for AMD to flourish. However, implicated for both forms of AMD are the involvement and degeneration of four principle ocular regions: the outer retina, the retinal pigment epithelium (RPE), Bruch's membrane (BM), and the choriocapillaris. Although the intricate processes explaining their degeneration still remain elusive, four mechanisms have been postulated as being imperative to the formation of AMD: lipofuscinogenesis, drusogenesis, inflammation, and choroidal neovascularisation; the former three aspects are critical to formation of both types of AMD, whereas the last represents the final stage in the development of neovascular AMD.


Over the course of senescence, there is progressive dysfunction of the RPE, thereby inducing a state of metabolic insufficiency which results in the formation and accumulation of lipofuscin. Deemed highly potent, due to the major component of lipofuscin being N-retinylidene-N-retinyl ethanolamine (A2E), the A2E produced has the ability to interfere with the functional aspects of the RPE, thus triggering apoptosis of the RPE with subsequent development of GA. Furthermore, the accumulation of A2E within the RPE has been shown to increase the risk of choroidal neovascularisation and so neovascular AMD.

Drusogenesis and Inflammation

Defined as "discrete lesions consisting of lipids and proteins", these amorphous deposits accumulate within the region situated between the RPE and the BM. Their clinical significance differs as relatively few quantities of small, hard drusen have been identified in over 95% of the elderly population and are regarded as a benign occurrence. Nevertheless, presence of large, hard and/or large, soft drusen has been recognised as increasing the risk of AMD. One component of this affiliation orientates around the physical displacement, and resulting death, of clusters of photoreceptors within the RPE overlying the drusen, thus leading to GA AMD.

Another dimension to the relationship between drusogenesis and AMD occurs through the indirect influence of drusen on the immune system. Indeed, identification of several components of the immune system within drusen has raised the possibility that drusen mediated inflammation may lead to notable degeneration and disruption.

Choroidal Angiogenesis

There is a delicate balance within endothelial cells residing in the retinal vasculature between factors that promote and inhibit angiogenesis. However, in neovascular AMD, there is a pathological shift in favour of factors promoting angiogenesis. It is postulated that the inflammation and recruitment of several components of the immune system trigger the release of proangiogenic mediators such as VEGF, thereby forming a milieu that favours angiogenesis. Regardless of the exact mechanism, progression to neovascularisation leads to the formation and extension of permeable, weak, and leaky vessels from the vascular choriocapillaris to the avascular choroid which, in turn, induces local oedema but, more profoundly, acute central vision loss resulting from haemorrhage with successive development of a fibrous scar.


Monday, December 8, 2014

The Golgi apparatus is a large structure in the cell that sets up transport of proteins to cell components by packaging and labeling the proteins to ensure they are sent to specific destinations. It is also involved in numerous other processes, such as the synthesis of some important proteins used by cell components, and far from all of these roles are fully cataloged and understood. It is known that rising levels of amyloid beta (Aβ) in and between brain cells characteristic of Alzheimer's disease harms the Golgi apparatus, and here researchers dig deep enough into this process to find a way to block that damage to see what happens:

Alzheimer's disease (AD) progresses inside the brain in a rising storm of cellular chaos as deposits of the toxic protein, amyloid-beta (Aβ), overwhelm neurons. An apparent side effect of accumulating Aβ in neurons is the fragmentation of the Golgi apparatus, the part of the cell involved in packaging and sorting protein cargo including the precursor of Aβ. But is the destruction the Golgi a kind of collateral damage from the Aβ storm or is the loss of Golgi function itself part of the driving force behind Alzheimer's?

The unsurprising part of the answer was that rising levels of Aβ do lead directly to Golgi fragmentation by activating a cell cycle kinase, cdk5. The surprising part of the answer was that Golgi function can be rescued by blocking cdk5 or shielding its downstream target protein in the Golgi, GRASP65. The even more surprising answer was that rescuing the Golgi reduced Aβ accumulation significantly, apparently by re-opening a normal protein degradation pathway for the amyloid precursor protein (APP).

The researchers now say that Golgi fragmentation is in itself a major - and until now an unrecognized - mechanism through which Aβ extends its toxic effects. They believe that as Aβ accumulation rises, damage to the Golgi increases, which in turn accelerates APP trafficking, which in turn increases Aβ production. This is a classic "deleterious feedback circuit". By blocking cdk5 or its downstream target, that circuit can be broken or greatly slowed.

Monday, December 8, 2014

In the field of tissue engineering at present the work on simpler tissues and smaller tissue sections is the closest to widespread commercial realization. Most of the leading lines of research and development involve the use of decellularization, in which donor tissue, which can be from a different species, is stripped of its cells leaving behind the intricate structure of the extracellular matrix. That acts as a scaffold to guide repopulation with cells grown from a patient sample, producing functional tissue ready for transplantation. Here is a short interview with a tissue engineer working on the generation of bone sections:

At the moment, the only way to get bone for grafts is to cut it out of a human. If you need a piece of bone for, say, your ankle, they'll cut it out of your hip. There are several million of these bone-grafting procedures done every year worldwide. The idea is to grow bone from a patient's own cells so they won't need that second surgery and so the implanted bone won't be immunologically rejected. First, we'll take a CT scan to get the 3D structure of a patient's bone and use a high-precision machine to carve a decellularised bovine bone into the required shape. Then we'll take fat tissue from a patient and extract stem cells from it. We combine the stem cells with the piece of carved bone and put it into a bioreactor. That's where the magic happens - after three weeks in the bioreactor we have a piece of bone ready for implantation.

We're working in pigs at the moment but will use the same principle for humans. Pigs are a good fit for the bone we're working on. We wanted a strong proof of concept so chose the most difficult bone in the head - the temporomandibular joint for the jaw. Pigs are great because they've got a very similar sized head to humans and use the bone in a similar way, in a kind of circular chewing motion. The science is getting really close. We're about to start a second, larger study in pigs and are doing work in preparation for human clinical trials with the FDA. We are also planning small-scale implantations in humans in the next year and a half. So pretty soon hopefully!

Tuesday, December 9, 2014

Paul Allen is funding a new large-scale life science project to follow up on the Brain Atlas. This time the goal is to fill in the unknown reaches of cellular metabolism:

Billionaire Paul Allen has a new target for scientific philanthropy: Unraveling the inner workings of human cells. The Microsoft co-founder announced a $100 million, five-year grant to establish the Allen Institute for Cell Science in Seattle. The grant is one of Allen's largest, on par with the $100 million he committed earlier this year to fight Ebola in West Africa, and a $100 million grant in 2003 to establish the Seattle-based Allen Institute for Brain Science. He has since plowed an additional $300 million into the brain institute.

The goal is to better understand the teeming world inside cells, where thousands of organelles and millions of molecules interact in a dynamic ballet that researchers are just beginning to fathom. Diagrams in biology textbooks make it seem like cell structure and function have already been nailed down. Scientists have, indeed, learned a lot about different cell types, the role of organelles like the nucleus, and specific pathways, like the chain of events that causes muscle cells to contract. But there's a big gap when it comes to understanding the way cells function as a whole. "We really don't have a good idea of how normal cells work, and what goes wrong in disease. People spend careers trying to understand little parts of the cell, but nobody has stitched it together - because it's too complicated for any individual to study."

The institute will take on the challenge by combining new technologies, like microscopes that can visualize living cells in three dimensions, with enough computational firepower to make sense of the flood of data that will result. [Researchers] hope to develop computer models that mimic living cells. If they succeed, those models could also shed light on what goes haywire in cancer and other diseases and help develop cures. "Our output will be a kind of visual, dynamic atlas that shows where all of these things are in the cell and how they change over time."

Tuesday, December 9, 2014

Comparative biology is a matter of studying differences between species that might provide insight into how particular cellular mechanisms of interest actually work - or might be altered so as to work better. The world has many species that regenerate more proficiently than we do, or live very much longer than would be expected for their size, or show other desirable characteristics as a result of their own particular evolved biology. How is this achieved at the level of cells and molecular mechanisms, and is it possible to recreate some of these changes in humans? These are questions that comparative biologists seek to answer, using the biology of other species as a shortcut to obtain environments that would otherwise be challenging or impossible at present to set up in the lab.

The authors of the paper quoted below argue that failing to take advantage of the panoply of varied evolved biochemistries in the natural world is holding back medical research. I'd suggest that disparities in regulation have a lot more to do with the differences they point out in progress in computing versus medicine. Regardless, there is certainly utility in the use of comparative biology to obtain new knowledge:

The pace at which science continues to advance is astonishing. From cosmology, microprocessors, structural engineering, and DNA sequencing our lives are continually affected by science-based technology. However, progress in treating human ailments, especially age-related conditions such as cancer and Alzheimer's disease, moves at a relative snail's pace. Given that the amount of investment is not disproportionately low, one has to question why our hopes for the development of efficacious drugs for such grievous illnesses have been frustratingly unrealized. Here we discuss one aspect of drug development - rodent models - and propose an alternative approach to discovery research rooted in evolutionary experimentation. Our goal is to accelerate the conversation around how we can move towards more translative preclinical work.

For more than a century, most biomedical research has relied primarily on mice and rats to study the basic biology, progression, and prevention of disease, with the overarching premise that "below the skin" all organisms are molecularly and biochemically alike. Indeed, several seminal discoveries and human therapies have been made using the premise of rodent models. However, advances in certain areas, especially age-related diseases, have been slow. In fact, one can argue that the numerous reported 'cures' for rodent obesity, cancer, and Alzheimer's disease have ultimately burdened the collective resources of the community to the point that a re-evaluation of the preclinical paradigm must be undertaken.

There is a growing call for additional discovery tools in biomedical research that provide more translative predictability for diseases that generally afflict humans in later life. Animal models that are considered long-lived on the basis of their body size are essential to fill the gap assessing the immutable role of time in aging and the manifestation of age-related diseases. Use of extremely long-lived models such as the naked mole-rat, or species that have adapted to extreme environments also enables one to evaluate whether nature has already evolved the appropriate mechanisms to overcome the environmental threats that contribute to sporadic and late onset diseases. An alternative approach towards target discovery employs natural, extreme biology where evolutionary experimentation has overcome many biological challenges. For instance, obesity is a natural and necessary state to survive months of fasting in hibernating animals. To this end we studied grizzly bears (Ursus arctos horribilis) before, during, and after hibernation to determine the effects of natural obesity on insulin sensitivity and cardiac function.

Wednesday, December 10, 2014

Cancer is thought to be a disease of aging because we accumulate randomly distributed damage to nuclear DNA as we age. The older you are the more of this damage you have. Sooner or later the right combination of mutations occur in a cell that slips past the monitoring of the immune system and other defensive systems, which themselves decline with age due to other forms of damage, and it runs amok to grow a cancer. It remains an open question as to whether this nuclear DNA damage in aging is significant in any other way besides cancer over the present length of a human life span, though it is the default assumption in the research community that this is the case.

There is no good evidence, however, to show that DNA damage and only DNA damage is the cause of other meaningful changes in cellular metabolism characteristic of aging. You can of course correlate damage with progress in aging, and show that calorie restriction - to pick one example - slows the accumulation of nuclear DNA damage along with other measures of aging, but aging is a global phenomenon: these correlations don't even come close to implying direct causation. Finding a more definitive connection is an experiment that lies somewhere in the near future, enabled by more capable biotechnologies and a novel study setup devised by clever researchers.

In any case, this recent research is one narrow example of a way in which random nuclear DNA damage causes cancer - or rather more cancer in this case:

For a small percentage of cancer patients, treatment aimed at curing the disease leads to a form of leukemia with a poor prognosis. Conventional thinking goes that chemotherapy and radiation therapy induce a barrage of damaging genetic mutations that kill cancer cells yet inadvertently spur the development of acute myeloid leukemia (AML), a blood cancer. But a new [study] challenges the view that cancer treatment in itself is a direct cause of what is known as therapy-related AML. Rather, the research suggests, mutations in a well-known cancer gene, P53, can accumulate in blood stem cells as a person ages, years before a cancer diagnosis. If and when cancer develops, these mutated cells are more resistant to treatment and multiply at an accelerated pace after exposure to chemotherapy or radiation therapy, which then can lead to AML, the study indicates.

The researchers initially sequenced the genomes of 22 cases of therapy-related AML, finding that those patients had similar numbers and types of genetic mutations in their leukemia cells as other patients who developed AML without exposure to chemotherapy or radiation therapy, an indication that cancer treatment does not cause widespread DNA damage. "This is contrary to what physicians and scientists have long accepted as fact. It led us to consider a novel hypothesis: P53 mutations accumulate randomly as part of the aging process and are present in blood stem cells long before a patient is diagnosed with therapy-related AML."

Researchers have known that patients with therapy-related AML are more likely than other AML patients to have a high rate of P53 mutations in their blood cells. The gene is a tumor suppressor and normally works to keep cell division in check and maintain the structure of chromosomes inside cells. But when both copies of the gene are disabled by mutations, cancer can develop. Surprisingly, when the researchers analyzed blood samples from 19 healthy people ages 68-89 with no history of cancer or chemotherapy, they found that nearly 50 percent had mutations in one copy of P53, an indicator that many people acquire mutations in this gene as they age.

Wednesday, December 10, 2014

Chronic inflammation is important in neurodegenerative conditions such as Alzheimer's disease, but how much of that is due to age-related dysfunction of the immune system versus the presence of pathogens? Inflammation is a necessary part of the immune response when it is working correctly, after all. Some thoughts on that matter in this open access paper:

Alzheimer's disease (AD) is a complex disease resulting in neurodegeneration and cognitive impairment. Investigations on environmental factors implicated in AD are scarce and the etiology of the disease remains up to now obscure. The disease's pathogenesis may be multi-factorial and different etiological factors may converge during aging and induce an activation of brain microglia and macrophages. This microglia priming will result in chronic neuro-inflammation under chronic antigen activation. Infective agents may prime and drive hyper-activation of microglia and be partially responsible of the induction of brain inflammation and decline of cognitive performances.

Age-associated immune dysfunctions induced by chronic subclinical infections appear to substantially contribute to the appearance of neuro-inflammation in the elderly. Individual predisposition to less efficient immune responses is another relevant factor contributing to impaired regulation of inflammatory responses and accelerated cognitive decline. Life-long virus infection may play a pivotal role in activating peripheral and central inflammatory responses and in turn contribute to increased cognitive impairment in preclinical and clinical AD.

Thursday, December 11, 2014

Researchers have successfully used a scaffold approach to regrow the menicus in a joint:

Researchers have devised a way to replace the knee's protective lining, called the meniscus, using a personalized 3D-printed implant, or scaffold, infused with human growth factors that prompt the body to regenerate the lining on its own. The therapy, successfully tested in sheep, could provide the first effective and long-lasting repair of damaged menisci, which occur in millions of Americans each year and can lead to debilitating arthritis. "At present, there's little that orthopedists can do to regenerate a torn knee meniscus. Some small tears can be sewn back in place, but larger tears have to be surgically removed. While removal helps reduce pain and swelling, it leaves the knee without the natural shock absorber between the femur and tibia, which greatly increases the risk of arthritis."

[The] approach starts with MRI scans of the intact meniscus in the undamaged knee. The scans are converted into a 3D image. Data from the image are then used to drive a 3D printer, which produces a scaffold in the exact shape of the meniscus [made] of polycaprolactone, a biodegradable polymer that is also used to make surgical sutures. The scaffold is infused [with] connective growth factor (CTGF) and transforming growth factor β3 (TGFβ3). [The] sequential delivery of these two proteins attracts existing stem cells from the body and induces them to form meniscal tissue. This is accomplished by encapsulating the proteins in two types of slow-dissolving polymeric microspheres, first releasing CTGF (to stimulate production of the outer meniscus) and then TGFβ3 (to stimulate production of the inner meniscus). Finally, the protein-infused scaffold is inserted into the knee. In sheep, the meniscus regenerates in about four to six weeks. Eventually, the scaffold dissolves and is eliminated by the body.

Thursday, December 11, 2014

Research in mice suggests that using cell therapies to remove scarring on the cornea that clouds vision might actually be a comparatively simple process:

Treating the potentially blinding haze of a scar on the cornea might be as straightforward as growing stem cells from a tiny biopsy of the patient's undamaged eye and then placing them on the injury site, according to mouse model experiments conducted by researchers. "The cornea is a living window to the world, and damage to it lead to cloudiness or haziness that makes it hard or impossible to see. The body usually responds to corneal injuries by making scar tissue. We found that delivery of stem cells initiates regeneration of healthy corneal tissue rather than scar leaving a clear, smooth surface."

[Researchers] had previously developed a technique to obtain ocular stem cells from tiny biopsies at the surface of the eye and a region between the cornea and sclera known as the limbus. Removal of tissue from this region heals rapidly with little discomfort and no disruption of vision. After collecting biopsies from banked human donor eyes, the team expanded the numbers of cells in a culture plate. They conducted several tests to verify that they these cells were, in fact, corneal stem cells.

The team then tested the human stem cells in a mouse model of corneal injury. They used a gel of fibrin, a protein found in blood clots that is commonly used as a surgical adhesive, to glue the cells to the injury site. They found the scarred corneas of mice healed and became clear again within four weeks of treatment, while those of untreated mice remained clouded. "Even at the microscopic level, we couldn't tell the difference between the tissues that were treated with stem cells and undamaged cornea. We were also excited to see that the stem cells appeared to induce healing beyond the immediate vicinity of where they were placed. That suggests the cells are producing factors that promote regeneration, not just replacing lost tissue."

Friday, December 12, 2014

Senescent cells stop dividing and secrete various factors that, among other things, damage surrounding tissue structure and encourage senesence in nearby cells. It would be best if they were removed, and they often are, either through programmed cell death or destroyed by the immune system. Some always remain however, and remain for the long term: their accumulation is one of the causes of degenerative aging. Senescence has some positive roles, however: when it occurs in response to a damaged tissue environment that leads to a greater risk of cells becoming cancerous then senescence can help reduce those odds by removing the cells most at risk from active duty. In addition senescence appears to be a necessary part of shaping tissue during embryonic growth.

Current investigations of senescence have turned up another beneficial role: some of the molecules secreted by senescent cells are a part of the processes of wound healing. Fortunately this is no obstacle to the future production of therapies to periodically clear senescent cells from the body, and thus remove this contribution to the aging process. Just don't use the treatments when you happen to be injured.

[Researchers] identified a single factor secreted by senescent cells that cause them to promote wound healing. It's a crucial discovery for researchers who are working on developing treatments to clear the body of senescent cells as a way to stem the development of age-related disease. "We are now able to identify what senescent cells express that makes them beneficial. This means we will be able to simply provide that factor while we eliminate senescent cells to prevent a deleterious side effect before it even occurs."

[Researchers] used two different mouse models: in the first, senescent cells can be visualized and eliminated in living animals; in the second, mutations in two key genes block the senescence program. Following a skin wound, senescence occurs early on in cells that produce collagen and line blood vessels. The senescent cells accelerated wound closure through the secretion of PDGF-AA, a growth factor contained within blood platelets, making it the "good guy" in this portrayal of senescence. "We were able to apply recombinant PDGF-AA topically to mice that had senescent-free wounds. It rescued delayed wound closure and allowed the mice to heal normally."

The researchers also found that senescent cells were present only for a short time during tissue repair, in contrast to the persistent presence of senescent cells in aged or chronically damaged tissues. Moreover, they say the fact that PDGF-AA was activated very early upon senescence induction in cell culture suggests the time-dependent regulation of secretory factors might, in part, explain the beneficial vs. deleterious effects of senescent cells. The possibility of eliminating senescent cells holds great promise and is one of the most exciting avenues currently being explored in efforts to extend healthspan. This study shows that we can likely harness the positive aspects of senescence to ensure that future treatments truly do no harm."

Friday, December 12, 2014

The next generation of cancer treatments are all about targeting, finding ways to distinguish and destroy only cancer cells, to as to produce therapies that are much more effective, even against late stage metastatic cancer, and have few side effects. The present staples of chemotherapy and radiation therapy are arduous and only partially effective precisely because they are not very selective. It is easy to destroy cells, but hard to destroy only particular cells. One of the more promising lines of research and development for targeted cell destruction is immunotherapy: making use of the existing capabilities of immune cells and directing them to attack cancer cells:

When immunologist Michel Sadelain launched his first trial of genetically engineered, cancer-fighting T cells in 2007, he struggled to find patients willing to participate. Studies in mice suggested that the approach - isolating and engineering some of a patient's T cells to recognize cancer and then injecting them back - could work. But Sadelain did not blame colleagues for refusing to refer patients. "It does sound like science fiction," he says. "I've been thinking about this for 25 years, and I still say to myself, 'What a crazy idea'."

Since then, early results from Sadelain's and other groups have shown that his 'crazy idea' can wipe out all signs of leukaemia in some patients for whom conventional treatment has failed. And today, his group at the Memorial Sloan Kettering Cancer Center in New York City struggles to accommodate the many people who ask to be included in trials of the therapy, known as adoptive T-cell transfer.

[This is] the promise of engineered T cells - commonly called CAR (chimaeric antigen receptor) T cells - for treating leukaemias and lymphomas. The field has been marred by concerns over safety, the difficulties of manufacturing personalized T-cell therapies on a large scale, and how regulators will view the unusual and complicated treatment. But those fears have been quelled for some former sceptics by data showing years of survival in patients who once had just months to live. "The numbers are pretty stunning. Companies have clearly decided that it's worth the pitfalls of how much this therapy is going to cost to develop."


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