Fight Aging! Newsletter, August 17th 2015

August 17th 2015

Fight Aging! provides a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress towards the medical control of aging in order to prevent age-related frailty, suffering, and disease, as well as improvements in the present understanding of what works and what doesn't work when it comes to extending healthy life. Expect to see summaries of recent advances in medical research, 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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  • Progress in Cartilage Engineering Over the Past Four Years
  • More Insight Into How Cells Clear Protein Aggregates
  • Recent Bioethical Ruminations on Longevity, Ranging From Sane to Offensive via Self-Parody
  • Partial Vision Restoration by Introducing Photoreceptor Functions into Retinal Neurons
  • Investigating the Molecular Mechanisms of Statins
  • Latest Headlines from Fight Aging!
    • The Mainstream Approach to Medical Research Must Change
    • More on TDP-43 Accumulation in Amyotrophic Lateral Sclerosis
    • Less Inflammation, Longer Telomeres in Centenarian Offspring
    • Advanced Glycation End-products in Aging and the Diet
    • Towards Xenotransplantation via Transgenic Pigs
    • Endurance Exercise and Selective Breeding in Fly Longevity
    • Insight Into Skin Regeneration: dsRNA and TLR3
    • Naked Mole Rats Maintain High Levels of Autophagy
    • Pondering the California Life Company
    • Hybrid Hepatocytes in Liver Regeneration


Here I'll point you to a recent open access review paper on the use of adult stem cells in the production of cartilage tissue. Cartilage regenerates poorly, and wear and tear in the load-bearing cartilage of joints over the course of aging is the cause of considerable disability and suffering. Any cartilage injuries accumulated along the way only make things worse.

Cartilage is a highly structured tissue, in which the precise arrangement of cells and extracellular matrix molecules provides the mechanical properties necessary to its function. This was perhaps less appreciated than it should have been, at least until researchers started trying in earnest to grow cartilage from stem cells. The complex molecular structure of cartilage has made it a real challenge to engineer this tissue, and only very recently have researchers made inroads into getting the structure right, such as through the mesenchymal condensation technique. Even so production of all of the varied types of cartilage tissue - elastic, hyaline, and fibrocartilage - is yet to be reliably accomplished. It is worth noting that, all this aside, cartilage is one of the "easy" tissues to engineer, being comparatively uniform and lacking in blood vessel networks. Forming and integrating blood vessels is one of the big challenges in building tissues of any significant size, and there is still no good, robust solution to that problem. Until researchers can manage cartilage, muscle, skin, and the like, it is premature to expect much more complex internal organs to be reliably grown from a patient's cells alone.

That said, the process of decellularization will soon allow patient-matched organs to be reliably created from donor organs, and probably even using organs from other species such as pigs. This approach to tissue engineering makes use of the extracellular matrix of the donor organ, stripped of its cells, to guide the patient's cells to reform an organ in the correct fashion. While it is possible to produce a functional organ this way, and this has been demonstrated for a few organs in mice and rats, the research community is still a long way away from being able to fabricate such a matrix or guide its creation by cells. Ultimately we wish to see organ engineering decoupled from the need for donors, which is why decellularization is only a stepping stone to later goals.

Looking back in the Fight Aging! archives, I noticed a very similar review from late 2011 that covers much the same ground as the paper linked below. Four years isn't all that much time in medical research, so the two reviews are much the same in content at a high level. One noteworthy difference is that the number of ongoing, official, by-the-regulations clinical trials for regrowth or regeneration of cartilage has grown considerably in the past few years. But take a look and see what you think; it is clear that this is a field still in the comparatively early stages of developing a practical technology platform for regenerative treatments.

Use of Adult Stem Cells for Cartilage Tissue Engineering: Current Status and Future Developments

Although initially considered as a tissue with a simple structure, reproducing the finely balanced structural interactions of cartilage has proven to be difficult. Articular cartilage is a stable tissue that functions for decades to keep normal joint movement possible. It is a hyaline tissue with no blood, lymphatic or nerve supply. It contains a single type of cells, called chondrocytes, maintained in an abundant connective tissue. This extracellular matrix is composed of collagen fibers, mainly type II collagen, and proteoglycan aggregates, mainly aggrecan, attached along a filament of hyaluronic acid. Collagens provide tensile strength, while proteoglycans are responsible for the compressive strength. The whole forms a viscoelastic structure well suited for both functions of cartilage: the absorption and distribution of forces and the sliding of the joint surfaces with a very low coefficient of friction.

During life, articular cartilage defects may happen and form areas of damaged or missing cartilage. These defects are often caused by acute trauma. Biochemical changes due to age may also stimulate the degradation of cartilage matrix and at term lead to chronic diseases such as osteoarthritis. These defects are the most often irreversible, since articular cartilage has very limited self-repair capability. Cartilage is an attractive candidate for use in tissue-engineering therapies since this tissue is avascular and has a limited capacity for repair.

The use of autologous chondrocyte implantation may represent a promising technology for cartilage repair in orthopedic research. However, we and other investigators have established that, during monolayer expansion of chondrocytes in vitro, this cell population loses its phenotype, as illustrated by a switch in collagen production from type II (typical of hyaline cartilage) toward types I and III (typical of fibrocartilage). The result of these phenotype changes is the production of an extracellular matrix with inferior biomechanical properties. In addition, the limited capacity of the donor site to provide a large amount of chondrocytes, as well as donor site morbidity, are major obstacles for autologous chondrocytes. Therefore, use of stem cells, such as mesenchymal stem cells (MSCs), may be preferred. MSCs can be relatively easily harvested and the procedures using them are less invasive or destructive than articular cartilage harvesting procedures.

Growth factors are essential to induce chondrogenic differentiation of adult stem cells. However, to promote/maintain cartilage differentiation/phenotype in culture, another critical requirement is to provide a 3D microenvironment. Indeed, research has demonstrated that MSCs hardly differentiate into cartilage cell lineage in a 2D culture system. For applications of cartilage tissue replacement, most investigators preferred transplantation of cells combined with scaffold. So, a huge expansion in biomaterial technologies and scaffolds took place to create functional tissue replacement to treat cartilage defects or osteoarthritis. Numerous biomaterials and scaffolds are being developed, influenced by the knowledge of the anatomical and structural complexity of articular cartilage.

Many clinical trials have been registered at regarding application of stem cells for regenerating cartilage. About 40 studies (phase 1 to 3) are in progress or are completed worldwide. Most of them aim to repair cartilage defects or treat degenerative damage, in knee, ankle, or hip, due to osteoarthritis. Some preliminary results have been published and are promising. In spite of the above-mentioned potential, there are some pitfalls associated with MSC application for articular cartilage regeneration. One is the qualities and mechanic properties of neoformed cartilage, and the second is the fabrication of anatomically relevant 3D engineered tissue and its integration into surrounding native joint tissues.


Proteins, the basis for all cellular machines, are very complex structures. Their properties depend upon correct folding, and so misfolded proteins are essentially broken, unable to perform their functions. Some forms of misfolded or otherwise damaged proteins can precipitate from cell and tissue fluids to form solid aggregates. The presence of these aggregates is a form of damage, and cellular quality control mechanisms toil constantly to recycle or repair broken proteins. Clearly these mechanisms fail or are overwhelmed with advancing age, as growing levels of aggregated and misfolded proteins are one of the hallmarks of old tissue. Researchers are investigating in ever greater detail how exactly cells act to clear aggregates, with the goal of finding ways to enhance these evolved processes. The research noted in this post is one example among many, in which the scientists look beyond chaperone proteins, such as heat shock proteins, that are responsible for enabling correct folding and prevention of aggregates, and focus on how the activities of these chaperones are coordinated.

The presence of many of types of aggregate are associated with specific age-related conditions, especially neurodegenerative diseases such as Parkinson's disease (aggregates of α-synuclein) and Alzheimer's disease (aggregates of one of the many types of amyloid). The evidence for aggregates as a direct cause of pathology varies in quality, but there is nonetheless considerable funding and energy directed towards the development of therapies to clear these aggregates. In Alzheimer's disease, for example, forms of immunotherapy are under development to attempt to manipulate immune cells into attacking and recycling the damaged proteins making up aggregates.

At this point the prospects for effective treatments via enhancement of existing cellular quality control mechanisms, as opposed to other forms of clearance such as immunotherapy, seem more distant. It is clearly an interesting proposal, as many ways of slowing aging in laboratory species have been shown to be accompanied by increased activity of chaperone proteins, clearance of damaged proteins, and recycling of cellular components. Calorie restriction is among these, to pick one example. Despite more than a decade of serious interest in finding therapies to boost the activity of quality control processes there is as of yet little progress towards clinical trials or drug candidates, however. Perhaps that will change when a new and more tractable point of influence is discovered in the relevant areas of cellular biochemistry, or perhaps it is another of those areas where progress is a matter of hard work and funding, but too few research groups are presently interested in this approach to generate real traction. For my part, I am more in favor of targeted clearance from the outside via strategies such as immunotherapy rather than attempting to alter existing cellular operations; the latter tends to be much harder to accomplish safely and without side-effects. On the other hand, more competition and diversity in research strategies is usually a good thing.

How Human Cells Can Dissolve Damaging Protein Aggregates

Proteins in all cells - from bacteria to human - are folded in their native state. Proteins are first manufactured as long, sequential chains of amino acids and must assume a specific three-dimensional structure, i.e., fold, to be functional. This correctly folded state, or protein homeostasis, is at constant risk from external and internal influences. Damaged proteins lose their structure, unfold and then tend to clump together. If such aggregates form, they can damage the cells and even cause the cells to die, which we see in neurodegenerative diseases such as Alzheimer's and Parkinson's, and even in ageing processes. The formation of protein aggregates in different organs of the human body is associated with a large number of diseases, including metabolic disorders.

"Dissolving protein aggregates is a critical step in recycling defective proteins and providing protection against stress-induced cell damage. We had several clues as to the main players in this process, but we didn't know exactly how it worked." The researchers succeeded in identifying a previously unknown, multi-component protein complex that efficiently solubilizes stress-induced protein aggregates in vitro. This complex consists of molecular folding helpers, the chaperones, which in this case belong to the heat shock protein 70 (Hsp70) class. These are proteins that aid other proteins in the folding process.

The researchers also studied the co-chaperones that regulate Hsp70 activity in the protein complex. The co-chaperones of the so-called J-protein family are key, in that they "lure" the Hsp70 folding helpers to the protein aggregates and activate them precisely at their target. "The key finding of our work is that two types of these J-proteins must dynamically interact to maximally activate the Hsp70 helper proteins to dissolve the protein aggregates. Only this launches the potent cellular activity to reverse these aggregates. Now we are faced with the challenge of understanding the physiological role and the potential of the newly discovered mechanism well enough to apply these findings from basic research and develop novel strategies for therapeutic interventions."

Crucial HSP70 co-chaperone complex unlocks metazoan protein disaggregation

Protein aggregates are the hallmark of stressed and ageing cells, and characterize several pathophysiological states. Healthy metazoan cells effectively eliminate intracellular protein aggregates, indicating that efficient disaggregation and/or degradation mechanisms exist. However, metazoans lack the key heat-shock protein disaggregase HSP100 of non-metazoan HSP70-dependent protein disaggregation systems, and the human HSP70 system alone, even with the crucial HSP110 nucleotide exchange factor, has poor disaggregation activity in vitro. This unresolved conundrum is central to protein quality control biology.

Here we show that synergic cooperation between complexed J-protein co-chaperones of classes A and B unleashes highly efficient protein disaggregation activity in human and nematode HSP70 systems. Metazoan mixed-class J-protein complexes are transient, involve complementary charged regions conserved in the J-domains and carboxy-terminal domains of each J-protein class, and are flexible with respect to subunit composition. Complex formation allows J-proteins to initiate transient higher order chaperone structures involving HSP70 and interacting nucleotide exchange factors. A network of cooperative class A and B J-protein interactions therefore provides the metazoan HSP70 machinery with powerful, flexible, and finely regulatable disaggregase activity and a further level of regulation crucial for cellular protein quality control.


Here I'll point out a few recent papers from the bioethics community on the topic of longevity and medical science. We are approaching the advent of therapies capable of effectively treating the underlying causes of the aging process, and for reasons we all still argue about this seems to require a lot more wailing and gnashing of teeth than, say, the prospects of developing a cure for cancer or heart disease. You won't see deep soul-searching treatises on how terrible it would be it cancer were done away with, at least not from people who like to avoid mockery, but treatments for aging appear to be fair game.

I should say here that I don't think highly of bioethics. The modern institution of bioethics is much like politics, in that it is a parasitical line of business that exists only to divert resources away from productive uses. Bioethicists as a group thrive on slowing down progress and inflicting additional costs on development: their funding comes from manufacturing problems where no problems exist, and the incentives follow on from that in a very straightforward manner. In short, bioethics is unneeded. It has no useful role. Yet, like the roil of politics, there it is, a bunch of people devoted to making vital activities such as medical development harder and more expensive. (This stands in contrast with the past of medical ethics as largely pragmatic business of formalizing triage and experiment when you cannot save everyone. Unfortunately once institutions become well established they inevitably drift in the direction of securing growth and perpetuation at the cost of their original goals. Hence bioethics).

Some truly reprehensible concepts are trafficked around in bioethics circles regarding aging, longevity, and medicine. The duty to die, the "fair innings" argument for cutting off provision of medicine to the old, suppression of research that might extend life, and so on and so forth. Meanwhile the average fellow in the street is suspicious or disinterested in living longer for entirely different reasons, but were he born a century from now, he would accept his indefinite future healthy life span without question. It's all a matter of culture. When it comes to the talking heads, there is no status quo so horrible that it won't be defended. We don't have to look far to see that; just count the hundred thousand lives lost every day to aging, and the ongoing suffering of hundreds of millions of others that is swept behind the curtains.

Of course one can also find bioethics writers, usually not of the professional sort, who write more favorably on the topic of enhanced longevity through medical science. Even so, the framing of the discussion is all too often one of rules and allowances: who should be permitted, who should be forbidden. Freedom and choice is something of a lost art as our governments grow bloated and every aspect of life is regulated by disinterested bureaucrats. In medicine particularly all that is not explicitly allowed is forbidden, and the effects of the modern biotechnology revolution are muted and suppressed by the enormous and growing costs imposed upon turning laboratory work into therapies.

Longevity and compression of morbidity from a neuroscience perspective: Do we have a duty to die by a certain age?

The search for longevity, if not for immortality itself, has been as old as recorded history. The great strides made in the standard of living and the advances in scientific medicine, have resulted in unprecedented increases in longevity, concomitant with improved quality of life. Thanks to medical progress senior citizens, particularly octogenarians, have become the fastest growing segment of the population and the number of centenarians is increasing, even though in the last two decades, spurred by the bioethics movement, the priority assigned to the prolongation of lifespan has taken a back seat to the containment of health care costs.

Four Ways Life Extension will Change Our Relationship with Death

Discussions of life extension ethics have focused mainly on whether an extended life would be desirable to have, and on the social consequences of widely available life extension. I want to explore a different range of issues: four ways in which the advent of life extension will change our relationship with death, not only for those who live extended lives, but also for those who cannot or choose not to. Although I believe that, on balance, the reasons in favor of developing life extension outweigh the reasons against doing so (something I won't argue for here), most of these changes probably count as reasons against doing so.

First, the advent of life extension will alter the human condition for those who live extended lives, and not merely by postponing death. Second, it will make death worse for those who lack access to life extension, even if those people live just as long as they do now. Third, for those who have access to life extension but prefer to live a normal lifespan because they think that has advantages, the advent of life extension will somewhat reduce some of those advantages, even if they never use life extension. Fourth, refusing life extension turns out to be a form of suicide, and this will force those who have access to life extension but turn it down to choose between an extended life they don't want and a form of suicide they may (probably mistakenly) consider immoral.

Slowed ageing, welfare, and population problems

Biological studies have demonstrated that it is possible to slow the ageing process and extend lifespan in a wide variety of organisms, perhaps including humans. Making use of the findings of these studies, this article examines two problems concerning the effect of life extension on population size and welfare. The first - the problem of overpopulation - is that as a result of life extension too many people will co-exist at the same time, resulting in decreases in average welfare. The second - the problem of underpopulation - is that life extension will result in too few people existing across time, resulting in decreases in total welfare. I argue that overpopulation is highly unlikely to result from technologies that slow ageing. Moreover, I claim that the problem of underpopulation relies on claims about life extension that are false in the case of life extension by slowed ageing. The upshot of these arguments is that the population problems discussed provide scant reason to oppose life extension by slowed ageing.

Lastly, as for all political and philosophical fields of discussion there are bioethics debates that run right off the rails and into never-never land. At some point reality is left behind and those involved might as well be building their own sort of secular theology for all the relationship it bears to practical concerns. The paper referenced below is a particular egregious example, but there are many others that come and go on a regular basis.

The Tortoise Transformation as a Prospect for Life Extension

The value of extending the human lifespan remains a key philosophical debate in bioethics. In building a case against the extension of the species-typical human life, Nicolas Agar considers the prospect of transforming human beings near the end of their lives into Galapagos tortoises, which would then live on decades longer. A central question at stake in this transformation is the persistence of human consciousness as a condition of the value of the transformation. Agar entertains the idea that consciousness could persist in some measure, but he thinks little is to be gained from the transformation because the experiences available to tortoises pale in comparison to those available to human beings. Moreover, he thinks persisting human consciousness and values would degrade over time, being remade by tortoise needs and environment. The value available in the transformation would not, then, make the additional years of life desirable. Agar's account does not, however, dispose of the tortoise transformation as a defensible preference. Some people might still want this kind of transformation for symbolic reasons, but it would probably be better that no human consciousness persist, since that consciousness would be inexpressible as such. Even so, it is not irrational to prefer various kinds of lifespan extension even if they involve significant modifications to human consciousness and values.


This is the barnstorming era of biotechnology, in which researchers continually demonstrate new and interesting ways to re-engineer cellular biochemistry. Many of these initiatives are very intriguing and tackle issues of age-related dysfunction, but nonetheless probably won't lead to the development of therapies that make it to widespread clinical use. The example here is one of these, I think. Researchers have found a way to use a gene therapy to introduce some of the functionality of photoreceptor cells into the retinal neurons that lie behind the layer of photoreceptors, and have demonstrated the results in mice. The result is that in cases of blindness where near all normal photoreceptors are lost, the converted neurons take up some of the slack to send signals to the brain. Formerly blind mice given the treatment exhibit the ability to pick up changes in movement and shade in their surroundings.

Given that outcome, why do I think that this has only a modest future? A combination of a few factors. Firstly, it is quite early stage research, so one should expect it to take a decade or so for it to progress to the point at which someone is mounting clinical trials. Secondly it is a form of restructuring and compensation: it is not restoring original cell populations in the retina, but rather creating new hybrids and a new variant architecture of vision, a state of affairs that will introduce all sorts of complexities not present in straight regeneration. The combination of these two points means that this type of approach will, I think, lose out to forms of regenerative medicine capable of restoring the original population of photoreceptors and supporting tissue in the retina. That research is further along at this point and has more funding behind it.

(Further, assuming that we longevity advocates get our act together in the next decade or two all of these approaches will become unneeded for most people due to the advent of SENS therapies that periodically clear out the accumulations of metabolic waste that contribute to photoreceptor cell death).

This all said, partial restoration of visual ability via gene therapy would probably compete well with partial restoration of visual ability via electrode grid retinal implants, were they at the same level of clinical development. Both aim to add new architecture in order to push signals to the optic nerve, but are otherwise very different, with equally different potential paths towards improvement of quality. That path is known for electrode grids - add ever more electrodes to gain better resolution, and attempt to better mimic the effect of real photoreceptor signaling on retinal neurons - but improvement is an open question for gene therapy to convert neurons into photoreceptors. Still, gene therapy doesn't require surgery and a camera device in order to work, and avoiding surgery is always a big plus.

Restoration of Vision with Ectopic Expression of Human Rod Opsin

Inherited retinal degenerations (retinal dystrophies), such as retinitis pigmentosa, affect 1:2,500 people worldwide. Irrespective of etiology, most affect the outer retina and lead to progressive and permanent loss of photoreception. Severe visual impairment is common in advanced stages of the degeneration, and these conditions are currently incurable. However, despite the loss of outer retinal photoreceptors, inner retinal neurons, including bipolar and ganglion cells, can survive and retain their ability to send visual information to the brain. These neurons therefore, represent promising targets for emerging optogenetic therapies that aim to convert them into photoreceptors and recreate the photosensitivity that has been lost during degeneration.

Pioneering work has shown that electrophysiological responses to light can be restored to animal models of retinal degeneration by introducing a variety of optogenetic actuators to the surviving inner retina.These interventions can also support behavioral light responses including, in some cases, maze navigation or optokinetic reflexes reliant upon detection of spatial patterns or fast temporal modulations (flicker). However, in most cases, these actuators function only under very bright light, and, to date, no clinically achievable optogenetic intervention has recreated spatiotemporal discrimination at commonly encountered light levels.

Here, we set out to determine whether it is possible to recreate vision in blind mice using ectopic expression of a natural human protein, rod opsin. We expressed human rod opsin in surviving inner retinal neurons of a mouse model of aggressive retinal degeneration with near complete loss of rod and cone photoreceptors (rd1) by intravitreal administration of clinically approved adeno-associated virus (AAV) vector, AAV2/2. Widespread light-evoked changes in firing were observed in neurons of the retina and dorsal lateral geniculate nucleus (dLGN) in treated mice. These responses could be elicited using physiologically encountered light levels and under natural light-adapted conditions. Behavioral studies indicated that the treated mice had regained the ability to detect modest changes in brightness, relatively fast flickers, spatial patterns, and naturalistic movie scenes.


In the paper referenced here researchers dig more deeply into the effects of statins on cellular metabolism, and in particular its effects on stem cell activities. Statins act to reduce cholesterol levels in the blood and are widely used to attempt to slow the onset of cardiovascular diseases, particularly atherosclerosis. The consensus view of the evidence suggests that overall the outcome of statin use is modestly positive, but there are always outlier studies, such as those suggesting statin use causes more harm than it prevents to the cardiovascular system. Like all drugs in widespread use today statins have very broad effects on the operation of cellular metabolism, and far from all of these effects are completely understood.

Still, statins were selected to be one of the components of a proposed polypill program aiming to slightly slow the later stages of aging. Trials have been carried out or are underway, but the proponents of polypills are still a fair way distant from implementing the original vision of blanket prescription of low doses of statins and a range of other drugs for everyone over the age of fifty. If we're lucky, this and all other similar programs will be overtaken by circumstances, rendered irrelevant by progress in rejuvenation therapies. Tinkering with metabolism and mining the world for drugs that might slightly slow aging isn't the path forward, but it is certainly expensive and time-consuming.

That both beneficial and harmful actions result from the interaction of drugs with tissues is well illustrated in this examination of statins, but the actual biochemistry involved is an unusually constrained case. A single type of change, a reduction in the ability of stem cells to deliver a supply of new cells into tissues, spirals out to bring both benefits and harms. These occur on different timescales and for different aspects of the integrity of the cardiovascular system. A drug can be seen as beneficial if slows a rapid cause of death but speeds up a slower cause of death, as might be argued is happening in the case of statins. Much of the downside will be masked because many people will die due to other causes along the way. With the advance of biotechnology and greater knowledge of cellular biochemistry some drugs will no doubt be altered to successfully split apart beneficial and harmful actions. This is underway for rapamycin, to pick one example, but I think it less likely to happen here.

This is also a good illustration of the point that altering the operation of metabolism away from its present evolved state always comes with trade-offs. Our biology is too complex for any other outcome: every system is connected in some way to every other system. Nothing can be altered in isolation, nothing can be easily switched around. The only approach to medicine free from considerations of benefit versus harm is to aim at repair of the root cause damage that causes age-related system failures in cells and tissues. Strive to maintain the metabolism we have when we are young through periodic repair, in other words, don't try to build a new system that can slightly better cope with being damaged. The former is the easier path, with much larger potential gains in health and longevity, while the latter is far harder and cannot produce anything more than a modest slowing of aging. Yet most research follows the latter path. It is a crazy world we live in.

New Research Shows Why Statins Should Be Viewed as a Double-Edged Sword

Atherosclerosis develops when plaques build up inside blood vessels, which can lead to heart attack, stroke and death. Statins lower the risk by blocking cholesterol production in the liver, reducing a person's "bad" cholesterol. The immune cells macrophages play a major role in plaque formation and rupture in atherosclerosis. Macrophages ingest fat deposits along the blood vessel wall and attract more macrophages, other cells and inflammation-related proteins to the injury site. The enhanced inflammation builds up the plaque within the vessel wall and further narrows the artery. Macrophages also release enzymes that weaken the fibrous cap that separates the plaque from the blood flow, increasing the likelihood that the plaque breaks open. Plaque ruptures lead to blood clots that result in strokes and heart attacks.

Macrophages primarily develop from stem cells that reside in the bone marrow, but can also develop from mesenchymal stem cells (MSCs), which are found throughout the body. While bone marrow stem cells mainly become blood cells, MSCs can become all cell types, including bone, cartilage, muscle cells and macrophages. In this study, the research team found that long-term statin use prevented MSCs from turning into macrophages, which could decrease inflammation and improve plaque stability in patients with cardiovascular disease. However, statins also prevented MSCs from becoming bone and cartilage cells. Statins increased aging and death rate of MSCs and reduced DNA repair abilities of MSCs. "While the effect on macrophage differentiation explains the beneficial side of statins, their impact on other biologic properties of stem cells provides a novel explanation for their adverse clinical effects."

The Impact of Statins on Biological Characteristics of Stem Cells Provides a Novel Explanation for Their Pleotropic Beneficial and Adverse Clinical Effects

Statins reduce atherosclerotic events and cardiovascular mortality. Their side effects include memory loss, myopathy, cataract formation, and increased risk of diabetes. As cardiovascular mortality relates to plaque instability, which depends on the integrity of the fibrous cap, we hypothesize that the inhibition of the potential of Mesenchymal Stem Cells (MSCs) to differentiate into macrophages would help to explain the long known, but less understood "Non Lipid Associated" or pleiotropic benefit of statins on cardiovascular mortality. While the effect on macrophage differentiation explain the beneficial side of statins, their impact on other biologic properties of stem cells provides a novel explanation for their adverse clinical effects.


Monday, August 10, 2015

At a recent conference appearance, scientist-advocate Aubrey de Grey of the SENS Research Foundation made a point that I think bears repeating. The mainstream approach to medical science is to screen for drug compounds that produce beneficial alterations in cellular mechanisms observed in late stage disease. This almost entirely focuses on proximate causes of harm in a diseased, dysfunctional metabolism, far removed from the root causes that created the medical condition in the first place. It thus produces therapies that do little good in the grand scheme of things since they don't address the real cause of disease. They are rather efforts to make a badly damaged system limp along a little longer with patches and compensations, which is always expensive and doomed to failure, whether we are talking about a mechanical device or a human being.

This strategy for medical research and development must change radically if we are to see meaningful progress towards prevention and cure of age-related disease. It must be replaced with something more like de Grey's SENS programs, in which carefully designed therapies repair specific forms of cell and tissue damage to achieve rejuvenation. The form of these therapies is already known in great detail; it is clear what must be built. Some are already under development, such as senescent cell clearance and allotopic expression of mitochondrial genes. This is the future of medicine, not continuing to mine the natural world in the hope of finding compounds that do marginally more good than harm, and can at best only slightly slow down the aging process.

de Grey attributed the gains in longevity over the last century to one primary factor - the reduction of infectious diseases. With infectious diseases largely gone in the developed world, he said we need to turn our attention to the main cause of death. "There's almost one thing that kills everybody now in the developed world. It's the accumulation of these various types of molecular and cellular damage that the body does to itself as a side effect of just being alive at all." According to his research and theories, that molecular and cellular damage can be repaired with new regenerative medicines, including stem cell therapies, gene therapies, drugs and vaccines.

de Grey challenged the wisdom of modern pharmaceutical research leading to really expensive drugs that delay diseases by very short periods of time. "We will not cure cancer this way. We will not cure Alzheimer's this way." The incentive structure for modern pharmaceuticals perpetuates this because "it can be done reasonably quickly, sold for a lot of money and because people are desperate for anything."

"I think it's really important to understand that the relationship between quality of life and quantity of life is not as most people think about it. Today most people think about those two things as some kind of trade off, and that makes sense today because there are many things we like doing that are not very good for us. But we are talking about a world in which quality will confer quantity, in which you will live longer because you are living better. That's the critical thing here."

Monday, August 10, 2015

Scientists have of late been making progress in understanding the role of TDP-43 accumulation in the nerve cell degeneration and death that characterizes amyotrophic lateral sclerosis (ALS) and some forms of frontotemporal dementia (FTD). Potential drug targets have emerged that may allow better clearing of unwanted TDP-43 through cellular quality control mechanisms, for example. The researchers quoted here have a different approach in mind, however, focusing on the use of other proteins that can perform the vital cellular functions that are disrupted when too much TDP-43 is present, but which are not themselves affected by high levels of TDP-43:

TDP-43 is normally responsible for keeping unwanted stretches of the genetic material RNA, called cryptic exons, from being used by nerve cells to make proteins. When TDP-43 bunches up inside those cells, it malfunctions, lifting the brakes on cryptic exons and causing a cascade of events that kills brain or spinal cord cells. Researchers deleted the gene for TDP-43 from both lab-grown mouse and human cells and detected abnormal processing of strands of RNA, genetic material responsible for coding and decoding DNA blueprint instructions for making proteins. Specifically, they found that cryptic exons - segments of RNA usually blocked by cells from becoming part of the final RNA used to make a protein - were in fact working as blueprints. With the cryptic exons included rather than blocked, proteins involved in key processes in the studied cells were abnormal.

When the researchers studied brain autopsies from patients with ALS and FTD, they confirmed that not only were there buildups of TDP-43, but also cryptic exons in the degenerated brain cells. In the brains of healthy people, however, they saw no cryptic exons. This finding, the investigators say, suggests that when TDP-43 is clumped together, it no longer works, causing cells to function abnormally as though there's no TDP-43 at all. TDP-43 only recognizes one particular class of cryptic exon, but other proteins can block many types of exons, so researchers next tested what would happen when they added one of these blocking proteins to directly target cryptic exons in cells missing TDP-43. Indeed, adding this protein allowed cells to block cryptic exons and remain disease-free. "What's thought provoking is that we may soon be able to fix this in patients who have lots of accumulated TDP-43."

Tuesday, August 11, 2015

Researchers have in the past demonstrated that the children of very long-lived individuals tend to themselves have greater longevity. Thus is isn't surprising to see evidence of better measures of health as well, such as in thus study where the offspring of centenarians have less inflammation and longer telomeres. Aging is a process of accumulating damage to cells and tissues, and both chronic inflammation and telomere shortening are largely or completely a reflection of that damage and its direct consequences, and in turn go on cause their own further consequences. Rising levels of inflammation, for example, are in part caused by immune system dysfunction and the effects of cross-link forming advanced glycation end-products on cell activities.

"Centenarians and supercentenarians are different - put simply, they age slower. They can ward off diseases for much longer than the general population." In groups of people aged 105 and over (semi-supercentenarians), those 100 to 104 (centenarians), those nearly 100 and their offspring, the team measured a number of health markers which they believe contribute towards successful ageing, including blood cell numbers, metabolism, liver and kidney function, inflammation and telomere length.

Scientists expected to see a continuous shortening of telomeres with age, however what they found was that the children of centenarians, who have a good chance of becoming centenarians themselves, maintained their telomeres at a 'youthful' level corresponding to about 60 years of age even when they became 80 or older. "Our data reveals that once you're really old, telomere length does not predict further successful ageing. However, it does show that those who have a good chance to become centenarians and those older than 100 maintain their telomeres better than the general population, which suggests that keeping telomeres long may be necessary or at least helpful to reach extreme old age."

Centenarian offspring maintained lower levels of markers for chronic inflammation. These levels increased in everybody with age including centenarians and older, but those who were successful in keeping them low had the best chance to maintain good cognition, independence and stay alive for longer. "It has long been known that chronic inflammation is associated with the ageing process in younger, more 'normal' populations, but it's only very recently we could mechanistically prove that inflammation actually causes accelerated ageing in mice. "This study, showing for the first time that inflammation levels predict successful ageing even in the extreme old, makes a strong case to assume that chronic inflammation drives human ageing too. Our study showed that over a wide age range, including unprecedentedly large numbers of the extremely old, inflammation is an important driver of ageing that might be something we can develop a pharmacological treatment for. Accordingly, designing novel, safe anti-inflammatory or immune-modulating medication has major potential to improve healthy lifespan."

I think that there are some cart and horse issues in the conclusions drawn here by the researchers involved. This is the case in much of modern medicine for age-related conditions: development focuses on addressing proximate causes and consequences of root causes rather than on the root causes themselves. It is trying to clean up the spill from a broken pipe without fixing the pipe, or trying to make an old, worn car run more effectively by being very diligent in changing the oil. Present research and development strategies result in expensive treatments that do comparatively little, and this must change if we are to see greater progress towards effective treatments for aging.

Tuesday, August 11, 2015

The open access paper linked here reviews evidence for the contribution of dietary advanced glycation end-products (AGEs) to aging. There is in fact some debate over the degree to which AGEs from the diet are important in aging versus AGEs generated within and between cells. There are many types of AGE capable of forming cross-links in the extracellular matrix. These cross-links degrade tissue structure and function, and while most are short-lived and soon broken down, the less common long-lived varieties build up over the years to contribute to age-related disease and degeneration. The overwhelming majority of cross-links in old human tissues involve glucosepane, a long-lived AGE that doesn't appear to arrive in significant amounts from the diet. The SENS Research Foundation is funding programs to find a way to safely break down glucosepane since our evolved biochemistry isn't capable of performing that job. AGEs don't just form cross-links, however. They can also spur chronic inflammation and other bad cellular behavior by interacting with the receptor for AGEs, RAGE. This is an area in which short-lived AGEs and dietary AGEs might be contributing meaningfully to aging, and is certainly a day to day concern for people with diabetes, for example.

An important mechanism by which lifestyle influences loss of health and function is oxidative stress. Oxidative stress results in oxidized cell macromolecules and disturbs cell signal transduction, especially insulin-mediated metabolic responses. Metabolic insulin resistance remains a poorly understood phenomenon of cell stress associated with aging and chronic degenerative diseases. Medical approaches focus on management of hyperglycemia, often at the expense of insulin-dependent cell stress. Systemic advanced glycation end-products (AGEs) formed endogenously or acquired from high temperature-cooked foods and tobacco products are powerful pro-oxidants. Emerging research reveals the compelling contribution of dietary AGEs (dAGEs) to systemic load of AGEs, cell stress and insulin resistance.

Advanced glycation end-products promote oxidative damage to proteins, lipids and nucleotides. Aging and chronic diseases are strongly associated with markers for oxidative stress, especially advanced glycation end-products, and resistance to peripheral insulin-mediated glucose uptake. High advanced glycation end-products overwhelm innate defenses of enzymes and receptor-mediated endocytosis and promote cell damage via the pro-inflammatory and pro-oxidant receptor for advanced glycation end-products. Here we review emerging evidence that restriction of dietary advanced glycation end-products significantly reduces total systemic load and insulin resistance in animals and humans in diabetes, polycystic ovary syndrome, healthy populations and dementia. Of clinical importance, this insulin sensitizing effect is independent of physical activity, caloric intake and adiposity level.

Wednesday, August 12, 2015

There are two paths to xenotransplantation, the use of animal organs from species such as pigs in human medicine. The first is decellularization, clearing out all of the cells from the organ and then repopulating it with cell types derived from the patient's stem cells. The second is genetic engineering of a donor lineage, such as the transgenic pigs mentioned in this article. In both cases this is a sizable incremental improvement on the present day situation in transplant medicine, either minimizing immune rejection issues or removing limits on the availability of donor organs. Bear in mind, however, that xenotransplantation and decellularization are only stepping stones on the way to future technologies of organ tissue engineering and regenerative medicine capable of organ repair in situ; these are unlikely to have a long life spans as active technologies given the present pace of progress.

Researchers have been shattering records in xenotransplantation, or between-species organ transplants. The researchers say they have kept a pig heart alive in a baboon for 945 days and also reported the longest-ever kidney swap between these species, lasting 136 days. The experiments used organs from pigs "humanized" with the addition of as many as five human genes, a strategy designed to stop organ rejection. The GM pigs are being produced by Revivicor, a division of the biotechnology company United Therapeutics. That company's founder and co-CEO, Martine Rothblatt, is a noted futurist who four years ago began spending millions to supply researchers with pig organs and has quickly become the largest commercial backer of xenotransplantation research. Rothblatt says her goal is to create "an unlimited supply of transplantable organs" and to carry out the first successful pig-to-human lung transplant within a few years.

The problem with xenotransplantation is that animal organs set off a ferocious immune response. Even powerful drugs to block the immune attack can't entirely stop it. All human tests of pig organs have ended quickly, and badly. Researchers continue to work with pigs because they're in ready supply, and the organs of young pigs are about the right size. In order to beat the rejection problem, researchers began trying to genetically modify the animals. One major step came in 2003 with pigs whose organs lacked a sugar molecule that normally lines their blood vessels. That molecule was the major culprit behind what's called hyperacute rejection, which had almost instantaneously destroyed transplanted pig organs. Removing the sugar molecule helped. But it wasn't enough. Tests in monkeys showed that other forms of organ rejection still damaged the pig tissue, albeit more slowly. To combat these effects, researchers have made pigs with more and more human genes. For instance, one gene that's been added produces the human version of thrombomodulin, a molecule that prevents clotting in blood vessels. Although pigs have their own version of thrombomodulin, it's the wrong shape and doesn't work correctly with human blood.

Transplant surgeons say one of the largest obstacles they face is the immense cost of carrying out xenotransplant experiments. A single transplant surgery costs 100,000 and involves eight people. Then there's the cost of keeping the primates, the red tape of animal regulations, and limited government grants. That's where Rothblatt's personal interest and her fortune have made a difference, they say. "She is the one that has rejuvenated the field. She has the money and a personal attachment. She wants to get it done fast."

Wednesday, August 12, 2015

The paper linked below looks at overlaps in the underlying mechanisms by which exercise and selective breeding can extend fly life spans, and is typical of much of the mainstream of aging research these days. A great deal of the field still involves finding natural ways to extend life and then digging through the biochemistry to gain more knowledge of its operational parameters. It is all very interesting, but we shouldn't expect these research programs to result in methods of significantly extending life in humans; the goal here is understand the relationship between the enormously complex operation of metabolism and natural variations in life span.

Aging is damage, and so natural variations in life span relate to the pace at which damage accumulates over time. Since living organisms self-repair, this is not a straightforward process, and there is room for decades of research yet for those interested in the fine details of every part of the downward spiral. In many ways a damaged, old metabolism is even more complicated that the correctly functioning younger version. When the research community does get around to building meaningful rejuvenation therapies, such as those detailed in the SENS proposals, they will not be created atop the knowledge of how metabolism determines longevity. The goal will be to halt and reverse degenerative processes through damage repair rather than trying to alter metabolism to slightly slow down the pace of damage accumulation. The nature of that damage and how to repair it are already well known, and the work left is to build the necessary technologies. How exactly damage spirals out to create dysfunction is a big empty space on the map, but if the damage can be repaired then researchers don't need that knowledge in order to create rejuvenation therapies.

Endurance exercise has emerged as a powerful intervention that promotes healthy aging by maintaining the functional capacity of critical organ systems. In addition, long-term exercise reduces the incidence of age-related diseases in humans and in model organisms. Despite these evident benefits, the genetic pathways required for exercise interventions to achieve these effects are still relatively poorly understood. Here, we compare gene expression changes during endurance training in Drosophila melanogaster to gene expression changes during selective breeding for longevity. Microarrays indicate that 65% of gene expression changes found in flies selectively bred for longevity are also found in flies subjected to three weeks of exercise training.

We find that both selective breeding and endurance training increase endurance, cardiac performance, running speed, flying height, and levels of autophagy in adipose tissue. Both interventions generally upregulate stress defense, folate metabolism, and lipase activity, while downregulating carbohydrate metabolism and odorant receptor expression. Several members of the methuselah-like (mthl) gene family are downregulated by both interventions. Knockdown of mthl-3 was sufficient to provide extension of negative geotaxis behavior, endurance and cardiac stress resistance. These results provide support for endurance exercise as a broadly acting anti-aging intervention and confirm that exercise training acts in part by targeting longevity assurance pathways.

Thursday, August 13, 2015

Researchers continue to explore the mechanisms of regeneration in search of both a greater understanding of why it falters in aging, as well as ways to enhance the normal processes of healing. Here they have focused on the role of double-stranded RNA and toll-like receptor 3 in triggering skin regeneration in response to damage:

Researchers have identified a novel cell signaling pathway in mice through which mammals - presumably including people - can regenerate hair follicles and skin while healing from wounds. "Medications that turn on this protein have the powerful potential to decrease scarring as healing of wounds takes place, thereby promoting skin and hair follicle regeneration. A lot of human disability is from scarring. After a heart attack, we're really good at replacing the blood flow, but it's the scar on the heart afterward that's the real problem. We and others in the field of regenerative medicine are interested in how to enhance or trigger regeneration in such situations."

Damaged skin releases double-stranded RNA (dsRNA) - genetic information normally carried by some viruses - that is sensed by a protein called toll-like receptor 3 (TLR3). TLR3, which in other contexts plays a fundamental role in recognizing some disease-causing organisms and activating the immune system, during wounding also activates the genes IL6 and STAT3 to promote hair follicle regeneration. TLR3 also activates other molecules involved in hair development, including the Wnt and Shh signaling pathways and a gene called EDAR, which makes the protein ectodysplasin and plays an important role in skin development.

Researchers compared the protein expression of certain genes in healed wounds in two groups of mice. One group was genetically proficient in wound-induced hair neogenesis, a process in mice and rabbits in which skin and hair follicles regenerate after wounds. The other inbred group of mice was noted to lack this ability. Expression of TLR3 was three times higher in the mice that were better able to regenerate hair. In other experiments, the team found that the expression of TLR3 was five times higher in scratched human skin cell samples compared to healthy skin cell samples, that adding synthetic dsRNA to mouse skin wounds led to a greater number of regenerated follicles, that adding a substance that breaks up dsRNA decreased the number of regenerated follicles, and that regeneration was nearly abolished in mice deficient in TLR3.

It has long been known that skin damage can trigger regeneration. Several cosmetic dermatological procedures, such as chemical peels, dermabrasion and laser treatments, have been used to do that for decades: "One implication from our work is that all of those different rejuvenation techniques are likely working through dsRNA pathways. It may also be that dsRNA could be directly used to stimulate rejuvenation in aging or hair follicle growth in burn patients to regain structures that have been lost."

Thursday, August 13, 2015

Naked mole rats live nine times longer than similarly sized rodents and show little sign of age-related decline across the majority of that span. Researchers are very interested in finding out why this is the case. Here a team is looking at levels of autophagy in the naked mole rat, a collection of cellular maintenance mechanisms that direct damaged cell structures to be engulfed by lysosomes for recycling. More active autophagy is seen in many of the methods shown to slow aging in mammals, and most likely contributes by reducing the presence and impact of forms of cellular damage such as mitochondrial DNA mutations.

Like all important cellular mechanisms autophagy falters with age, and this harms long-lived cell populations such as those of the central nervous system by allowing damage to accumulate. In mice and humans we can point to growing levels of the hardy garbage compounds known collectively as lipofuscin. These clutter up cellular lysosomes and degrade their function, providing one important cause of failing autophagy, as well as a target for efforts to produce drugs capable of breaking down lipofuscin. In naked mole rats, however, autophagy is maintained at high levels into late age, though at present the precise reasons why remain to be uncovered:

The naked mole-rat (NMR) is the longest-lived rodent and possesses several exceptional traits: marked cancer resistance, negligible senescence, prolonged genomic integrity, pronounced proteostasis, and a sustained healthspan. The underlying molecular mechanisms that contribute to these extraordinary attributes are currently under investigation to gain insights that may conceivably promote and extended human healthspan and lifespan.

The ubiquitin-proteasome and autophagy-lysosomal systems play a vital role in eliminating cellular detritus to maintain proteostasis and have been previously shown to be more robust in NMRs when compared to shorter-lived rodents. Using a proteomics approach, differential expression and phosphorylation levels of proteins involved in proteostasis networks were evaluated in the brains of NMRs in an age-dependent manner. We identified 9 proteins with significantly altered levels and/or phosphorylation states that have key roles involved in proteostasis networks. To further investigate the possible role that autophagy may play in maintaining cellular proteostasis, we examined aspects of the PI3K/Akt/mammalian target of rapamycin (mTOR) axis as well as levels of Beclin-1, LC3-I, and LC3-II in the brain of the NMR as a function of age. Together, these results show that NMRs maintain high levels of autophagy throughout the majority of their lifespan and may contribute to the extraordinary health span of these rodents. The potential of augmenting human health span via activating the proteostasis network will require further studies.

Friday, August 14, 2015

The sad truth about Google's Calico initiative is that, for all the hype at the outset, what is going on under the hood looks very much like building a standard issue Big Pharma institution to work on commercializing drug discovery programs that won't make much of a difference to aging. The charitable view of that picture is that they are setting up a sustainable revenue stream in order to later investigate more relevant and interesting things. The more realistic view is that they intend to invest in what is currently the mainstream of aging research, a matter of trying to slightly alter the operation of metabolism to slightly slow down the aging process, and will never go beyond that. There are scores of larger companies capable of doing relevant and interesting things in aging, but they never go beyond tinkering with drug discovery to produce marginal therapies; once a revenue stream and mode of operation is established there is little incentive to do more.

This all suggests that the way in which disruptive ventures working on methods of rejuvenation gain traction with Calico is no different than the methods of gaining traction with the rest of Big Pharma: bootstrap the production of technology demonstrations that work. Gain support through the slow process of networking and incremental progress in research. Become the mainstream. Large scale funding is unimaginative and almost never backs radical new directions until all the excitement is done and the new new thing is obviously taking over. That is simply the way things are, and it is why our grassroots efforts to raise research funding and gain greater attention to the cause continue to be very important.

For the first year of its existence, all we knew about Calico was that the company had 'moonshot goals' and a team of scientific superstars. However, in September 2014 it finally sprang into action by announcing two research collaborations. The first was with AbbVie (a global, research-based biopharmaceutical company) and aimed to 'accelerate the discovery, development and commercialization of new therapies.' The two companies then immediately invested in the creation of a new research and development facility in San Francisco focused on aging and age-related diseases. Initially, AbbVie and Calico provided 250 million each to fund this project, and it was agreed that both sides would potentially contribute an additional 500 million in the future. The two also agreed to share the costs and profits equally.

The second collaboration was with the UT Southwestern Medical Center and 2M, to advance research and drug development for neurodegenerative disorders caused by the aging and death of nerve cells. Basically, Calico managed to muscle in on a deal which already been made between UT Southwestern and 2M concerning the licensing of P7C3 compounds (which had the potential to combat neurodegeneration). 2M and Calico entered into a new license agreement under which Calico took chief responsibility for developing and commercializing the compounds resulting from the research program. Calico no doubt persuaded 2M to agree to the new deal by promising to fund research laboratories in the Dallas area (where 2M is based) and elsewhere to support the program.

All went quiet again until March 2015, when The Broad Institute of MIT and Harvard entered into a partnership with Calico, concerning the genetics of aging and early-stage drug discovery. The partnership aimed to support several efforts at the Broad to advance the understanding of age-related diseases and to propel the translation of these findings into new therapeutics. The Institute agreed to use its genetics expertise and novel drug-discovery tools in pursuit of goals shared with Calico.

In the same month Calico formed a partnership with QB3, a University of California institute specialising in the advancement of biotechnological innovation. The purpose of this partnership was to conduct research into longevity and age-related diseases and, in the process of doing so, foster an interdisciplinary community of scientists in the relevant fields. Funding from Calico was to support QB3 research projects focused on aging; some in collaboration with Calico, others led solely by QB3. In exchange for providing the funds, Calico acquired the option to claim exclusive rights to discoveries made under the sponsored research agreement.

The third partnership made in March was with UC San Francisco (UCSF) (a University of California health sciences campus), on a project to develop potential therapies for cognitive decline. Under the agreement, Calico received an exclusive license to technology discovered in the laboratory of Peter Walter, Professor of Biochemistry and Biophysics at UCSF. This technology could potentially address the damage to cells caused by the Integrated Stress Response (ISR) mechanism. For an an undisclosed up-front fee, UCSF allowed Calico to take responsibility for further research, development and commercialization of the resulting therapeutics.

By April 2015 it was clear that Calico was splashing the cash in order to facilitate the formation of partnerships. For this reason, Calico started to become more tight-lipped about the financial aspect of its deals. In fact, they categorically refused to disclose the financial terms of a new partnership with the Buck Institute for Research on Aging. This partnership was to support research into longevity and age-related diseases. Calico was permitted to cherry-pick innovative research projects at the Institute and, in exchange for funding, obtain exclusive rights to the discoveries made.

Calico's most recent partnership was announced in July 2015 with AncestryDNA (an industry leader in consumer genetics). This partnership aimed to investigate the heredity of human lifespan. The two companies planned to evaluate anonymized data from millions of public family trees, as well as AncestryDNA's database of over one million genetic samples. Calico would then use the findings from the analysis to develop and commercialize potential therapeutics. Again, Calico refused to disclose just how much it had parted with in order to get its hands on AncestryDNA's data.

Looking at Calico's impressive array of employees and collaborations, it would seem, at the moment, that Calico is merely trying to make money using other people's knowledge. However, Chief Science Officer at SENS, Aubrey de Grey, claims that this is just a facade: "they are doing a bunch of highly lucrative irrelevant short-term stuff that lets them get on with unlucrative critical long-term stuff without distraction."

Friday, August 14, 2015

The liver is the most regenerative of organs, capable of regrowing lost sections even in mammals. Here researchers identify a novel population of cells that contributes to that capacity for regrowth, and which might prove to be the basis for regenerative therapies:

The mechanisms that allow the liver to repair and regenerate itself have long been a matter of debate. Of all major organs, the liver has the highest capacity to regenerate -- that's why many liver diseases, including cirrhosis and hepatitis, can often be cured by transplanting a piece of liver from a healthy donor. The liver's regenerative properties were previously credited to a population of adult stem cells known as oval cells. But recent studies concluded that oval cells don't give rise to hepatocytes; instead, they develop into bile duct cells. These findings prompted researchers to begin looking elsewhere for the source of new hepatocytes in liver regeneration.

Researchers traced the cells responsible for replenishing hepatocytes following chronic liver injury induced by exposure to carbon tetrachloride, a common environmental toxin. That's when they found a unique population of hepatocytes located in one specific area of the liver, called the portal triad. These special hepatocytes, the researchers found, undergo extensive proliferation and replenish liver mass after chronic liver injuries. Since the cells are similar to normal hepatocytes, but express low levels of bile duct cell-specific genes, the researchers called them "hybrid hepatocytes."

Meanwhile, many other research labs around the world are working on ways to use induced pluripotent stem cells (iPSCs) to repopulate diseased livers and prevent liver failure. While iPSCs hold a lot of promise for regenerative medicine, it can be difficult to ensure that they stop proliferating when their therapeutic job is done. As a result, iPSCs carry a high risk of giving rise to tumors. To test the safety of hybrid hepatocytes, the team examined three different mouse models of liver cancer. They found no signs of hybrid hepatocytes in any of the tumors, leading the researchers to conclude that these cells don't contribute to liver cancer caused by obesity-induced hepatitis or chemical carcinogens. "Although hybrid hepatocytes are not stem cells, thus far they seem to be the most effective in rescuing a diseased liver from complete failure. Hybrid hepatocytes represent not only the most effective way to repair a diseased liver, but also the safest way to prevent fatal liver failure by cell transplantation."


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