Fight Aging! Newsletter, September 28th 2015

September 28th 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.

This content is published under the Creative Commons Attribution 3.0 license. You are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!

To subscribe or unsubscribe please visit:


  • Crowdfunding Update: SENS Mitochondrial Research Project is Two-Thirds Funded
  • Demonstrating an Integrated and Functional Kidney Organoid
  • Results from a Initial Clinical Trial of CPHPC to Treat Systemic Amyloidosis
  • Recent Examples of Modestly Slowing Aging through Genetic Manipulation in Laboratory Species
  • Incentives at Work in Medical Regulation
  • Latest Headlines from Fight Aging!
    • A Printed Scaffold Guides Nerve Regrowth
    • Evidence for Nuclear Pore Dysfunction in ALS
    • More on Alzheimer's and Tight Junction Alterations
    • Investigating the Mechanisms by which 7-Ketocholesterol Contributes to Age-Related Macular Degeneration
    • Some Age-Related Loss of Cognitive Function Correlates With Greater Noise in Neural Circuits
    • Silencing MicroRNA-195 Restores Activity in Old Stem Cells
    • Combining EEG, Electrical Stimulation, and Physical Therapy to Bypass Spinal Cord Injury
    • Correlation of Remaining Life Expectancy and Education Continues into Extreme Old Age
    • Delivering a Synthetic Stem Cell Niche Alongside Transplanted Stem Cells Can Improve the Therapy
    • TFEB-Induced Autophagy to Increase Clearance of α-synuclein


Today an update on the MitoSENS mitochondrial repair project showcased at the crowdfunding site: after a few weeks of publicity, more than 200 backers have pledged more than 20,000 of the original 30,000 goal. Congratulations are due the team and their supporters on the progress to date. Have you helped out yet?

MitoSENS is a branch of SENS rejuvenation research coordinated by the SENS Research Foundation: one of a number of efforts to produce the foundations needed to repair the specific known forms of cell and tissue damage that cause aging. MitoSENS is focused on the accumulation of mutations in mitochondrial DNA and their contribution to degenerative aging. DNA provides blueprints for the proteins making up cellular machinery, particularly vital cellular machinery in the case of mitochondria. Thus when the blueprint becomes damaged in certain ways dysfunctional machinery results, and given enough cells fallen into that state over the course of a lifetime, organs and tissues begin to fail. Any method that ensures reliable delivery of the correctly formed proteins to the mitochondria is a possible basis for a therapy, and there are numerous options. The SENS approach is gene therapy to copy vulnerable mitochondrial genes from the mitochondrial DNA to nuclear DNA, a process called allotopic expression, along with sufficient instructions to ensure that proteins are delivered back to the mitochondria after manufacture.

This line of research has been under way in bits and pieces for a decade or more, but not in earnest until fairly recently. The SENS Research Foundation was using donated funds back in 2008 to assist research that has since blossomed into the French company Gensight, where staff are producing an implementation of allotopic expression for a single gene involved in inherited mitochondrial disease. With the sizable commercial funding involved that should go a long way towards hammering out implementation details and robustness of this class of therapy, as well as providing a proof of concept in clinical practice to quell the grumblings of skeptics. In parallel to that the broader task of developing the methodologies needed for transport back to mitochondria for all mitochondrial genes must still be carried out, hence the ongoing MitoSENS project.

We are fortunate to live in in the opening years of the biotechnology revolution, a time when early stage life science and medical research is becoming ever cheaper. Far more can be done with far less, and the trend is accelerating year after year. A few tens of thousands of dollars in the hands of a good researcher with access to an established lab for six months can produce significant incremental progress at the cutting edge of a field, something that would have required millions or tens of millions in funding and years of effort twenty years ago. This rapid drop in the cost of research is why the crowdfunding of science is becoming much more important. There is a great deal that might be done today in medical research that will never funded by the very conservative and risk-averse traditional sources of institutional research money. But now philanthropy is for everyone, not just the wealthy. We can all band together and help to create meaningful progress that will help our own health in the future, funding early stage work that is ignored by institutions, but which will later go on to pull in millions for clinical development once the prototypes are constructed and the case made.

Groups like are important because they bring a different perspective, a different set of networks to the table. You can see them at work on Twitter, for example. In a time when every dollar donated can do so much more, and influential people are talking openly about aging research, it is ever more important to expand the community of people willing to materially support the development of rejuvenation therapies.


Researchers have recently demonstrated in pigs the integration of an engineered kidney organoid, a few centimeters of kidney tissue grown from stem cells. The tissue functions as a kidney should, but it is far from full size, and does not bear all of the hallmarks of the real thing. However, enough of the normal suite of additional connections were also produced by the researchers involved to allow surgical integration of the organoid with the excretory system, and thus demonstrate generation of urine.

This work well illustrates the nature of the challenges that lie ahead for the field of tissue engineering. It isn't enough to build correctly functioning organ tissue, challenging as that is and still very much a work in progress. Connections to circulatory and other systems in the body must also exist, and each of these is its own distinct engineering task. A replacement organ whose principal job is chemical processing or filtration of one sort or another doesn't have to be shaped or structured in exactly the same way as the evolved version we're all equipped with at birth, but it does have to integrate with all of the surrounding organs and systems. That places constraints on the development of engineered organs, and presents a set of intricate challenges akin to those involved in carrying out an organ transplant.

The kidney organoids demonstrated in pigs in the research linked below are a step ahead of the first prototypes to get the tissue structure and functionality correct, but they are still many incremental steps removed from something that could replace the need for human kidney donors. Still, things are headed in the right direction, and quite rapidly at that. It was only three years ago that the first kidney organoids were unveiled, so it doesn't seem unreasonable to predict that the first practical proto-kidneys that are medically useful in humans might enter clinical trials in the early 2020s.

Lab-grown kidneys work in animals

Scientists say they are a step closer to growing fully functioning replacement kidneys, after promising results in animals. When transplanted into pigs and rats, the kidneys worked, passing urine just like natural ones. The researchers used a stem cell method, but instead of just growing a kidney for the host animal, they set about growing a drainage tube too, along with a bladder to collect and store the urine. They used rats as the incubators for the growing embryonic tissue. When they connected up the new kidney and its plumbing to the animal's existing bladder, the system worked. Urine passed from the transplanted kidney into the transplanted bladder and then into the rat bladder. And the transplant was still working well when they checked again eight weeks later. They then repeated the procedure on a much larger mammal - a pig - and achieved the same results.

Urine excretion strategy for stem cell-generated embryonic kidneys

There have been several recent attempts to generate, de novo, a functional whole kidney from stem cells using the organogenic niche or blastocyst complementation methods. However, none of these attempts succeeded in constructing a urinary excretion pathway for the stem cell-generated embryonic kidney.

First, we transplanted metanephroi from cloned pig fetuses into gilts; the metanephroi grew to about 3 cm and produced urine, although hydronephrosis eventually was observed because of the lack of an excretion pathway. Second, we demonstrated the construction of urine excretion pathways in rats. Rat metanephroi or metanephroi with bladders (developed from cloacas) were transplanted into host rats. Histopathologic analysis showed that tubular lumina dilation and interstitial fibrosis were reduced in kidneys developed from cloacal transplants compared with metanephroi transplantation. Then we connected the host animal's ureter to the cloacal-developed bladder, a technique we called the "stepwise peristaltic ureter" (SWPU) system. The application of the SWPU system avoided hydronephrosis and permitted the cloacas to differentiate well, with cloacal urine being excreted persistently through the recipient ureter.

Finally, we demonstrated a viable preclinical application of the SWPU system in cloned pigs. The SWPU system also inhibited hydronephrosis in the pig study. To our knowledge, this is the first report showing that the SWPU system may resolve two important problems in the generation of kidneys from stem cells: construction of a urine excretion pathway and continued growth of the newly generated kidney.


Results were recently published for the first trial of CPHPC as a therapy to clear out age-related deposits of the type of amyloid formed from misfolded transthyretin, normally responsible for transporting the thyroid hormone thyroxine in blood and cerebrospinal fluid. Amyloids are one of the distinguishing features of older tissues, and clearing them will be one of the necessary outcomes produced by any comprehensive suite of rejuvenation therapies developed in the near future.

The accumulation of transthyretin amyloid creates a condition known as senile systemic amyloidosis where it occurs to varying degrees for everyone in later life, and TTR amyloidosis when it arises in young people due to inherited mutations. Senile systemic amyloidosis is known to be responsible for a sizable fraction of deaths in supercentenarians, as the amyloid deposits clog the cardiovascular system to the point of failure. This process is also thought to play an underappreciated role in heart failure in the younger old demographic, however, and is involved in other age-related degenerative conditions such as spinal stenosis.

CPHPC works in an indirect way: it attacks an unfortunate aspect of our biochemistry that prevents existing clearance systems from getting rid of transthyretin amyloid. Serum amyloid P component (SAP) binds to amyloids such as misfolded transthyretin and blocks the normal mechanisms of clearance. Removing SAP led to clearance of amyloid, but the action of CPHPC wasn't good enough on its own. The trial combined CPHPC with an antibody also aimed at removing SAP from the picture, as the two together produced far better results in pre-trial studies.

At present there are few good treatments for amyloidosis, and those that do exist are fairly specific to narrow demographics and circumstances. CPHPC is one of a number of potentially broad and effective treatments somewhere in the development process, however, so we have cause to be fairly optimistic about the near future in this field. Some of these potential treatments have been helped along in their early stages by the SENS Research Foundation; take a look back in the Fight Aging! archives at the development of catabolic antibodies for TTR amyloidosis for example. In the case of CPHPC the trial results been a long time in the making: development of CPHPC as a therapy for systemic amyloidosis started more than a decade ago, and the deal to set up a clinical trial was struck back in 2009. The wheels of medical science move very slowly indeed. Still, the news is good by the sound of it:

Potential new approach to the treatment of systemic amyloidosis

In 2009 GSK and Pentraxin Therapeutics Ltd entered into collaboration to develop the world's first dual drug-antibody treatment for the rare disease systemic amyloidosis. The results of the first in human clinical trial have today been published. The publication shows the results of the first 15 patients treated with a therapeutic partnership of CPHPC (a small chemical molecule) and an anti-SAP antibody.

Amyloid is an abnormal protein material that accumulates in the tissues, damaging their structure and function and causing a rare and usually fatal disease called amyloidosis. Present treatments can stabilise some patients and substantially prolong life but about 20% of patients still die within 6 months of diagnosis. The results of the phase I study showed that the antibody was generally well tolerated and produced rapid clearance of amyloid from various organs. Removal of amyloid from the liver was associated with improved function. Whole body anterior amyloid scans of a patient with systemic amyloidosis show abundant amyloid in the liver before treatment and the almost complete absence of amyloid after a single dose of the new anti-SAP antibody.

Therapeutic Clearance of Amyloid by Antibodies to Serum Amyloid P Component

We conducted an open-label, single-dose-escalation, phase 1 trial involving 15 patients with systemic amyloidosis. After first using CPHPC to deplete circulating SAP, we infused a fully humanized monoclonal IgG1 anti-SAP antibody. Patients with clinical evidence of cardiac involvement were not included for safety reasons. Organ function, inflammatory markers, and amyloid load were monitored.

There were no serious adverse events. Infusion reactions occurred in some of the initial recipients of larger doses of antibody; reactions were reduced by slowing the infusion rate for later patients. At 6 weeks, patients who had received a sufficient dose of antibody in relation to their amyloid load had decreased liver stiffness, as measured with the use of transient elastography. These patients also had improvements in liver function in association with a substantial reduction in hepatic amyloid load, as shown by means of SAP scintigraphy and measurement of extracellular volume by magnetic resonance imaging. A reduction in kidney amyloid load and shrinkage of an amyloid-laden lymph node were also observed.


It is no longer remarkable to modestly extend life via genetic manipulation in worms, flies, and smaller mammals. Many demonstrations pass by without comment, a score or more new approaches explored every year. Below you'll find links to five recently published papers, each a different approach in flies or worms that slows aging and extends longevity by a small amount.

At this point much of the goal of this research is mapping: everything in cellular biochemistry is intricately interconnected, and so while there are probably only a handful of core mechanisms that slow aging, there is a near unlimited set of ways to influence those mechanisms. This situation makes it hard to figure out the identity of many of these biochemical switches, and equally hard to figure out which of the known switches are more important to aging. The operation of cellular metabolism is enormously, fantastically complicated, and still only superficially cataloged. There is a big difference between having a parts list and having full blueprints of the engine, and currently the state of knowledge is somewhere between those two extremes.

Extending life in lower animals through genetic alterations is a tool that can add to the overall knowledge of metabolism and how aging progresses: how the forms of damage that cause aging produce a chain of cause and consequence leading to dysfunction and age-related disease. A great deal is known of this damage, and a great deal is known about age-related diseases, but the middle of the chain is a big empty space on the map. Researchers aim to fill that in, and thus provide a complete accounting of aging at the molecular level. This process is unlikely to lead to methods of meaningfully extending healthy life span in humans in the near term, however. Its output along the way is well demonstrated by sirtuin research, or the focus on metformin, or on drugs influencing the mTOR pathway: marginal therapies capable of only slightly slowing aging, if that. These are all ways of adjusting the operation of metabolism to slightly slow down the rate of damage accumulation. The best path to near-future therapies for aging, a path capable of producing rejuvenation and greatly extended healthy life spans, is instead to build methods of repairing the well-cataloged forms of damage. That should be far less expensive, the roadmap to therapies is far more established, and the benefits provided by those therapies should be far greater.

So which of these approaches to pour funds into? It should be no contest, yet repair remains a hard sell. The disruption of existing institutions of aging research to focus more on repair of the known forms of damage than on exploration of metabolism is an ongoing battle, and repair-based approaches are still a minority concern in the broader field of medicine. Again, the purpose and culture of science is to create knowledge, not outcomes, and perhaps there is the challenge in this particular situation.

Enhancing S-adenosyl-methionine catabolism extends Drosophila lifespan

Methionine restriction extends the lifespan of various model organisms. Limiting S-adenosyl-methionine (SAM) synthesis, the first metabolic reaction of dietary methionine, extends longevity in Caenorhabditis elegans but accelerates pathology in mammals. Here, we show that, as an alternative to inhibiting SAM synthesis, enhancement of SAM catabolism by glycine N-methyltransferase (Gnmt) extends the lifespan in Drosophila. Gnmt strongly buffers systemic SAM levels by producing sarcosine in either high-methionine or low-sams conditions. During ageing, systemic SAM levels in flies are increased. Gnmt is transcriptionally induced in a dFoxO-dependent manner; however, this is insufficient to suppress SAM elevation completely in old flies. Overexpression of gnmt suppresses this age-dependent SAM increase and extends longevity. Pro-longevity regimens, such as dietary restriction or reduced insulin signalling, attenuate the age-dependent SAM increase, and rely at least partially on Gnmt function to exert their lifespan-extending effect in Drosophila. Our study suggests that regulation of SAM levels by Gnmt is a key component of lifespan extension.

Bmk-1 regulates lifespan in Caenorhabditis elegans by activating hsp-16

The genetics of aging is typically concerned with lifespan determination that is associated with alterations in expression levels or mutations of particular genes. Previous reports in C. elegans have shown that the bmk-1 gene has important functions in chromosome segregation, and this has been confirmed with its mammalian homolog, KIF11. However, this gene has never been implicated in aging or lifespan regulation. Here we show that the bmk-1 gene is an important lifespan regulator in worms. We show that reducing bmk-1 expression using RNAi shortens worm lifespan by 32%, while over-expression of bmk-1 extends worm lifespan by 25%, and enhances heat-shock stress resistance. Moreover, bmk-1 over-expression increases the level of hsp-16 and decreases ced-3 in C. elegans. Genetic epistasis analysis reveals that hsp-16 is essential for the lifespan extension by bmk-1. These findings suggest that bmk-1 may act through enhanced hsp-16 function to protect cells from stress and inhibit the apoptosis pathway, thereby conferring worm longevity. Though it remains unclear whether this is a distinct function from chromosomal segregation, bmk-1 is a potential new target for extension of lifespan and enhancement of healthspan.

Inhibition of elongin C promotes longevity and protein homeostasis via HIF-1 in C. elegans

The transcription factor hypoxia-inducible factor 1 (HIF-1) is crucial for responses to low oxygen and promotes longevity in Caenorhabditis elegans. We previously performed a genomewide RNA interference screen and identified many genes that act as potential negative regulators of HIF-1. Here, we functionally characterized these genes and found several novel genes that affected lifespan. The worm ortholog of elongin C, elc-1, encodes a subunit of E3 ligase and transcription elongation factor. We found that knockdown of elc-1 prolonged lifespan and delayed paralysis caused by impaired protein homeostasis. We further showed that elc-1 RNA interference increased lifespan and protein homeostasis by upregulating HIF-1. The roles of elongin C and HIF-1 are well conserved in eukaryotes. Thus, our study may provide insights into the aging regulatory pathway consisting of elongin C and HIF-1 in complex metazoans.

Nmdmc overexpression extends Drosophila lifespan and reduces levels of mitochondrial reactive oxygen species

NAD-dependent methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase (NMDMC) is a bifunctional enzyme involved in folate-dependent metabolism and highly expressed in rapidly proliferating cells. However, Nmdmc physiological roles remain unveiled. We found that ubiquitous Nmdmc overexpression enhanced Drosophila lifespan and stress resistance. Interestingly, Nmdmc overexpression in the fat body was sufficient to increase lifespan and tolerance against oxidative stress. In addition, these conditions coincided with significant decreases in the levels of mitochondrial ROS and Hsp22 as well as with a significant increase in the copy number of mitochondrial DNA. These results suggest that Nmdmc overexpression should be beneficial for mitochondrial homeostasis and increasing lifespan.

Heart-specific Rpd3 downregulation enhances cardiac function and longevity

Downregulation of Rpd3, a homologue of mammalian Histone Deacetylase 1 (HDAC1), extends lifespan in Drosophila melanogaster. Once revealed that long-lived fruit flies exhibit limited cardiac decline, we investigated whether Rpd3 downregulation would improve stress resistance and/or lifespan when targeted in the heart. Contested against three different stressors (oxidation, starvation and heat), heart-specific Rpd3 downregulation significantly enhanced stress resistance in flies. However, these higher levels of resistance were not observed when Rpd3 downregulation was targeted in other tissues or when other long-lived flies were tested in the heart-specific manner. Interestingly, the expressions of anti-aging genes such as sod2, foxo and Thor, were systemically increased as a consequence of heart-specific Rpd3 downregulation. Showing higher resistance to oxidative stress, the heart-specific Rpd3 downregulation concurrently exhibited improved cardiac functions, demonstrating an increased heart rate, decreased heart failure and accelerated heart recovery. Conversely, Rpd3 upregulation in cardiac tissue reduced systemic resistance against heat stress with decreased heart function, also specifying phosphorylated Rpd3 levels as a significant modulator. Continual downregulation of Rpd3 throughout aging increased lifespan, implicating that Rpd3 deacetylase in the heart plays a significant role in cardiac function and longevity to systemically modulate the fly's response to the environment.


The situation with respect to the effects of medical regulation on scientific and technological progress in the US is horrible and getting worse. Regulators at the FDA follow their incentives: they are only castigated in public when an approved treatment causes issues, but never suffer consequences from increasing the time and cost of development, nor from rejecting treatments outright, nor from the suppression of medical progress by making many viable approaches too costly for profitable development. The outcome is - of course - a continued increase in cost, a continued flow of demands for an extra test, for more data, for more rigorous certainty in an uncertain field, and so ever more money is required to commercialize ever fewer new treatments. To develop a drug a decade ago took a billion in funding all told, accounting for inflation since then, and is now more like two and a half billion. There is no benefit here for all that extra funding - or at least not unless you happen to be a bureaucrat who likes his or her job.

Sooner or later other incentives are going to come into play. Medical tourism is cheap. Entrepreneurs can run viable, professional medical businesses outside the US based on research carried out inside the US, and charge far less money for better and more recent types of treatment. The more that FDA staff protect their own careers at the expensive of commercial development of new therapies, the more likely it becomes that a solid, organized pipeline will emerge to carry the results from US labs to clinics outside the US, rather than the much more ad-hoc process that takes place at the moment. Simple economics will make the FDA irrelevant at some point absent significant reformation, but change is slow in coming, despite the situation for stem cell therapies in which the new and the best treatments have so far been available outside the US for years prior to final capitulation on the part of the regulators.

There are other important incentives here. Regulators and politicians are people too, albeit misguided examples of such. They suffer the same illnesses and age-related degeneration as the rest of us, and so there is only so much that any rational individual will do in order to block progress towards effective medicines for these conditions. Today I'll point out two economics posts from recent months, the first a look at the harms done by the FDA, and the second a note that Japanese regulators are backing off in the face of an aging population and the prospect of new therapies for age-related disease. I see the latter as a modestly encouraging sign for the decades ahead - that at least some bureaucrats are willing to do something other than watch the world burn.

Is the FDA Too Conservative or Too Aggressive?

I have long argued that the FDA has an incentive to delay the introduction of new drugs because approving a bad drug (Type I error) has more severe consequences for the FDA than does failing to approve a good drug (Type II error). In the former case at least some victims are identifiable and the New York Times writes stories about them and how they died because the FDA failed. In the latter case, when the FDA fails to approve a good drug, people die but the bodies are buried in an invisible graveyard.

In an excellent new paper researchers use a Bayesian analysis to model the optimal tradeoff in clinical trials between sample size, Type I and Type II error. Failing to approve a good drug is more costly, for example, the more severe the disease. Thus, for a very serious disease, we might be willing to accept a greater Type I error in return for a lower Type II error. The number of people with the disease also matters. Holding severity constant, for example, the more people with the disease the more you want to increase sample size to reduce Type I error. All of these variables interact. The authors use the U.S. Burden of Disease Study to find the number of deaths and the disability severity caused by each major disease. Using this data they estimate the costs of failing to approve a good drug. Similarly, using data on the costs of adverse medical treatment they estimate the cost of approving a bad drug. Putting all this together the authors find that the FDA is often dramatically too conservative. FDA regulations may appear to be creating safe and effective drugs but they are also creating a deadly caution.

Japan Liberalizes Regenerative Medicine

Japan is liberalizing its approval process for regenerative medicine. Regenerative medicines in Japan can now get conditional marketing approval based on results from mid-stage, or Phase II, human trials that demonstrate safety and probable efficacy. Once lagging behind the United States and the European Union on approval times, there is now an approximately three-year trajectory for approvals. That compares with seven to 10 years before.

Japan is liberalizing because with their aging population treatments for diseases like Alzheimer's and Parkinson's disease are in high demand. Under the new system, a firm with a gene or regenerative therapy (e.g. stem cells) can get conditional approval with a small trial. Conditional approval means that the firm will be able to sell its procedure while continuing to gather data on efficacy for a period of up to seven years. At the end of the seven year period, the firm must either apply for final marketing approval or withdraw the product. The system is thus similar to what Bart Madden proposed for pharmaceuticals in Free to Choose Medicine.

Due to its size and lack of price controls, the US pharmaceutical market is the most lucrative pharmaceutical market in the world. Unfortunately, this also means that the US FDA has an outsize influence on total world investment. The Japanese market is large enough, however, that a liberalized approval process if combined with a liberalized payment model could increase total world R&D. Breakthroughs made in Japan will be available for the entire world so we should all applaud this important liberalization.

I remain of the opinion that all these regulatory bodies would be better gone entirely, not just cutting back to inflict half of the needless cost and suppression of development that is currently the case. In the US that much of a reduction wouldn't even turn the clock back a decade, and the FDA was plenty onerous back then. In a better world, entrepreneurs and a free market would give rise to a competing set of review and certification organizations, just as it has for any number of other fields, and just as already exist for medical services in numerous areas. That is all that is needed to set standards, review effectiveness, and identify fraud, and it can be achieved at a tiny fraction of the cost of the present much worse regulatory edifice.


Monday, September 21, 2015

The use of carefully structured scaffolds to guide tissue regrowth where it would not normally happen shows considerable promise as an approach to regenerative medicine. Here is a recent example of the state of the art for nerve regrowth:

Nerve regeneration is a complex process. Because of this complexity, regrowth of nerves after injury or disease is very rare. In a new study, researchers used a combination of 3D imaging and 3D printing techniques to create a custom silicone guide implanted with biochemical cues to help nerve regeneration. The guide's effectiveness was tested in the lab using rats. To achieve their results, researchers used a 3D scanner to reverse engineer the structure of a rat's sciatic nerve. They then used a specialized, custom-built 3D printer to print a guide for regeneration. Incorporated into the guide were 3D-printed chemical cues to promote both motor and sensory nerve regeneration. The guide was then implanted into the rat by surgically grafting it to the cut ends of the nerve. Within about 10 to 12 weeks, the rat's ability to walk again was improved.

"This represents an important proof of concept of the 3D printing of custom nerve guides for the regeneration of complex nerve injuries. Someday we hope that we could have a 3D scanner and printer right at the hospital to create custom nerve guides right on site to restore nerve function." Scanning and printing takes about an hour, but the body needs several weeks to regrow the nerves. Previous studies have shown regrowth of linear nerves, but this is the first time a study has shown the creation of a custom guide for regrowth of a complex nerve like the Y-shaped sciatic nerve that has both sensory and motor branches. "The exciting next step would be to implant these guides in humans rather than rats."

Monday, September 21, 2015

This article looks at a few recent papers providing initial evidence for nuclear pore dysfunction to be a important contributing cause of at least some forms of Amyotrophic lateral sclerosis (ALS). This is perhaps of general interest to those of us following aging research, as nuclear pore proteins in at least some long-lived neurons seem to last as long as we do; they are either never replaced over the length of a human life span, or replaced only very slowly. Nuclear pore structures are responsible for the transport of molecules across the nuclear membrane in cells, and there is speculation that accumulated molecular damage to these pores might contribute to aspects of brain aging. From this viewpoint, ALS might be a condition that occurs due to one specific form of age-related cellular damage progressing at a much faster pace than usual, a pattern that exists in a number of age-related diseases only suffered by a portion of the population.

Three studies, analyzing in different ways the leading ALS gene, came to what is being called a remarkably similar conclusion: the most common form of ALS may be caused by clogged pores in brain cell nuclear membranes. One of the studies identified two drug options that eradicated the pore clogging. All identified druggable targets. "These are the first studies to implicate altered nucleo-cytosolic transport as a mechanism of pathology in ALS. The findings are presently limited to the significant subset of ALS cases caused by the C9 mutation that is found in 40 percent of inherited ALS and frontotemporal dementia (FTD)." Two of the papers also showed that TDP-43, a protein known as key in ALS, appears mislocalized by the C9 mutation, and the authors show that this mislocalization can be rescued.

"Discovery of TDP-43 mislocalization - from nucleus into cytoplasm - as a predominant occurrence in ALS and FTD has provided a major change of perspective on these diseases. The complexity of underlying processes that can cause TDP-43 proteinopathy has been highlighted by the discovery of C9 in ground-breaking studies. However, none connected C9 with the major pathology in patients: TDP-43 proteinopathy. These new studies bring this connection closer. They show RNA from C9 mutation can disrupt nuclear pore shuttling by binding to proteins driving this process. The bigger question is whether nuclear import defects contribute to the pathogenesis of sporadic as well as inherited familial ALS. This is being looked at by multiple labs. If the answer is 'yes,' one can imagine modulators of nuclear import might emerge as a major therapeutic avenue in ALS. No doubt such drugs will be given a hard look."

Tuesday, September 22, 2015

The tight junctions between cells of the blood brain barrier are a part of the system controlling passage of molecules between the blood system and brain tissue. They appear to change and fail with age, and this may be one of the ways in which ongoing clearance of amyloid-β falters, allowing the buildup of amyloid associated with Alzheimer's disease. Equally some of the changes may be due to increased but still insufficient efforts at clearance via this mechanism due to the failure of other, primary modes of clearance:

Alzheimer's disease is characterized, in part, by the build-up of a small protein ('amyloid-beta') in the brains of patients. Impaired clearance of this protein appears to be a major factor in the build-up of plaques, and then in the disease process itself. While the mode by which amyloid-beta is cleared remains unclear, it is evident that it needs to be removed from the brain via the bloodstream.

Unlike blood vessels anywhere else in the body, those in the brain have properties that strictly regulate what gets in and out of the delicate tissue - this is what is known as the blood-brain barrier (BBB). The BBB functions as a tightly regulated site of energy and metabolite exchange between the brain tissue and the bloodstream. "We have shown that distinct components of these blood vessels termed tight junctions are altered in Alzheimer's disease. We think that this alteration could be an entrained mechanism to allow for the clearance of toxic amyloid-beta from the brain in those living with Alzheimer's disease."

The researchers examined brain tissues of individuals who were affected by Alzheimer's disease during their lifetime and then compared results to those observed in model systems in the laboratory. "Our recent findings have highlighted the importance of understanding diseases at the molecular level. The concept of periodic clearance of brain amyloid-beta across the BBB could hold tremendous potential for Alzheimer's patients in the future. The next steps are to consider how this might be achieved. Given the recent advances in clinical trials of anti-amyloid beta antibodies, we hope our findings may lead to improved and adjunctive forms of therapy for this devastating condition."

Tuesday, September 22, 2015

Here researchers construct a model to try to identify the precise mechanisms by which the buildup of 7-ketocholesterol (7KCh) in cells with age contributes to the development of macular degeneration. 7-ketocholesterol is one of the forms of metabolic waste that our biochemistry struggles to break down, and its accumulation is associated with a range of conditions from macular degeneration to atherosclerosis - it is one of the causes of aging. The scientific staff of the SENS Research Foundation have been working for years on mining the bacterial world for enzymes that can break down 7-ketocholesterol and other hardy waste compounds that contribute to age-related disease. Progress is slow, but candidates have been identified: a company was recently launched based on that work. Safely breaking down and removing waste compounds like 7-ketocholesterol is a necessary part of any future toolkit of rejuvenation therapies capable of holding back the aging process and preventing age-related disease, so progress on this front is to be encouraged.

The progression of age-related macular degeneration (AMD) involves a transition from an early or intermediate stage, in which extracellular deposits called drusen accumulate on the inner surface of Bruch's membrane, to an advanced stage featuring photoreceptor and retinal pigment epithelium (RPE) atrophy and/or choroidal neovascularization (CNV), which lead to central vision loss. While the mechanisms driving this progression are unknown, they have been linked to lipid transport and metabolism in the retina as variants in genes involved in these processes have been found to confer increased risk of AMD progression in several genome-wide association studies. Additionally, histological studies have demonstrated the accumulation of phospholipids and cholesterol in the Bruch's membrane (BrM)-retinal pigment epithelium (RPE) complex, which increases with aging and AMD stage. In the highly oxidative environment of the outer retina, these lipids have been noted to undergo conversion to oxidized species, which exert deleterious changes resembling those found in advanced AMD.

One particular species of oxidized lipid is 7-ketocholesterol, an oxysterol commonly found in oxidized low-density lipoprotein (oxLDL) that is associated with cellular toxicity in vascular endothelial and smooth muscle cells as well as in RPE cells. Previous studies have shown that 7KCh is formed by photodamage in the rodent retina via a free radical-mediated mechanism, it localizes to presumed lipoprotein deposits in the non-human primate BrM, choriocapillaris, and RPE layer, and it accumulates with increasing age, particularly in RPE-capped drusen in aged human eyes.

Microglia, the resident immune cell of the retina, are responsible for the local modulation of neuroinflammatory change. Microglia in the young, healthy retina are confined to the inner retina, but with aging, these cells migrate to the subretinal space, where they demonstrate increased activation. This subretinal accumulation of microglia have been associated with disease lesions in AMD histological specimens and in AMD-relevant animal models, and have therefore been hypothesized to drive photoreceptor and RPE degeneration, as well as choroidal neovascularization. The mechanisms driving the migration of aging microglia into the outer retina and their subsequent activation have not been well defined.

In this study, we hypothesize that the age-related deposition of 7KCh is related to subretinal microglial recruitment and activation that in turn contributes to progression to neovascular AMD. We evaluated the specific effects that 7KCh exerts on retinal microglial physiology and explored the notion that 7KCh induces pathogenic microglial changes. Our findings described here indicate that 7KCh acts as a chemoattractant capable of inducing the translocation of retinal microglia to the subretinal space. Once there, uptake of 7KCh by microglia can increase microglial activation, M1 polarization, and expression of angiogenic factors in ways that potentiate AMD progression.

Wednesday, September 23, 2015

Researchers can measure the level of noise in the signals of neural circuits in the brain, and see that it is higher in older brains. The proximate cause of this noise is an open question. With an eye to finding out more about the mechanisms involved, it would be interesting to see if there is any correlation of magnitude with measures such as epigenetic dysregulation or the low level of demyelination of nerves that occurs in aging.

Researchers found that background noise in key cortical regions of the brain responsible for higher functions was associated with poorer memorization of visual information, and that this noise also was associated with age. They concluded that neural noise might be the mechanism behind aging-associated loss of cognitive ability, slowing of behavioral responses, uncertain memories and wavering concentration. The noise measured in the studies was random signaling that did not fit the pattern of the brain's natural oscillations. These oscillations are rhythmic patterns of electrical activity generated by nerve cells, or neurons, linked within the brain's circuitry. This activity occurs in addition to electrical signals generated by individual neurons.

In recent years brain oscillations have become an intense focus of research by scientists seeking to discover any functional roles they might play. Emerging evidence suggests that oscillations might prime nerve circuits to respond more efficiently to stimuli. "Imagine that individual neurons are like surfers. Nearby surfers experience the same waves, which are like the oscillations linking neurons in the brain. But like noise, additional interfering factors often disrupt the perfect wave at different times and different spots along the beach."

Researchers flashed one, two or three colored squares for less than one-fifth of a second, gave the subjects almost one second to memorize the colors, and then flashed a second display and asked the participants if the colors matched. The researchers used mathematical algorithms to extract measures of noise in the oscillations from EEG data collected during the interval when the subjects were trying to memorize the colors. On average, older subjects performed worse than younger subjects. The scientists determined that this poorer performance was due to additional noise in nerve circuits in the visual cortex; neurons did not appear to coordinate as well in generating lower-frequency oscillations. When the researchers accounted for the noise, age was no longer an independent, significant factor in performance in this experiment.

"Instead of having a normal conversation, the neurons that make up the memory networks in older adults seemed to be talking over one another, leading to a communication breakdown and degrading their memory performance. I think these types of experiments will allow neuroscientists to explore the neural underpinnings of cognitive changes across normal aging and in a variety of disease states, including autism, Parkinson's and schizophrenia, each of which is associated with breakdowns in neural oscillations."

Wednesday, September 23, 2015

Stem cell activity declines with age, resulting in increased tissue frailty and dysfunction. Researchers are finding a variety of ways to increase the activity of old stem cell populations, with most of this work focusing on the better known and characterized muscle and bone marrow stem cells. It is likely that different populations all require subtly different methodologies given their different cell states, but so far it seems that ramping up the processes of telomere lengthening works broadly, and that this does boost stem cell activity may be the underlying reason why telomerase therapy extends life in mice, though there are other potential mechanisms to consider, and telomere dynamics in mice are quite different from those in humans. In our species the consensus is that more telomerase activity is probably the path to more cancer.

Sufficient control over native stem cells may prove an adequate substitute for stem cell transplants, but there is still the question of just how much risk this entails given the age-related damage accumulated by stem cells and stem cell niches in old tissues. Based on data gathered so far, there is less risk of cancer than was expected, but in the grand scheme of things these are still the early days of manipulating stem cells. Old stem cell populations most likely require repair or replacement as a part of any comprehensive regenerative medicine targeted at the aging process, but it seems plausible that there are benefits to be had by awakening dormant stem cells even without that sort of comprehensive rejuvenation treatment.

Previously, we reported that a novel sub-population of young mesenchymal stem cells (YMSCs) existed in old bone marrow, which possessed high anti-aging properties as well as excellent efficacy for cardiac repair. MicroRNAs (miRNAs) have emerged as key regulators in post-transcriptional gene expression programs, however it is unknown whether miRNAs directly control stem cell senescence. Here we present the first evidence that miR-195 overexpressed in old MSCs (OMSCs) induces stem cell senescence deteriorating their regenerative ability by directly deactivating telomerase reverse transcriptase (Tert), and abrogation of miR-195 can reverse stem cell aging.

MiRNAs profiling analysis in YMSCs and OMSCs by microarray showed that miR-140, miR-146a/b and miR-195 were significantly upregulated in OMSCs, which led us to hypothesize that these are age-induced miRNAs involved in stem cell senescence. Of these miRNAs, we found miR-195 directly targeted 3'-untranslated region of Tert gene by computational target prediction analysis and luciferase assay, and knockdown of miR-195 significantly increased Tert expression in OMSCs. Strikingly, miR-195 inhibition significantly induced telomere re-lengthening in OMSCs along with reduced expression of senescence-associated β-galactosidase. Moreover, silencing miR-195 in OMSCs by transfection of miR-195 inhibitor significantly restored anti-aging factors expression including Tert and Sirt1 as well as phosphorylation of Akt and FOXO1. Notably, abrogation of miR-195 markedly restored proliferative abilities in OMSCs. Transplantation of OMSCs with knocked out miR-195 reduced infarction size and improved left ventricular function in an animal model of myocardial infarction.

In conclusion, rejuvenation of aged stem cells by miR-195 inhibition would be a promising autologous therapeutic strategy for cardiac repair in the elderly patients.

Thursday, September 24, 2015

The research noted here is a good example here of inventively combining presently available technologies to achieve a positive result. The scientists involved have demonstrated a way to work around paralysis following spinal cord injury to allow physical activity. It is interesting to consider that this result could probably have been achieved twenty or more years ago had someone put in the effort. We should all no doubt ask ourselves what else could be achieved today in medicine, and doesn't exist simply because no-one has yet tried in earnest, or assembled the right building blocks in the right way:

The ability to walk has been restored following a spinal cord injury, using one's own brain power. The preliminary proof-of-concept study shows that it is possible to use direct brain control to get a person's legs to walk again. This is the first time that a person with complete paralysis in both legs (paraplegia) due to spinal cord injury was able to walk without relying on manually controlled robotic limbs, as with previous walking aid devices. "Even after years of paralysis the brain can still generate robust brain waves that can be harnessed to enable basic walking. We showed that you can restore intuitive, brain-controlled walking after a complete spinal cord injury. This noninvasive system for leg muscle stimulation is a promising method and is an advance of our current brain-controlled systems that use virtual reality or a robotic exoskeleton."

The participant, who had been paralyzed for five years, walked along a 3.66m long course using an electroencephalogram (EEG) based system. The system takes electrical signals from the participant's brain, which then travel down to electrodes placed around his knees to create movement. Mental training was initially needed to reactivate the brain's walking ability. Seated and wearing an EEG cap to read his brainwaves, the participant trained to control an avatar in a virtual reality environment. He also required physical training to recondition and strengthen his leg muscles. The participant later practiced walking while suspended 5cm above ground, so he could freely move his legs without having to support himself. On his 20th visit, he translated these skills to walk on the ground and wore a body-weight support system for aid and to prevent falls. Over the 19 week testing period, he gained more control and performed more tests per visit.

This proof-of-concept study involved a single patient so further studies are needed to establish whether these results are true for a larger population of individuals with paraplegia. "Once we've confirmed the usability of this noninvasive system, we can look into invasive means, such as brain implants. We hope that an implant could achieve an even greater level of prosthesis control because brain waves are recorded with higher quality. In addition, such an implant could deliver sensation back to the brain, enabling the user to feel their legs."

Thursday, September 24, 2015

It is well known that education level correlates with life expectancy, one link in a web of correlations between wealth, status, intelligence, and a wide range of related statistics derived from demographic and epidemiological studies. There may in fact be a biological link between robust health and greater intelligence, but the general consensus is that these observed correlations arise from better lifestyle choices, better access to medicine, and greater ability to make use of the medical establishment. It is nonetheless interesting to see that the education correlation continues into very late life, when individuals are struggling with a high load of cell and tissue damage, and genetic factors start to become more important in determining remaining life expectancy:

Socioeconomic inequalities in life expectancy have been shown among the middle aged and the youngest of the old individuals, but the situation in the oldest old is less clear. The aim of this study was to investigate trends in life expectancy at ages 85, 90 and 95 years by education in Norway in the period 1961-2009. This was a register-based population study including all residents in Norway aged 85 and over. Individual-level data were provided by the Central Population Register and the National Education Database. For each decade during 1961-2009, death rates by 1-year age groups were calculated separately for each sex and three educational categories. Annual life tables were used to calculate life expectancy at ages 85, 90 and 95.

Educational differentials in life expectancy at each age were non-significant in the early decades, but became significant over time. For example, for the decade 2000-9, a man aged 90 years with primary education had a life expectancy of 3.4 years, while a man with tertiary education could expect to live for 3.8 years. Similar numbers in women were 4.1 and 4.5 years, respectively. Even among 95-year-old men, statistically significant differences in life expectancy were found by education in the two last decades. Education matters regarding remaining life expectancy also for the oldest old in Norway. Life expectancy at these ages is low, so a growth of 0.5 years in the life expectancy differential is sizeable.

Friday, September 25, 2015

Stem cells reside within a stem cell niche, a supporting environment that provides stem cells with the conditions they need. The lack of this niche is why most transplanted stem cells survive only a short time. Many of the potential incremental improvements to stem cell transplants under development work because they incorporate some of the functions of the niche into the therapy, usually by delivering specific signals or nutrients for a period of time. This is an example of the type:

Although stem cells have shown enormous promise in repairing organs after injury, using them in the heart itself has not yielded the expected results because very few of the transplanted cells survive in the heart. When the heart beats, it pushes cells injected into the heart wall out into the lungs before they get a chance to attach to the wall. Additionally, when stem cells move from the culture flasks they are grown in and into a solution for injection in the heart, their metabolism slows, causing them to die in several hours unless they are given the opportunity to attach to tissue. Researchers have tried to improve stem cell retention in the heart by injecting millions, only to have a mere 10-to-20 percent stick around an hour after injection. And even then a large number of these cells die within 24 hours due to a sluggish metabolism. "If we could inject fewer cells soon after heart attacks and coax them to proliferate following transplantation, we could limit scar formation and be more successful with re-growing new heart muscle."

The researchers developed a hydrogel that combines serum, a protein-filled component of blood that contains everything cells need to survive, with hyaluronic acid, a molecule already present in the heart and in the matrix that surrounds and supports cells. By mixing these two components, the researchers created a sticky gel that functioned as a synthetic stem cell niche: It encapsulated stem cells while nurturing them and rapidly restored their metabolism. Tests in petri dishes showed that both adult and embryonic stem cells encapsulated in this material not only survived at levels near 100 percent but thrived for days and proliferated. The encapsulated cells also showed markedly higher production of growth factors known to be involved in cardiac repair compared with stem cells that weren't encapsulated in the gel.

When the cell-gel combination was injected into living rat hearts, about 73 percent of the cells were retained in the hearts after an hour, compared with 12 percent of cells suspended in a solution. Over the next seven days, the number of regular solution-based transplanted cells continued to decline, whereas cells within the hydrogel increased in number. In rat models of heart attack damage, moreover, the team reports that the hydrogel with encapsulated cells improved pumping efficiency of the left ventricle over the four weeks after injection by 15 percent, compared with 8 percent from cells in solution. Even injections of the hydrogel on its own significantly improved heart function and increased the number of blood vessels in the region of the heart attack.

Friday, September 25, 2015α-synuclein.php

Transcription factor EB (TFEB) is a regulator of autophagy, one of the processes by which cells clear out unwanted junk and damaged components. Enhancing autophagy via TFEB for therapeutic ends has been explored in a very preliminary fashion to date, such as in the context of treating atherosclerosis. Continuing in this vein, researchers here show that manipulating TFEB can increase clearance of the α-synuclein aggregates whose increased presence is associated with the age-related diseases collectively known as synucleinopathies:

Aggregation of α-synuclein (α-syn) is associated with the development of a number of neurodegenerative diseases, including Parkinson's disease (PD). The formation of α-syn aggregates results from aberrant accumulation of misfolded α-syn and insufficient or impaired activity of the two main intracellular protein degradation systems, namely the ubiquitin-proteasome system and the autophagy-lysosomal pathway.

Novel insights into the mechanisms of autophagy regulation have emerged with the recent discovery that the transcription factor EB (TFEB) controls the coordinated activation of the CLEAR (Coordinated Lysosomal Expression and Regulation) network. TFEB regulates lysosome biogenesis as well as autophagosome formation and autophagosome-lysosome fusion, thereby promoting cellular clearance. Based on this evidence we hypothesized that TFEB activation could prevent accumulation of α-syn aggregates by enhancing autophagic clearance.

We tested this hypothesis by using a human neuroglioma stable cell line that accumulates aggregated α-syn and demonstrated that overexpression of TFEB reduces the accumulation of aggregated α-syn. Specifically, we provide evidence that the reduced accumulation of α-syn aggregates correlates with TFEB activation and with upregulation of the CLEAR network and the autophagy system. We also show that chemical activation of TFEB using 2-hydroxypropyl-β-cyclodextrin (HPβCD) mediates autophagic clearance of aggregated α-syn. These results support the role of TFEB as a therapeutic target for the treatment of PD and potentially other neurodegenerative diseases characterized by protein aggregation.


Post a comment; thoughtful, considered opinions are valued. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.