Fight Aging! Newsletter, May 5th 2014

FIGHT AGING! NEWSLETTER
May 5th 2014

The Fight Aging! Newsletter is a weekly email containing news, opinions, and happenings for people interested in aging science and engineered longevity: making use of diet, lifestyle choices, technology, and proven medical advances to live healthy, longer lives. This newsletter is published under the Creative Commons Attribution 3.0 license. In short, this means that you are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!

To subscribe or unsubscribe to the Fight Aging! Newsletter, please visit the newsletter site:
http://www.fightaging.org/newsletter/

CONTENTS

  • Rejuvenation Biotechnology Conference: Emerging Regenerative Medicine Solutions for the Diseases of Aging
  • Age-Related Y Chromosome Loss Correlates With Mortality
  • Cardiomyocytes Derived From Human Embryonic Stem Cells Regenerate Primate Hearts
  • Predation Associated With Bird Longevity
  • The Trouble With Popular Journalism and Life Extension Science
  • Latest Headlines from Fight Aging!
    • Molecular Tweezers Targeting Transthyretin Amyloidosis
    • Envisaging 3-D Printing of Replacement Cartilage Inside an Injured Joint
    • Heat Shock Protein 25 and Naked Mole Rat Longevity
    • Clearance of Senescent Liver Cells Following Cell Transplant
    • Investigating Salamander Heart Regeneration
    • Biodegradable Nanoparticles Target Brain Cancer Cells
    • Pig Extracellular Matrix as a Scaffold for Muscle Regeneration
    • Tissue Engineered Cartilage via Mesenchymal Condensation
    • A New Potential Treatment for Progeria
    • Extending Life in Mice With Artificially Shortened Life Spans is Rarely Directly Relevant or Useful

REJUVENATION BIOTECHNOLOGY CONFERENCE: EMERGING REGENERATIVE MEDICINE SOLUTIONS FOR THE DISEASES OF AGING
https://www.fightaging.org/archives/2014/04/rejuvenation-biotechnology-conference-emerging-regenerative-medicine-solutions-for-the-diseases-of-aging.php

Registration is open for Rejuvenation Biotechnology 2014, which will be held later this year in Santa Clara, California on August 21st. This is hopefully the first of many events to be organized by the SENS Research Foundation in the gap years between the main SENS conferences in the UK, to encourage work on - and enthusiasm for - developing the means to treat and ultimately cure degenerative aging. SENS, the Strategies for Engineered Negligible Senescence, provides a clear research and development plan to build the first versions of treatments capable of repairing the known root causes of aging: various forms of cellular and molecular damage that accumulate with age.

A critical part of the process of establishing any new technology or paradigm - medical or otherwise - is broadening the base of developers as soon as possible. Work must spread beyond the academic research community and into the business research and development community, becoming more attractive to large companies and entrepreneurs alike. Some portions of SENS are presently within striking distance of early commercial products for groups with a long-term view, willing to bet on up to five year development plans to reach a large payoff. Those products would likely not be actual therapies, but rather stepping stone proof of concept technologies that facilitate further development at a lower cost and faster pace.

For example, the SENS Research Foundation currently funds the development of the necessary fundamental technologies for working with glucosepane, the dominant advanced glycation end-product (AGE) in human tissues that causes harm as it accumulates with age. For various historical reasons the biochemistry community has neglected the development of means to work effectively with compounds like glucosepane, and so formalizing and licensing the results of such research forms a product in and of itself, something that will make other developers more able to make progress towards treatments that can break down and remove glucosepane, thus reversing its contribution to age-related degeneration.

The SENS vision and research programs have made more than enough progress within the scientific community for advocates to now also be working on bringing in allies and interested partners from the medical development and pharmaceutical industry. These things progress one step at a time. As is always the case for SENS Research Foundation events, a stellar lineup of leading researchers are scheduled to attend and present at the forthcoming conference:

Rejuvenation Biotechnology Conference 2014

SENS Research Foundation is proud to present the Rejuvenation Biotechnology Conference: Emerging Regenerative Medicine Solutions for the Diseases of Aging. This conference will bring together leaders from the Alzheimer's, cardiovascular, cancer, and other age-related disease communities to discuss preventative and combinatorial strategies to address the diseases of old age.

The Rejuvenation Biotechnology Conference will build upon novel strategies being pioneered by the Alzheimer's and cancer communities by convening the foremost leaders from academia, industry, investment, policy, and advocacy from multiple disease communities to consider the wider potential of these strategies and evaluate the feasibility of preventative and combinatorial medicine applications to treat all aging-related diseases. Through a series of presentations and panel discussion, Alzheimer's disease, cancer, cardiovascular disease, diabetes, macular degeneration, musculoskeletal disease and Parkinson's disease will be examined with scientific, economic, regulatory and other considerations in mind.

Confirmed speakers include:

Richard Barker (CASMI)
Maria Blasco (Spanish National Cancer Research Centre)
Judith Campisi (Buck Institute for Research on Aging)
George Church (Harvard and MIT)
Laura Esserman (University of California, San Francisco)
Caleb Finch (USC Davis School of Gerontology)
W. Gray Jerome (Vanderbilt University Medical Center)
Jeffrey Karp (Harvard Medical School)
Jeanne Loring (Scripps Research Institute)
Stephen Minger (GE Healthcare Life Sciences, UK)
Brock Reeve (Harvard Stem Cell Institute)
David Schaffer (Berkeley Stem Cell Center)
Evan Snyder (Sanford/Burnham Medical Research Institute)
Matthias Steger (Hoffmann-La Roche)
Michael West (Biotime, Inc.)

AGE-RELATED Y CHROMOSOME LOSS CORRELATES WITH MORTALITY
https://www.fightaging.org/archives/2014/04/age-related-y-chromosome-loss-correlates-with-mortality.php

Cells accumulate all sorts of mutations and other damage, and the damage load rises over the years despite the best efforts of our evolved repair systems. This is the basis of aging: degeneration and disease is driven by damage and reactions to damage.

The research community has cataloged this damage, and can make strong arguments as to what is fundamental and what is a secondary effect. Our biology is enormously complex, however, and so many specific forms of damage and their progression are far from fully understood. The research community doesn't have a solid case for what exactly it is that some forms of amyloid - clumps of misfolded proteins that accumulate with age - are actually doing to cause harm, for example. Many other examples can be found in the specifics of nuclear DNA damage, the innumerably stochastic mutations scattered about the cells of the body. What are all of these different mutations really actually doing, individually and in aggregate? To answer that question comprehensively would involve generations of study with today's technology.

So it shouldn't be terribly surprising to find that comparatively little is known about the consequences of the loss of the Y chromosome in a small proportion of male cells that occurs with aging. Chromosome loss is a form of DNA damage that occurs in both genders, but for the purposes of this post we'll restrict ourselves to considering just the Y chromosome. If you go digging around for articles and papers you'll find that most work on this topic is coming from the cancer research community, and thus don't have a great deal to say on what this might mean outside of the context of cancer tissue and cancer patients, who are not a representative sample of the population at large.

The paper below, however, goes further and shows an association between Y chromosome loss and all-cause mortality in men. This is a starting point, though it doesn't say anything about why this might be the case. The cancer link is evident, as DNA damage is firmly established as a cause of cancer, but the rest is an open question. As for all associations with age-related damage, it is always possible that this is just a case of aging being a global phenomenon in the body. If there is more of any one measured type of damage, then mortality rates will tend to be higher in that population because there is also more of all the other unmeasured forms of damage.

Mosaic loss of chromosome Y in peripheral blood is associated with shorter survival and higher risk of cancer

Incidence and mortality for sex-unspecific cancers are higher among men, a fact that is largely unexplained. Furthermore, age-related loss of chromosome Y (LOY) is frequent in normal hematopoietic cells, but the phenotypic consequences of LOY have been elusive.

From analysis of 1,153 elderly men, we report that LOY in peripheral blood was associated with risks of all-cause mortality (hazards ratio (HR) = 1.91) and non-hematological cancer mortality (HR = 3.62). LOY affected at least 8.2% of the subjects in this cohort, and median survival times among men with LOY were 5.5 years shorter.

Association of LOY with risk of all-cause mortality was validated in an independent cohort (HR = 3.66) in which 20.5% of subjects showed LOY. These results illustrate the impact of post-zygotic mosaicism on disease risk, could explain why males are more frequently affected by cancer and suggest that chromosome Y is important in processes beyond sex determination. LOY in blood could become a predictive biomarker of male carcinogenesis.

CARDIOMYOCYTES DERIVED FROM HUMAN EMBRYONIC STEM CELLS REGENERATE PRIMATE HEARTS
https://www.fightaging.org/archives/2014/04/cardiomyocytes-derived-from-human-embryonic-stem-cells-regenerate-primate-hearts.php

Transplants of adult stem cells with the aim of spurring regeneration from injury and age-related dsyfunction have been a going concern for some years now, at first only available through medical tourism. It was that state of affairs that finally pressured US regulators to begin permitting these treatments to take place inside the US. Absent the widespread use of stem cell transplants throughout the rest of the world, I'm sure that the FDA would be requesting more data and more studies still, while forbidding clinical applications of stem cell science. The bureaucrats there exist to put roadblocks in place, as they derive only risk from actually permitting any new treatment to move forward. Only when they are made to look backwards and foolish is there enough of a counterbalancing risk to enable significant movement. As for all entrenched systems of government regulation it is a shameful, squalid, and petty situation: this would be laughable if not for the great harms it causes through ensuring that medical progress is far slower and more expensive than it should be.

In any case, while adult stem cell therapies are a going concern, the same is far from true for the use of embryonic stem cells as a source of cells for therapeutic use. That line of work was quite effectively sabotaged by a combination of politics and inherent difficulty and is only now reaching milestones envisaged a decade ago. Much of the early energy and enthusiasm passed instead to research into cellular reprogramming, such as that involved in the creation of induced pluripotent stem cells that can be used to generate any type of cells on demand.

Nonetheless there are research groups working with human embryonic stem cells as the basis for regenerative medicine. Here is an example of heart cells sourced from embryonic stem cells producing regeneration in primate hearts:

Stem cell therapy regenerates heart muscle in primates

Stem cell therapy can regenerate heart muscle in primates. The scientists on this and related projects are seeking way to repair hearts weakened by myocardial infarctions. This all-too-common type of heart attack blocks a major artery and deprives heart muscle of oxygen.

People who survive a severe episode often continue their lives in poor health because their hearts no longer work properly. The researchers hope eventually to restore such failing hearts to normal function. Their approach uses heart cells created from human embryonic stem cells. The researchers tested the possibility of producing enough of these cardiac muscle cells to remuscularize damaged hearts in a large animal whose heart size and physiology are human-like.

Human embryonic-stem-cell-derived cardiomyocytes regenerate non-human primate hearts

Pluripotent stem cells provide a potential solution to current epidemic rates of heart failure by providing human cardiomyocytes to support heart regeneration. Studies of human embryonic-stem-cell-derived cardiomyocytes (hESC-CMs) in small-animal models have shown favourable effects of this treatment. However, it remains unknown whether clinical-scale hESC-CM transplantation is feasible, safe or can provide sufficient myocardial regeneration.

Here we show that hESC-CMs can be produced at a clinical scale (more than one billion cells per batch) and cryopreserved with good viability. Using a non-human primate model of myocardial ischaemia followed by reperfusion, we show that that cryopreservation and intra-myocardial delivery of one billion hESC-CMs generates extensive remuscularization of the infarcted heart.

In contrast to small-animal models, non-fatal ventricular arrhythmias were observed in hESC-CM-engrafted primates. Thus, hESC-CMs can remuscularize substantial amounts of the infarcted monkey heart. Comparable remuscularization of a human heart should be possible, but potential arrhythmic complications need to be overcome.

PREDATION ASSOCIATED WITH BIRD LONGEVITY
https://www.fightaging.org/archives/2014/05/predation-associated-with-bird-longevity.php

Why does any species live as long as it does? The high-level answer is that present length of life is an evolved consequence of adaptations that allow a species to succeed in occupying its niche, via competitive success for individuals in propagating their genes. You don't see the losers in this process, as they have vanished. There is fierce debate over the nature of the relationship between desirable adaptions that provide evolutionary success and consequent length of life, and the debate is very different for different species and different circumstances. In general, however, researchers who hold that aging is a process caused by accumulated cellular and molecular damage view aging as a sort of shadow cast by natural selection operating on youthful individuals. There is great selection pressure upon young biology, the fight for success in early life, and a species can boast successful adaptations that enhance reproductive success but which nonetheless exist at the expense of individual health and survival in later life.

Some models suggest that this shadow of aging is in and of itself necessary for the long-term survival and success of species, as aging species tend to outcompete ageless species during periods in which the environment changes. Since there have been innumerable such episodes in our evolutionary past, it is perhaps not too surprising that aging species are far more numerous than those few species that might be ageless.

A process that is advantageous in youth but becomes harmful in aging is known as a form of antagonistic pleiotropy: the human immune system is perhaps a good example of a system that has this property. It is structured so as to be effective in youth, but some of the very same aspects that make it so effective at the outset of life - such as the inflammatory immune response and the ability to remember specific threats indefinitely - contribute to immune system failure in later life.

In humans a big question lingers over our comparative longevity. Why did we evolve to live for so much longer than our primate cousins? One proposal is the grandmother hypothesis, which essential points to a combination of culture and intelligence as the root of human longevity. Once a post-reproductive individual can materially contribute to the success of his or her descendants, then a selection effect for greater longevity comes into play, one that doesn't exist in primate species that are not intelligent enough to have this ability.

To pick another species in which the situation is radically different, we could look at salmon. Salmon undergo a very sudden aging process after spawning, and the details of this process are strongly driven by the habits of bears who feed on salmon. Some bear populations prefer to feed on older salmon, and in those rivers salmon age more slowly.

The influence of predation on the evolution of aging is an established body of theory in the evolutionary science community. It is generally accepted that greater predation will tend to favor the evolution of shorter life spans, even if only because it allows for adaptations that ensure early reproductive success but which place a great physiological burden on later life. Mechanisms that instead ensure a longer reproductive life span will not be selected if individuals are largely eaten young.

All species are different, however, and there is always room for argument in this field. Which is why you will see such things as researchers crunching the numbers in support of the dominant viewpoint on predation and longevity:

Predators predict longevity of birds

In birds, variation in life-span extends from parrots such as the Sulphur-crested cockatoo that can become more than 100 years old, to the small Allen's hummingbird with a maximum life-span of only 4 years, a 25 fold difference. How can this variation be explained?

The classical evolutionary theory of ageing, first proposed by the famous evolutionary biologist George C. Williams over 50 years ago, gives an answer. The theory predicts that high mortality rates in adult animals due to predation, exposure to parasites and other randomly occurring events will be associated with shorter maximum life-spans. This is because under high external mortality most individuals will already be dead (eaten or succumbed to disease) before natural selection can act on rare mutations that cause healthier ageing. The theory has since been further developed and tested in a number of experimental and comparative studies. Yet contradictory results have caused scientists to cast doubt on its validity.

[Researchers] have now tested this theory using a comprehensive database on estimates of maximum life-span of 1396 bird species, 1128 from free-living species and 268 from birds kept in captivity. The researchers used a global distribution map of these species, included data on their morphology and reproductive rate, and estimated predation rate.

By means of complex statistical analysis methods they found that in the investigated bird species maximum longevity is negatively related to the number of predator species occurring within the same geographical area. This means that the more predator species are present in the same habitat and the more evenly they are distributed, the lower is the life span of the respective species. This relationship supports the classical theory of ageing, and remains valid when other life history traits known to influence longevity such as body mass and clutch size are included into the statistical model. Indeed, larger species live longer, and those that reproduce fast (lay more eggs) live shorter lives. Remarkably, the observed pattern showing longer life-spans when fewer predators are present emerges no matter how the analysis was done: at the species level, at a finer regional scale (groups of species within a certain area) or even when comparing entire bioregions.

THE TROUBLE WITH POPULAR JOURNALISM AND LIFE EXTENSION SCIENCE
https://www.fightaging.org/archives/2014/05/the-trouble-with-popular-journalism-and-life-extension-science.php

The US popular press turns out a few articles each year on the topic of longevity science, and most are intrinsically flawed. The problem here is that your average journalist will structure such a piece as a partial survey of all aspects of a topic that are either easily noticed - or easily interviewed - and which seem applicable to the general theme. All of these items are given equal weight, however, so there is no real distinction made between serious research into therapies to treat aging, frivolous pronouncements by health gurus, the "anti-aging" supplement industry, efforts to produce calorie restriction mimetics, research into the genetics of aging, practicing calorie restriction and exercise, and so forth. All of these absolutely night-and-day different things are treated as though they are of equal import and consequence, all just the same sort of widget clustered together in the same box.

Even positions and disputes between researchers and people outside the scientific community are flattened into equality in such an article. Thus outright nonsense is ranked equally in importance with serious research, and research that might greatly extend life is placed at the same level as research that cannot possibly achieve that goal. Simple good health practices that can add a few years to life are treated as being just as valuable and important as work on ways to create actual, working rejuvenation treatments that could extend healthy life by centuries. This is the poisonous rubric of journalistic balance at work. Somewhere along the way sense is dispensed with and meaning thrown out.

It is like reading a tourist guide to your home town written by someone who has never set foot there. It is a mere echo of reality, a fiction using real names and in which all of the useful data is omitted and obscured. Of course every subject is covered just as poorly by the media, not just the one I happen to know something about. It is simply hard to discern when you are unfamiliar with the topic at hand - and this is something to bear in mind while reading the news.

The even-handed pretense that everything has the same level of significance begins with the subtitle in this article and goes on from there. This practice is one of the many things that we seek to change through advocacy: to raise the level of awareness to the point at which the press will begin to include some hierarchy of usefulness in their coverage of longevity science. So here I'll just quote a SENS-related portion of this article, and note that the rest exhibits the issues mentioned above:

So You Want to Live Forever: Immortality through advanced technology and primitive diet

Aubrey de Grey believes that the current approach of geriatric medicine to the systemic breakdowns that aging entails is "pitiful." "Cardiovascular disease is the number-one killer in the West today, and we know that it's caused by fatty deposits in the major arteries. So we try stents or manipulating cholesterol levels with Lipitor. But we know now that the problem isn't so much cholesterol as oxidized cholesterol [small, dense, chemically-modified particles that the aging human body isn't able to deal with via its own natural enzymes]. Oxidized cholesterol isn't properly processed, that is, carried away by the enzymes, so it poisons the arteries."

He maintains that his SENS-sponsored research, some of it conducted on the foundation's premises and some in university laboratories, has pointed to a better way to clear that "bad" cholesterol out of clogged arteries: "We've been able to identify genes and enzymes in bacteria that we should be able to inject into our own human cells to bring about this cleansing process," de Grey explained. "In 2006-2007 we succeeded in identifying some of them, and we've been able to have that research published. We put extra enzymes that kill bad cells into a human cell culture, and they worked. They're the kind of [bacteria] that we need to fix problems in the human body. Then we can work on arteriosclerosis in mice, and then we'll have clinical trials in humans.

"The problem right now is that people think of aging as a universal phenomenon, but diseases such as heart disease are thought of as separate phenomena. But they're universal! Ninety-nine percent of the money spent on age-related research is spent on attempts to cure those diseases. But you can't cure people of side effects; you have to be able to cure aging itself. So what we want to see is preventative medicine, periodically cleaning up certain areas. Let's take Alzheimer's. We know that there are three factors: senile plaques in the brain, tangles in neurons, and cell death. We solved the plaque problem 15 years ago. You can clean up the plaques​ - ​but no cognitive goals for patients are being met. That's because we don't know the role that plaques play or their cause. Aging is this multifaceted. What we need to do is clean up lots of things at the same time. Initially, this could be a cleanup every 10 years. Then later, we might develop injections or oral medications. Right now, though, we have a 50-50 chance of getting it all into place in about 25 years."

Indeed, de Grey is confident that if we can figure out how to repair just seven bodily systems prone to breakdown​ - ​ranging from chromosomal mutations over time to protein junk accumulated from the cell disintegration that accompanies aging​ - there is no reason for any of us to die. The only obstacle he sees to our living, say, at least 5,000 years (unless we're unlucky enough to be hit by a car or whatever will substitute for a car in 7000 a.d.) is the money that SENS and its affiliated scientists committed to the hope of realizing eternal or near-eternal life need to develop those complex repair systems that they envision. "If we had ten times the money we have now, we could work at three times the speed," de Grey told me.

LATEST HEADLINES FROM FIGHT AGING!

MOLECULAR TWEEZERS TARGETING TRANSTHYRETIN AMYLOIDOSIS
Monday, April 28, 2014
https://www.fightaging.org/archives/2014/04/molecular-tweezers-targeting-transthyretin-amyloidosis.php

Various forms of amyloid build up in tissues with age, forming fibrils and clumps. These are precipitates of misfolded proteins, and while the harm caused by amyloids is not fully understood in all cases they are associated with numerous specific diseases of aging. The amyloid plaques that accompany Alzheimer's disease are perhaps the best known, for example.

It is thought that the oldest people, those who live longer than 110 years of age, are largely felled in end by senile systemic amyloidosis which involves amyloids formed of misfolded transthyretin. There is also a rare genetic disease in which this occurs early in life, called transthyretin-related hereditary amyloidosis or familial amyloidotic polyneuropathy - and as is often the case in such matters research into the rare genetic disease has more funding than research into the common age-related condition. Fortunately any potential treatment involving removal of amyloid is directly applicable to both types of condition.

Transthyretin (TTR) amyloidoses comprise a wide spectrum of acquired and hereditary diseases triggered by extracellular deposition of toxic TTR aggregates in various organs. Despite recent advances regarding the elucidation of the molecular mechanisms underlying TTR misfolding and pathogenic self-assembly, there is still no effective therapy for treatment of these fatal disorders.

Recently, the "molecular tweezers", CLR01, has been reported to inhibit self-assembly and toxicity of different amyloidogenic proteins in vitro, including TTR, by interfering with hydrophobic and electrostatic interactions known to play an important role in the aggregation process. In addition, CLR01 showed therapeutic effects in animal models of Alzheimer's disease and Parkinson's disease. Here, we assessed the ability of CLR01 to modulate TTR misfolding and aggregation in cell culture and in an animal model.

In cell culture assays we found that CLR01 inhibited TTR oligomerization [and] alleviated TTR-induced neurotoxicity by redirecting TTR aggregation into the formation of innocuous assemblies. To determine whether CLR01 was effective in vivo, we tested the compound in mice expressing TTR V30M, a model of familial amyloidotic polyneuropathy, which recapitulates the main pathological features of the human disease. Immunohistochemical and Western blot analyses showed a significant decrease in TTR burden in the gastrointestinal tract and the peripheral nervous system in mice treated with CLR01, with a concomitant reduction in aggregate-induced endoplasmic reticulum stress response, protein oxidation, and apoptosis. Taken together, our preclinical data suggest that CLR01 is a promising lead compound for development of innovative, disease-modifying therapy for TTR amyloidosis.

ENVISAGING 3-D PRINTING OF REPLACEMENT CARTILAGE INSIDE AN INJURED JOINT
Monday, April 28, 2014
https://www.fightaging.org/archives/2014/04/envisaging-3-d-printing-of-replacement-cartilage-inside-an-injured-joint.php

An ambitious form of 3-D printing is envisaged by these researchers: they want to develop the means to print out replacement cartilage tissue in place inside the body by use of minimally invasive techniques such as the introduction of a catheter threaded with the print head machinery that deposits cells and matrix materials:

Osteoarthritis is marked by a gradual disintegration of cartilage, a flexible tissue that provides padding where bones come together in a joint. Artificial cartilage built using a patient's own stem cells could offer enormous therapeutic potential. "Ideally we would like to be able to regenerate this tissue so people can avoid having to get a joint replacement, which is a pretty drastic procedure and is unfortunately something that some patients have to go through multiple times."

Creating artificial cartilage requires three main elements: stem cells, biological factors to make the cells grow into cartilage, and a scaffold to give the tissue its shape. [The] 3-D printing approach achieves all three by extruding thin layers of stem cells embedded in a solution that retains its shape and provides growth factors. The ultimate vision is to give doctors a tool they can thread through a catheter to print new cartilage right where it's needed in the patient's body.

In another significant step, [researchers have] successfully used the 3-D printing method to produce the first "tissue-on-a-chip" replica of the bone-cartilage interface. Housing 96 blocks of living human tissue 4 millimeters across by 8 millimeters deep, the chip could serve as a test-bed for researchers to learn about how osteoarthritis develops and develop new drugs. "With more testing, I think we'll be able to use our platform to simulate osteoarthritis, which would be extremely useful since scientists really know very little about how the disease develops. Osteoarthritis has a severe impact on quality of life, and there is an urgent need to understand the origin of the disease and develop effective treatments. We hope that the methods we're developing will really make a difference, both in the study of the disease and, ultimately, in treatments for people with cartilage degeneration or joint injuries."

HEAT SHOCK PROTEIN 25 AND NAKED MOLE RAT LONGEVITY
Tuesday, April 29, 2014
https://www.fightaging.org/archives/2014/04/heat-shock-protein-25-and-naked-mole-rat-longevity.php

Naked mole rats live up to nine times longer than other similarly sized rodents and are to all appearances immune to cancer. These facts make the species of considerable interest to researchers who study aging: what exactly are the biological mechanisms by which this longevity is achieved? So far it seems that naked mole rats are very resistant to the consequences of high levels of oxidative damage to molecular machinery within cells, and they have exceptionally good maintenance of proteostasis, the ability to keep protein levels stable over time and avoid the buildup of amyloids made up of misfolded proteins. But there is still much to be determined of the mechanisms by which these attributes are managed.

Here is a recent report from researchers involved in these investigations, focusing on cellular quality control mechanisms:

A new study links the naked mole rat's remarkable lifespan to a molecular chaperone protein known as heat shock protein 25 (HSP25). HSP25 and other chaperone proteins act like a tiny quality-control team within an animal's cells, quickly eliminating incorrectly manufactured or damaged proteins before they can cause a problem. Researchers say understanding changes in the actions of HSP25 during aging could shed light on age-related diseases like Alzheimer's and Parkinson's.

The researchers compared HSP25 levels in naked mole rats to levels of the protein found in rodents with different maximum lifespans, from mice (four years) to guinea pigs (12 years) to Damaraland mole rats (20 years) and others in between.

"Using a variety of rodents, we found that the amount of HSP25 present in their tissues positively correlated with the animal's maximum lifespan. If we can understand how HSP25 levels are regulated, what its function is and how it contributes to cell health, we might find ways to use this protein to combat devastating age-related diseases. In animals with higher levels of HSP25, having more of these quality-control proteins means they are primed to react when there is a problem, so they can quickly transport the faulty protein to cellular garbage dumps and maintain the health of the cell."

CLEARANCE OF SENESCENT LIVER CELLS FOLLOWING CELL TRANSPLANT
Tuesday, April 29, 2014
https://www.fightaging.org/archives/2014/04/clearance-of-senescent-liver-cells-following-cell-transplant.php

Cellular senescence is an important topic in aging: the number of senescent cells increases with age, and they cause harm to surrounding tissues. The research community is on the verge of being able to effectively remove these cells, however, using the tools under development by the cancer research community to target and destroy cancer cells with minimal side effects.

There may also be other ways to deal with senescent cells. The research result below was published earlier this year and makes for an interesting companion piece to a more recently published paper in which researchers showed that a method of growing large numbers of liver cells called hepatocytes via serial transplantation in mice was reversing cellular senescence along the way. Here cancer researchers find that cell transplants into rats have a similar effect, at least for cellular senescence that is artificially induced via introduction of a mild toxin that causes DNA damage and other cellular dysfunction leading to cancer. I would have to see a similar result in old animals with natural levels of cellular senescence before becoming too enthusiastic about this:

Increasing evidence indicates that carcinogenesis is dependent on the tissue context in which it occurs, implying that the latter can be a target for preventive or therapeutic strategies. We tested the possibility that re-normalizing a senescent, neoplastic-prone tissue microenvironment would exert a modulatory effect on the emergence of neoplastic disease.

Rats were exposed to a protocol for the induction of hepatocellular carcinoma (HCC). Using an orthotopic and syngeneic system for cell transplantation, one group of animals was then delivered 8 million normal hepatocytes, via the portal circulation. Hepatocytes transplantation resulted in a prominent decrease in the incidence of both pre-neoplastic and neoplastic lesions.

At the end of 1 year 50% of control animals presented with HCC, while no HCC were observed in the transplanted group. Extensive hepatocyte senescence was induced by the carcinogenic protocol in the host liver; however, senescent cells were largely cleared following infusion of normal hepatocytes. Furthermore, levels of Il-6 increased in rats exposed to the carcinogenic protocol, while they returned to near control values in the group receiving hepatocyte transplantation. These results support the concept that strategies aimed at normalizing a neoplastic-prone tissue landscape can modulate progression of neoplastic disease.

INVESTIGATING SALAMANDER HEART REGENERATION
Wednesday, April 30, 2014
https://www.fightaging.org/archives/2014/04/investigating-salamander-heart-regeneration.php

Researchers hope that continued study of salamanders and other species with exceptional regenerative capabilities will yield results that can inform the development of regenerative treatments for humans:

We have known for hundreds of years that newts and other types of salamanders regenerate limbs. If you cut off a leg or tail, it will grow back within a few weeks. "To our surprise, if you surgically remove part of the heart, (the creature) will regenerate a new heart within just six weeks or so. In fact, you can remove up to half of the heart, and it will still regenerate completely!"

Before the research team dove deeper into this finding, [they] had to determine how a salamander could even live with a partial heart. It turns out that a clot forms at the surgical site, acting much like the cork in a wine bottle, to prevent the amphibian from bleeding to death. What is the cork made of? In part, stem cells. Stem cells have unlimited potential for growth and can develop into cells with a specialized fate or function. Embryonic stem cells, for example, can give rise to all of the cells in the body and, thus, have promising potential for therapeutics.

As it turns out, stem cells play an important role in regeneration in newts. "We discovered that at least some of the stem cells for heart regeneration come from the blood, including the clot." This finding could have exciting implications for therapies in humans with heart damage. By finding the genes responsible for regeneration in the newt, researchers may be able to identify pathways that are similar in newts and people and could be used to induce regeneration in the human heart.

BIODEGRADABLE NANOPARTICLES TARGET BRAIN CANCER CELLS
Wednesday, April 30, 2014
https://www.fightaging.org/archives/2014/04/biodegradable-nanoparticles-target-brain-cancer-cells.php

The future of cancer treatment will be based upon a wide range of methodologies that selectively target cancer cells to deliver payloads that destroy only those cells. The end result will be highly effective treatments that can eliminate even metastatic cancer with minimal side effects. Here is an example of work in progress:

Biomedical engineers and neurosurgeons report that they have created tiny, biodegradable "nanoparticles" able to carry DNA to brain cancer cells in mice. "In our experiments, our nanoparticles successfully delivered a test gene to brain cancer cells in mice, where it was then turned on. We now have evidence that these tiny Trojan horses will also be able to carry genes that selectively induce death in cancer cells, while leaving healthy cells healthy."

[The researchers produced] tiny, round particles made up of biodegradable plastic whose properties can be optimized for completing various medical missions. By varying the atoms within the plastic, the team can make particles that have different sizes, stabilities and affinities for water or oil. For this study, [they] created dozens of different types of particles and tested their ability to carry and deliver a test sequence of DNA - specifically a gene for a red or green glowing protein. By assessing the survival of the cells that engulf the particles and measuring the levels of red or green light that they emitted, the researchers determined which formulation of particles performed best, then tested that formulation in mice with human brain cancer derived from their patients.

They injected the particles directly into mice with an experimental human brain cancer, and into the brains of healthy mice for use as comparison. Surprisingly, healthy cells rarely produced the glowing proteins, even though the DNA-carrying particles were entering tumor cells and non-tumor cells in similar numbers. "This is exactly what one would want to see, cancer specificity, but we are still researching the mechanism that allows this to occur. We hope our continued experiments will shed light on this so that we can apply what we learn to other scenarios."

The particles can be freeze-dried and stored for at least two years without losing their effectiveness. "Nanoparticles that remain stable for such a long time allow us to make up formulations well in advance and in large batches. This makes them easy to use consistently in experiments and surgeries; we add water to the particles, and they're good to go."

PIG EXTRACELLULAR MATRIX AS A SCAFFOLD FOR MUSCLE REGENERATION
Thursday, May 1, 2014
https://www.fightaging.org/archives/2014/05/pig-extracellular-matrix-as-a-scaffold-for-muscle-regeneration.php

Mirroring some of the work taking place in the tissue engineering field with decellularized donor tissue, in which the donor's cells are removed and then the structure left behind repopulated with the recipients cells, researchers here are using extracellular matrix (ECM) material from pig tissue as the basis for scaffolds to spur regrowth in large muscle injuries:

When a large volume of muscle is lost, typically due to trauma, the body cannot sufficiently respond to replace it. Instead, scar tissue can form that significantly impairs strength and function. Pig bladder ECM has been used for many years as the basis for medical products for hernia repair and treatment of skin ulcers. It is the biologic scaffold that remains left behind after cells have been removed. [Previous research] suggested that ECM also could be used to regenerate lost muscle by placing the material in the injury site where it signals the body to recruit stem and other progenitor cells to rebuild healthy tissue.

For the Muscle Tendon Tissue Unit Repair and Reinforcement Reconstructive Surgery Research Study, five men who had at least six months earlier lost at least 25 percent of leg muscle volume and function compared to the uninjured limb underwent a customized regimen of physical therapy for 12 to 26 weeks until their function and strength plateaued for a minimum of two weeks. Then [researchers] surgically implanted a "quilt" of compressed ECM sheets designed to fill into their injury sites. Within 48 hours of the operation, the participants resumed physical therapy for up to 26 additional weeks.

The researchers found that three of the participants, two of whom had thigh injuries and one a calf injury, were stronger by 20 percent or more six months after the surgery. Biopsies and scans all indicated that muscle growth had occurred. Two other participants with calf injuries did not have such dramatic results, but both improved on at least one functional measure and said they felt better.

TISSUE ENGINEERED CARTILAGE VIA MESENCHYMAL CONDENSATION
Thursday, May 1, 2014
https://www.fightaging.org/archives/2014/05/tissue-engineered-cartilage-via-mesenchymal-condensation.php

Recently researchers have made inroads in using the embryonic development process of mesenchymal condensation to generate tissue engineered teeth, or at least to show promising signs of progress along that road. Here this same process is turned to building cartilage, a type of tissue that has proven to be very challenging to engineer. Its mechanical properties are crucial to its role in the body, and these properties depend absolutely on the small-scale arrangement of cells and extracellular matrix. Even slight differences result in artificial tissue that is just an arrangement of cartilage cells, not the real thing, and not up to the task of supporting weight in joints.

Here researchers are claiming to have generated cartilage that is sufficiently similar to natural cartilage to be a candidate for use in the clinic:

[Researchers] have successfully grown fully functional human cartilage in vitro from human stem cells derived from fat tissue. "We've been able - for the first time - to generate fully functional human cartilage from mesenchymal stem cells by mimicking in vitro the developmental process of mesenchymal condensation. This could have clinical impact, as this cartilage can be used to repair a cartilage defect, or in combination with bone in a composite graft grown in the lab for more complex tissue reconstruction."

Many groups studied cartilage as an apparently simple tissue: one single cell type, no blood vessels or nerves, a tissue built for bearing loads while protecting bone ends in the joints. While there has been great success in engineering pieces of cartilage using young animal cells, no one has, until now, been able to reproduce these results using adult human stem cells from bone marrow or fat, the most practical stem cell source. [This] team succeeded in growing cartilage with physiologic architecture and strength by radically changing the tissue-engineering approach.

The general approach to cartilage tissue engineering has been to place cells into a hydrogel and culture them in the presence of nutrients and growth factors and sometimes also mechanical loading. But using this technique with adult human stem cells has invariably produced mechanically weak cartilage. [So the researchers] came up with a new approach: inducing the mesenchymal stem cells to undergo a condensation stage as they do in the body before starting to make cartilage.

The lubricative property and compressive strength - the two important functional properties - of the tissue-engineered cartilage approached those of native cartilage. The researchers then used their method to regenerate large pieces of anatomically shaped and mechanically strong cartilage over the bone, and to repair defects in cartilage. The team plans next to test whether the engineered cartilage tissue maintains its structure and long-term function when implanted into a defect.

A NEW POTENTIAL TREATMENT FOR PROGERIA
Friday, May 2, 2014
https://www.fightaging.org/archives/2014/05/a-new-potential-treatment-for-progeria.php

The accelerated aging condition Hutchinson-Gilford Progeria Syndrome (HGPS) is not in fact accelerated aging, but only appears that way. It is caused by dysfunctional lamin A, a protein vital to nuclear structure in cells, and this dysfunction leads to all sorts of cellular issues and damage. Malformed lamin A does show up in normal aging in very small amounts, but it is unclear whether or not this is significant in comparison to other causes of aging, and whether it is a primary or secondary effect. Researchers have also managed to extend life in mice by manipulation of lamins, which is intriguing but may not be relevant to either human aging or progeria as the mechanisms of action are not yet fully understood. Still, all told it seems worth keeping an eye on progress in the development of treatments for progeria:

In cells from people with HGPS, the nucleus is marked out because, unlike a normal cell's round nucleus, HGPS cell nuclei are drastically misshapen. Scientists believe this makes the cells more fragile, contributing to HGPS patients' symptoms. Proteins called Lamin A and Lamin C play a vital role in nuclear architecture, acting as 'scaffolding' for the nucleus. In HGPS, however, mutations in the gene that makes these proteins mean they cannot shape the nucleus correctly.

[Researchers] found that one compound - which they were able to improve, yielding a molecule that they have named Remodelin - effectively improved the damaged nuclei, restoring their shape. Further tests revealed that doing so also improved the health of the cells, making them grow and divide more normally. "Most drugs work by binding to something in the cell, so we went fishing. We attached a chemical 'hook' to Remodelin, incubated it with cell extracts, and examined what was attached to it when we reeled it back in." The target they fished out was NAT10, a protein not previously associated with ageing or HPGS. "From our following work, we now know that Remodelin works by inhibiting NAT10, so we have gone from finding a potential drug to identifying its target and mechanism-of-action."

The next stage of the research, which is already underway, is to see if Remodelin works in animal models of the disease; if it does, the researchers will be able to trial the drug in patients.

EXTENDING LIFE IN MICE WITH ARTIFICIALLY SHORTENED LIFE SPANS IS RARELY DIRECTLY RELEVANT OR USEFUL
Friday, May 2, 2014
https://www.fightaging.org/archives/2014/05/extending-life-in-mice-with-artificially-shortened-life-spans-is-rarely-directly-relevant-or-useful.php

There are numerous examples of studies that use mice genetically engineered to suffer forms of shortened life span with the appearance of accelerated aging. One has to be very cautious in reading anything into this sort of work, however: it is rarely of any great relevance to normal aging, as it creates and then attempts to ameliorate an entirely artificial situation. The appearance of accelerated aging is not in fact accelerated aging, but is rather often caused by mechanisms that are of little importance in normal aging. Even when the mechanisms are relevant, the overall metabolic circumstances can render it impossible to determine whether or not a partial treatment will be of any use in normal aging. The gold standard for relevance when evaluating new methods is the extension of life in unmodified mice, but unfortunately this is expensive and slow.

The publicity materials quoted below are a good example of research in animals exhibiting shortened life spans. Here scientists are investigating a protein involved in the induction of cellular senescence. As is often the case, however, from the structure of the work it is impossible to tell whether or not their drug candidate will be of any use as a treatment to lower levels of cellular senescence in normal aging and thus produce benefits such as extended health and life span. Those tests will still have occur:

When cells or tissue age - called senescence - they lose the ability to regenerate and secrete certain proteins, like a distinctive fingerprint. One of those proteins, PAI-1 (plasminogen activator inhibitor) has been [a focus of] research, originally as it relates to cardiovascular disease. "We made the intellectual leap between a marker of senescence and physiological aging. We asked is this marker for cell aging one of the drivers or mechanisms of rapid physiological aging?"

For the study, [researchers] used mice bred to be deficient in a gene (Klotho) that suppresses aging. These mice exhibit accelerated aging in the form of arteriosclerosis, neurodegeneration, osteoporosis and emphysema and have much shorter life spans than regular mice. [These] rapidly aging mice produce increased levels of PAI-1 in their blood and tissue.

Then scientists fed the rapidly aging mice TM5441 - the experimental drug - in their food every day. The result was a decrease in PAI-1 activity, which quadrupled the mice's life span and kept their organs healthy and functioning. "This is a completely different target and different drug than anything else being investigated for potential effects in prolonging life. It makes sense that this might be one component of a cocktail of drugs or supplements that a person might take in the future to extend their healthy life."

Comments

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.