Fight Aging! Newsletter, February 23rd 2015

FIGHT AGING! NEWSLETTER
February 23rd 2015

Fight Aging! provides a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress towards the medical control of aging in order to prevent age-related frailty, suffering, and disease, as well as improvements in the present understanding of what works and what doesn't work when it comes to extending healthy life. Expect to see summaries of recent advances in medical research, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more.

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CONTENTS

  • A Focus on NLRP3 in Inflammatory and Age-Related Disease
  • Inhibiting Oligomer Formation in Alzheimer's Disease
  • Targeting Anti-Inflammatory Drugs Directly to Atherosclerotic Lesions in Blood Vessel Walls
  • An Examination of Recent Historical Variability in Life Spans
  • Greater Ageism Correlates with Greater Ability to Treat the Consequences of Aging
  • Latest Headlines from Fight Aging!
    • A Speculative Example of Slowing Aging via Plasma Transfer
    • Advanced Glycation End-Products in Neurodegenerative Disease
    • Artesunate as a Possible Calorie Restriction Mimetic
    • Silica Nanoparticles Partially Reverse Osteoporosis in Mice
    • Arterial Stiffness, Elevated Blood Pressure, and Aging
    • Targeting Cholesterol Homeostasis in Hearing Loss
    • An Update on Efforts to Use Chimeric Antigen Receptor T-Cells as a Treatment for Cancer
    • Tissue Engineered Bone Marrow Creates Functional Blood Cells
    • Investigating Epigenetic Drift in Aging
    • Camelid Antibodies in Cancer Targeting

A FOCUS ON NLRP3 IN INFLAMMATORY AND AGE-RELATED DISEASE
https://www.fightaging.org/archives/2015/02/a-focus-on-nlrp3-in-inflammatory-and-age-related-disease.php

Raised levels of chronic inflammation play an important role in degenerative aging, as well as in many medical conditions. Much of this inflammation in aging is driven by systemic changes, as it is very similar in every individual: it is partly a consequence of the evolved limits of the immune system when operating over a long period of time and faced with the presence of persistent pathogens like cytomegalovirus that cannot be permanently cleared from tissues. There are of course numerous other mechanisms at work, and the big picture is still being filled in by ongoing research - a lot of the immune system remains poorly understood. One way of looking at the evolution of biological systems is that they tend to be optimized for survival during youth at the expense survival at later ages. Reproductive success is the primary measure of selection, and this seems to product outcomes such as an adaptive immune system that is highly effective at birth, yet runs off the rails after being exposed to too many diverse threats, or even a single persistent viral threat it cannot deal with, such as herpesviruses, HIV, or similar.

In recent years the characteristic age-related malfunctioning of the immune system has come to be called inflammaging as researchers explore its details. The immune system even considered portion by portion is immensely complex, and so is the character of the inflammatory response, especially when it becomes harmful. Inflammatory contributions to various medical conditions, aging included, can be spurred by many different mechanisms. Immune activity is regulated and influenced by numerous genes and proteins, and so naturally many research groups are attempting to catalog this space in order to find the basis for potential treatments to suppress inflammation, or better, ways to exert more sophisticated control over inflammation.

One gene of particular interest of late is NLRP3, a part of the inflammasome of the innate immune system. Here are a couple of recently published research results relating to this narrow slice of the broader field, one of which identifies a mechanism triggered by activities that reduce inflammation while the other is news of a possible new drug aimed at roughly the same area.

Anti-inflammatory mechanism of dieting and fasting revealed

The compound β-hydroxybutyrate (BHB) directly inhibits NLRP3, which is part of a complex set of proteins called the inflammasome. The inflammasome drives the inflammatory response in several disorders including autoimmune diseases, type 2 diabetes, Alzheimer's disease, atherosclerosis, and autoinflammatory disorders. "These findings are important because endogenous metabolites like BHB that block the NLRP3 inflammasome could be relevant against many inflammatory diseases, including those where there are mutations in the NLRP3 genes."

BHB is a metabolite produced by the body in response to fasting, high-intensity exercise, caloric restriction, or consumption of the low-carbohydrate ketogenic diet. It is well known that fasting and calorie restriction reduces inflammation in the body, but it was unclear how immune cells adapt to reduced availability of glucose and if they can respond to metabolites produced from fat oxidation. Working with mice and human immune cells, researchers focused on how macrophages -- specialized immune cells that produce inflammation -- respond when exposed to ketone bodies and whether that impacts the inflammasone complex. The team introduced BHB to mouse models of inflammatory diseases caused by NLP3. They found that this reduced inflammation, and that inflammation was also reduced when the mice were given a ketogenic diet, which elevates the levels of BHB in the bloodstream.

Scientists uncover marvel molecule that could lead to treatments for inflammatory diseases

Researchers showed how the molecule MCC950 can suppress the 'NLRP3 inflammasome', which is an activator of the key process in inflammatory diseases. Inflammasomes have been identified as promising therapeutic targets by researchers over the last decade. And now the discovery of MCC950's abilities represents a hugely significant development in the effort to find treatments for inflammatory diseases, for which current therapies are either highly ineffective or have major limitations. "MCC950 is blocking what was suspected to be a key process in inflammation. There is huge interest in NLRP3 both among medical researchers and pharmaceutical companies and we feel our work makes a significant contribution to the efforts to find new medicines to limit it."

So far, the results have shown great promise for blocking multiple sclerosis in a model of that disease, as well as in sepsis, where in response to bacteria, potentially fatal blood poisoning occurs. However, the target for MCC950 is strongly implicated in diseases such as Alzheimer's disease, atherosclerosis, gout, Parkinson's disease and rheumatoid arthritis, which means it has the potential to treat all of these conditions.

Reading between the hype there, it sounds like the next generation of anti-inflammatory treatments for various conditions will probably be an incremental improvement over the present state of the art, which is much as one would expect. At some point the methods of tinkering with the controlling signals may become useful enough to apply to the common processes of inflammaging that occur in every older individual, though this is a very top-down, messing-with-metabolism approach. If not addressing the underlying causes for increased chronic inflammation, even sophisticated means of suppression are just papering over the real issue. Lowering the rate at which some tertiary damage occurs by suppressing some secondary damage doesn't tackle the primary damage, which remains to grow as the root causes of all degeneration and dysfunction - so benefits from this approach to therapy will by necessity be limited.

This unfortunately describes the majority of modern medicine when it comes to age-related disease, and is why it is very important for the research and development community to unite behind the new approach of treating the mechanisms of aging as the cause of age-related disease. No more patching, and much more going after root causes should be the name of the game. Ultimately medicine for aging should consist of forms of repair for the damage that lies at the base of the pyramid of consequences: that is the place where the lion's share of the effort should be directed if we want to see real progress.

INHIBITING OLIGOMER FORMATION IN ALZHEIMER'S DISEASE
https://www.fightaging.org/archives/2015/02/inhibiting-oligomer-formation-in-alzheimers-disease.php

The molecular biology of Alzheimer's disease is enormously complex, and efforts to better understand it have spurred a great deal of the broader work that has taken place to decipher and catalog the biology of the brain over the past twenty years. Even given the rapid improvements in biotechnology taking place over that time and the large-scale funding pouring into Alzheimer's research, the present state of knowledge is still incomplete, a work in progress.

Alzheimer's is a disease of protein aggregation, its progression and severity associated with the formation of deposits of misfolded proteins known as amyloid and neurofibillary tangles (NFTs). It isn't just this, however, that is the crux of the condition, but rather the fine details of how amyloid and NFTs form and interact with their surroundings. In those fine details lie mechanisms that cause cellular dysfunction and death, and that is still a very active area of research. These mechanisms, in play once there are significant amounts of misfolded protein in the brain, are completely separate from the question of how an older individual gets to that point, however. Levels of misfolded proteins are dynamic over short time frames, and Alzheimer's has the look of a condition that develops due to a slow failure of the mechanisms that clear metabolic waste from brain fluids. There is as much debate in the research community over those root causes as there is over the precise details of the mechanisms that disrupt brain function in the later stages of the condition. Is it damage to the choroid plexus that filters cerebrospinal fluid, is it declining function in small vessels that drain that fluid, or something entirely different? These details are all open for further evidence, discussion, and argument.

The main thrust of Alzheimer's research when it comes to building prospective treatments remains the clearance of amyloid, such as via immunotherapies. It has been a long haul since this strategy was first proposed, however, and still there is no practical treatment to show for all the effort expended. This is despite a number of attempts that made it all the way to clinical trials. As is often the case, protracted delay in reaching treatment milestones has led to a certain degree of discontent and rebellion against the amyloid clearance consensus, and a healthy diversity of alternative approaches are in the works. This I think is for the better whether or not clearance of amyloid falters in the end, or simply turns out - like everything in biology - to be much harder and more complex than anticipated.

The research reported below is, I think, I good illustration of some of the complexity involved in the biochemistry of Alzheimer's disease. On the one hand this complexity makes everything harder, and on the other hand it offers a plethora of points at which well designed drugs might interfere with the disease process. Still, I would prefer to see work on repair of clearance mechanisms rather than work on sabotaging the disease process that becomes important once there is a lot of amyloid present. It should always be better - more efficient, more comprehensive - to strike at the root causes rather than even very effectively neutering later stages of the cascade of consequences.

Molecular inhibitor breaks cycle that leads to Alzheimer's

Alzheimer's disease is one of a number of conditions caused by naturally occurring protein molecules folding into the wrong shape and then sticking together - or nucleating - with other proteins to create thin filamentous structures called amyloid fibrils. Proteins perform important functions in the body by folding into a particular shape, but sometimes they can misfold, potentially kick-starting this deadly process. Recent research has however suggested a second critical step in the disease's development. After amyloid fibrils first form from misfolded proteins, they help other proteins which come into contact with them to misfold and form small clusters, called oligomers. These oligomers are highly toxic to nerve cells and are now thought to be responsible for the devastating effects of Alzheimer's disease.

This second stage, known as secondary nucleation, sets off a chain reaction which creates many more toxic oligomers, and ultimately amyloid fibrils, generating the toxic effects that eventually manifest themselves as Alzheimer's. Without the secondary nucleation process, single molecules would have to misfold and form toxic clusters unaided, which is a much slower and far less devastating process. By studying the molecular processes by which each of these steps takes effect, the research team assembled a wealth of data that enabled them to model not only what happens during the progression of Alzheimer's disease, but also what might happen if one stage in the process was somehow switched off. Researchers were able to identify a molecular chaperone, Brichos, that effectively inhibits secondary nucleation.

The research team then carried out further tests in which living mouse brain tissue was exposed to amyloid-beta, the specific protein that forms the amyloid fibrils in Alzheimer's disease. Allowing the amyloid-beta to misfold and form amyloids increased toxicity in the tissue significantly. When this happened in the presence of the molecular chaperone, however, amyloid fibrils still formed but the toxicity did not develop in the brain tissue, confirming that the molecule had suppressed the chain reaction from secondary nucleation that feeds the catastrophic production of oligomers leading to Alzheimer's disease.

A molecular chaperone breaks the catalytic cycle that generates toxic Aβ oligomers

Alzheimer's disease is an increasingly prevalent neurodegenerative disorder whose pathogenesis has been associated with aggregation of the ​amyloid-β peptide (​Aβ42). Recent studies have revealed that once ​Aβ42 fibrils are generated, their surfaces effectively catalyze the formation of neurotoxic oligomers. Here we show that a molecular chaperone, a human Brichos domain, can specifically inhibit this catalytic cycle and limit human ​Aβ42 toxicity.

We demonstrate in vitro that Brichos achieves this inhibition by binding to the surfaces of fibrils, thereby redirecting the aggregation reaction to a pathway that involves minimal formation of toxic oligomeric intermediates. We verify that this mechanism occurs in living mouse brain tissue. These results reveal that molecular chaperones can help maintain protein homeostasis by selectively suppressing critical microscopic steps within the complex reaction pathways responsible for the toxic effects of protein misfolding and aggregation.

TARGETING ANTI-INFLAMMATORY DRUGS DIRECTLY TO ATHEROSCLEROTIC LESIONS IN BLOOD VESSEL WALLS
https://www.fightaging.org/archives/2015/02/targeting-anti-inflammatory-drugs-directly-to-atherosclerotic-lesions-in-blood-vessel-walls.php

Precision targeting makes all medicine better: delivering smaller total doses to precise locations in the body opens many doors. Types of therapeutic compound that would otherwise be impractical to use become practical. Localized dosage levels that would otherwise be impossible can be obtained. Many examples of targeted medicine under development in recently involve the delivery entirely new types of drug or therapy, but there is also a strong incentive to generalize that delivery platform and walk back through the existing library of potential therapeutics to find those that can now be made much more useful.

Most of the targeting mechanisms reported in the media are associated with cancer research: a matter of finding ways to kill specific cells with certain characteristics with minimal collateral damage. Killing cells is easy. The hard part is doing it while leaving their neighbors - and the patient - alive and healthy. So it is the targeting mechanism that is the important part of this line of development, not the method for cell destruction, of which there are many. The next generation of cancer treatments aims to leave behind the fine line between harming the cancer and harming the patient that shapes chemotherapy and radiation therapy, building a basis for treatments that cause no discomfort while seeking out and destroying tumor cells wherever they may be. This is an important line of research, as it turns out that there are numerous types of cell in the aged body that we'd like to be able to safely and effectively destroy: senescent cells, fat cells, cells with damaged mitochondria, dysregulated immune cells, and so forth.

There are also other uses for targeting beyond cell destruction. Let us say, for example, that you can target therapeutics to the precise areas in blood vessel walls in which the characteristic fatty lesions of atherosclerosis are in a late stge of development, and either slow down or reverse that process. The type of approach demonstrated below may also be useful in the early stages of the condition, long before any noteworthy damage develops, but of course that is never going to be the goal in initial proof of concept studies. In the present regulatory environment researchers must work towards a therapy for the late stages of age-related disease if they want their work to progress towards clinical application:

Keeping Atherosclerosis in-check with Novel Targeted Inflammation-Resolving Nanomedicines

Targeted biodegradable nano 'drones' that delivered a special type of drug that promotes healing ('resolution') successfully restructured atherosclerotic plaques in mice to make them more stable. This remodeling of the plaque environment would be predicted in humans to block plaque rupture and thrombosis and thereby prevent heart attacks and strokes. Targeted nanomedicines made from polymeric building blocks that are utilized in numerous FDA approved products to date were nanoengineered to carry an anti-inflammatory drug payload in the form of a biomimetic peptide. Furthermore, this peptide was derived from one of the body's own natural inflammatory-resolving proteins called Annexin A1. The way the nanomedicines were designed enabled this biological therapeutic to be released at the target site, the atherosclerotic plaque, in a controlled manner.

In mouse models with advanced atherosclerosis, researchers administered nanomedicines and relevant controls. Following five weeks of treatment with the nanomedicines, damage to the arteries was significantly repaired and plaque was stabilized. Specifically, researchers observed a reduction of reactive oxygen species; increase in collagen, which strengthens the fibrous cap; and reduction of the plaque necrotic core, and these changes were not observed in comparison with the free peptide or empty nanoparticles.

Researchers caution that although plaques in mice look a lot like human plaques, mice do not have heart attacks, so the real test of the nanoparticles will not come until they are tested in humans. "In this study, we've shown, for the first time, that a drug that promotes resolution of inflammation and repair is a viable option, when the drug is delivered directly to plaques via nanoparticles." To be ready for testing in humans, the team plans to fine-tune the nanoparticles to optimize drug delivery and to package them with more potent resolution-inducing drugs. "We think that we can obtain even better delivery to plaques and improve healing more than with the current peptides."

Targeted nanoparticles containing the proresolving peptide Ac2-26 protect against advanced atherosclerosis in hypercholesterolemic mice

Chronic, nonresolving inflammation is a critical factor in the clinical progression of advanced atherosclerotic lesions. In the normal inflammatory response, resolution is mediated by several agonists, among which is the glucocorticoid-regulated protein called annexin A1.

The proresolving actions of annexin A1 can be mimicked by an amino-terminal peptide encompassing amino acids 2-26 (Ac2-26). Collagen IV (Col IV)-targeted nanoparticles (NPs) containing Ac2-26 were evaluated for their therapeutic effect on chronic, advanced atherosclerosis in fat-fed Ldlr−/− mice. When administered to mice with preexisting lesions, Col IV-Ac2-26 NPs were targeted to lesions and led to a marked improvement in key advanced plaque properties, including an increase in the protective collagen layer overlying lesions, suppression of oxidative stress, and a decrease in plaque necrosis. These findings support the concept that defective inflammation resolution plays a role in advanced atherosclerosis, and suggest a new form of therapy.

AN EXAMINATION OF RECENT HISTORICAL VARIABILITY IN LIFE SPANS
https://www.fightaging.org/archives/2015/02/an-examination-of-recent-historical-variability-in-life-spans.php

The long upward trend in human life expectancy derives from progress in medicine in its broadest definition. The varied technologies and techniques involved have very different contributions to the shape of life expectancy, however. To pick the obvious examples: control of infectious disease improves the proportion of the population who can expect to reach adulthood, while better treatments for age-related disease improve the quality and remaining length of life of the old. In a number of past studies, researchers have worked through data sets on human life span to quantify the effects of various facets of medical progress. One such work estimates the upward trend in life expectancy is produced by an equal contribution from (a) reduction in premature deaths, such as via infectious disease, and (b) reduction in late life mortality rates, such as through better treatments for age-related disease.

If there was a more equal mortality rate at all ages, then life spans would vary more widely. In the past there was a high mortality rate at all ages due to infectious disease. In the future there will be a very low mortality rate at all ages, thanks to medical technologies capable of maintaining youth through periodic repair of the causes of aging, the various forms of cellular and molecular damage that accumulate over the years. In both cases the outcome would be a larger variation in life spans than is presently the case. Today, however, the state of medicine has created a distribution of mortality rates that runs from low in youth to high in old age, and this acts to decrease the variability of life span. Many more people make it to old age than was the case, and old age is where they die. The point to bear in mind is that this is both unusual considered in the broader scope of history and also a transient state of affairs: it wasn't the case in the past, and it won't be the case in the future.

Is it fair that some people will live much longer than others? Is life fair at all? Can it be made to be fair? No to all three counts. In a world in which aging is treatable and life is only limited by fatal accidents, some people will live for thousands of years longer than others. That is simply the way it will be, even if everyone sets out to keep accident rates as low as possible. Unfairness is looked upon with grave displeasure these days; ours is a culture that drinks deeply of the shallow waters of egalitarianism. The prospect of unfairness is often put forward in opposition to forms of development that might improve matters for everyone. It is shameful that some people would choose to ensure a continuation of present death and suffering because they feel uncomfortable about the inherently unfair nature of accident statistics. Yet this is not an unusual position.

If you are among the population of demographers who like to dig more deeply into the data, then there are numerous epicycles to be found beyond the high-level picture noted above, some counter-intuitive:

Why do lifespan variability trends for the young and old diverge? A perturbation analysis

For much of human history, mortality rates at all ages were relatively high and the length of human life was highly variable. During the course of the demographic transition, mortality rates declined, life expectancy rose, and the variability of the distribution of lifespans, or ages at death, changed in response. Two stages in the history of lifespan variability have been identified. In the first stage, spanning the late nineteenth and early twentieth century "the level of mortality fell ... resulting in a very large reduction in the disparities of life spans." The second stage, starting in the 1950s, was one in which "the increase in life expectancy is no longer associated with a reduction in the dispersion of life spans - or with only a very small reduction." A closer examination of variability trends suggests another key, yet overlooked, aspect of this story. In high-longevity populations, survival improvements have taken place at all ages, including the oldest, but trends in the variability of the distribution of ages at death have not exhibited a uniform pattern. Variation in the length of life has declined as life expectancy at birth has risen, but the variation in lifespan among survivors to older ages (e.g. 65 and above) has increased.

Previous research has shown that lives saved at younger ages reduce lifespan disparity, while lives saved at older ages increase it, with the threshold demarcating early and late ages changing in response to changes in the mortality schedule and the historical contingencies that shape it. Our results likewise indicate that early and late deaths have different implications for the variability of lifespan conditional on survival to successive ages. Perturbation analysis enabled us to quantify this relationship, showing the differential responses of variability measure conditional on survival to younger and older ages to the parameters defining the course of child, adult, and background mortality levels. In particular, we showed that lifespan variability decreases for younger ages because of its sensitivity to the childhood mortality parameters, and that lifespan variability at older ages has increased because its sensitivity to the decline in adult mortality is in fact negative.

Notably, the expansion of lifespan variability at older ages takes place despite the fact that deaths are being concentrated into older ages. While the classic description of mortality compression predicts that lifespan variability will decline as life expectancy rises, this decline in variability doesn't materialize at older ages because, as we show, the relationship between mortality rates and lifespan variability is negative at those ages. While the data leave no doubt that deaths are indeed being delayed into increasingly older ages, our analysis shows that the implications of such changes for lifespan variability patterns are not pre-determined, but rather depend in intricate ways on the specific pattern of mortality change by age and over time.

The longitudinal nature of our analysis further highlights the impact of the temporal pattern of mortality change (i.e. an initial decline in childhood mortality followed by a decline in adult mortality some decades later) on the differential trends in lifespan variability at younger and older ages. Mortality has declined at all ages, but not at the same time or to the same extent. For the successive cohorts aging through the dramatic population changes of the twentieth century, survival has improved at all ages, but more so in early life than in adulthood. At the same time, each successive cohort is reaching older ages with added benefits of lower mortality (and likely better health) throughout the life course, suggesting that the period trends we describe here may also be explained by cohort effects and changing distributions of health and vulnerability to mortality within cohorts.

GREATER AGEISM CORRELATES WITH GREATER ABILITY TO TREAT THE CONSEQUENCES OF AGING
https://www.fightaging.org/archives/2015/02/greater-ageism-correlates-with-greater-ability-to-treat-the-consequences-of-aging.php

All societies have a complex relationship with aging and the old, but in the English-language Western cultures that I'm most familiar with it seems especially convoluted and strange. Individualism and a high value placed on future potential and raw talent do not have to go hand in hand with a lack of respect for older folk who have found their way to positions of authority on their own merits, but it certainly seems that way at times. Any number of fields in which older people can do well, such as hands-on software engineering, shut their doors to anyone with more than three decades of active experience. Media outlets relentlessly display youth and only youth: the state of being old is hidden away. The comparatively small number of young entrepreneurs are idolized, while the vast majority of successful captains of industry, largely older folk, fade into the backdrop.

There is simultaneously a fear of being old, an unwillingness to talk about the realities of being old, and a knee-jerk rejection of serious attempts to extend healthy life through medical science. Yet at the same time, the marketing of obviously fake "anti-aging" potions is a multi-billion dollar industry. The drawn-out details of the late stages of aging to death are hidden away to be rediscovered by every family, one small group at a time, and never to be shared in public or polite society. Everyone looks away.

Conflicted doesn't even begin to describe this morass. I think it is ancient at root, and what we have today is the modern iteration of fears and apprehensions that are as old as human society. No-one wants to look their own mortality in the face. Consider the old fable of The Three Living and the Three Dead, often presented in the form of three nobles meeting with three corpses while out riding in the woods, who tell them: "What you are, we were. And what we are, you will be." Ageism has an impact on medicine because it has an impact on every aspect of life:

Ageism and its clinical impact in oncogeriatry: state of knowledge and therapeutic leads

Cancer is a major health problem that is widespread in elderly people. Paradoxically, older people suffering from cancer are often excluded from clinical trials and are undertreated when compared to younger patients. One explanation for these observations is age stigma (ie, stereotypes linked to age, and thus ageism). These stigmas can result in deleterious consequences for elderly people's mental and physical health in "normal" aging. This discrimination against elderly patients is not limited to research; it is observed in the clinic too. Older patients are undertreated when compared to younger patients. Yet it should be remembered that "advanced" age alone should not be a contraindication for treatments that can increase a patient's quality of life or significantly extend a patient's survival.

A recent paper, quoted below, marshals evidence to suggest that ageism in its present form is not in fact an ancient thing at all, but rather a modern phenomenon. The authors argue that correlations between the rise of modern medicine, lengthening life expectancy, and ageism suggest that there is something in the growing ability of medical science to treat the consequences of aging that encourages ageist views. Ironic if so, as ageism is one of the hurdles we face when trying to direct more resources to help eliminate suffering and pain in aging. Most people would rather devote resources to any of the presently popular charitable causes instead, and you often hear arguments along the lines of "the old have had their fair innings at life." But are the old not people too?

Increasing Negativity of Age Stereotypes across 200 Years: Evidence from a Database of 400 Million Words

Scholars argue about whether age stereotypes (beliefs about old people) are becoming more negative or positive over time. No previous study has systematically tested the trend of age stereotypes over more than 20 years, due to lack of suitable data. Our aim was to fill this gap by investigating whether age stereotypes have changed over the last two centuries and, if so, what may be associated with this change. We hypothesized that age stereotypes have increased in negativity due, in part, to the increasing medicalization of aging.

This study applied computational linguistics to the recently compiled Corpus of Historical American English (COHA), a database of 400 million words that includes a range of printed sources from 1810 to 2009. After generating a comprehensive list of synonyms for the term elderly for these years from two historical thesauri, we identified 100 collocates (words that co-occurred most frequently with these synonyms) for each of the 20 decades. Inclusion criteria for the collocates were: (1) appeared within four words of the elderly synonym, (2) referred to an old person, and (3) had a stronger association with the elderly synonym than other words appearing in the database for that decade. This yielded 13,100 collocates that were rated for negativity and medicalization.

We found that age stereotypes have become more negative in a linear way over 200 years. In 1880, age stereotypes switched from being positive to being negative. In addition, support was found for two potential explanations. Medicalization of aging and the growing proportion of the population over the age of 65 were both significantly associated with the increase in negative age stereotypes.

LATEST HEADLINES FROM FIGHT AGING!

A SPECULATIVE EXAMPLE OF SLOWING AGING VIA PLASMA TRANSFER
Monday, February 16, 2015
https://www.fightaging.org/archives/2015/02/a-speculative-example-of-slowing-aging-via-plasma-transfer.php

As a result of parabiosis research there is presently some interest in exploring transfer of blood from young donors and direct alteration of levels of circulating proteins to try to impact the progression of aging in the old. Making old blood more like young blood appears to reactivate dormant stem cell populations to some degree, and thus produce benefits due to increased tissue maintenance. At this stage it remains to be seen what else is happening under the hood, as well as what the cancer risk profile of doing this might be. Stem cell activity falters with age because it reduces cancer incidence, a part of the evolutionary trade off that enables we humans to live much longer than other primates.

In any case, here is an example of slowing aging via transfer of blood plasma, but the researchers are doing this in a breed of senescence-accelerated mice. So what is happening here might have some similarities to the case of young blood for old animals at the detail level - and here the researchers are looking at cellular senescence in particular - but it is really a situation in which researchers cause a specific narrow form of damage and then prevent some of the consequences of that damage by delivering functional biological parts. In all such studies the relevance to normal biology and normal aging is strained at best, and often there turns out to be no relevance. It is worth bearing in mind that a team did in fact recently conduct a blood transfusion study for young blood to old individuals in normal mice, and saw no benefit.

Aging is related to loss of functional stem cells accompanying loss of tissue and organ regeneration potentials. Previously, we demonstrated that the life span of ovariectomy-senescence accelerated mice (OVX-SAMP8) was significantly prolonged and similar to that of the congenic senescence-resistant strain of mice after platelet rich plasma (PRP)/embryonic fibroblast transplantation. The aim of this study is to investigate the potential of PRP for recovering cellular potential from senescence and then delaying animal aging.

We first examined whether stem cells would be senescent in aged mice compared to young mice. Primary adipose derived stem cells (ADSCs) and bone marrow derived stem cells (BMSCs) were harvested from young and aged mice, and found that cell senescence was strongly correlated to animal aging. Subsequently, we demonstrated that PRP could recover cell potential from senescence, such as promote cell growth (cell proliferation and colony formation), increase osteogenesis, decrease adipogenesis, restore cell senescence related markers and resist the oxidative stress in stem cells from aged mice.

The results also showed that PRP treatment in aged mice could delay mice aging as indicated by survival, body weight and aging phenotypes (behavior and gross morphology) in term of recovering the cellular potential of their stem cells compared to the results on aged control mice. In conclusion these findings showed that PRP has potential to delay aging through the recovery of stem cell senescence and could be used as an alternative medicine for tissue regeneration and future rejuvenation.

ADVANCED GLYCATION END-PRODUCTS IN NEURODEGENERATIVE DISEASE
Monday, February 16, 2015
https://www.fightaging.org/archives/2015/02/advanced-glycation-end-products-in-neurodegenerative-disease.php

Advanced glycation end-products (AGEs) of various types are both generated in the body and arrive via the diet. Some are short-lived and easily broken down, but still a problem in people with abnormal metabolisms, such as diabetics, as well as through promotion of chronic inflammation for the rest of us via their interaction with RAGE, the receptor for AGEs. Some forms of AGE, most notably glucosepane in humans, are hard or impossible for our biochemistry to deal with, however, and they linger to form cross-links that glue together important proteins in tissues. These unwanted additions progressively degrade structural properties such as elasticity of blood vessels and strength of bone, and are a contributing factor in many of the aspects of degenerative aging.

When it comes to the contribution of AGEs to the progression of neurodegenerative conditions such as Alzheimer's disease the focus is on inflammation and RAGE. Here the most studied AGE is N(6)-Carboxymethyllysine (CML), as the relevant mechanisms are very different from those involving glucosepane and cross-linking. This open access paper provides a tour of the biochemistry, but note that the full thing is only available in PDF format (link above the title):

Protein glycation occurs through a complex series of very slow reactions in the body, including the Amadori reaction, Schiff base formation, and the Maillard reaction. These give rise to the formation of advanced glycation end products (AGEs). Since these glycation reactions were slow, it was believed that this process predominantly affected long-lived proteins. However, it was later found that even short-lived compounds such as lipids, nucleic acids, and intracellular growth factors are glycated. N(6)-carboxymethyllysine (CML) is thus far the most important AGE that occurs in vivo. It has been extensively studied and implicated in neurodegenerative disorders.

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases. A recent report suggests that glycation plays a key role in the formation of amyloid protein. AGEs are also formed from the reaction of reactive carbonyl or dicarbonyl compounds with lysine or arginine groups on proteins, and are present in beta-amyloid plaques and neurofibillary tangles (NFTs). The plaque fractions of AD brains contain higher levels of AGEs than samples from age-matched controls. Furthermore, immunohistochemical methods have convincingly demonstrated that AGEs are present in NFTs and senile plaques. Although some authors suggested that AGEs are very late markers of the disease, it is now widely accepted that they are active participants in the progression of the disease.

A link between diabetes mellitus and AD was recently postulated because humans with diabetes show a greater deposition of brain AGEs and RAGE, which may mediate a common pro-inflammatory pathway in neurodegenerative disorders. Immunohistochemical studies of human postmortem samples showed that patients with the combination of AD and diabetes had higher AGE levels, increased numbers of beta-amyloid dense plaques, higher RAGE- and tau-positive cells, and major microglial activation in their brains when compared to the brains of patients with AD alone.

The AGE-RAGE damaging axis is now considered to be a promising drug target. The main molecular approaches used to inhibit RAGE activation are inactivation of the ligand, inactivation of RAGE and downregulation of RAGE expression. Additionally, there are defense enzymes and protein present in the body that protect the neuronal cell from glycation and carbonyl stress. The formation of toxic oligomeric species could be controlled by using novel inhibitors. Using combination therapies, novel drugs could be designed that simultaneously target multiple pathways and may obviously be more efficient than those drugs that modify a single pathway and thereby decrease the risk of side effects.

ARTESUNATE AS A POSSIBLE CALORIE RESTRICTION MIMETIC
Tuesday, February 17, 2015
https://www.fightaging.org/archives/2015/02/artesunate-as-a-possible-calorie-restriction-mimetic.php

One of the detrimental consequences of the high cost of medical regulation is that researchers spend a lot of time looking for marginal new uses for the existing catalog of approved drugs rather than building better technologies. Thus most of the current crop of possible calorie restriction mimetic drugs, none of which you should be particularly excited about, are compounds known for years and used for other means, such as rapamycin. Here is news of another possible candidate mined from the present drug library, determined by testing in yeast cultures:

Calorie restriction (CR) promotes longevity among distinct organisms from yeast to mammals. Although CR-prolonged lifespan is believed to associate with enhanced respiratory activity, it is apparently controversial for accelerated energy consumption regardless of insufficient nutrient intake. In reconciling the contradiction of less food supply versus much metabolite dispense, we revealed a CR-based mode of dual-phase responses that encompass a phase of mitochondrial enhancement (ME) and a phase of post-mitochondrial enhancement (PME), which can be distinguished by the expression patterns and activity dynamics of mitochondrial signatures. ME is characterized by global antioxidative activation, and PME is denoted by systemic metabolic modulation.

CR-mediated aging-delaying effects are replicated by artesunate, a semi-synthetic derivative of the antimalarial artemisinin that can alkylate heme-containing proteins, suggesting artesunate-heme conjugation functionally resembles nitric oxide-heme interaction. A correlation of artesunate-heme conjugation with cytochrome c oxidase activation has been established from adduct formation and activity alteration. Exogenous hydrogen peroxide also mimics CR to trigger antioxidant responses, affect signaling cascades, and alter respiratory rhythms, implying hydrogen peroxide is engaged in lifespan extension. Conclusively, artesunate mimics CR-triggered nitric oxide and hydrogen peroxide to induce antioxidative networks for scavenging reactive oxygen species and mitigating oxidative stress, thereby directing metabolic conversion from anabolism to catabolism, maintaining essential metabolic functionality, and extending life expectancy in yeast.

SILICA NANOPARTICLES PARTIALLY REVERSE OSTEOPOROSIS IN MICE
Tuesday, February 17, 2015
https://www.fightaging.org/archives/2015/02/silica-nanoparticles-partially-reverse-osteoporosis-in-mice.php

At the small scale, bone structure is constantly remodeled throughout life. We lose bone mass and strength as we age, a condition known as osteoporosis, in part due to a systemic shift of the balance of activities between osteoclasts that remove bone structure and osteoblasts that create it. In older people there is too much absorption of bone and not enough bone deposition. Here researchers demonstrate a way to tilt that balance back towards a more youthful measure:

We recently reported that in vitro, engineered 50 nm spherical silica nanoparticles promote the differentiation and activity of bone building osteoblasts but suppress that of bone-resorbing osteoclasts. Furthermore, these nanoparticles promote bone accretion in young mice in vivo.

In the present study the capacity of these nanoparticles to reverse bone loss in aged mice, a model of human senile osteoporosis, was investigated. Aged mice received nanoparticles weekly and bone mineral density (BMD), bone structure, and bone turnover were quantified. Our data revealed a significant increase in BMD, bone volume, and biochemical markers of bone formation. Biochemical and histological examinations failed to identify any abnormalities caused by nanoparticle administration. Our studies demonstrate that silica nanoparticles effectively blunt and reverse age-associated bone loss in mice by a mechanism involving promotion of bone formation. The data suggest that osteogenic silica nanoparticles may be a safe and effective therapeutic for counteracting age-associated bone loss.

ARTERIAL STIFFNESS, ELEVATED BLOOD PRESSURE, AND AGING
Wednesday, February 18, 2015
https://www.fightaging.org/archives/2015/02/arterial-stiffness-elevated-blood-pressure-and-aging.php

Like skin, the walls of blood vessels lose their elasticity over the course of aging. Mechanisms involved in this loss include rising levels of long-lived cross-links in the extracellular matrix, wherein metabolic byproducts such as glucosepane glue together proteins and so alter the structural properties of important tissues. Our biochemistry struggles to break these cross links and so they accumulate as a consequence of the natural operation of metabolism. In blood vessels the consequences of loss of elasticity become increasingly serious over time, as this is a part of a feedback loop of dysfunction in the cardiovascular system that causes hypertension, heart abnormalities, and damage to blood vessels and surrounding tissues throughout the body. All of this could be dialed back just by maintaining elasticity in blood vessels, which would involve the development of treatments to clear cross-links, among other items, a field of research that sadly sees little funding and interest given its potential:

Isolated systolic hypertension is a major health burden that is expanding with the aging of our population. There is evidence that central arterial stiffness contributes to the rise in systolic blood pressure (SBP); at the same time, central arterial stiffening is accelerated in patients with increased SBP. This bidirectional relationship created a controversy in the field on whether arterial stiffness leads to hypertension or vice versa. Given the profound interdependency of arterial stiffness and blood pressure, this question seems intrinsically challenging, or probably naïve.

The aorta's function of dampening the pulsatile flow generated by the left ventricle is optimal within a physiological range of distending pressure that secures the required distal flow, keeps the aorta in an optimal mechanical conformation, and minimizes cardiac work. This homeostasis is disturbed by age-associated, minute alterations in aortic hemodynamic and mechanical properties that induce short- and long-term alterations in each other. Hence, it is impossible to detect an "initial insult" at an epidemiological level.

Earlier manifestations of these alterations are observed in young adulthood with a sharp decline in aortic strain and distensibility accompanied by an increase in diastolic blood pressure. Subsequently, aortic mechanical reserve is exhausted, and aortic remodeling with wall stiffening and dilatation ensue. These two phenomena affect pulse pressure in opposite directions and different magnitudes. With early remodeling, there is an increase in pulse pressure, due to the dominance of arterial wall stiffness, which in turn accelerates aortic wall stiffness and dilation. With advanced remodeling, which appears to be greater in men, the effect of diameter becomes more pronounced and partially offsets the effect of wall stiffness leading to plateauing in pulse pressure in men and slower increase in pulse pressure (PP) than that of wall stiffness in women. The complex nature of the hemodynamic changes with aging makes the "one-size-fits-all" approach suboptimal and urges for therapies that address the vascular profile that underlies a given blood pressure, rather than the blood pressure values themselves.

TARGETING CHOLESTEROL HOMEOSTASIS IN HEARING LOSS
Wednesday, February 18, 2015
https://www.fightaging.org/archives/2015/02/targeting-cholesterol-homeostasis-in-hearing-loss.php

This open access paper presents an interesting view on age-related hearing loss, a contrast to more frequently reported efforts to regenerate hair cells in the ear known to be lost in old age:

Hearing loss constitutes a major health problem affecting 16% of the adult population worldwide. Aging is the main risk factor associated with hearing impairment. Age-related sensorineural hearing loss (SNHL) is the third most common disability of the elderly affecting about half of the population over 75 years old. SNHL is a pathology of the cochlea that is generally regarded as mechanical or chemical damage-induced hair cell death triggering spiral ganglion neuron (SGN) death and subsequent dysfunction of auditory nerve. Recent researches in SNHL field have lead to a more complex vision of the relationship between inner ear damage and SNHL. Indeed, SGN loss without hair cell damage or death was observed.

Interestingly, cholesterol homeostasis and metabolism are central to numerous pathologies including neurodegenerative diseases, and regulate the many of the processes involved in neuron survival and functionality. Consequently, interfering with cholesterol homeostasis should afford innovative therapeutic strategies to improve the care of SNHL. Even if studies related to cholesterol homeostasis in inner ear are scarce, some reports support a relationship between cholesterol homeostasis deregulation and SNHL. Indeed, atherosclerosis, high plasma total cholesterol, and low HDL levels are positively correlated with SNHL. The most plausible explanation is that hypercholesterolemia triggers the stenosis of spiral modiolar artery leading to cochlear ischemia and subsequent SNHL. Consequently, therapies that limit high plasma cholesterol level could be useful to prevent SNHL caused by cochlear ischemia.

AN UPDATE ON EFFORTS TO USE CHIMERIC ANTIGEN RECEPTOR T-CELLS AS A TREATMENT FOR CANCER
Thursday, February 19, 2015
https://www.fightaging.org/archives/2015/02/an-update-on-efforts-to-use-chimeric-antigen-receptor-t-cells-as-a-treatment-for-cancer.php

Engineering a patient's own T-cells to express chimeric antigen receptors (CARs) has shown considerable promise as a cancer treatment. This alteration steers the immune cells to attack tumor cells, and has for example been used to drive leukemia into remission in trials. Here researchers are preparing a trial to test the use of CARs in targeting the brain cancer glioblastoma:

Immune cells engineered to seek out and attack a type of deadly brain cancer were found to be both safe and effective at controlling tumor growth in mice that were treated with these modified cells. The results paved the way for a newly opened clinical trial for glioblastoma patients. The new preclinical study details the design and use of T cells engineered to express a chimeric antigen receptor (CAR) that targets a mutation in the epidermal growth factor receptor protein called EGFRvIII, which is found on about 30 percent of glioblastoma patients' tumor cells.

First, the team developed and tested multiple antibodies, or what immunologists call single-chain variable fragments (scFv), which bind to cells expressing EGFRvIII on their surface. The scFvs recognizing the mutated EGFRvIII protein must be rigorously tested to confirm that they do not also bind to normal, non-mutated EGFR proteins, which are widely expressed on cells in the human body. Out of the panel of humanized scFvs that were tested, the researchers selected one scFv to explore further based on its binding selectivity for EGFRvIII over normal non-mutated EGFR.

The lead scFv was then tested for its anti-cancer efficacy. Using human tumor cells, the scientific team determined that the EGFRvIII CAR T cells could multiply and secrete cytokines in response to tumor cells bearing the EGFRvIII protein. Importantly, the researchers found that the EGFRvIII CAR T cells controlled tumor growth in several mouse models of glioblastoma. On the basis of these preclinical results, the investigators designed a phase 1 clinical study of CAR T cells transduced with humanized scFv directed to EGFRvIII for both newly diagnosed and recurrent glioblastoma patients carrying the EGFRvIII mutation.

The investigational approach begins when some of each patient's T cells are removed via an apheresis process similar to dialysis, the cells are engineered using a viral vector that programs them to find cancer cells that express EGFRvIII. Then, the patient's own engineered cells are infused back into their body, where a signaling domain built into the CAR promotes proliferation of these "hunter" T-cells. In contrast to certain T cell therapies that also target some healthy cells, EGFRvIII is believed to be found only on tumor tissue, which the study's leaders hope will minimize side effects.

TISSUE ENGINEERED BONE MARROW CREATES FUNCTIONAL BLOOD CELLS
Thursday, February 19, 2015
https://www.fightaging.org/archives/2015/02/tissue-engineered-bone-marrow-creates-functional-blood-cells.php

Scientists continue to make progress in this first phase of tissue engineering, in which real and mock tissues of various types grown from cells will largely be used to expand and speed up further research rather than in treatment:

Researchers have reported development of the first three-dimensional tissue system that reproduces the complex structure and physiology of human bone marrow and successfully generates functional human platelets. Using a biomaterial matrix of porous silk, the new system is capable of producing platelets for future clinical use and also provides a laboratory tissue system to advance study of blood platelet diseases. "There are many diseases where platelet production or function is impaired. New insight into the formation of platelets would have a major impact on patients and healthcare. In this tissue system, we can culture patient-derived megakaryocytes - the bone marrow cells that make platelets - and also endothelial cells, which are found in bone marrow and promote platelet production, to design patient-specific drug administration regimes."

The new system can also provide an in vitro laboratory tissue system with which to study mechanisms of blood disease and to predict efficacy of new drugs - providing a more precise and less costly alternative to in vivo animal models. The new system combined microtubes spun of silk, collagen and fibronectin surrounded by a porous silk sponge. Megakaryocytes - some of which were derived from patients - were seeded into the engineered microvasculature. The researchers were able to increase platelet production in the bioreactor by embedding the silk with active endothelial cells and endothelial-related molecular proteins that support platelet formation.

Laboratory tests showed that the platelets being generated and recovered from the tissue system were able to aggregate and clot. While the number of platelets produced per megakaryocyte was lower than normally made in the body, the researchers note that the system represents a significant advance over previous models. The scalable nature of the bioreactor system provides engineering options to increase yields of platelets in ongoing studies. In addition to providing a platform for studying the processes that regulate platelet production and related diseases, the researchers hope the platelets produced can be used as a source of growth factors for wound healing in regenerative medicine, including healing of ulcers and burns.

INVESTIGATING EPIGENETIC DRIFT IN AGING
Friday, February 20, 2015
https://www.fightaging.org/archives/2015/02/investigating-epigenetic-drift-in-aging.php

Epigenetics is the study of dynamic alterations to DNA that affect the rate at which specific proteins are generated from its blueprint, but do not change the blueprint itself. One example is DNA methylation, the decoration of DNA with methyl groups. Patterns of DNA methylation change with advancing age, and some of those changes are similar enough between individuals to be used as a measure of age.

Why do epigenetic patterns change with aging? The obvious suggestion, though at this point it remains a challenge to drawn direct lines from cause to effect, is that it is a reaction to rising levels of the cellular and molecular damage that causes degenerative aging. The same forms of damage occur in everyone, so reactions to that damage should be similar in everyone. Epigenetic changes occur in reaction to other environmental circumstances, so it shouldn't be surprising to find them happening in response to the damage of aging.

Two well-known features of aging are the gradual decline of the body's ability to regenerate tissues, as well as an increased incidence of diseases like cancer and Alzheimers. One of the most recent exciting findings which may underlie the aging process is a gradual modification of DNA, called epigenetic drift, which is effected by the covalent addition and removal of methyl groups, which in turn can deregulate the activity of nearby genes. However, this study presents the most convincing evidence to date that epigenetic drift acts to stabilize the activity levels of nearby genes.

This study shows that instead, epigenetic drift may act primarly to disrupt DNA binding patterns of proteins which regulate the activity of many genes, and moreover identifies specific regulatory proteins with key roles in cancer and Alzheimers. The study also performs the most comprehensive analysis of epigenetic drift at different spatial scales, demonstrating that epigenetic drift on the largest length scales is highly reminiscent of those seen in cancer. In summary, this work substantially supports the view that epigenetic drift may contribute to the age-associated increased risk of diseases like cancer and Alzheimers, by disrupting master regulators of genomewide gene activity.

CAMELID ANTIBODIES IN CANCER TARGETING
Friday, February 20, 2015
https://www.fightaging.org/archives/2015/02/camelid-antibodies-in-cancer-targeting.php

One approach to targeting cancer cells for destruction is to employ viruses as the kill mechanism, coupled with antibodies that can discern the type of cell to kill. The ideal outcome is that viruses infect only cancer cells, multiply inside them, destroy the cells and burst out to seek more victims, and then die out when there are no more cancer cells to target. There are, as always, challenges along the way to attaining this result, however:

Antibodies are proteins of the immune system that travel through the bloodstream and recognize potential threats to the body, whether bacteria, viruses or abnormal cells. Most antibodies have a characteristic Y shape. The tips of the Y form a "lock" that binds to a specific "key" carried by foreign bodies that the immune system should destroy. For decades, investigators have been putting human or mouse antibodies on viruses, and they haven't worked - the antibodies would lose their targeting ability. It was a technical problem. During replication, the virus is made in one part of the cell, and the antibody is made in another. To incorporate the two, the antibody is dragged through the internal fluid of the cell. This is a harsh environment for the antibodies, so they unfold and lose their targeting ability.

Now, scientists showed that unlike human antibodies or those of most other animals, the antibodies of camels and alpacas survive the harsh environment inside cells and retain the ability to seek out targets, potentially solving a longstanding problem in the field of gene therapy. The "lock" of camelid antibodies consists of the stem of the Y only, so it can't unfold in the harsh internal environment of the cell. The researchers used human cells grown in the lab for the study. They say it demonstrates the possibility of directly delivering genetically engineered viruses to specific cells. The goal is to infect only cancer cells and then trigger the virus to replicate until the cells burst, killing them and releasing more of the targeted viruses.

"We found that when we incorporated the camelid antibodies into the virus, they retained their binding specificity. This opens the door to targeting these antibodies to specific tumor markers. We want this new level of targeting specificity because it would allow us to inject the virus into the bloodstream, where it would exclusively infect and replicate in tumor cells, even if they are disseminated throughout the body. These viruses are already engineered to replicate only in tumors. These camelid antibodies would enable them to become even more tumor-specific and open the door for use in metastatic cancer."

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