Fight Aging! Newsletter, December 14th 2015

December 14th 2015

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

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

To subscribe or unsubscribe please visit:


  • Telomerase Therapy Proposed to Reverse Cellular Senescence
  • Scores of Labs Should be Gearing Up to Work on Glucosepane Cross-Link Breakers, But Are They?
  • Nature Medicine's December 2015 Focus on Aging Issue
  • Science Magazine on Aging and the Path Towards Treatments
  • Mitochondrial Dysfunction Demonstrated to Induce a Form of Cellular Senescence
  • Latest Headlines from Fight Aging!
    • Blood Plasma Protein Profile as a Biomarker of Aging
    • A Potentially Important Advance in the Control of Pain
    • A Popular Science Article on the Comparative Biology of Aging
    • DNA Damage in the Oldest Individuals
    • Confirming Data for the Agelessness of Hydra
    • An Approach to Reversing Liver Fibrosis
    • Red Blood Cells as Engineered Drug Manufactories
    • The Latest US Life Expectancy and Mortality Figures
    • Investigating the Aging of the Lymphatic System
    • Methylene Blue Rescues Progeria Cells, and Will Be Tested as a Potential Therapy for the Condition


There is a growing interest in the delivery of additional telomerase to tissues, usually via gene therapy, as a method to either partly reverse the progression of some specific symptoms of aging, or to slow the progression of aging in general. The open access research linked below is an example of the type, with the authors focused on measures relating to cellular senescence and atherosclerosis in the vascular system.

Delivery of telomerase to tissues is one of many potential approaches to generating increased stem cell activity. Everything from stem cell transplants through to exercise may produce at least some of its effects by either slowing or temporarily reversing the characteristic decline in a patient's stem cell activity with age. Stem cells are responsible for maintaining tissues, delivering a supply of new cells to replace those come to the end of their useful life spans. The loss of stem cell activity over the course of a lifetime, most likely regulated by epigenetic changes that are themselves a reaction to rising levels of cell and tissue damage, is thought to be an evolved balance between death by cancer (too much stem cell activity in age-damaged tissues) and death by organ failure (too little stem cell activity in age-damaged tissues). One of the most interesting developments in the growing scientific industry of stem cell manipulation is that treatments, experimental and clinical, have so far produced less cancer than feared at the outset. There may be a fair amount of wiggle room in the evolved balance to make things better via increased stem cell activity.

Stem cell activity isn't really the goal of the researchers here, however. They want to activate telomerase in all cells in the vascular system, not just stem cells, aiming to reduce the number that become senescent and suppress the harmful activities of those that are senescent. Senescent cells accumulate in tissues with age, and when present in greater numbers they cause significant harm, generating chronic inflammation, degrading tissue structure, and altering the behavior of surrounding cells for the worse as well. The goals of the researchers here are more akin to the goals of early efforts to produce treatments based on telomerase, building on its primary function of lengthening telomeres. Telomeres cap the ends of chromosomes and are a part of a counter mechanism that determines cell life span: each cell division results in the loss of a little telomere length, and when they become too short the cell self-destructs or becomes senescent. In human somatic cells, the vast majority of any tissue, there is no telomerase activity, and the counter only counts down. The stem cells supporting that tissue use telomerase to maintain their cell lines indefinitely, however, retaining the ability to deliver new cells with long telomeres to replace those that have reached the end of their replicative life span. Thus average telomere length in tissue is some function of how fast cells replicate and how fast new cells are delivered. This average seems to decline with aging, but is fairly dynamic on shorter timeframes, given transient illness and other changing circumstances.

This whole baroque system probably evolved due to the constraints imposed by cancer. Limiting unfettered replication to only a tiny proportion of cells must be in some way absolutely necessary to produce large, complex animals. Delivering telomerase to somatic cells obviously puts a large thumb on one side of the balance here, and this is where the concerns about cancer continue to appear pressing enough for caution. Still, we have telomerase gene therapy in mice producing extended healthy life spans and being used to treat heart attacks. It seems certain based on the evidence to date and the breadth of interest that this is going to be tried in human medicine by more than just the adventurous startups at the head of the pack.

For my part, this all looks like work that isn't quite aligned with the goals of damage repair after the SENS model. If it produces benefits over and above the present state of medicine, then great. But if we think that aging is caused by damage, then overriding either stem cell decline or the senescent state still needs to be coupled with repair of cell and tissue damage: mitochondrial DNA, amyloids, lipofusin, cross-links, and so forth. It is arguably the case that dealing with those forms of damage would in and of itself restore stem cell activity and reduce the development of cellular senescence, returning the tissue microenvironment to a more youthful appearance, and in doing so reduce or remove these reactions to damage. That, of course, remains to be tested. But as for senescent cells, it seems more effective to destroy them than to try to modulate their behavior.

Telomerase Therapy to Reverse Cardiovascular Senescence

Aging of the vascular system is considered a major contributor in the development of atherosclerotic lesions. The structural and functional integrity of the arterial wall progressively declines with aging, as manifested by endothelial and vascular smooth muscle cell dysfunction, reduced regenerative capacity, and a decline in circulating and tissue resident progenitor cells. Cellular aging and associated cellular dysfunction is caused by multiple factors, such as accumulation of DNA damage, misfolded proteins, and telomere attrition. In some cells, telomere length may be restored by activity of the enzyme telomerase reverse transcriptase (TERT) together with its RNA component (TERC). The ability of embryonic or induced pluripotent stem cells to replicate indefinitely is due to the expression by these cells of functional TERT and TERC. Notably, TERT and TERC are reactivated in about 90% of malignancies, accounting for their transformation into essentially immortalized cells. Accordingly, one potential therapeutic approach to treating some malignancies would be to antagonize the activity of telomerase in cancer stem cell. On the other hand, a transient restoration of telomerase activity to somatic cells could have therapeutic effects. Evidence suggests that inducing telomerase activity in somatic cells and thereby restoring telomere length may reverse cell senescence and restore a functional phenotype.

Cellular senescence of endothelial cells, vascular smooth muscle cells, tissue resident cells, and circulating progenitor cells plays an important role in the early stages of a developing vascular lesion that ultimately leads to an atherosclerotic plaque. Aged endothelial cells manifest increased expression of proinflammatory surface markers, a decrease in nitric oxide (NO) production, and a change of structural phenotype that compromises the barrier function of the endothelial monolayer of arterial vessel walls. Additionally, the decrease in circulating endothelial progenitors fails to compensate for micro-injuries of the arterial vessel wall, in turn exposing the subendothelial vessel structures to circulating factors that further promote lesion formation. Preclinical studies suggest that activation of telomerase can delay or even reverse the senescent phenotype of aged vascular cells.

With aging, phenotypic changes occur within endothelial cells as they switch to an activated state, expressing inflammatory surface markers such as VCAM-1 and ICAM-1 and secreting proinflammatory cytokines. The chronic activation of the immune system and leukocyte recruitment to the dysfunctional regions of endothelial cell layers further accelerates the aging process. Aging of the endothelium is accelerated at sites of disturbed flow such as the iliac artery bifurcation, where the telomeres of human endothelial cells are demonstrably shorter and analysis reveals an increased number of senescent endothelial cells. This accelerated aging at vascular bifurcations may be due in part to the hemodynamic activation of an inflammatory phenotype by low and oscillating shear stress at these sites. Thus, a pathologic cycle of inflammation and aging occurs at the very sites (bends, branches, and bifurcations) where the most severe atherosclerotic lesions typically occur.

This pathologic cycle could potentially be reversed by therapeutic extension of telomeres. Previously, we have shown that aged human aortic endothelial cells manifest many attributes of a senescent vasculature, including reduced ability to proliferate and respond normally to shear stress, to generate nitric oxide, and to resist adhesion of leukocytes. When we transfected these endothelial cells using a lentiviral vector to overexpress telomerase, these senescent properties were reversed. Telomerase transfected endothelial cells made more nitric oxide, manifested fewer adhesion molecules, were less adhesive for mononuclear cells, and had greater replicative capacity. Such changes would be expected to reduce the progression of atherosclerosis if vascular regeneration by telomere extension could be achieved in patients.


As we age skin and blood vessels lose their elasticity. People care too much about the skin and too little about the blood vessels, but that is always the way of it. Appearance first and substance later, if at all. Yet you can live inside an aged skin; beyond the raised risk of skin cancer its damaged state arguably only makes life less pleasant, and the present state of medical science can ensure that the numerous age-related dermatological dysfunctions can be kept to a state of minor inconvenience. Loss of blood vessel elasticity, on the other hand, will steadily destroy your health and then kill you. Arterial stiffening causes remodeling of the cardiovascular system and hypertension. The biological systems that regulate blood pressure become dysfunctional as blood vessels depart from ideal youthful behavior, creating a downward spiral of increasing blood pressure and reactions to that increase. Small blood vessels fail under the strain in ever larger numbers, damaging surrounding tissue. In the brain this damage contributes to age-related cognitive decline by creating countless tiny, unnoticed strokes. Ultimately this process leads to dementia. More important parts of the cardiovascular system are likely to fail first, however, perhaps causing a stroke, or a heart attack, or the slower decline of congestive heart failure.

From what is known today, it is reasonable to propose that the two main culprits driving loss of tissue elasticity are sugary cross-links generated as a byproduct of the normal operation of cellular metabolism and growing numbers of senescent cells. Elasticity is a property of the extracellular matrix, an intricate structure of collagens and other proteins created by cells. Different arrangements of these molecules produce very different structures, ranging from load-bearing tissues such as bone and cartilage to elastic tissues such as skin and blood vessel walls. Disrupting the arrangement and interaction of molecules in the extracellular matrix also disrupts its properties. Persistent cross-links achieve this by linking proteins together and restricting their normal range of motion. Senescent cells, on the other hand, secrete a range of proteins capable of breaking down or remodeling portions of the surrounding extracellular matrix, and altering the behavior of nearby cells for the worse.

The most important cross-linking compound in humans is glucosepane. Our biochemistry cannot break down glucosepane cross-links, and as a result it accounts for more than 99% of cross-links in our tissues. This isn't a big secret. Given this you might expect to find researchers working flat out in scores of laboratories to find a viable way to break it down. After all here we have one single target molecule, and any drug candidate capable of clearing even half of existing cross-links would provide a treatment that can both reverse skin aging and vascular aging to a much greater degree than any presently available therapy. The size of the resulting market is every human being, the potential for profit staggering. Yet search on PubMed, and this is all of relevance that you will see published on the topic in the past few years:

  • Preferential sites for intramolecular glucosepane cross-link formation in type I collagen: A thermodynamic study.
  • Glucosepane and oxidative markers in skin collagen correlate with intima media thickness and arterial stiffness in long-term type 1 diabetes.
  • Skin advanced glycation end products glucosepane and methylglyoxal hydroimidazolone are independently associated with long-term microvascular complication progression of type 1 diabetes.
  • Glucosepane: a poorly understood advanced glycation end product of growing importance for diabetes and its complications.
  • The association between skin collagen glucosepane and past progression of microvascular and neuropathic complications in type 1 diabetes.

This is a tiny output of work. The research and development world is not beating a path here as it should. The thesis is that this lack of enthusiasm exists because the state of tools and processes needed to work with glucosepane has long been somewhere between underdeveloped and nonexistent. No group will choose to work in an area in which they have to build the tools first when there are so many other choices available. This sort of chicken and egg situation exists in numerous places in every field of science and technology, small fields where a great deal might be achieved, but no-one does anything because the short-term rational choice is to do something else in an area where the tooling already exists. This is why we need advocacy and philanthropy, to fix problems of this nature. In recent years the SENS Research Foundation has been funding development of the tools needed for research groups to work with glucosepane in living tissues, and just this year we have seen the first published results: a simple, cheap, efficient method of creating as much glucosepane as needed for ongoing cell and tissue studies. There is now no roadblock standing in the way of any researcher wanting to run up batches of glucosepane, create small sections of engineered skin and blood vessel tissue, generate cross-links in that tissue, and then carry out assessments of drug candidates for clearing those cross-links.

The tools are a big deal, I think. Glucosepane clearance is a very narrow, very small pharmacological problem with a huge pot of gold on the other side. Pharmaceutical companies and established laboratories should be packed with staff running, not walking, to work on this. It is crazy that anyone has to be out there banging the drum to draw attention.


The Nature Medicine journal's December 2015 issue is focused on aging and the present mainstream view of the road ahead towards treatments. Sadly, to my eyes at least, the mainstream view is still very much focused on investigating the mechanisms that cause variations between individuals in the outcomes and pace of aging - the scientific impulse towards generating full understanding at work. Genetics are at the forefront of this investigation, alongside prosaic environmental factors such as diet and lifestyle choices. This is, of course, absolutely the proven, correct path for the scientific method, and in the very long term all knowledge is useful. The mapping of the molecular biology of all observed states of human metabolism should continue, and in a better world it and all other scientific investigation would have a hundred times the funding it does at present.

To think this approach is the sum of the possible misses a very important aspect of our situation today, however. We stand at a point at which the research community might, given the right choices in funding research and development, bypass the need for the full understanding of the progression of aging and eliminate that progression by repairing its causes. The causes of aging are forms of cell and tissue damage that are comparatively well understood; there is consensus, good mapping of the basics of the biochemistry involved, little in the way of new additions to the list in the past twenty years, and where there is bickering, it is over which of these things is more or less important than the others, or over the big unexplored gulf of interlinked chains of cause and effect that lies between these well-understood causes and the complex mess they create given decades of aging. So we should skip the mess and fund the research to fix them all; the fastest and cheapest way to figure out relevance is to repair the damage in mice and see what happens. Well planned research programs and proposed treatments exist for all of these forms of damage, at varying stages of progress and funding, with the aim of producing novel forms of regenerative medicine capable of rejuvenation, turning back aging by removing its root causes.

There isn't yet much enthusiasm for this path from the mainstream. These researchers are focused on genetic variance, obesity, diet, calorie restriction mimetics, and a hundred other similar things that can swallow billions and decades to produce only knowledge and marginal gains in health and life span. It is a great pity, but at least there are some signs of progress towards better approaches. The Alzheimer's research community is working on clearance of amyloid, which is a form of repair technology that is much needed. Senescent cell clearance has gained more attention over the past few years after technology demonstrations proving the point that removal of these cells - which are themselves a form of damage when they gather in numbers - produces significant benefits when tried. Selling the damage repair approach as a coherent philosophy of action for the treatment of aging is still an uphill battle despite these gains. The zeitgeist of today is longevity-related genes and expensive programs proposing to use drugs to make the metabolisms of some people more like those of some other people who have a marginally greater - but still tiny - chance of living to extreme old age in a state of frailty. Seems a waste when we could spend the same resources to implement SENS rejuvenation treatments with a good expectation of the ability to turn back aging as a result.

Aging: toward avoiding the inevitable

Although many would say that aging is a normal part of human biology, age is also the greatest risk factor for a wide variety of chronic disease. Whereas the passing of time cannot be stopped, a growing body of research in model organisms suggests that it may be possible to delay the concurrent decline in health. Preclinical data support a 'unifying aging hypothesis,' that a common pathway or pathways regulate the aging process and its associated disease indications. Examples of these pathways are covered in the two reviews in this issue on senescence, and metabolism, and in a perspective on proteostasis. However, a recurring theme is the heterogeneity of human aging. As noted in a recent report from the World Health Organization, we do not all age at the same rate with the same prevalence of age-related diseases. Understanding the genetic and/or environmental factors accounting for this heterogeneity, faithfully modeling them in preclinical studies and controlling for them in clinical studies are perhaps the biggest challenges facing the field.

With regard to understanding the genetic underpinnings of aging, inbred model organisms will take us only so far. Interrogating the diversity of the human genome and correlating it with aging phenotypes will be essential. Thanks in part to ever-improving next-generation sequencing technology, these efforts are well under way. In 2007 the Scripps Translational Science Institute launched the Wellderly Study, starting by sequencing a panel of candidate genes associated with aging in cohorts of people and working towards whole-genome coverage. The Longevity Genes Project, which was initiated at Albert Einstein College of Medicine in 2008, also aims to find genes associated with longevity by using a cohort of centenarians, their offspring, and age-matched individuals unrelated to these offspring. More recently, Human Longevity, Inc., a company founded by J. Craig Venter, declared that it is "building the world's most comprehensive database on human genotypes and phenotypes to tackle the diseases associated with aging-related human biological decline." These data sets, which are increasing in terms of their numbers of patients and coverage of the genome, will be invaluable to researchers seeking to unravel the genetic factors that influence human aging.

In terms of clinical studies of therapies aimed at extending healthspan, there are several the challenges unique to this field. But all indications suggest that therapies will be coming. They may be established agents repurposed for treating aging, such as the rapamycin analogs used by Novartis in a proof-of concept trial to boost immune function in the elderly. They might also be new agents dedicated to 'drugging' aging. In addition to profiling the genomic and phenotypic aspects of human aging, Human Longevity, Inc. is developing cell therapies aimed at regenerating human tissues. Calico - a company launched by Google - has partnered with the Buck Institute for Research on Aging and the Broad Institute of Massachusetts Institute of Technology to identify therapeutic targets, and with AbbVie to develop drugs to hit these targets. Even with candidate drugs in hand, testing them in clinical trials will require innovation and collaboration with regulatory agencies. The Targeting Aging with Metformin (TAME) study is paving the way toward having healthspan recognized as an indication by regulatory bodies. The challenges ahead in dissecting the factors that contribute to aging and age-related disease loom large. With technology, collaboration and innovation, the aging research community will overcome them.

But not by using calorie restriction mimetics or by mapping and mimicking the differences between people slightly more likely to live to 100 and people slightly less likely to live to 100. Aging is caused by damage, and that root cause damage is the same in everyone. Repair the damage - in the same way in everyone, using mass-produced therapies - and you don't have to care in the slightest about understanding the vast complexity and genetic diversity inherent in the way in which a heavily damaged human biology fails in one way or another. Trying to nurse along a failing machine in its heavily damaged state with the hope that it will fall apart a little later than it would otherwise have done is a fool's game: expensive, hard, and with little to show for it at the end. The meaningful approach is to instead repair the machine, replace its parts, remove the rust and damage and dysfunction. That is the right path to extending or restoring a functional, healthy life span.


To go along with Nature Medicine's latest focus issue on aging and the prospects for producing therapies to treat aging, I see that Science Magazine's December 4th special issue covers much the same topic. It is interesting to see this example of a convergence of discussion in respected publications, representative of a greater willingness by the scientific community to earnestly consider and plan a path towards the medical control of aging.

I used the occasion of the Nature Medicine issue to complain about the present mainstream research focus; when it comes to aging, the majority of scientists involved in the field undertake research programs that cannot possible produce meaningful results in terms of additional years of healthy life. Meanwhile approaches that can in principle produce real, actual rejuvenation in old people, and prevent aging in the young, are neglected in comparison. Today I'll instead focus on the more positive side of things, which is that the treatment of aging is now a serious, accepted, legitimate field of research within the broader scientific community. It took twenty years of persuasion and slow bootstrapping of research results to get to this point, but now here we are.

Ten or fifteen years ago for scientists to talk in public about extending healthy human life spans was to risk funding and career, which certainly stunted the pace of progress. There has been a sea change in the last few years as the results of advocacy flourished - things couldn't be more different now. Within the extended research community the important arguments today are over how aging should be treated, not whether or not it is plausible, useful, or desirable. The common sense position has finally won out among scientists: aging should be treated because it is the cause of age-related disease, and it is a given that we should work towards curing and preventing age-related disease because it is a source of suffering, pain, and death. If you think that suffering, pain, and death are bad things, then you should be all for working as hard as possible to end degenerative aging. It is the greatest single cause of suffering, pain, and death in the world by a very broad margin: more than 100,000 lives lost every day, and hundreds of millions of others in various states of pain, frailty, and disability.

Toward Healthy Aging, Putting Off the Inevitable

The dream of cheating death has evolved into a scientific quest to extend healthy life span. Scientists and doctors are looking for ways to maximize the number of years that we live free of chronic diseases, cancer, and cognitive decline. But before we can intervene, we have to understand the cellular and molecular mechanisms that drive aging and senescence. Some clues reside in our telomeres, the tips of our chromosomes that shrink with age. Others lie in our stem cells, which can only go on for so long repairing our tissues. Our mitochondria, too, the so-called powerhouses of the cell, may hold some answers to prolonging youthfulness. Other research points to changes in the gut microbiota associated with frailty in the aged. At a mechanistic level, the modulation of coenzyme NAD+ usage or production can prolong both health span and life span. Current geroscience initiatives aim to harness basic insights in aging research to promote general advances in healthy aging.

Questions remain throughout the aging field. By tweaking everything from genes to diets to environmental temperature and mating, scientists have created Methuselah flies and other remarkably long-lived animals while garnering fundamental insights into the biology of aging. Still, researchers puzzle over the most basic questions, such as what determines the life spans of animals. Meanwhile, a handful of molecular biologists are searching for ways to measure a person's biological, as opposed to chronological, age, but that quest, too, has proved elusive. An ever-growing literature addresses both theoretical and pragmatic approaches to the challenge of aging. In this special issue, we have focused mainly on the cellular aspects of mammalian aging, with the goal of spurring future developments in promoting health span, if not life span.

Death-defying experiments

The longest lived laboratory animals shed light on the forces that lead some to any early grave and others to beat the odds and see many more birthdays than the norm. Experiments with mice, flies, and worms have won that manipulating genes, restricting calorie intake, and giving animals drugs can extend life span - by as much as 10-fold. Researchers also have elucidated several biochemical pathways that lead to longevity. And one lab animal, the hydra, appears to have found a fountain of youth of sorts: Unless it sexually reproduces, it appears immortal.

Stem cells and healthy aging

Research into stem cells and aging aims to understand how stem cells maintain tissue health, what mechanisms ultimately lead to decline in stem cell function with age, and how the regenerative capacity of somatic stem cells can be enhanced to promote healthy aging. Here, we explore the effects of aging on stem cells in different tissues. Recent research has focused on the ways that genetic mutations, epigenetic changes, and the extrinsic environmental milieu influence stem cell functionality over time. We describe each of these three factors, the ways in which they interact, and how these interactions decrease stem cell health over time. We are optimistic that a better understanding of these changes will uncover potential strategies to enhance stem cell function and increase tissue resiliency into old age.

Healthy aging: The ultimate preventative medicine

Age is the greatest risk factor for nearly every major cause of mortality in developed nations. Despite this, most biomedical research focuses on individual disease processes without much consideration for the relationships between aging and disease. Recent discoveries in the field of geroscience, which aims to explain biological mechanisms of aging, have provided insights into molecular processes that underlie biological aging and, perhaps more importantly, potential interventions to delay aging and promote healthy longevity. Here we describe some of these advances, along with efforts to move geroscience from the bench to the clinic. We also propose that greater emphasis should be placed on research into basic aging processes, because interventions that slow aging will have a greater effect on quality of life compared with disease-specific approaches.


Researchers have discovered a new form of cellular senescence, created by engineering mitochondrial dysfunction in cell cultures and genetically altered mice. This is quite interesting in that both growing numbers of senescent cells and rising levels of mitochondrial damage are recognized as distinct contributions to degenerative aging, fundamental forms of tissue damage that occur as a side-effect of the normal operation of metabolism.

We shouldn't be at all surprised to find forms of aging-associate damage interacting with one another or spurring one another along. While there is an excellent catalog of fundamental damage, the enumerated differences between old tissue and young tissue, and there is a less comprehensive but still very good catalog of the ways in which we humans fall apart when we are old, linking these two catalogs together with detailed chains of cause and effect is a massive undertaking. The complex interactions that happen in between initial damage and final disease state are at present more a matter of blank space on the map than a matter of filled lines and connections. There are exceptions: the contribution of lipofusin accumulation to age-related retinal disease is fairly direct, for example. Most of the picture is far less clear, and looks like the situation for mitochondrial damage and cellular senescence, however: numerous conflicting sketches of what is thought to happen, chains of cause and consequence have many steps, and there is a lot of room for debate and discovery. The way in which aging progresses at the detail level is enormously complex, and a full understanding of aging in this sense would require a full understanding of the molecular biology of the cell in all of its states. This is a work in progress that researchers expect to remain in progress for decades yet.

What this means to many scientists is that those decades of work must take place before any real impact on the aging process can be produced. Full understanding before action is the mantra. There are other approaches, however: it would be much faster to start in on repairing forms of age-associated damage in laboratory animals and see what happens. That is a rapid path to both answers and the possibility of rejuvenation therapies, skipping over the expensive and time-consuming need to understand the huge blank spaces on the map. Getting to rejuvenation therapies more rapidly is the entire point of the SENS approach to aging, based on damage repair, and where SENS or SENS-like work has reached the stage of technology demonstrations in laboratory animals, as is the case for senescent cell clearance, it is pretty clear that meaningful health benefits are the outcome.

Returning to cellular senescence created by mitochondrial damage, the real question here is whether or not this exact situation is something that happens in the course of normal aging. It is very possible to create cell states in the laboratory that do not occur in a normal aged organism, or do occur but not to a significant degree. Fortunately for the knowledge-seekers among us this form of senescence is distinctive, so an answer to that question lies somewhere in the near future. That said, this is arguably one of the complexities buried in the progression of aging that can be skipped over on the way to human rejuvenation; if therapies are deployed to both repair mitochondrial damage and clear senescent cells, then does it matter how these two forms of damage build on one another? Not all that much. This is the power of the repair approach to treating aging. It side-steps an enormous amount of investigative work that would be required by other forms of research and development.

Signaling from dysfunctional mitochondria induces cellular senescence with a distinct secretory phenotype

Researchers need to stop thinking of cellular senescence, now accepted as an important driver of aging, as a single phenotype that stems from genotoxic stress. Research now reveals that cellular senescence, a process whereby cells permanently lose the ability to divide, is also induced by signaling from dysfunctional mitochondria - and that the arrested cells secrete a distinctly different "stew" of biologically active factors in a process unrelated to the damaging free radicals that are created in mitochondria as part of oxygen metabolism. "We don't yet know how much this process contributes to natural aging. But we do think the findings are important in addressing mitochondrial diseases, and those age-related diseases, such as some forms of Parkinson's, which involve mitochondrial dysfunction."

The discovery was unexpected and was made by eliminating sirtuins, a class of proteins long linked to longevity, one by one in human cell cultures. "The senescent phenotype only occurred when we eliminated the mitochondrial sirtuins." In addition, the senescent cells secreted a different SASP (senescence-associated secretory phenotype) than expected - one that lacks the IL-1-dependent inflammatory arm - a major factor in the more familiar form of SASP. The authors dubbed this new phenomenon MiDAS - mitochondrial dysfunction-associated senescence. "For any disease that has a mitochondrial component this research adds a potential explanation for the real driver of the dysfunction - and it's not free radicals, which we ruled out in our study. Our finding suggest a new role for mitochondria when it comes to affecting physiology."

Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype

Cellular senescence permanently arrests cell proliferation, often accompanied by a multi-faceted senescence-associated secretory phenotype (SASP). Loss of mitochondrial function can drive age-related declines in the function of many post-mitotic tissues, but little is known about how mitochondrial dysfunction affects mitotic tissues. We show here that several manipulations that compromise mitochondrial function in proliferating human cells induce a senescence growth arrest with a modified SASP that lacks the IL-1-dependent inflammatory arm. Cells that underwent mitochondrial dysfunction-associated senescence (MiDAS) had lower NAD+/NADH ratios, which caused both the growth arrest and prevented the IL-1-associated SASP through AMPK-mediated p53 activation. Progeroid mice that rapidly accrue mitochondrial DNA mutations accumulated senescent cells with a MiDAS SASP in vivo, which suppressed adipogenesis and stimulated keratinocyte differentiation in cell culture. Our data identify a distinct senescence response and provide a mechanism by which mitochondrial dysfunction can drive aging phenotypes.


Monday, December 7, 2015

I think you'll find this open access work on a potential biomarker of aging to be interesting; the researchers use it to assess the results of different lifestyle choices, finding that some of those known to shorten life expectancy produce a higher measure of biological age in their biomarker. This seems a small step closer to validating the usefulness of such biomarkers. A number of research groups are presently developing biomarkers of aging based on characteristic patterns of epigenetic modifications or altered protein levels. We should expect to find common patterns because the cell and tissue damage that causes aging, and the evolved reactions to that damage, are the same in everyone. The challenge lies in identifying these common patterns amidst the complex, varied alterations that occur due to individual circumstances and environment, but solid progress has being made in recent years.

Human ageing is associated with a number of changes in how the body and its organs function. On the molecular level, ageing is associated with numerous processes, such as telomere length reduction, changes in metabolic and gene-transcription profiles and an altered DNA-methylation pattern. In addition to chronological time, lifestyle factors such as smoking or stress can affect both the pattern of DNA-methylation and telomere length and thereby the aging of an individual. Ageing and lifestyle are the strongest known risk factors for many common non-communicable diseases, hence, various predictor models have been developed using measures of facial morphology, physical fitness and physiology, telomere length and methylation pattern to predict ones chronological age.

Comparisons of the actual chronological age with the predicted age, sometimes denoted the biological age, can be used as an indicator of health status, monitor the effect of lifestyle changes and even aid in the decision on treatment strategies. To date, no current models have explored the potential of using the plasma protein profile for age prediction. We have previously characterized abundance levels of 144 circulating plasma proteins and have found over 40% of investigated proteins to be significantly correlated with one or more of the following factors, age, weight, length and hip circumference. We therefore reasoned that the plasma protein profile might also be predictive of these traits. Here we demonstrate for the first time that the profile of circulating plasma proteins can be used to accurately predict chronological age, as well as anthropometrical measures such as height, weight and hip circumference. Moreover, we used the plasma protein-based model to identify lifestyle choices that accelerate or decelerate the predicted age.

Here we demonstrate by analysis of 77 plasma proteins in 976 individuals, that the abundance of circulating proteins accurately predicts chronological age, as well as anthropometrical measurements such as weight, height and hip circumference. The plasma protein profile described herein is highly accurate in predicting chronologic age. The plasma protein profile can also be used to identify lifestyle factors that accelerate and decelerate ageing. We found smoking, high BMI and consumption of sugar-sweetened beverages to increase the predicted chronological age by 2-6 years, while consumption of fatty fish, drinking moderate amounts of coffee and exercising reduced the predicted age by approximately the same amount.

Monday, December 7, 2015

Some rare few individuals do not feel pain, and are consequently a danger to themselves, often dying young. Unfortunately little headway has been made in manipulating the mechanisms thought to cause this condition, not just as a matter of treatment, but also as a way to create much safer and more sophisticated methods to temporarily switch off pain in the rest of us. Now, researchers have succeeded in reversing painlessness in an afflicted individual, better characterized the central mechanism of this condition, and this should directly result in a new methodology for efficient pain suppression. While this research is not directly relevant to aging, pain is an important consideration everywhere in medicine, especially in chronic disease, and this has the look of a profound step forward:

People born with a rare genetic mutation are unable to feel pain, but previous attempts to recreate this effect with drugs have had surprisingly little success. Using mice modified to carry the same mutation, researchers have now discovered the recipe for painlessness. 'Channels' that allow messages to pass along nerve cell membranes are vital for electrical signalling in the nervous system. In 2006, it was shown that sodium channel Nav1.7 is particularly important for signalling in pain pathways and people born with non-functioning Nav1.7 do not feel pain. Drugs that block Nav1.7 have since been developed but they had disappointingly weak effects.

The new study reveals that mice and people who lack Nav1.7 also produce higher than normal levels of natural opioid peptides. To examine if opioids were important for painlessness, the researchers gave naloxone, an opioid blocker, to mice lacking Nav1.7 and found that they became able to feel pain. They then gave naloxone to a 39-year-old woman with the rare mutation and she felt pain for the first time in her life. "After a decade of rather disappointing drug trials, we now have confirmation that Nav1.7 really is a key element in human pain. The secret ingredient turned out to be good old-fashioned opioid peptides, and we have now filed a patent for combining low dose opioids with Nav1.7 blockers. This should replicate the painlessness experienced by people with rare mutations, and we have already successfully tested this approach in unmodified mice."

Broad-spectrum sodium channel blockers are used as local anaesthetics, but they are not suitable for long-term pain management as they cause complete numbness and can have serious side-effects over time. By contrast, people born without working Nav1.7 still feel non-painful touch normally and the only known side-effect is the inability to smell. Opioid painkillers such as morphine are highly effective at reducing pain, but long-term use can lead to dependence and tolerance. As the body becomes used to the drug it becomes less effective so higher doses are needed for the same effect, side effects become more severe, and eventually it stops working altogether. "Used in combination with Nav1.7 blockers, the dose of opioid needed to prevent pain is very low. People with non-functioning Nav1.7 produce low levels of opioids throughout their lives without developing tolerance or experiencing unpleasant side-effects. We hope to see our approach tested in human trials by 2017 and we can then start looking into drug combinations to help the millions of chronic pain patients around the world."

Tuesday, December 8, 2015

Many researchers are involved in the study of aging in different species with varied life spans, with the aim of identifying important factors in the molecular biology of aging. What drives these differences in life span? Researchers are interested in finding answers from both the evolutionary and cell biology perspectives. This article focuses on the relationships between species life span, predation, and size:

Aristotle's observation that bigger animals tend to live longer has lasted. Indeed, it's the only trend today's scientists agree on. "All of the other hypotheses have fallen apart," says Steven Austad, a biogerontologist at the University of Alabama, Birmingham. One of the most popular ideas of the past 100 years has been that animals with higher metabolic rates live shorter lives because they run out their body clock faster. But "it hasn't held up," Austad says. Parrot hearts can beat up to 600 times per minute, for example, but they outlive by decades many creatures with slower tickers. Other assumptions, for example that short-lived animals generate more tissue-damaging free radicals or have cells that stop dividing sooner, also lack strong evidence. "A lot of simple stories have vanished."

By the mid-1980s, Austad was observing opossum behavior in Venezuela as a postdoc when he began to notice how quickly the marsupials aged. "They'd go from being in great shape to having cataracts and muscle wasting in 3 months." Austad also noticed something even more intriguing: Opossums on a nearby island free from predators seemed to age slower - and live longer - than their mainland counterparts. The observation helped explain why Aristotle's key insight continues to hold true. Large animals tend to live longer, says Austad, because they face fewer dangers. It's not a simple question of survival, he says, but rather the result of millions of years of evolutionary pressure. Whales and elephants can afford to take their time growing because no one is going to attack them, he explains. And that means they can invest resources in robust bodies that will allow them to sire many rounds of offspring. Mice and other heavily preyed-on small animals, on the other hand, live life in fast-forward: They need to put their energy into growing and reproducing quickly, not into developing hardy immune systems.

When it comes to our pets, the bigger-is-better theory gets flipped on its ear. Cats live an average of 15 years, compared with about 12 years for dogs, despite generally being smaller. And small dogs can live twice as long as large ones. Yet the lesson of Austad's opossums may still apply. Gray wolves, the ancestors of dogs, live a maximum of 11 or 12 years in the wild, whereas wildcats can live up to 16 years. This suggests that the two species face different evolutionary pressures, Austad says. Wolves are more social than cats and thus more likely to spread infectious disease, he says; wildcats, on the other hand, keep to themselves, reducing the spread of disease, and are adept at defending against predators. "Cats are so incredibly well-armed, they're like porcupines" - an animal that notably also has a long life span for its size, more than 20 years. Indeed, two other small animals that are good at avoiding danger, naked mole rats and bats, can live 30 and 40 years, respectively. (Mole rats spend most of their time underground, whereas bats can simply fly away.)

Despite the differences between cats and dogs, both pets are living longer than ever before. Dog life expectancy has doubled in the past 4 decades, and housecats now live twice as long as their feral counterparts. The reasons can largely be chalked up to better health care and better diet. Americans will spend 60 billion on their pets this year, with a large chunk of that going to humanlike health care (think annual physicals and open-heart surgery) and premium food. "The same things that allow us to live longer also apply to our pets."

Tuesday, December 8, 2015

This paper notes that long-lived humans show lower levels of nuclear DNA damage and better preservation of mechanisms that repair and prevent that damage - which is as one would expect given that interventions that slow aging in laboratory species tend to produce much the same comparative outcomes in DNA integrity over a life span. Damage to nuclear DNA occurs constantly, but is repaired very efficiently. Nonetheless, mutational damage accumulates randomly in an individual's cells, a change here, a change there. The level of this damage correlates with age, and is lowered in individuals of the same chronological age as a result of interventions that slow aging, such as calorie restriction. Rising levels of nuclear DNA damage are definitely a cause of the increased cancer risk in aging, but it is the general consensus in the research community that, going beyond cancer, this damage also contributes to degenerative aging in other ways, such as by producing increasing disarray in cellular activities. This consensus doesn't have the robust demonstrations in animal studies needed to back it up at the present time, however, and has been challenged. It is difficult to split apart this aspect of aging from all others in a living organism so as to produce a study in which just the effects of DNA damage can be isolated.

Reductions in DNA integrity, genome stability, and telomere length are strongly associated with the aging process, age-related diseases, and the age-related loss of muscle mass. However, in people reaching an age far beyond their statistical life expectancy the prevalence of diseases, such as cancer, cardiovascular disease, diabetes or dementia, is much lower compared to "averagely" aged humans. These inverse observations in nonagenarians (90-99 years), centenarians (100-109 years) and super-centenarians (110 years and older) require a closer look into dynamics underlying DNA damage within the oldest old of our society.

Available data indicate improved DNA repair and antioxidant defense mechanisms in "super old" humans, which are comparable with much younger cohorts. Partly as a result of these enhanced endogenous repair and protective mechanisms, the oldest old humans appear to cope better with risk factors for DNA damage over their lifetime compared to subjects whose lifespan coincides with the statistical life expectancy. This model is supported by study results demonstrating superior chromosomal stability, telomere dynamics and DNA integrity in "successful agers". There is also compelling evidence suggesting that life-style related factors including regular physical activity, a well-balanced diet and minimized psycho-social stress can reduce DNA damage and improve chromosomal stability. The most conclusive picture that emerges from reviewing the literature is that reaching "super old" age appears to be primarily determined by hereditary/genetic factors, while a healthy lifestyle additionally contributes to achieving the individual maximum lifespan in humans.

More research is required in this rapidly growing population of super old people. In particular, there is need for more comprehensive investigations including short- and long-term lifestyle interventions as well as investigations focusing on the mechanisms causing DNA damage, mutations, and telomere shortening.

Wednesday, December 9, 2015

It has long been suspected that hydra, small freshwater animals, are immortal in that they do not suffer degenerative aging. In practice this means that no changes in mortality rate, reproduction rate, and measures of cellular metabolism are observed over time. This is a highly regenerative species, with individuals capable of rebuilding themselves from fragments, and it may be the case that their constant regeneration is the source of their agelessness. Regarding that agelessness, the challenge for researchers is that verifying the lack of aging in a species is a slow statistical business of wait and see, and one can always suspect at the end of any given study that the authors did not check rigorously enough for signs of aging. Perhaps it is there, just too slow to show up over the time allotted. Certainly there has been some back and forth debate over the last twenty years regarding what the data does or does not support. This latest research provides a set of much more robust evidence in support of hydra agelessness:

The common perception that the bodies of all living beings age, is wrong. This has now been proved by a long-term experiment with the freshwater polyp Hydra, a microscopic animal. Observing many hundreds of them for almost ten years, they calculated that Hydra's mortality permanently stays constant and extremely low. For most species, including humans, the probability of dying within a specific year rises with age. Scientists regard this as an indicator of the decay of the aging body. For Hydra, evolution seems to have found a way to escape the mechanisms of the physical deterioration of getting older. For humans the probability of dying within one year is reaching levels as high as 50 percent for advanced ages. For Hydra, however, it remains constant at a low 0.6 percent. Humans only experience such small values when they are between 20 and 30 years old. Additionally, Hydra's reproduction rate did not diminish with age, instead the small animals continued to breed. In this sense the Hydra stayed forever young.

In a unique long-term experiment researchers created artificial conditions for the tiny water animals with their flimsy tentacles, which were free of fatal natural threats like predators. For almost ten years they have cared for of about 1,800 of the Hydras. Overall, the team has counted 3.9 million observation days of individual Hydra. The number of natural deaths per year, however, can be counted on one hand. On average there have been only five. When a Hydra passed away it was mostly due to laboratory accidents, such as a polyp sticking to the lid of its bowl and then drying up or simply having been dropped on the floor. From of the few natural deaths that remained researchers calculated Hydra's mortality. It is so low that even several lifetimes of researchers would not suffice to observe the end of the lifecycle of the polyps. Even after 500 years five percent of a cohort will still be alive. For two out of twelve of the Hydra cohorts under investigation, the risk of death was actually so small, that it will take 3,000 years until only five percent of the polyps remained.

"Hydra apparently manages to keep its body young because it does not senesce by accumulating damages and mutations, as most other living beings do. Hydra are probably able to follow a special self-preservation strategy, as its body and cellular processes are rather simple." For instance, Hydra are capable of completely replacing parts of the body that are damaged or are somehow lost. It can even fully regenerate if its body is destroyed almost completely thanks to a high number of stem cells. Stem cells are capable of developing into any part of the body at any time. Additionally, as Hydra replaces all of their cells within only four weeks, it regularly and quickly expels all cells that have been changed genetically by mutations. Thus, damages have little chance to accumulate.

Wednesday, December 9, 2015

This is one example of a number of lines of research aimed at interfering in the process of fibrosis, the generation of harmful scar tissue that can cause severe dysfunction in organs once underway:

Chronic damage to the liver eventually creates a wound that never heals. This condition, called fibrosis, gradually replaces normal liver cells - which detoxify the food and liquid we consume - with more and more scar tissue until the organ no longer works. Scientists have identified a drug that halts this unchecked accumulation of scar tissue in the liver. The small molecule, called JQ1, prevented as well as reversed fibrosis in animals and could help the millions of people worldwide affected by liver fibrosis and cirrhosis. "After too much damage in the liver, the scar tissue itself causes more scar tissue. We can actually reverse liver fibrosis in animals and are now exploring potential therapeutic applications for humans."

When the liver is damaged, small collections of hepatic stellate cells that specialize in storing vitamin A are called upon to tend to the wound. These activated stellate cells shed their vitamin A, travel to the site of injury and create thick, fibrous scar tissue to wall off and repair the damage. However, with prolonged organ stress, healthy liver cells become replaced by scar tissue, eventually leading to organ failure. "Traditional therapies targeting inflammation don't work because these cells have multiple ways to bypass the drug. In contrast, our strategy was to stop the fibrotic response at the genome level where these pathways converge."

The search for the critical genome pathway struck gold, uncovering a regulatory protein, called BRD4, that is a master regulator of liver fibrosis. With this new knowledge in hand, the team found JQ1 successfully inhibited BRD4 and halted the transformation of hepatic stellate cells into fiber-producing cells. This is good news, as JQ1 is a prototype of a new class of drugs currently being tested in human clinical trials for various cancers. "JQ1 doesn't just protect against the wound response, but also reverses the fibrotic response in mice. Our results indicate that BRD4 is a driver of chronic fibrosis and a promising therapeutic target for treating liver disease. We think this discovery may also treat fibrosis in other organs, like the lung, pancreas and kidney."

Thursday, December 10, 2015

Researchers are working on the use of red blood cells engineered to act as drug manufactories, a way to deliver sustained doses of a therapy to patients while circumventing some of the challenges inherent in other delivery methods:

The new technology draws on recent advances in the ability to genetically modify and grow human red blood cells from stem cells in culture. Using established molecular biology techniques, scientists can engineer progenitor cells taken from human bone marrow and grow blood cells that produce specific therapeutic proteins on their surface or inside the cell. Before they become fully mature, mammalian red blood cells eject their genetic material, so as a therapy they are easier to control and less risky than other stem cell and gene therapies, which can lead to abnormal cell growth and tumors. Human red blood cells circulate for as long as four months, meaning they could potentially form the basis of long-term therapies. The cells can get anywhere in the body through the bloodstream and can protect the therapeutic agent from the immune system.

The first drug will be for phenylketonuria, or PKU, a devastating genetic disorder that renders people with the disease unable to digest the amino acid phenylalanine, which is found in most high-protein foods. Researchers have so far tested the PKU drug in animals and in human blood in the lab, and it aims to begin clinical testing next year. Researchers have identified enzymes that can break down phenylalanine, "but you can't just inject an enzyme into the bloodstream," because the body will clear it quickly, and it could induce an immune reaction that would render future treatments with the same enzyme useless. Engineering red blood cells to produce the desired enzyme "answers both problems."

Animal tests suggest that engineered red blood cells can be a "very potent" therapy for a range of diseases. Not-yet-published work has shown that cells modified to produce an antibody to a specific bacterial toxin render mice resistant to many times the lethal dose of that toxin. It takes only a few weeks to grow cells that produce a new protein of interest, and the potential for new drugs based on red blood cells is "only limited by your imagination."

Thursday, December 10, 2015

The mortality data for 2014 was recently published by the CDC. The popular press has been making a big deal of the fact that the statistical measure of life expectancy at birth has remained much the same these past few years. This is something that epidemiologist S. Jay Olshansky has suggested might happen as a result of the consequences of greater obesity temporarily outweighing progress in medicine, but a few years is too short a period of time to confirm any departure from the long slow upward trend in life expectancy established over past decades. Meanwhile we should bear in mind that present trends are the outcome of a period of development in which researchers were making no efforts to treat the causes of aging; gains in life expectancy were incidental. That is now changing, and future trends will reflect a research community increasingly involved in building therapies that target the mechanisms of aging. The past will not reflect the future, and this is a time of transition.

This report presents 2014 U.S. final mortality data on deaths and death rates by demographic and medical characteristics. These data provide information on mortality patterns among U.S. residents by such variables as sex, race and ethnicity, and cause of death. Information on mortality patterns is key to understanding changes in the health and well-being of the U.S. population. Life expectancy estimates, age-adjusted death rates by race and ethnicity and sex, the 10 leading causes of death, and the 10 leading causes of infant death were analyzed by comparing 2014 final data with 2013 final data.

Life expectancy at birth represents the average number of years that a group of infants would live if the group was to experience, throughout life, the age-specific death rates present in the year of birth. In 2014, life expectancy at birth was 78.8 years for the total U.S. population - 81.2 years for females and 76.4 years for males, the same as in 2013. Life expectancy for females was consistently higher than life expectancy for males. In 2014, the difference in life expectancy between females and males was 4.8 years, the same as in 2013. Life expectancy at age 65 for the total population was 19.3 years, the same as in 2013. Life expectancy at age 65 was 20.5 years for females, unchanged from 2013, and 18.0 years for males, a 0.1-year increase from 2013. The difference in life expectancy at age 65 between females and males decreased 0.1 year, to 2.5 years in 2014 from 2.6 years in 2013.

In 2014, the 10 leading causes of death - heart disease, cancer, chronic lower respiratory diseases, unintentional injuries, stroke, Alzheimer's disease, diabetes, influenza and pneumonia, kidney disease, and suicide - remained the same as in 2013. The 10 leading causes accounted for 73.8% of all deaths in the United States in 2014. From 2013 to 2014, age-adjusted death rates significantly decreased for 5 of the 10 leading causes of death and significantly increased for 4 leading causes. The rate decreased by 1.6% for heart disease, 1.2% for cancer, 3.8% for chronic lower respiratory diseases, 1.4% for diabetes, and 5.0% for influenza and pneumonia. The rate increased by 2.8% for unintentional injuries, 0.8% for stroke, 8.1% for Alzheimer's disease, and 3.2% for suicide. The rate for kidney disease in 2014 remained the same as in 2013.

Friday, December 11, 2015

This open access paper describes detrimental age-related changes in the lymphatic system that involve disruption of the extracellular matrix and inflammation-associated biochemistry, something that suggests the involvement of senescent cells. Like old blood vessels, lymph vessels become leaky and less capable with age:

The lymphatic system comprises blunt-ended lymphatic capillaries, collecting lymphatic vessels, lymph nodes, and the thoracic duct. The role of lymphatic vessels is to transport fluid, soluble molecules, and immune cells to the draining lymph nodes. Here, we analyze how the aging process affects the functionality of the lymphatic collectors and the dynamics of lymph flow. Our ultrastructural and proteomic analysis indicated a loss of the basal membrane and the extracellular matrix supporting the lymphatic endothelial cells as well as the proteins related to GAP junction formation. Functionally, the aged lymphatic vessels were impaired in their ability to actively support lymph flow. Significant reduction in pumping indices, including amplitude, frequency, and fractional pump flow, were observed. Under resting conditions these changes can generate low level of tissue edema, particularly when associated with increased vessel permeability as also observed in this study. However, in pathological conditions, such as acute and chronic inflammation, the increased volumetric loads imposed on the lymphatic collectors could further enhance their impaired ability to support the lymph flow.

A reduced thickness in the glycocalyx, with increased protein glycation and oxidation, was also observed. These modifications help explain the increased permeability observed in the aged collectors. Functionally, these modifications translate into apparent hyperpermeability of the lymphatics with pathogen escaping from the collectors into the surrounding tissue and a decreased ability to control tissue fluid homeostasis. Microvascular dysfunction with hyperpermeability was also previously observed in aged blood vessels and was attributed to oxidative stress, inflammation, and activation of apoptotic signaling. Likely, the same mechanism contributes to the hyperpermeability observed in the aged lymphatic collectors. Indeed, analysis confirmed the presence of posttranslational modifications associated with oxidative stress. These modifications can alter proteins half-life, increase protein degradation, and decrease cellular functionality. Indeed, several of the collagen proteins as well as cadherins and GAP junction proteins were decreased in aging collectors. Disruption of these proteins was previously observed to be associated with paracellular permeability in blood capillaries. Similarly, we observed endothelial cells barrier dysfunction and increased permeability in aged lymphatic collectors. Functionally, the ability of pathogens to more readily escape the aged lymphatic collectors would contribute to the decreased ability of the immune system to control infections in aging. Indeed, decreased lymph transport to the lymph nodes is associated with an increase in the number of tissue colony-forming units.

Friday, December 11, 2015

In recent news, researchers have found methylene blue to be a promising drug candidate for the treatment of progeria. This is one of the oldest of modern synthetic medical compounds, as it is getting on for 140 years since it was first created by chemists. Nearly a decade ago it was shown to delay cellular senescence and enhance mitochondrial activity in cell cultures. The results for progeria to date look very good in much the same sort of cell studies, but the important qualifying next stage of animal studies has yet to happen.

Progeria is often called an accelerated aging condition. It is not accelerated aging, however, but a form of genetic damage to lamin-A, a protein central to the correct operation of cells. This global dysfunction results in degenerative conditions that have many similarities to those of the later stages of aging, and which are fatal over the course of ten to twenty years. Few patients live past their teens. It is thought that the same damage as runs rampant in progeria is present to a much lesser degree in normal aging, though it is an open question as to whether there is enough of it to have any meaningful impact in comparison to the contribution of other forms of cell and tissue damage. Still, this small shared commonality is why it is worth paying attention to progress towards therapies for progeria, as you'll sometimes see results like these:

Research suggests that a common, inexpensive and safe chemical called methylene blue could be used to treat progeria - and possibly the symptoms of normal aging as well. A new study shows for the first time that small doses of methylene blue can almost completely repair defects in cells afflicted with progeria, and can also repair age-related damage to healthy cells. "We tried very hard to examine the effect of methylene blue on all known progeria symptoms within the cell. It seems that methylene blue rescues every affected structure within the cell. When we looked at the treated cells, it was hard to tell that they were progeria cells at all. It's like magic."

Progeria results from a defect in a single gene. This gene produces a protein called lamin A, which sits just inside the cell's nucleus, under the nuclear membrane. Healthy cells snip off a small piece of each new lamin A molecule - a small edit that is necessary for lamin A to work properly. Cells with progeria, however, skip this important editing step. The defective lamin A interferes with the nuclear membrane, causing the nucleus to form bulges and deformations that make normal functioning impossible. Cells with progeria also have misshapen and defective mitochondria, which are the small organelles that produce energy for the cell. Although previous studies suggested damage to mitochondria in progeria cells, the current study is the first to document the nature and extent of this damage in detail. A majority of the mitochondria in progeria cells become swollen and fragmented, making it impossible for the defective mitochondria to function.

The team found that methylene blue reverses the damages to both the nucleus and mitochondria in progeria cells remarkably well. The precise mechanism is still unclear, but treating the cells with the chemical effectively improved every defect, causing progeria cells to be almost indistinguishable from normal cells. The researchers also tested methylene blue in healthy cells allowed to age normally. The normal aging process degrades mitochondria over time, causing these older mitochondria to resemble the mitochondria seen in progeria cells. Once again, methylene blue repaired these damages. "So far, we have done all of our work in stem cell lines. It is critical to see whether the effect extends to whole animals. We also want to see if methylene blue can repair specific effects of progeria in various cell types, such as bone, skin, cardiovascular cells and others. Further down the line, other groups might begin human clinical trials. It's very exciting."


Post a comment; thoughtful, considered opinions are valued. New comments can be edited for a few minutes following submission. 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.