Fight Aging! Newsletter, June 25th 2018

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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  • Newfound Enthusiasm in Mining Senescent Cells for Mechanisms Relevant to Therapy
  • Exercise versus the Hallmarks of Aging
  • Forever Healthy Foundation is Hiring to Build a Longevity Strategy Guide
  • A Failure of the Imagination when it comes to Human Longevity
  • CD36 as a Potentially Important Marker and Mechanism in Cellular Senescence
  • The World Health Organization Must Consider Rejuvenation Research
  • Investigating the Direction of Causation in Frailty and Cardiovascular Disease
  • Exosome Signaling in Vascular Calcification
  • Cellular Senescence in Aging versus Chronic Obstructive Pulmonary Disease
  • Why Would Pancreatic Cell Size Correlate Well with Mammalian Species Longevity?
  • You Can't Fight Ageism by Pretending that Aging isn't Harmful
  • TXNIP as a Target to Protect Against Oxidative Stress and Slightly Slow Aging
  • Uncovering Genes that Might be Sabotaged to Block Metastasis
  • Neuromelanin Organelles, a Garbage Dump of Last Resort in Aging Brain Cells
  • An Approach to Interfering in Mitochondrially Mediated Cell Death due to Amyloid-β in Alzheimer's Disease

Newfound Enthusiasm in Mining Senescent Cells for Mechanisms Relevant to Therapy

Cellular senescence is one of the root causes of aging. Nonetheless, the study of cellular senescence used to be a comparative backwater in aging research, and as a topic it was mostly of interest to cancer researchers seeking ways to better shut down the replication of cancerous cells. But there is nothing quite like having a company raise 300 million in venture funding for rejuvenation therapies based on manipulation and destruction of senescent cells to bring a little excitement to this part of fundamental aging research. Who knows how many useful, exploitable mechanisms are yet to be found in senescent cells and the signals they generate? Each one is a potential lottery ticket for the discovering institution and research group.

This was in fact always the case, and for decades a compelling set of evidence has strongly suggested that the accumulation of senescent cells is a significant contribution to aging. Yet next to no-one was funding or working on it seriously until the high-profile proof of concept study in mice reported in 2011, in which senescent cells were eliminated and health and life span improved as a consequence. After that point, the avalanche started, leading to today's crop of first generation senolytic therapies capable of selectively destroying a fraction of the senescent cells present in older individuals.

Today I thought I'd point out a couple of examples of the sort of paper that results from an influx of funding and interest to the study of the fundamental biochemistry of senescent cells. The research community is mining for gold. The first explores the harmful signals secreted by senescent cells, the major way in which they cause tissue dysfunction in aging and age-related disease. A faction within the research community is more comfortable interfering in these signals rather than destroying senescent cells, despite it likely being a far worse and more challenging approach to therapy. The second paper is one of many in which researchers explore the role of mitochondrial activity in senescence, in search of approaches that might modulate the activity in beneficial ways. Both papers are quite different in focus, but they emerge from the same newfound interest in senescence as a cause of aging.

Small extracellular vesicles and their miRNA cargo are anti-apoptotic members of the senescence-associated secretory phenotype

Senescent cells lose their cell type specific functionality and replicative potential required for tissue regeneration and acquire a senescence-associated secretory phenotype (SASP). The SASP is characterized by the secretion of growth factors, pro-inflammatory cytokines and chemokines, as well as extracellular matrix (ECM) remodeling enzymes. These SASP factors are considered to over-proportionally exert negative effects on tissue homeostasis and regeneration in vivo if chronically present by acting in a paracrine manner on the neighboring cells and ECM. Attenuation of the negative effects of the SASP have been shown to restore the formation of functional human skin equivalents and has been suggested as a putative target in preventing age-associated diseases and frailty.

Recently, extracellular vesicles (EVs) and their cargo have been reported to act in a similar manner as hormones or cytokines during intercellular communication. They are secreted by many, if not all cells, and by encapsulation of their cargo, they transport proteins, mRNAs, lipids, and non-coding RNAs, specifically miRNAs, over short or long distances. Thus, although many protein based SASP factors have been identified, miRNAs and EVs are under suspicion to be part of the SASP. However, a systematic catalogue of SASP-miRNAs has not yet been established and their selective secretion during senescence has not been studied so far. Here, we confirm that EVs and their miRNA cargo are indeed part of the SASP (EV-SASP) and identified a set of selectively retained and secreted miRNAs after the onset of senescence. In addition, senescent cell derived EVs might contribute to an anti-apoptotic environment in tissues where senescent cells have accumulated.

Mitochondrial peptides modulate mitochondrial function during cellular senescence

Mitochondria play important roles in cellular energy production, metabolism, and cellular signaling. These organelles have their own genomes, the mitochondrial DNA (mtDNA). Epigenetic modification of mitochondrial DNA, including DNA methylation, is still controversial. The overall mitochondrial DNA methylation occurs at a lower frequency compared to nuclear DNA, but specific locations have been found to be differentially methylated in certain cellular conditions or in different biological samples.

Humanin is a 24-amino acid peptide encoded within the mtDNA. It is secreted in response to cellular stress and has broad cytoprotective and neuroprotective effects. MOTS-c is a 16-amino acid peptide encoded within the mtDNA that improves metabolic functions. Among the basic processes that are known to drive aging phenotypes and pathology are genomic instability, epigenetic alterations, mitochondrial dysfunction, and cellular senescence. Although humanin and MOTS-c have protective roles in multiple age-associated diseases, the roles of these peptides in cellular senescence have not been explored.

Senescent cells are metabolically active, producing energy-consuming effectors of senescence, despite the loss of proliferative activity. Depending on the inducer, senescent cells show higher levels of glycolysis, fatty acid oxidation, and mitochondrial respiration. Manipulating bioenergetic status can induce senescence and a SASP, suggesting that bioenergetics play a role in the senescence phenotype. Thus, altering the metabolic status of senescence cells may be an important strategy for eliminating the deleterious effects of senescence. In this study, we investigate mitochondrial energetics and mtDNA methylation in senescent cells, and evaluate the potential of humanin and MOTS-c as novel senolytics or SASP modulators that can alleviate symptoms of frailty and extend health span by targeting mitochondrial bioenergetics.

Exercise versus the Hallmarks of Aging

The paper I'll point out today walks through the ways in which exercise is known to beneficially affect the Hallmarks of Aging. The Hallmarks are a list of the significant causes of aging that I disagree with about half of. The SENS catalog of root causes of aging, first published earnestly in the literature back in 2002, isn't cited anywhere near as much as the much later Hallmarks of Aging - which owes a great deal to its predecessor while failing to mention it in any way. There is some overlap between the two, but many of the Hallmarks are not causes of aging, but rather manifestations of aging, meaning secondary and later consequences of underlying molecular damage.

This question of whether not any specific manifestation of aging is or is not a root cause is important. The strategy adopted in the development of therapies to treat aging matters. Addressing root causes is far more effective than addressing downstream consequences. Near all medical technology employed to date to treat age-related diseases fails to touch on the root causes of aging, however, and this is why these therapies are only marginally effective at best. They modestly slow progression, or modestly ease suffering, but they cannot meaningfully turn back any aspect of the progression of aging. We can continue along that road, or we can choose to attempt a better strategy.

Exercise is beneficial, and the degree to which it is beneficial is fairly well defined. Knowing something about the molecular biology taking place under the hood won't make exercising any more or less beneficial, but it is an interesting topic. Exercise, like calorie restriction, modestly slows the impact of aging. Unlike calorie restriction it doesn't have a large impact on maximum life span in mice, but does raise the average life span. Both are just as reliable and just as cheap - even small effects are worth the effort when they cost little and are guaranteed. It is when we start to talk about the cost of research and development for new medical technologies to treat aging that we must think about the expected size of the outcome on human longevity. Why chase small, expensive gains? If the cost is significant, it only makes sense to pursue a strategy that can produce sizable gains in health and life span.

Aging Hallmarks: The Benefits of Physical Exercise

Traditionally, aging was not seen as an adaptation or genetically programmed phenomenon. More recently, biologic currents point to two main theories: the programmed aging and the damage or error-based theories. The first suggests an intrinsic biologic programmed deterioration of the structural and functional capacity of the human cells. The latter highlights the cumulative damage to living organisms leading to intrinsic aging. Nonetheless, a combination of these theories is usually preferred. In this sense, a state-of-the-art review, proposed nine cellular and molecular hallmarks that contribute to the process of aging, including (1) genomic instability, (2) telomere attrition, (3) epigenetic alterations, (4) loss of proteostasis, (5) deregulated nutrient sensing, (6) mitochondrial dysfunction, (7) cellular senescence, (8) stem cell exhaustion, and (9) altered intercellular communication. These hallmarks should be expressed during normal aging, with their experimental aggravation speeding up the aging process, and in contrast, their experimental amelioration retards the normal aging process, thus increasing a healthy life span.

Along with the nine cellular and molecular hallmarks stated above, aging is known to be correlated with several cardiovascular, cardiorespiratory, musculoskeletal, metabolic, and cognitive impairments. In this sense, regular physical activity in the older population - especially aerobic and resistance training - plays an important role at a multisystem level, preventing severe muscle atrophy, maintaining cardiorespiratory fitness and cognitive function, boosting metabolic activity, and improving or maintaining functional independence. In addition, physical exercise has a positive antiaging impact at the cellular level, and its specific role in each aging hallmark is described below.

Genomic Instability

In the face of genomic instability, the organism has developed a panoply of DNA repair mechanisms that skirmish altogether to overcome nuclear DNA damage. Exercise plays a role in maintaining genomic stability. In rodent models, aerobic exercise improves DNA repair mechanisms. It augments DNA repair and decreases the number of DNA adducts (up to 77%), related to aging and several risk factors for cardiovascular diseases. In addition, a six-month resistance training program in an institutionalized elderly population showed a tendency to reduce cell frequency with micronuclei (~15%) and the total number of micronuclei (~20%), leading to a higher resistance against genomic instability.

Telomere Attrition

Telomere shortening is described during normal aging in human and mice cells. The fact that telomere length decreases with aging, contributing to the normal cell senescence process, suggested that this could be a potential marker for biological aging. Although the potential mechanism is unclear, exercise exhibits a favorable impact on telomere length, especially on a chronic pattern and particularly in older individuals antagonizing the typical age-induced decrements in telomere attrition. Several potential mechanisms have been discussed linking exercise and telomere length decrements to changes in telomerase activity, inflammation, oxidative stress, and decreased skeletal muscle satellite cell content.

Epigenetic Alterations

The relationship between epigenetic regulation and aging is controversial and complex. A multiplicity of epigenetic modifications affects all tissues and cells throughout life. The literature clearly reveals that the epigenetic response is highly dynamic and influenced by different environmental and biological factors, such as aging, nutrient availability, and physical exercise. Regular aerobic exercise can change the human genome through DNA methylation. Thus, by using epigenetic mechanisms, aerobic exercise can induce the transcription of genes encoding telomere-stabilizing proteins and telomerase activity not only in animals but also in humans.

Loss of Proteostasis

Aging and some aging-related diseases are linked to impaired protein homeostasis, also known as proteostasis. The array of quality control is guaranteed through distinct quality control mechanisms that prevent the aggregation of damage components and ensure the continuous renewal of intracellular proteins, degrading altered proteins. Aerobic exercise induces autophagy, thus preventing the loss of strength and muscle mass through the modulation of signaling pathways. Chaperone associated functions, such as folding and protein stability, are impaired in aging. In animal models, the upregulation of co-chaperones of the heat-shock proteins (HSPs) was associated with prolonged life-span phenotypes. Despite limited comparison studies, evidence supports that acute endurance- and resistance-type exercise protocols are associated with increased HSPs transcription not only during activity but also immediately postexercise or several hours following exercise, which points out the possible favorable impact of physical activity on proteostasis.

Deregulated Nutrient Sensing

Exercise plays an important role in not only the glucose-sensing GH / IGF-1 somatotrophic axis but also other nutrient-sensing systems, promoting a beneficial anabolic cellular state. The effect of exercise on glucose metabolism through increased glucose transporter type 4 production is another well-known mechanism of improved insulin sensitivity associated with physical activity. Additionally, exercise-induced GH and IGF-1 levels are influenced by exercise intensity, duration, and type (higher in intense interval protocols and resistance exercise).

Mitochondrial Dysfunction

The clear causal relationship between mitochondrial dysfunction and aging has long been a target of great discussion. With increasing age comes a decline in mitochondrial integrity and biogenesis because of alterations in mitochondrial dynamics and mitophagy inhibition, impairing dysfunctional mitochondria removal. The regular practice of physical exercise has a positive impact in mitochondrial function. In this sense, endurance-trained humans presented higher levels of mitochondrial proteins expression. Regular physical exercise may maintain a pool of bioenergetically functional mitochondria that, by improving the systemic mitochondrial function, contribute to morbidity and mortality risk reduction throughout one's life span.

Cellular Senescence

Senescent cell accumulation in different tissues seems to be dependent, in one hand, on an increased rate of senescent cell generation and, in other hand, on a decreased rate of clearance. Exercise, specifically aerobic, induces the secretion of antitumorigenic myokines and greater natural killer cell activity, contributing to a decreased incidence of oncologic disease and improved cancer prognosis. This may also impact clearance of senescent cells. Aerobic exercise has been inversely correlated with p16INK4a mRNA levels in peripheral blood T lymphocytes, which might promote protective outcomes against age-dependent alterations. Aerobic exercise suppresses liver senescence markers and downregulates inflammatory mediators.

Stem Cell Exhaustion

For the long-term maintenance of the organism, the deficient proliferation of stem and progenitor cells is harmful, but an excessive proliferation can also be deleterious by speeding up the exhaustion of stem cell niches. Within this line, physical exercise is one of the most potent stimuli for the migration/proliferation of the stem cell subsets from their home tissue to impaired tissues for later engraftment and regeneration. In this sense, regular physical exercise attenuates age-associated reduction in the endothelium reparative capacity of endothelial progenitor cells. In addition, exercise activates pluripotent cells' progenitors, including mesenchymal and neural stem cells, which improve brain regenerative capacity and cognitive ability.

Altered Intercellular Communication

The physiological aging process implicates several alterations on intracellular communication mechanisms, namely, in neuroendocrine, endocrine, and neuronal levels. Inflammation plays a central role in this age-related alteration. Muscle contraction is traditionally associated with myokine secretion (proteins, growth factors, cytokines, or metallopeptidases) elevated during and after exercise. Interestingly, the muscle-released IL-6 creates a healthy influence, inducing the production of anti-inflammatory cytokines. Within these lines, several authors associated lifelong aerobic exercise training with lower inflammatory levels, particularly in advanced decades of life.

Forever Healthy Foundation is Hiring to Build a Longevity Strategy Guide

We stand at the very beginning of the era of rejuvenation therapies. The first of those therapies, the repurposed chemotherapeutic pharmaceuticals called senolytics that can clear a fraction of senescent cells from aged tissue, exist but are not yet approved by regulators. They are not widely understood to provide a likelihood of benefit. While these therapies can be obtained, and some cost little as they are old enough to be generic, they are not exactly easily available for the average individual, someone without a background in the field as it stands today. Senolytics will likely not be approved by regulators until the mid 2020s, given the usual pace of the FDA and its peer organizations elsewhere in the world.

Thus there a lasting, hazy period of transition exists between the time at which a class of treatment is created and the time at which the first concrete implementation of that class is approved, well known, and widely available. It might be a decade or two in today's regulatory environment - just look at the progression of stem cell therapies since the turn of the century. Meanwhile, the clock is ticking and none of us are getting any younger yet.

What to do about this? The Forever Healthy Foundation, allied with the SENS Research Foundation and a strong material supporter of SENS rejuvenation research programs, is planning to build a longevity strategy guide. This will be a living how-to document for people who want to do what can be done about aging in advance of the very slow turning of wheels in the medical regulatory system. The Foundation is hiring research analysts, and it looks this project will build upon the start they have made on a database of approaches. There is certainly a need for a well defined and well researched strategy for the everyday individual: all of the organizations that might produce such a guide are either hopeless compromised by their commercial entanglement with the "anti-aging" industry of fraud, pills, and potions, or have neither the interest nor the resources to tackle this project.

What I would like to see emerge from this initiative is a line drawn under every past supplement and drug that has nothing but marginal evidence, all of the over-hyped approaches that cannot in principle produce meaningful impacts on aging. That baggage does nothing but slow and clutter any attempt to work seriously on human longevity. I'd advocate a fresh start, beginning with senolytics and moving forward from there as new technologies emerge. We shall see how close to that desired goal this project comes.

Forever Healthy Foundation is Hiring a Scientific Analyst for Rejuvenation Therapies

These are exciting times. The world has started the transition from an era where we were utterly helpless about our aging process to one where aging is under full medical control, and age-related diseases are a thing of the dark past. The theoretical groundwork has been laid out, scientists have started working on the fundamentals, and the first human rejuvenation therapies are already under development and might become available in the near future.

Even with future full-scale rejuvenation therapies still out of today's reach, there is already a growing array of early-stage therapies that can be used right now to slow our aging process or reverse some aspects of aging. As much as it is a blessing to live in an amazing time like is it also a great challenge. To take advantage of these exciting developments, most of us cannot wait for half a century until we have all the knowledge, perfect therapies and decades of experience on how to implement such treatments. To navigate this time of transition, we continuously need to make very personal decisions about which treatments to apply and when. Arming ourselves with the best knowledge about therapeutic options is key.

However, most of that knowledge is distributed over various experts, specialized communities, blogs, and websites, or buried in scientific research. Thus it is quite challenging to gather reliable information and make informed decisions on planning and implementing one's own early stage rejuvenation treatments. To change this, we have set out to continuously screen the knowledge on available and up-coming therapeutic options, turn it into actionable information and make it available to those interested. To accelerate this process, we are building a dedicated team of skilled professionals.

Personal Longevity Strategy

Even with future rejuvenation therapies still out of today's reach, there is already a lot of cutting edge medical knowledge and technology that can be used right now to significantly extend our healthy life spans. However, most of that knowledge remains unused because it is either distributed over various experts, specialized communities, blogs, websites, books and news feeds or buried deeply in scientific research results. Thus it can be quite hard to gather reliable information and make informed decisions regarding our personal health and longevity.

To change this, we have set out to unify the knowledge from the world's leadings sources, turn it into actionable information and create the most effective personal longevity strategy that can be implemented at present. In the spirit of the open source community we freely share our knowledge and invite everyone to participate.

A Failure of the Imagination when it comes to Human Longevity

Researchers recently published a study on attitudes to longevity that is reminiscent of the 2013 Pew survey. When asked, people want to live a little longer than their neighbors, at the high end of the normal life span for old individuals today. When asked how long they want to live given the guarantee of perfect health, people pick a number close to the maximum recorded human life span. This sounds like a collusion between the instinctive desires for first conformity and secondly hierarchy, deeply entwined with the human condition, present in all of our primate cousins, a self-sabotaging gift from our evolutionary heritage. We are hardwired to feel comfortable in a hierarchical social structure. We desire to be higher in the hierarchy than those around us, yet not so high that we are non-conforming.

One might argue that the interaction between the need for hierarchy and need for conformity is also at the root of the essential conservatism in human nature: the urge to preserve the present state of the world, to change it as little as possible. Given a teacup, ambition is restrained to the safe, conformist goal of two teacups - rather than, say, the disruptive change of a tea set factory, a house, an end to aging, the colonization of Mars, the cure for cancer. We live in an age of radical change, a revolution in the capabilities of biotechnology presently underway, but when you ask people what they want for their health, they'll claim nothing more than ten more years. That is the least of what might be achieved soon in the medical sciences, but without the desire for more than that, the rejuvenation research projects capable of providing far more will continue to struggle to find funding.

At the same time as the potential has arisen for a future in which the suffering and death of aging is banished, all disease controlled through advanced medicine, the vast majority of people still march stolidly towards what they assume to be the same fate as their grandparents. They are conforming. They expect to live a life that is the same in shape as it was for those born in the early to mid 1900s, somehow holding this idea in their minds at the same time as retaining the memory of living through the computing and internet revolutions, alongside any number of other sweeping changes in the nature of the human experience. How do we change this story that people are telling themselves? That is the fundamental question for all advocacy for radical change, such as the radical change of bringing an end to aging.

Around the World, People Have Surprisingly Modest Notions of the 'Ideal' Life

It seems reasonable that people would want to maximize various aspects of life if they were given the opportunity to do so, whether it's the pleasure they feel, how intelligent they are, or how much personal freedom they have. In actuality, people around the world seem to aspire for more moderate levels of these and other traits. People said, on average, that they ideally wanted to live until they were 90 years old, which is only slightly higher than the current average life expectancy. Even when participants imagined that they could take a magic pill guaranteeing eternal youth, their ideal life expectancy increased by only a few decades, to a median of 120 years old.

In one study, researchers analyzed data from a total of 2,392 participants in Australia, Chile, China, Hong Kong, India, Japan, Peru, Russia, and the United States. Participants in each region received a questionnaire translated into their native language. In response to a series of questions, participants reported their ideal level of intelligence; they also reported how long they would choose to live under normal circumstance and how long they would choose to live if they could take a magic pill ensuring eternal youth. A second study with 5,650 participants in 27 countries produced a similar pattern of results.

How Much Is Enough in a Perfect World? Cultural Variation in Ideal Levels of Happiness, Pleasure, Freedom, Health, Self-Esteem, Longevity, and Intelligence

The maximization principle - that people aspire to the highest possible level of something good if all practical constraints are removed - is a common yet untested assumption about human nature. We predict that in holistic cultures - where contradiction, change, and context are emphasized - ideal states of being for the self will be more moderate than in other cultures. In two studies (N = 2,392 and N = 6,239), we asked this question: If participants could choose their ideal level of happiness, pleasure, freedom, health, self-esteem, longevity, and intelligence, what level would they choose? Consistent with predictions, results showed that maximization was less pronounced in holistic cultures; members of holistic cultures aspired to less happiness, pleasure, freedom, health, self-esteem, longevity, and IQ than did members of other cultures. In contrast, no differences emerged on ideals for society. The studies show that the maximization principle is not a universal aspect of human nature and that there are predictable cultural differences in people's notions of perfection.

CD36 as a Potentially Important Marker and Mechanism in Cellular Senescence

The accumulation of senescent cells with age causes age-related disease and dysfunction. The most important factor driving this accumulation may be the decline of the immune system, as immune cells are responsible for cleaning up the tiny fraction of all senescent cells that fail to self-destruct, but that has yet to be determined with any great rigor. Regardless of the reasons for this accumulation, periodic removal of senescent cells has been shown to improve health and extend life span in mice, as well as reverse specific aspects of tissue aging in a variety of organs. Therefore a great deal of interest is currently focused on finding new and better ways to go about the targeted destruction of senescent cells. That starts with further mining of the biochemistry of these cells, such as in the research results noted here.

There are at present a limited number of proven approaches to senolytic therapies, those that can selectively destroy senescent cells without causing any great harm to normal cells. Immunotherapy targeting surface markers on senescent cells, as at SIWA Therapeutics, suicide gene therapy tied to expression of senescence-associated proteins inside senescent cells, as at Oisin Biotechnologies, and small molecule / pharmacological approaches, as at Unity Biotechnology. Of these, the latter has the broadest variety at the moment, each class of pharmaceutical targeting a different mechanism associated with senescence, usually those involved in holding back programmed cell death in lingering senescent cells.

In the pharmacological camp, the known mechanisms include: the Bcl-2 inhibition common to most of the repurposed chemotherapeutics, such as navitoclax; whatever it is that dastinib is doing under the hood instead of Bcl-2 inhibition, not well understood at this time; interfering in the FOXO4-p53 interaction; interfering in the MDM2-p53 interaction; and so forth. Anyone turning up a new approach beyond these few, and people will do just that, since all molecular mechanisms inside cells have many surrounding connections, has the potential to create in a lucrative line of research and development. The market for a working rejuvenation therapy based on removal of senescent cells is so large that many competing approaches could thrive, and all of the existing pharmacological approaches under development could be improved upon. That is the incentive for further exploration of the detailed biochemistry of cellular senescence, and why much more funding is available for that line of work these days.

Cells stop dividing when this gene kicks into high gear, study finds

Senescence is a natural occurrence in the life of a cell, and researchers have sought to learn about it for a couple of reasons. First, it's connected to old age: Senescent cells are thought to contribute to heart disease, arthritis, cataracts, and a bevy of other age-linked conditions. Second, a lack of senescence is a hallmark of cancer cells, which bypass this process to replicate in an uncontrolled manner.

A new study illuminates genes involved in cellular senescence, and highlights one in particular that seems tightly associated with this crucial biological process.In experiments, researchers discovered that a gene called CD36 is unusually active in older, senescent cells. What's more, the scientists were able to cause young, healthy cells to stop dividing by heightening CD36 activity within those cells. The effect spread to nearby cells, with almost all of the cells in a petri dish showing signs of senescence when only a small fraction of those cells - about 10 to 15 percent - were overexpressing CD36. New cells placed in the growth medium that previously housed the senescent cells also stopped replicating.

The results point to CD36 as an exciting topic of future research. The gene's exact role in senescence remains a mystery: Scientists know that the gene guides the body in building a protein of the same name that sits on the surface of cells, but this protein's functions are still being studied. Proposed activities include helping cells import lipids, and influencing how these lipids are used within cells.

An evolutionary transcriptomics approach links CD36 to membrane remodeling in replicative senescence

Cellular senescence, the irreversible ceasing of cell division, has been associated with organismal aging, prevention of cancerogenesis, and developmental processes. As such, the evolutionary basis and biological features of cellular senescence remain a fascinating area of research. In this study, we conducted comparative RNAseq experiments to detect genes associated with replicative senescence in two different human fibroblast cell lines and at different time points. We identified 841 and 900 genes (core senescence-associated genes) that are significantly up- and downregulated in senescent cells, respectively, in both cell lines.

Our functional enrichment analysis showed that downregulated core genes are primarily involved in cell cycle processes while upregulated core gene enrichment indicated various lipid-related processes. We further demonstrated that downregulated genes are significantly more conserved than upregulated genes. Using both transcriptomics and genetic variation data, we identified one of the upregulated, lipid metabolism genes, CD36, as an outlier.

We found that overexpression of CD36 induces a senescence-like phenotype and, further, the media of CD36-overexpressing cells alone can induce a senescence-like phenotype in proliferating young cells. Moreover, we used a targeted lipidomics approach and showed that phosphatidylcholines accumulate during replicative senescence in these cells, suggesting that upregulation of CD36 could contribute to membrane remodeling during senescence. Overall, these results contribute to the understanding of evolution and biology of cellular senescence and identify several targets and questions for future studies.

The World Health Organization Must Consider Rejuvenation Research

Ilia Stambler, historian of our longevity science community, is in illustrious company in the author list for this open access position paper. Regular readers will recall that the World Health Organization (WHO) is among the most conservative and hidebound of institutions when it comes to the development of means to treat aging. The WHO positions on aging studiously avoid any mention of the idea that aging can be changed at all through medical science. This is somewhere between ridiculous and outrageous, given what is going on in the labs and clinical development today. More activist members of the scientific community have, accordingly, berated and advocated by turn in journal articles these past few years.

Should a broken system be changed from within, or should it be rejected entirely and worked around? In my experience, the latter approach is the one more likely to produce change, but as a general rule far more effort goes towards the first. We can speculate as why this might be the case. Perhaps because those people most able to identify and articulate the problem in question tend to be experienced with, embedded in, and thus invested in, the broken system. It is comparatively rare for outsiders to appear with sufficient knowledge to build viable alternatives; matters must usually decline for a long time before that happens. That is certainly happening elsewhere in the scientific and medical communities, but not yet here.

It can be confidently stated that global population aging is both the greatest success of global public health efforts of the past, as well as the greatest challenge for the further global public health efforts of the future. Over the past decades, life expectancy at birth has increased globally. Considering that both rising longevity and population aging are likely demographic events in the coming decades, by 2050 the proportion of people over 60 years is expected to double from about 13% to nearly 25%, which, in absolute terms, means an increase from 962 million to 2.1 billion people. Rising longevity during the last 150 years is a testament to human ingenuity, and there is reason to believe further advances are possible.

According to World Health Organization's data, "Noncommunicable diseases (NCDs) kill 40 million people each year, equivalent to 70% of all deaths globally. Cardiovascular diseases account for most NCD deaths. Each year, 15 million people die from a NCD between the ages of 30 and 69 years; over 80% of these premature deaths occur in low- and middle-income countries." In other words, of the 57 million deaths in the world each year, nearly 50% occur due to chronic non-communicable diseases in the world's oldest population (70+), and over 60% in the older population (60+), making the health of older persons the worst and most urgent global health problem.

In view of the urgency of the problem, it seems highly surprising that in the forthcoming draft 13th General Programme of Work of the World Health Organization for 2019-2023 the issue of aging and aging-related ill health is excluded completely! Beside a cursory mention of the word "aging," this work program does not contain any specific objectives, deliverables, and actions to improve the health of the aged. This means that, through 2023, according to this document, the World Health Organization is not obliged to provide any services to care for the health of older persons or to improve their health, not to mention conduct any research and development to create new therapies and technologies for improving the health of the aged. The issues of aged health are not in the WHO work program!

How can this exclusion coexist with the mission of WHO's division on Ageing and Life Course? How can it coexist with the recently adopted WHO's Global Strategy and Action Plan on Ageing and Health (GSAP) for 2016-2020, endorsed by all the WHO member states? According to its goal statement, the GSAP must prepare for the "Decade of Healthy Ageing from 2020 to 2030" which was also announced by WHO. The coordination and consultation between various arms and branches of the WHO must improve. The developers of the WHO Work Program must avail of the world expertise on ageing health, within the WHO and externally, to develop an effective, strategically-minded and inclusive global health program. We also urge the readers to make your voice heard, advocate and increase publicity about the need to include and implement concrete measures to improve aging health, including research and development for healthy longevity, as a priority in the WHO work program.

Investigating the Direction of Causation in Frailty and Cardiovascular Disease

It remains the case that a great deal of aging research these days is purely observational, which is, I think, unfortunate. This is an age in which more than mere observation of aging might be achieved; the first interventions likely to reliably slow or reverse aspects of aging are making their way out of the laboratory and into clinical development. There should be a lesser emphasis in the research community on watching what happens to a population of older individuals who lack effective treatments for aging, and a correspondingly greater emphasis on getting those treatments built and into the clinic.

Given this, does it really matter how frailty and cardiovascular disease interact? Would the world be changed by knowing, in detail, the exact relationship between the two? Both of these conditions will be banished in the wealthier half of the world fifty years from now, defeated and controlled by forms of regenerative medicine that are periodically applied to remove the root causes of these conditions. That will be achieved by focusing on those causes, ignoring the detailed end-stage mechanisms and relationships of the conditions that result.

Aging as it exists today will be a curio of the past given a further fifty years of development after that point. How much scientific work today goes towards considering how exactly different patient populations experienced the now extinct condition smallpox in the absence of effective treatments? How valuable was that sort of research during the years in which the first meaningful treatments were deployed? I'd say that, at that time, observational lines of research added very little to progress in defeating smallpox - and the situation will be much the same for aging.

In older adults both cardiovascular disease (CVD) and frailty are highly prevalent. Novel and advanced cardiovascular therapeutic treatments have improved life expectancy and consequently led to an increasing number of older adults suffering from chronic CVD. This presents an enormous clinical and public health burden. Frailty describes a state of vulnerability due to an age-related decline in many physiological systems and is associated with a considerably increased risk of falling, disability, hospitalisation, and mortality. According to cross-sectional data, CVD appears to be positively associated with frailty in community-dwelling older adults. However, cross-sectional studies do not clarify if CVD leads to frailty or if frailty precedes the development of CVD.

From a pathophysiological point of view, both directions are plausible. For example, exercise related symptoms in patients with CVD could lead to physical inactivity making them more likely to become frail. Additionally, comorbidities, as well as physical and cognitive decline are common in older adults with CVD. This could lead to a loss of homeostatic capability to withstand stressors and increase the risk of frailty. Yet, one could also argue that physical inactivity and its sequelae (e.g. obesity) due to frailty is a risk factor for development of CVD. Also, frailty is associated with a chronic state of low-grade inflammation which could trigger CVD.

The present study studied the bidirectional effect of CVD on frailty among community-dwelling older adults. First, we observed cross-sectional associations between CVD and frailty. Patients with CVD, especially those with peripheral arterial disease and heart failure, were more likely to be frail. Longitudinally, mainly HF was associated with incident frailty. These patients were at least twice as likely to become frail, which puts these patients at an equal or even higher risk of incident frailty than subjects with chronic lung disease, arthritis, or diabetes. Analyses studying the reverse association revealed that in this older population, frailty does not precede development of CVD during three years of follow-up.

Exosome Signaling in Vascular Calcification

Calcification of soft tissues occurs in the cardiovascular system with age, one of the processes that causes arterial stiffening and other pathogenic conditions such as aortic stenosis. Considered at a very high level, this happens because a fraction of cells in the blood vessel walls malfunction and begin to act in ways more appropriate to a bone environment, laying down deposits of minerals. The causes of this malfunction are incompletely understood, but evidence suggests that the presence of senescent cells and their inflammatory signaling is an important cause.

In this open access paper, researchers investigate cellular signals carried via exosomes in the context of vascular calcification. Exosomes are a class of extracellular vesicle, small membrane-bound packages of molecules that carry a sizable fraction of the signaling traffic between cells. In recent years, scientists have been paying a lot more attention to these packages, as they appear to carry most of the signals that are important in, for example, the beneficial effects of stem cell transplants. They are also probably a sizable part of the harmful signals produced by senescent cells. While the authors don't mention cellular senescence here, it is interesting to speculate on the overlap between this research and what is being discovered of the role of vesicles in senescent signaling.

Vascular calcification (VC) is caused by hydroxyapatite deposition in the intimal and medial layers of the vascular wall, leading to severe cardiovascular events in patients. Importantly, exosomes have been demonstrated to be involved in VC recently. Exosomes have up-regulated secretion from vascular smooth muscle cells (VSMCs) in vivo after pro-calcifying stimulation and become "calcifying" exosomes to induce VC. Calcium binds with phosphate to form hydroxyapatite nodes on the inner and outside of "calcifying" exosomes membranes, which further initializes mineral deposition. Although these studies did reveal that exosomes participated in the calcification procession through promoting mineral deposition sites formation, they did not discuss exosomes functioning as mediators for RNAs transportation, which is vital for exosome function.

Exosomes are secreted by diverse cells to mediate cell-to-cell communications. However, how exosomes regulate VC has been only preliminarily explored. It is found that exosomes with diverse origins mainly mediate microRNAs (miRs) transporting to VSMCs in coronary artery calcification. A bioinformatics analysis revealed that cultured in osteogenic medium, mesenchymal stem cells secreted exosomes with alterations of miRs, comparing with normal culturing. Such alterations were suggested to accelerate calcification in other mesenchymal stem cells to modulate osteogenic phenotype transition. Thus, it implies that besides heterogeneous mineral deposition inside vessel wall, exosomes can also promote VC by transporting messages among cells.

Cellular Senescence in Aging versus Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) is caused by long-term inhalation of smoke or other particulate or chemical irritants. In wealthier parts of the world, that usually means smoking. In less wealthy parts of the world, cooking fires and industrial processes also contribute. The condition shares some mechanisms with aging, particularly the accumulation of senescent cells and the chronic inflammation produced by those cells. In some ways, it is possible to consider aspects of COPD to be accelerated lung aging. In other ways it is entirely different. This is generally true of the environmental contributions that make up secondary aging, the various exposures that cause harm and dysfunction by speeding up specific, narrow forms of cell and tissue damage. The open access paper here is interesting for the comparisons it draws between aging and smoking as causes of increased cellular senescence in the lungs.

Most parts of the body including the lungs experience progressive damage with aging as well as impaired function. Lung aging is associated with loss of elasticity, a decrease in pulmonary function, loss of structural integrity, and an increase in inflammation which are among the key characteristics of chronic obstructive pulmonary disease (COPD). COPD is the third leading cause of chronic morbidity and mortality on a global scale. Growing evidence suggest that age-associated structural and functional alterations enhance pathogenetic susceptibility to COPD.

Along with other toxic gases, the most common etiological factor that develops COPD is cigarette smoke (CS) which results in several pathophysiological changes in the lung. Recent reports suggest that CS induces oxidative stress-mediated DNA damage and triggers cellular senescence in the lungs. Cellular senescence is a process of complete and permanent cell cycle arrest. The accumulation of metabolically active senescent cells in tissues during aging impairs tissue repair and function. Pro-inflammatory mediators are secreted which give rise to a phenomenon known as senescence-associated secretory phenotype (SASP). Senescent cells increase the damage of neighboring cells by virtue of their SASP phenotype. Previous reports proposed a network of cellular senescence, inflammatory response, and premature lung aging in the pathogenesis of COPD.

We hypothesized that aging-associated changes in lungs worsen the COPD by CS exposure. Younger and older groups of C57BL/6J mice were exposed to chronic CS for 6 months with respective age-matched air-exposed controls. CS caused a decline in lung function and affected the lung structure of both groups of mice. No alterations were observed in the induction of inflammatory mediators between the air-exposed younger and older controls, but aging increased the severity of CS-induced lung inflammation. Aging per se increased lung cellular senescence. Thus our data suggest that normal aging and chronic CS exposure independently induce cellular senescence in the lungs.

Why Would Pancreatic Cell Size Correlate Well with Mammalian Species Longevity?

Researchers recently found that the size of pancreatic cells is inversely correlated with species longevity, given data obtained from a few dozen different types of mammal. Since this is an unexpected new discovery, the paper here contains little more than an initial educated guess at why this might be the case. At first glance this metric doesn't obviously relate to any of the usual mechanisms linking the operation of cellular metabolism with pace of aging, and thus I expect that we'll have to wait for some years of further investigation and theorizing to learn more.

How organs reach and maintain their proper size is a major question in biology. Organ size is the product of total cell number, average cell size, and volume of the extracellular space. Cell number is considered the main determinant of organ size, and differences in cell number explain much of the size difference between organisms, such as mice and humans. However, within a given species, different organs vary considerably in the relative contribution of cell number and cell size to total organ size. For example, the increase in the total mass of blood from birth to adult life results from larger cell numbers, while postnatal growth of cardiac and skeletal muscle largely relies on increased cell size.

Despite the major differences in final size among mammalian species, the molecular and cellular mechanisms underlying organ growth are usually thought to be highly similar. In the case of the pancreas, embryonic progenitor cells initially proliferate and differentiate to form a miniature organ. After birth, progenitor cells largely disappear. The current consensus is that postnatal growth of the pancreas, in mice and by extension also in humans, relies on simple duplication of differentiated cells, consistent with the classic description of the pancreas as an "expanding tissue."

The size of cells in the adult pancreas is recognized to be plastic. For example, acinar cells shrink when luminal nutrients are not available, and beta cell size increases transiently in pregnant rodents. However, increased cell size is not typically considered a significant contributor to normal postnatal pancreas growth. Here we report surprising differences in the mode of postnatal pancreas growth among different mammals. While the human pancreas grows by pure hyperplasia, the rodent pancreas grows mostly by cellular hypertrophy. Acinar cells of the salivary glands present a similar trend, namely larger cells in mice compared with humans. Finally, we identify a surprising negative correlation between acinar cell size and organismal lifespan, based on analysis of 24 mammalian species.

Our findings suggest that the associations of metabolic rate and body weight with lifespan are mediated by differences in cell size. This suggests that animals employing acinar hypertrophy live shorter lifespans. What might be the evolutionary advantage of hypertrophy as a mode of organ growth? We propose that the key is the speed of postnatal growth. Both humans and mice (and their organs, including the pancreas) grow approximately 15-fold from birth to reproductive age; however, this age is reached ∼100 times faster in mice. We hypothesize that cellular hypertrophy contributes to the rapid growth of short-lived mammals. Indeed, the rate of postnatal growth is negatively correlated with lifespan, and this correlation is eliminated when controlling for cell size. This result supports a model whereby cellular hypertrophy promotes rapid postnatal growth rate and earlier sexual maturity at the expense of lifespan.

You Can't Fight Ageism by Pretending that Aging isn't Harmful

There is a certain mode of writing positively about aging, with the intent of opposing ageism, in which the author pretends that aging isn't a harmful process of decline in health and capabilities. It seems to me that the best practical solution for ageism is to build the medical technologies that enable older people to be just as physically and mentally capable as younger people. I'm not sure that anything else is likely to work, given the length of time over which all of the other forms of attempt have been made. While it is worthy goal to convince people that is inhumane to reject and persecute others simply because they are less capable, that undesirable aspect of human nature has persisted since prehistory, despite the best efforts of better individuals than you or I. Using technology to change the nature of the human condition seems more likely to succeed than any amount of persuasion and philosophy.

A report by the Royal Society For Public Health, "That Age Old Question," endeavors to expose ageism and help end discrimination against older people. While it does make a handful of valid points, however, it seems to suggest that sweeping the true nature of aging under the rug will help to end ageism. Everything in the report revolves around attitudes towards aging and how the authors think that these should change in order to eliminate age-related discrimination. There is no mention of aging as the chronic, progressive process of deterioration found in the scientific literature; there is not a word about medical research with the potential to prevent age-related diseases, nor is the importance of intervening on the root causes of aging to prevent diseases, and indirectly, ageism, even hinted at.

Quite frankly, if you were an alien who had never heard of aging before and you read this report, you'd likely get the impression that the ill health of humans in old age is just a myth fueled by stereotypes and negative perception of the phenomenon. The poor mental and physical health of old age are described as being merely "negative stereotypes" very early on in the report's foreword, yet later sections of the report suggest bringing together nursing homes and youth clubs to better integrate generations; however, if nursing homes for the elderly exist, age-related ill health is obviously not merely a stereotype.

Similarly, while individual elderly people may be able to make meaningful contributions to the economy before age-related disease takes their lives, the economic burden of an aging population is a real problem, not just a stereotype. It is hard to believe that any society would come up with retirement if elderly people's ability to work was mostly comparable to that of younger people; it is similarly hard to believe that governments and economists who worry about the expected surge in the elderly population of the next few decades, and about the consequences that they might have on our pension systems, are worrying about something that originates in prejudice rather than biology - or that they're not worrying at all but didn't go through the trouble of letting the rest of us know.

To be clear, the authors of the report don't openly oppose medical research against aging. Given that no mention of it was made, it's unclear whether they're even aware of the possibility and if they would endorse it or not. Their intent to undo age-based discrimination is genuine, if misguided. Ending ageism is nearly as important as ending aging; for one, if ageism wasn't a thing, rejuvenation advocates wouldn't have to spend time debating people who think that older people living too long would lead to cultural stagnation because of their alleged "old people mentality". However, ageism won't be defeated by sugarcoating aging, which only adds insult to injury.

TXNIP as a Target to Protect Against Oxidative Stress and Slightly Slow Aging

Researchers here overstate the potential relevance of an approach demonstrated to improve defenses against molecular damage caused by oxidation in flies. Looking over the diagrams in the paper, reduced levels of TXNIP don't in fact increase life span all that much in flies - and consider that fly life span is far more plastic in response to this sort of manipulation than is the case in humans. A range of approaches that greatly increase fly life span, or nematodes, or mice, are known to do no such thing in our species, even though some may help to improve the quality of health along the way. This is the nature of aging and metabolism in short-lived versus long-lived species.

The researchers also lean heavily on oxidative theories of aging, which are showing their age these days. Oxidative stress certainly increases in later life, and that increase causes downstream issues, but it is entirely possible to argue based on the evidence that it isn't as important as other aspects of aging. It is also secondary to issues such as mitochondrial dysfunction and chronic inflammation. Removing excessive oxidative molecules or improving defenses against them can evidently produce some degree of benefits, but the details of the biochemistry are very important. Few of the approaches illustrated to date have sizable, unambiguous results that are worthy of further interest - perhaps mitochondrially targeted antioxidants, for example. Even those don't seem capable of significant rejuvenation, however, versus a slight slowing of aging.

Oxidative stress causes cells and entire organisms to age. If reactive oxygen species accumulate, this causes damage to the DNA as well as changes in the protein molecules and lipids in the cell. The cell ultimately loses its functionality and dies. Over time, the tissue suffers and the body ages. Researchers have now discovered the key regulator that is responsible for shifting the sensitive balance from vital to harmful amounts of reactive oxygen molecules and thus accelerating the aging process: A protein molecule called TXNIP (thioredoxin-interacting protein).

One way in which the body disposes of harmful reactive oxygen species is their conversion by the enzyme thioredoxin-1 (TRX-1). TRX-1 has been proven to play a role in protecting DNA from oxidative stress and slowing down aging processes. Its antagonist TXNIP inhibits thioredoxin-1 and thus ensures that the reactive oxygen molecules are retained. The researchers wanted to know whether more TXNIP is formed in the body with increasing age, thereby undermining the protective mechanism against oxidative stress. To this end, they first compared T cells from the blood of a group of over 55-year-old volunteers with the T cells of younger blood donors, who were between 20 and 25 years old. It turned out that the cells of older subjects produce significantly more TXNIP. The scientists have also observed similar findings in other human cell and tissue types.

The researchers also found that more TXNIP is produced in the fly Drosophila with increasing age. In order to test whether TXNIP is actually responsible for aging, they bred flies that produce significantly more TXNIP than their relatives as well as flies in which TXNIP synthesis is greatly reduced. "Flies that produced more TXNIP lived on average much shorter, while flies with less TXNIP had a longer average life. TRX-1 and its opponent TXNIP are highly conserved in the course of evolution; they hardly differ between flies and humans." It can therefore be assumed that the two proteins perform similar functions in flies and humans. If more TXNIP is produced with increasing age, this means that TRX is gradually switched off with its protection function. This leads to more oxidative stress, which damages cells and tissue and eventually causes them to die.

Uncovering Genes that Might be Sabotaged to Block Metastasis

Cancer research will accelerate meaningfully towards the goal of control of all cancer only when a majority of researchers are working on mechanisms common to large number of different cancer types. There are too many subtypes of cancer and too few scientists to make real progress when tackling cancers one by one. Shutting down metastasis is one grail of cancer research, as the majority of cancer deaths are caused when cancer spreads throughout the body, not by the initial tumor. Thus a search for common mechanisms of metastasis is one of the few presently viable approaches to the production of broader cancer therapies. Researchers here find eleven genes that are critical to low-level processes in metastasis, broadly common across cancers. This provides a new set of targets that may lead to future ways to suppress the spread of cancer, making the condition much less dangerous.

"Metastasis kills 90 per cent of all patients who have cancer, and with this study we have discovered new ways to potentially end metastasis." In the study, the team used a unique platform it created - a shell-less avian embryo - to visualize the growth and spread of cancer cells in real time. The researchers used a molecular tool called a knockout library to insert short hairpin RNA (shRNA) vectors into cancer cells that bound to specific genes in the cells and stopped them from activating. They then inserted those cancer cells into the shell-less embryos and observed as they formed clusters of cancer, identifying which ones showed properties of being non-metastatic.

"When we found compact colonies of cancer, that meant that the key steps of metastasis were blocked. After that we could pull them out, query what the gene is and then validate that the gene is actually responsible for metastasis." The approach allowed the team to detect and identify 11 genes that play essential roles in cancer cell metastasis. According to the researchers, the genes discovered are widely involved in the process of metastasis and not unique to any one cancer. They now plan to test the metastasis-associated genes and gene-products as drug targets with an aim of stopping metastasis.

"We know that cancer, once it becomes metastatic, will keep spreading to other parts of the body and continue to get worse because of that. If we can stop metastasis at any step of progression in cancer patients, we're going to have a significant effect on survival." The team is now hoping to progress its research to human trials over the next few years. The team is also expanding efforts to explore for other types of genes called microRNAs that may present even stronger therapeutic targets for preventing metastasis.

Neuromelanin Organelles, a Garbage Dump of Last Resort in Aging Brain Cells

Autophagy is a collection of several quality control processes in which broken cell components, damaged proteins, and metabolic waste are broken down and recycled. In the most familiar of these processes, the material to be recycled is wrapped in a membrane, an autophagosome, which then migrates to a lysosome, another membrane-bound organelle packed with enzymes capable of taking apart just about any molecule it is likely to encounter.

Unfortunately, this recycling process falters with age in a number of ways, the consequences particularly apparent in very long-lived cells such as the neurons of the central nervous system. Lysosomes become packed with the few classes of compound that they struggle to break down, growing inefficient and bloated. Autophagosomes lose the mechanisms required to transport their contents efficiently to their destination. Cells become overwhelmed with metabolic waste, and dysfunctional as a result.

This open access paper describes one of the outcomes of this decline, the accumulation of garbage dump organelles inside brain cells, probably lysosomes or autophagosomes or the fusion of both that have come to the point of outright failure of function. If autophagy can be restored in aged neurons, will these additional waste-packed organelles start to vanish? That would be one of the more direct ways to try to get a handle on cause and effect, and there are a few possible approaches to that end that might work well enough in the lab to obtain useful data. The ones I tend to favor are those of the LysoSENS program: find ways to break down the worst and most persistent metabolic waste, which should allow lysosomes to cope with the rest.

During aging, neuronal organelles filled with neuromelanin (a dark-brown pigment) and lipid bodies accumulate in the brain, particularly in the substantia nigra, a region targeted in Parkinson's disease. We have investigated protein and lipid systems involved in the formation of these organelles and in the synthesis of the neuromelanin of human substantia nigra. Membrane and matrix proteins characteristic of lysosomes were found in neuromelanin-containing organelles at a lower number than in typical lysosomes, indicating a reduced enzymatic activity and likely impaired capacity for lysosomal and autophagosomal fusion.

The presence of proteins involved in lipid transport may explain the accumulation of lipid bodies in the organelle and the lipid component in neuromelanin structure. The major lipids observed in lipid bodies of the organelle are dolichols with lower amounts of other lipids. Proteins of aggregation and degradation pathways were present, suggesting a role for accumulation by this organelle when the ubiquitin-proteasome system is inadequate. The presence of proteins associated with aging and storage diseases may reflect impaired autophagic degradation or impaired function of lysosomal enzymes.

The identification of typical autophagy proteins and double membranes demonstrates the organelle's autophagic nature and indicates that it has engulfed neuromelanin precursors from the cytosol. Based on these data, it appears that the neuromelanin-containing organelle has a very slow turnover during the life of a neuron and represents an intracellular compartment of final destination for numerous molecules not degraded by other systems.

An Approach to Interfering in Mitochondrially Mediated Cell Death due to Amyloid-β in Alzheimer's Disease

While present thinking in the research community is leaning towards tau rather than amyloid-β as the primary cause of cell death and dysfunction in later stage Alzheimer's disease, it is still the case that too much amyloid-β is toxic to cells. Researchers here propose a treatment based on suppressing one of the mitochondrial mechanisms of programmed cell death that is triggered by the presence of amyloid-β. This is in many ways a classic example of what I consider to be a problematic focus in medical research: ignoring the root cause damage, the amyloid-β, in favor of tinkering with cellular mechanisms in the hope of improving the dysfunctional, damaged state of cells and tissues.

There are no doubt a hundred places in which one could reasonably try to intervene downstream of the presence of amyloid-β - and a good twenty of those are probably fairly independent of one another, requiring separate research and development project to address. But why build twenty projects when you could build one to achieve the same effect? Target the root causes. Don't mess with the downstream state. I wish that more of that philosophy of development was in evidence in the research community. Sadly it remains a minority viewpoint, barely worked on, judging by what I see in the output of the medical life sciences.

Alzheimer's disease (AD) is the most prevalent type of dementia in the developed world. Despite the enormous efforts made by the scientific community, an effective therapeutic strategy against AD has yet to be developed. The importance of mitochondrial dysfunction in the pathogenesis of AD and other neurodegenerative diseases has been increasingly recognized. A causal relationship has been found between mitochondrial dysfunction and amyloid β (Aβ)-induced neuronal and vascular degeneration. Indeed, mitochondrial pathology, oxidative stress, and energy metabolism impairment are implicated in the pathogenesis of AD, preceding formation of Aβ plaques, cell death, and memory loss.

Mitochondrial-specific therapies are emerging as promising therapeutic tools. It is interesting that mitochondrial therapies have shown beneficial effects in different models of neurodegenerative pathologies, where mitochondrial dysfunction and apoptotic cell death are known to be involved, such as AD, Parkinson's disease, and Huntington's disease.

Carbonic anhydrases (CA) are enzymes involved in the reversible conversion of carbon dioxide and water into bicarbonate and protons. They are present in all the vertebrates, showing different intracellular locations and regulating pH and ion transport. CA-VA and CA-VB have a mitochondrial localization. CA-II, known as cytoplasmic, was also recently shown to be increased in brain mitochondria in aging and neurodegeneration. CA inhibitors (CAIs) are used to treat a variety of disorders. In this study, we examine multiple mitochondrial pathways of amyloid toxicity in neuronal and cerebral endothelial cells (ECs), and evaluate CAIs methazolamide (MTZ) and, for the first time, its analog acetazolamide (ATZ), on specific Aβ-mediated pathways of mitochondrial dysfunction and apoptotic cell death. The CAIs selectively inhibited mitochondrial dysfunction pathways induced by Aβ, without affecting metabolic function.

Due to the long-term use of MTZ and ATZ in chronic conditions, the efficacy and the safety of their systemic administration have been widely assessed, making clinical trials for CAIs in AD a concrete possibility. Our novel findings on the mitochondrial effects of MTZ and ATZ against neuronal and vascular amyloid toxicity justify the selection of these drugs as a therapeutic strategy for AD and cerebral amyloid angiopathy.


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