FIGHT AGING! NEWSLETTER
May 4th 2015
Fight Aging! provides a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress towards the medical control of aging in order to prevent age-related frailty, suffering, and disease, as well as improvements in the present understanding of what works and what doesn't work when it comes to extending healthy life. Expect to see summaries of recent advances in medical research, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more.
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- Forthcoming Gerontology Research Group Online Meetings
- A Little Research on the Metabolism of the Aging Brain
- Determination and Vision for a Better Future, Achieved via the Medical Control of Degenerative Aging
- Treating Aging in Advance of Fully Understanding Aging
- The Latest on Heterochromatin and Aging
- Latest Headlines from Fight Aging!
- An Update on Using TALENS to Edit Mitochondrial DNA
- Interventions to Slow Aging in Humans: Are We Ready?
- A Mechanism Linking Inflammation and Bone Loss
- The Moral Bankruptcy of Bioethics
- Biocompatible Artificial Blood Vessels Guide Regrowth
- Calico Life Sciences Partners with the Buck Institute for Research on Aging
- Predicted Future Life Expectancy Continues to Increase
- Visceral Fat Correlates With Brain Tissue Damage
- The Dog Aging Project
- Investigating Factors Relating to Survival After Age 50
FORTHCOMING GERONTOLOGY RESEARCH GROUP ONLINE MEETINGS
The Gerontology Research Group is a long-standing point of connection and networking hub for a range of scientists and advocates interested in slowing or reversing degenerative aging. It was set up by the late Stephen Coles of the UCLA faculty back in 1990, right at the dawn of the modern era of scientific interventions in the aging process. A mailing list has been running for about as long as I've been interested in the defeat of aging and extension of healthy life span as a goal, and nowadays there is a linked blog as well.
Of late the GRG volunteer staff have been experimenting with online meetings as a way to expand access to the regular presentations on aging research and related science that have been taking place on at least a monthly basis for more than two decades. A couple of meetings are coming up at the start of May, for example. If interested in listening in, you'll want to click through for connection instructions, which I won't reproduce here:
Gerontology Research Group Online Meetings
Dear GRG Member, Two GRG online meetings are scheduled.
1) Saturday May 2 - 10:00 am Pacific, 1:00 pm ET, 5:00 pm GMT
We will meet with GoToMeeting. A test run will be done the day before, so if you are not familiar with GoToMeeting but would like to join or watch - and make sure it works for you - contact us.
Robert Young, Director of the Supercentenarian Research and Database division will bring us up to date on recent supercentenarian activities. I'll briefly discuss the severe problem that currently exists with pre-clinical testing and solutions involving engineered (lab grown) tissue systems for drug and aging therapy assessment. Here and now there is Organovo's exVive3D™ liver and tissue testing services, and under development other varied systems such as tissue chips and engineered tissue systems for heart, liver, lung, kidney, brain and others.
Then as the main event, Vince Giuliano of Anti-Aging Firewalls will make a presentation on liposome delivered aging intervention therapies in humans: principles, research, and practical experience.
2) Friday May 8 - 10:00 am Pacific, 1:00 pm ET, 5:00 pm GMT
We will meet via NIH's WebEx system. You will receive instructions on how to join before the meeting.
This will be an extension of the tissue chips and engineered tissue systems section of the previous meeting. Our presenter will be Kristen Fabre, Scientific Program Manager, NIH National Center for Advancing Translational Science (NCATS) and Manager of the Tissue Chip for Drug Screening program.
Topic: The Tissue Chip for Drug Screening Initiative. This NIH/DARPA/FDA collaboration aims to develop 3-D human tissue chips that model the structure and function of human organs, such as the lung, liver and heart, and then combine these chips into an integrated system that can mimic complex functions of the human body. Once developed and integrated, researchers can use these models to predict whether a candidate drug, vaccine or biologic agent is safe or toxic in humans in a faster and more cost-effective way than current methods, and how effective a therapeutic candidate would be in clinical studies.
A LITTLE RESEARCH ON THE METABOLISM OF THE AGING BRAIN
The brain is enormously complex, and as is true of almost every aspect of metabolism there is far more left to map than is already known. The entirely of the knowledge of human biochemistry is really just a sketch of the starting points for further exploration. The final finished catalog of everything there is to know about how a baseline human functions and ages will be truly vast in comparison to today's databases. Building this catalog will be the work of decades yet, even given the rapid and accelerating pace of progress in biotechnology. This is why many researchers believe that little meaningful progress is possible in the near term towards treating aging and extending healthy life spans. To their eyes the process of development is to first achieve a much greater understanding of how exactly every relevant cellular mechanism changes during aging, and then build ways to alter the operation of aged metabolism based on that new knowledge. This is not a short term vision, and making any meaningful progress will be a slow and expensive undertaking.
This state of affairs is exactly why we need more proactive shortcuts based on an engineering approach to medicine and aging. A great deal is in fact known, proven, and hypothesized with reasonable evidence when it comes to the cellular and molecular damage that causes aging. There is a solid list of the types of damage involved, a list finalized more than twenty years ago with no new additions since then even in this period of great progress in biotechnology. Thus it is reasonable to think it is fairly complete. If researchers develop means to repair that damage, then knowing how exactly the damage interacts and progresses - with great complexity - to cause aging becomes much less important. This is how the engineering approach works: you build using present knowledge where it is cost-effective to bypass the need to gain further knowledge. You won't win all the time, but it is a strategy that should produce far better results in the near term. There is every reason to hurry development of treatments for degenerative aging, given that the cost of delaying a day in the effective treatment of aging is more than 100,000 lives lost.
Here are two examples of the sort of research presently underway into the unmapped areas of brain biochemistry relevant to aging. These are very thin slices of a vast field of science:
Neuropeptides and Aging: Breaking the Signaling Barriers Within the Body
The complexities of the brain are still largely unrevealed. Associations between neuronal decline with age and the onset of disease have been identified, but the specific mechanisms that regulate this decline are still unknown. Between neuron morphological changes, alterations of neuronal signals, and accumulation of protein masses in various brain regions, the realms of research are far and wide. As brain functions are responsible for approximately 20% of the body's energy usage, further understanding of neurological function is essential for ensuring a longer and healthier life.
Neuropeptides are responsible for communicative signals between neurons and other regions of the body. Neuropeptide signaling changes with age, and frequently these changes induce detrimental effects in neurons. They are packaged in large dense core vesicles and cleaved by enzymes at each end to reach their mature forms, which then interact with G protein-coupled receptors to induce signaling. These receptors can be local, but may also be found in other regions of the body, which means that malfunction in a given neuropeptide's production or transport can result in dysfunction in multiple systems.
Interestingly, levels of the neuropeptide oxytocin are decreased in old mice plasma. Furthermore, knocking out oxytocin can diminish the formation of new muscle fibers upon injury induction, providing evidence to the possibility that age-related decreases in oxytocin can cause an age-related inability to regenerate muscle. Another neuropeptide that decreases with age is gonadotropin-releasing hormone (GnRH1), which is linked to inflammation and the stress response. Injection of GnRH1 into the brains of older mice restored neurogenesis in the hippocampus (the memory-forming center of the brain), which is a process known to decrease with age. The effects of altered neuropeptide levels can be profound, as is seen in the example of montane and prairie voles. Differing levels of vasopressin and oxytocin result in drastically differing social patterns, despite similar genetics between the two species. Such subtle differences in the regulation of neuropeptides are just an example of why it's important to understand how alteration in neuropeptide signaling with age can contribute to a potential decline in health.
The Aging Brain: Synaptic Regulation and Aging
Our brain is constantly changing, adjusting to the environment based on input. At the same time, there seems to be mechanisms in place to resist change. At the junctions between neurons and their targets, known as "synapses", there are mechanisms to ensure that the amount of signal sent from neurons and the sensitivity of the target cells are in constant balance. There is increased interest in how this homeostatic mechanism changes with age, as disruption in synaptic homeostasis may be causal to disease. Hence it may be possible to increase lifespan via interventions that restore optimal activity of synapses.
Involvement of TOR in increasing synaptic function is particularly interesting in light of the association of TOR inhibition and longevity. Disruption of the TOR pathway in yeast, nematodes, fruit flies, and mice increases lifespan significantly. Could the benefits of reducing TOR activity in part be explained by TOR's role in increasing synaptic function? There seems to be an overarching theme of disrupted synaptic function in neurodegenerative diseases, but whether this synaptic dysfunction is causal or consequential is still unknown.
DETERMINATION AND VISION FOR A BETTER FUTURE, ACHIEVED VIA THE MEDICAL CONTROL OF DEGENERATIVE AGING
In the long run, the span of decades and centuries, the only thing that really matters is technological progress. It is how we measure the division of eras, it is what makes the difference between poverty and wealth. It is why we live longer than our immediate ancestors and suffer far less pain and disease. Of all our technologies, the most important at this time are all in the field of medical science. Biotechnology is advancing at a rapid pace, and this is the era in which all of the manifold ills caused by aging will be eliminated. The causes of aging will be treated successfully, and in the fullness of time all age-related disease will be banished as a relic of a barbaric past, alongside smallpox, scurvy, and many other medical conditions that existed only because our knowledge and ability was lacking.
Significant, rapid progress in medical science and its clinical application requires large-scale research, however, and sad to say but medical research is funded at a tiny fraction of the level of investment it merits given the potential benefits. In our societies more funding is devoted to drinks with pretty umbrellas in them, or the lighting of game fields, or the tools of organized murder used upon the members of other tribes. Better medicine is a very low priority, and most people don't give any thought to medical research at all - or at least not until they are ill, which is far too late. Progress in a newly wealthy society full of distractions therefore depends on the unreasonable, the zealots, the motivated, the visionaries, and there are never enough of them to go around.
When we are out there raising funds for early stage research into human rejuvenation that won't pay off for another decade or two, strong motivations and compelling visions are very necessary. We must paint a persuasive picture of the terrible cost of aging today, and show a vision of a near future vastly improved by cures for age-related disease. Most people won't think about this and won't help to make it happen unless it is put in front of them at some point, and that is really all that advocacy is at root; persuading the world to help make things better, one person at a time.
The most significant event in a person's life is death. It changes everything. More precisely, it takes everything that a person had. If he was in love, he no longer is. If he was aspiring to pleasures, there will be none any longer. The world will be gone for the person. Every single neuron will disappear that was responsible for the wishes, desires, and feelings. We don't realize this, but everything single thing we accomplish, we do so looking in the face of inevitable death. Death takes away the sense of a person's life.
That little human being that you were once, who looked at the world with eyes wide open, got surprised, laughed, sometimes cried, this human being will cease to exist. Will disappear. Forever. Death is the triumph of unfairness. It is bloodcurdling that everybody will die. Kids, olds people, adults, women, men. Every person's life is a tragedy, because it ends badly every time. Death is so horrible that a man denies the very fact of its existence to protect himself. He simply doesn't think he is mortal or comes up with a unproven theory that there is no death whatsoever.
The inevitability of death is defined by the fact that people age. Therefore, the most rational behavior will be to study aging, and to try to slow it down and stop. I am standing in the middle of the hall in the institute where aging will be defeated. When? When there is enough funding. When there are large-scale scientific projects. When a lot of people understand that aging has to be eliminated without proposing any additional requirements.
A Vision of a Future Free of Alzheimer's
It is the year 2025 and it seems like a miracle reminiscent of John F. Kennedy's moonshot. A multi-modality cure for Alzheimer's disease was recently discovered, fast-tracked and approved by the FDA. Not just a prevention (although that came first, back in 2020), but breakthroughs in science and technology have actually caused a reversal of the disease. Just a decade earlier in 2015, the statistics were alarming and held the potential to create a global pandemic of catastrophic proportions. Half of all those over age 85 - the fastest-growing segment of the population - had some form of dementia. People of all ages cited Alzheimer's disease as the scariest of all disabling diseases in later life.
And for good reason. Back then, we didn't even know the cause of the disease let alone how to slow it, prevent it or cure it. And for the sufferers, the progression of the disease got worse over time until memory and judgment faded, followed by vast mood and behavioral changes, and eventually dementia victims had no ability to care for themselves in the most fundamental ways. Yet many often lived up to 20 years after diagnosis ... a life sentence for both the victims and their families. The projections for the future were staggering: By the year 2050, more than 115 million people world-wide could be suffering from Alzheimer's disease and other dementias.
But fast forward to the future when we woke up from that nightmare with a cure that combines advanced stem cell therapeutics, precision pharmaceuticals, trans-cranial direct-current stimulation and a highly specific lifestyle regimen. The results have been phenomenal. Suddenly cognitively impaired older adults who had been either living in long-term-care facilities or at home with around-the-clock caregiving could not only live with dignity but gain back their ability to remember, think, and live active lives again. And, it transformed the way everyone thinks about aging and the potential for the later years of life.
With the end of Alzheimer's disease, the world has changed for us in some very significant ways. More than half of all nursing-home beds have been emptied, saving hundreds of billions of dollars for families and governments world-wide. Tens of millions of caregivers have been unshackled from the burden of providing physical, emotional and financial care to loved ones suffering from the disease. And the health of these caregivers has improved dramatically, giving them a second chance at life. Research dollars aimed at finding a cure for Alzheimer's disease and other dementias can now be funneled into finding a solution for other diseases. Millions of individuals cured of Alzheimer's disease have now come out of the shadows to live independently, be a loving and interdependent part of their families, and find ways to be productive, contributing their wisdom and experience to their communities and society at-large. The fear of living a long life but being struck down by Alzheimer's disease has now been quashed. It has liberated us all to think about the future through the prism of possibilities which could include work, giving back, time with family and friends and the opportunity to stay active, engaged, and productive.
Of course, this isn't yet fact because we're here in 2015, speculating about the future. However, many share the hope and are working hard to turn that hope into a reality: that one of the biggest fears of aging - Alzheimer's disease and other dementias - can be thought of as a thing of the past by the year 2025.
TREATING AGING IN ADVANCE OF FULLY UNDERSTANDING AGING
Engineering is in essence the business of producing good, workable solutions in absence of complete knowledge. The Romans could construct excellent bridges with a tiny fraction of the knowledge of materials science, mathematics, and modeling possessed by today's architects. Medical technologies today are in much the same position: we might know about as much of the fine details of biology as the Romans did of the deeper sciences underlying architecture. A vast scope of discovery and cataloging is yet to be accomplished in the life sciences. Yet we can still produce good therapies well in advance of a full understanding of human biochemistry.
Pure science as practiced today is the polar opposite of engineering. The goal is to produce complete understanding, and only then hand over that knowledge to those who will apply it to produce technologies. This is an ideal rather than the reality, of course: at some point in the development process there are always those who will make the last leap to clinical application because it is more cost effective to take a chance than to grind to the very end of the research process. The last stages of medical research are ever a compromise between the ethic of science, full understanding first, and the ethic of engineering, let's just get it done when there's a reasonable chance of success. Building proposed therapies and trying them out is sometimes the best path forward for both learning and application of knowledge.
In aging research the archetype of the engineering approach is the SENS program, scientific projects aimed at moving as rapidly as possible towards practical rejuvenation therapies. The SENS vision for development is explicitly a way to use our present knowledge of forms of cellular and tissue damage that cause aging in order to work around our present lack of knowledge regarding how exactly metabolism and aging interact over time. The damage is comparatively simple, but the details of how that damage spreads and interacts, and how it forms age-related disease, are intricate and poorly understood. We are very complex self-adjusting biochemical factories, so it is a given that even simple malfunctions have complicated outcomes. Because the malfunctions are simple, however, they themselves are the best and most cost-effective point of intervention: the first step towards treatment of aging should be to repair the breakages known to cause it.
The very readable open access paper linked below is a similar argument for engineering (take action now) over science (wait for full understanding), but for less ambitious efforts to intervene in the aging process. These are drug development programs aimed at manipulating the operation of metabolism so as to gently slow the accumulation of damage, and thus slightly slow the pace of degenerative aging. The expected outcome here in terms of additional healthy life delivered per billion dollars invested is not great; you might look at the past decade of sirtuin research to see the median expected outcome, which is to say a lot of data on a tiny slice of metabolism and aging, but no practical therapies. In comparison given a billion dollars and ten years there is a reasonable shot at implementing prototype SENS rejuvenation treatments in mice. The challenge for now is to persuade enough people that this is the best path forward to have a hope of expanding the SENS funding and research community to this scale.
Why Is Aging Conserved and What Can We Do about It?
Aging is something everyone can relate to. From grandparents, to parents, and ultimately our own bodies, we are intimately familiar with the declines in form and function that accompany old age. Yet, we don't all appear to age at the same rate. Many individuals are healthy and active well into their 70s, 80s, or even 90s, while others will suffer from chronic disease and disability by the time they reach their 40s or 50s. Those of us that have companion animals also observe that different animal species or even subspecies, as in the case of dog breeds, age at profoundly different rates. Defining the factors that influence individual rates of aging is a major focus of aging research.
From a biomedical perspective, it is critically important to gain a better understanding of the mechanisms that drive biological aging, as age is the single greatest risk factor for the leading causes of death in developed nations. The fact that aging influences so many different conditions is particularly curious. What is it about aging that creates an environment within our cells, tissues, and organs that is permissive for all of these seemingly disparate pathological states?
In order to understand the biological mechanisms of aging, scientists have turned to laboratory model organisms such as rats and mice, fruit flies, nematodes, and even yeast. While some have questioned the utility of these systems as models for human aging, it is now clear that similar pathways and processes affect longevity in each of these species. These studies have resulted in the identification of interventions that slow aging in taxa spanning broad evolutionary distances. Although it is still unknown whether these interventions will slow human aging, the potential impact on human health, if they do, is enormous.
In general, the known conserved modifiers of longevity tend to mediate the relationship between fundamental environmental and physiological cues (i.e., temperature, nutrient status, and oxygen availability) and the regulation of growth and reproduction. One school of thought holds that this relationship results from the ability of organisms to forgo reproduction and invest in somatic maintenance during times of adversity. In other words, based on the quality of the environment, the organism has evolved to make the appropriate choice between allocating its limited resources toward reproducing rapidly, and hence aging more quickly, versus delaying reproduction and allocating resources toward maintaining the soma, thereby aging more slowly.
Although conserved longevity pathways clearly exist, it has been challenging to identify their primary molecular mechanisms of action or even to definitively determine whether they directly modulate the rate of aging. This is true, in part, because there are no generally accepted molecular markers of aging rate in any organism. In mammals, several phenotypes are known to correlate with chronological age, and a handful have been suggested to have some predictive power for future life expectancy; however, none have been demonstrated convincingly in prospective studies.
In addition to gaining an understanding of the molecular mechanisms of aging, a primary goal of aging research is to identify interventions that will slow aging in people. Advanced age is the primary risk factor for the majority of diseases in developed nations, and there are enormous social and financial pressures associated with demographic shifts toward more elderly populations. Interventions that expand the period of healthy life and reduce the period of chronic disease and disability (referred to as "compression of morbidity") offer the potential to alleviate these pressures while simultaneously increasing individual productivity and quality of life.
In practical terms, it may not be necessary to understand in detail why aging is conserved in order to do something about it. In several cases, components of the insulin signaling / mTOR network, as well as the sirtuins, have been shown to be associated with longevity and age-associated disease risk in people. While it remains unclear how difficult it will be to develop interventions to improve healthy aging in humans, there is reason for optimism that this may not be far off. Drugs that target these pathways, including some already shown to increase life span and health span in rodents, are beginning to be tested for effects on age-associated phenotypes or disease in humans. Unfortunately, because of the glacial pace of human aging when compared to common animal models, it will likely take several decades to determine whether rapamycin or other such compounds generally improve age-associated outcomes in people.
THE LATEST ON HETEROCHROMATIN AND AGING
Heterochromatin is the name given to the more tightly packed structural arrangement of chromosomal DNA in the cell nucleus. Changes in the way in which chromosomes are arranged within the cell nucleus are far from simple and, like various epigenetic modifications to DNA, have considerable influence over the pace of production of proteins. Circulating amounts of various proteins are the switches and dials of cellular machinery, changing constantly, determining behavior, and participating in countless feedback loops to further alter the production of other proteins. Every aspect of the cell plays a part in this dance, including the changing structural arrangement of nuclear DNA: it is characteristic of evolved complex systems that any given discrete part of the machine might be involved in a score of different important mechanisms.
It has been suspected for some time that heterochromatin has some influence on aging. Indeed, why shouldn't it? There are any number of ways to increase or shorten life span by altering levels of specific proteins in lower animals ranging from flies to mice. Alterations to the packing structure of DNA are likely to have many further effects, including changing levels of proteins known to alter the workings of longevity-associated processes. When researchers found a way to alter the proportion of DNA packed as heterochromatin in flies, they could dial up and dial down lifespan to a modest degree. There is considerable speculation as to why this works, but no definitive proof of the underlying mechanism as of yet. Sadly there is definitely an upper ceiling on the process: too much heterochromatin and the flies die.
Another interesting line of research links modifications to heterochromatin levels and cellular senescence. Increasing numbers of senescent cells with old age is well known to be a cause of degenerative aging, but here again the nature of the link with changing packaging of nuclear DNA is all very speculative. Much more research is needed to answer even the most basic of questions regarding how and why with any authority.
It is the case that researchers have used the so-called accelerated aging conditions of progeria and Werner syndrome, among others, to explore concepts and mechanisms that might be of relevance to normal aging. I say "so-called" because these conditions only have the superficial appearance of rapid aging: their underlying causes are in fact largely unrelated to ordinary aging. More than a decade after the identification of the critical breakage in cellular metabolism that causes progeria, for example, it is still far from clear whether this mechanism plays any meaningful role in human aging. It shows up to a small degree in old individuals, but is this significant over the present human life span? Perhaps not.
Here researchers investigating Werner syndrome make progress in understanding the disease mechanisms, which appear to involve heterochromatin. The publicity teams putting out the release are greatly overstating the relevance of this work to normal aging, however. Hype in research is a real problem, and sadly many groups who should know better are just as bad as the tabloids these days. So for my two cents, the relevance of this work on the causes of Werner syndrome to normal aging is just as speculative as is the case for work on the causes of progeria. It is likely that both conditions are the result of forms of damage that just don't happen to a meaningful level in a normal metabolism. When you are looking at broken biochemistry there is no guarantee that any of its operational characteristics are of use when understanding normal biochemistry, and breaking things to create a shorter life span usually has little relevance for any attempts to lengthen life span. Or at least that is the case until researchers can turn things around and demonstrate longer-lived animals via a reversal of the mechanism they are studying. Pay attention to longevity demonstrations, not demonstrations of shortened life spans.
Scientists discover key driver of human aging
Werner syndrome is a genetic disorder that causes people to age more rapidly than normal. People with the disorder suffer age-related diseases early in life, including cataracts, type 2 diabetes, hardening of the arteries, osteoporosis and cancer, and most die in their late 40s or early 50s. The disease is caused by a mutation to the Werner syndrome RecQ helicase-like gene, known as the WRN gene for short, which generates the WRN protein. Previous studies showed that the normal form of the protein is an enzyme that maintains the structure and integrity of a person's DNA. When the protein is mutated in Werner syndrome it disrupts the replication and repair of DNA and the expression of genes, which was thought to cause premature aging. However, it was unclear exactly how the mutated WRN protein disrupted these critical cellular processes.
Scientists sought to determine precisely how the mutated WRN protein causes so much cellular mayhem. To do this, they created a cellular model of Werner syndrome by using a cutting-edge gene-editing technology to delete WRN gene in human stem cells. This stem cell model of the disease gave the scientists the unprecedented ability to study rapidly aging cells in the laboratory. The resulting cells mimicked the genetic mutation seen in actual Werner syndrome patients, so the cells began to age more rapidly than normal. On closer examination, the scientists found that the deletion of the WRN gene also led to disruptions to the structure of heterochromatin, the tightly packed DNA found in a cell's nucleus. This points to an important role for the WRN protein in maintaining heterochromatin. And, indeed, in further experiments, scientists showed that the protein interacts directly with molecular structures known to stabilize heterochromatin - revealing a kind of smoking gun that, for the first time, directly links mutated WRN protein to heterochromatin destabilization.
"Our study connects the dots between Werner syndrome and heterochromatin disorganization, outlining a molecular mechanism by which a genetic mutation leads to a general disruption of cellular processes by disrupting epigenetic regulation. More broadly, it suggests that accumulated alterations in the structure of heterochromatin may be a major underlying cause of cellular aging. This begs the question of whether we can reverse these alterations - like remodeling an old house or car - to prevent, or even reverse, age-related declines and diseases."
A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging
Werner syndrome (WS) is a premature aging disorder caused by WRN protein deficiency. Here, we report on the generation of a human WS model in human embryonic stem cells (ESCs). Differentiation of WRN-null ESCs to mesenchymal stem cells (MSCs) recapitulates features of premature cellular aging, a global loss of H3K9me3, and changes in heterochromatin architecture. We show that WRN associates with heterochromatin proteins SUV39H1 and HP1α and nuclear lamina-heterochromatin anchoring protein LAP2β. Targeted knock-in of catalytically inactive SUV39H1 in wild-type MSCs recapitulates accelerated cellular senescence, resembling WRN-deficient MSCs. Moreover, decrease in WRN and heterochromatin marks are detected in MSCs from older individuals. Our observations uncover a role for WRN in maintaining heterochromatin stability and highlight heterochromatin disorganization as a potential determinant of human aging.
LATEST HEADLINES FROM FIGHT AGING!
AN UPDATE ON USING TALENS TO EDIT MITOCHONDRIAL DNA
Monday, April 27, 2015
Mitochondria are the power plants of the cell, a host of organelles evolved from symbiotic bacteria. They each carry a small amount of DNA, and this accumulates damage with age. Some sorts of damage can spread rapidly within a cell's mitochondria, causing all of them to become dysfunctional. The cell itself also malfunctions as a result, exporting damaging reactive molecules into surrounding tissues. A small but significant portion of all the cells in the body suffer this fate by the time old age rolls around, and their presence contributes to degenerative aging.
Any comprehensive rejuvenation toolkit developed in the near future must include some way to deal with this issue. One possibility is a form of gene therapy for all cells in the body, delivering fixed and fully functional mitochondrial DNA, coupled with removal of the damaged strains to prevent them from spreading once more. The use of TALENs is showing some promise here, but at this point the research community is focused on inherited mitochondrial diseases rather than aging:
Mutations in mitochondrial DNA (mtDNA) can be specifically targeted and removed by transcription activator-like effector nucleases (TALENs) in murine oocytes, single-celled mouse embryos, and fused human-mouse hybrid cells, providing proof of principle for a method that could one day be used to treat certain hereditary mitochondrial disorders in people.
Between 1,000 and 100,000 mitochondria power each human cell. Often, mitochondria in the same cell have different genomes, or haplotypes, a condition known as heteroplasmy. Certain haplotypes include mutations that impact mitochondrial function and cause disease, particularly in energy-hungry organs such as the brain and heart. Because mitochondria segregate randomly as cells divide, it is impossible to determine early in embryonic development how a mix of wild-type and mutated mitochondria inherited from the mother will affect an organism.
To rid mitochondria of these harmful mutations, researchers have used restriction enzymes as well as zinc-finger nucleases (ZFNs) and TALENs, which can be designed to recognize any DNA sequence, to cut and eliminate mutated mitochondrial genomes from heteroplasmic cells. "Because the cell likes keeping the number of mtDNA molecules constant, after elimination of the faulty ones, the wild-type copy will repopulate the cell."
Now, an international team has used mitochondria-targeting restriction enzymes and TALENs in the mammalian germline and early-stage mouse embryos for the first time. Injecting mRNAs encoding each enzyme into mouse cells with two different wild-type mtDNA haplotypes selectively removed the targeted genome variant, and the edited embryos grew into normal mice. The team did not observe any off-target effects. To determine whether the enzymes could be used to edit human mtDNA, the researchers fused mouse oocytes with fibroblast cells from patients with one of two mitochondrial disorders - Leber's hereditary optic neuropathy or neurogenic muscle weakness, ataxia, and retinitis pigmentosa. Unlike in the mouse experiment, mutant mtDNA was still detectable, albeit at lower levels, after TALEN mRNA injection. Mutated mtDNA usually only causes disease if more than 60 percent to 75 percent of a cell's mitochondria harbor the error, so "the reduction that we observed was more than enough for the phenotype to disappear."
INTERVENTIONS TO SLOW AGING IN HUMANS: ARE WE READY?
Monday, April 27, 2015
The more conservative end of the aging research community is not in favor of engineering approaches like SENS, which focus on repair of the known causes of aging as a way to evade very slow and expensive investigations of the details of how aging progresses, where understanding is still minimal and the unexplored spaces on the map remain very large. Engineering is a matter of doing the best you can in advance of full understanding, and can be highly effective. The Romans built great bridges without modern materials science and architectural understanding, for example. The conservative scientific viewpoint is to require something much closer to full understanding before progressing any further, however.
In the pure science view the only viable way forward to treat aging is to indeed follow the very slow and expensive process of obtaining full understanding of all the relevant complexity of our metabolism, followed by attempting to manipulate the operation of metabolism so as to slightly slow the aging process. Scientists putting forward this position avoid the claim that adding decades to human life spans is possible within the foreseeable future. Some don't believe it to be the case, others are merely not going to say so in public. The wheels turn slowly enough in the sciences that it has taken the better part of fifteen years to even come to the point of generally agreeing in print that gently slowing down the process of degenerative aging is possible and desirable.
All of this is why we need greater support for engineering approaches to the treatment of aging, such as the SENS research programs carried out by the SENS Research Foundation. If we wait around for the pure science community to catch up to what is plausible and worth trying, we'll all be aged and dead before there is significant progress. It is much better to forge ahead and build proposed rejuvenation therapies based on a reasonable expectation of providing benefits than to continue the slow and steady path. None of the approaches discussed in the paper below are capable in principle of providing more than a fraction of the additional years of healthy life span that a prototype rejuvenation toolkit based on SENS programs could in theory produce. They will further be of very limited use in old people: they don't repair the damage causing degeneration and disease, but only slow down the pace at which it continues to accumulate.
Human aging and age-associated diseases are emerging as among the greatest challenges and financial burdens faced by developed and developing countries. Research related to longevity extension has traditionally been viewed with skepticism and with concerns that it could lead to an increase in the size of the elderly population and the prevalence of diseases associated with aging. However, studies in a wide range of organisms have demonstrated that major lifespan extension is accompanied by reduced or delayed morbidity in most cases.
There was a general consensus among this panel of experts on the following points: (i) aging can be slowed by many interventions; (ii) slowing aging typically delays or prevents a range of chronic diseases of old age; (iii) dietary, nutraceutical, and pharmacologic interventions that modulate relevant intracellular signaling pathways and can be considered for human intervention have been identified. Additional potential targets will continue to emerge as research progresses; and (iv) it is now necessary to cautiously proceed to test these interventions in humans.
The strategies believed to be most promising by the panel of invited experts and authors of this manuscript are as follows: (1) Pharmacological inhibition of the GH/IGF-1 axis, (2) Protein restriction and Fasting Mimicking Diets, (3) Pharmacological inhibition of the TOR-S6K pathway, (4) Pharmacological regulation of certain sirtuin proteins and the use of spermidine and other epigenetic modulators, (5), Pharmacological inhibition of inflammation, (6) Chronic metformin use. These choices were based in part on: (i) consistent evidence for their pro-longevity effects in simple model organisms and rodents; (ii) evidence for their ability to prevent or delay multiple age-related diseases and conditions; and/or (iii) clinical evidence for their safety in small mammals and/or nonhuman primates.
Accumulating scientific evidence from studies conducted in various organisms and species suggests that targeting aging will not just postpone chronic diseases but also prevent multiple age-associated metabolic alterations while extending healthy lifespan. A number of pathways affecting metabolism, growth, inflammation, and epigenetic modifications that alter the rate of aging and incidence of age-related diseases have been identified. Interventions with the potential to target these pathways safely and to induce protective and rejuvenating responses that increase human healthspan are becoming available. We believe that the time has come not only to consider several therapeutic options for the treatment of age-related comorbidities, but to initiate clinical trials with the ultimate goal of increasing the healthspan (and perhaps longevity) of human populations, while respecting the guiding principle of physicians primum non nocere.
A MECHANISM LINKING INFLAMMATION AND BONE LOSS
Tuesday, April 28, 2015
Your bones are not as static as you might think, and are constantly being remodeled on the small scale by the activities of distinct populations of cells. It is known that a growing imbalance between the activities of osteoblasts, cells responsible for creating bone, and osteoclasts, cells responsible for breaking down bone, is involved in age-related loss of bone mass and strength. Researchers are making some progress towards understanding why inflammation causes more rapid bone loss, and one of the mechanisms turns out to be very similar:
Gum disease affects millions of North Americans each year. In fact, as much as $125B is spent each year in the US in an attempt to tackle periodontitis - considered an "osteoimmune" condition similar to osteoarthritis and osteoporosis - and its attendant complication: bone loss. Osteoinflammation produces larger osteoclasts. These "superosteoclasts" cause damage as they form on the bone surface, and, once attached, spit out enzymes that chew away at the bone - and loosen the teeth in the process. The larger the osteoclasts, the more efficient they are at resorbing bone. The question has always been, though: why does inflammation create larger osteoclasts?
To find the answer, the group looked carefully at the role of cytokines, chemicals released by cells in the body as part of an immune response. The team discovered that the cytokines spurred the production of adseverin, and from there, were able to trace a clear role for the protein through study models. "Adseverin appears to be critical for the generation or formation of super large osteoclasts responsible for the rapid bone loss associated with periodontal disease - and potentially other bone-related diseases such as osteoarthritis and osteoporosis. Adseverin has a very limited distribution in the body and very few cells express this protein at significant levels, which make it easier to target from a pharmacotherapeutic standpoint. It's an exciting drug target."
THE MORAL BANKRUPTCY OF BIOETHICS
Tuesday, April 28, 2015
I have to think that all too many bioethicists see it as their job to manufacture reasons not to make progress towards better medical technologies capable of preventing more pain, suffering, and death. The more self-evident the potential benefits of new medicine, the more ridiculous these manufactured reasons become, but these individuals are nonetheless striving hard to act as grit in the wheels, a spanner in the works. Some are even proud of it. How is it that we supposedly sensible human beings have created an entire infrastructure with the purpose of draining funding away from real medical research into order to slow it down? This entire field and all of its practitioners should be evicted from the halls of polite society.
Discussions of life extension ethics have focused mainly on whether an extended life would be desirable to have, and on the social consequences of widely available life extension. I want to explore a different range of issues: four ways in which the advent of life extension will change our relationship with death, not only for those who live extended lives, but also for those who cannot or choose not to. Although I believe that, on balance, the reasons in favor of developing life extension outweigh the reasons against doing so (something I won't argue for here), most of these changes probably count as reasons against doing so.
First, the advent of life extension will alter the human condition for those who live extended lives, and not merely by postponing death. Second, it will make death worse for those who lack access to life extension, even if those people live just as long as they do now. Third, for those who have access to life extension but prefer to live a normal lifespan because they think that has advantages, the advent of life extension will somewhat reduce some of those advantages, even if they never use life extension. Fourth, refusing life extension turns out to be a form of suicide, and this will force those who have access to life extension but turn it down to choose between an extended life they don't want and a form of suicide they may (probably mistakenly) consider immoral.
BIOCOMPATIBLE ARTIFICIAL BLOOD VESSELS GUIDE REGROWTH
Wednesday, April 29, 2015
Researchers have demonstrated a new method of implanting artificial blood vessel structures to guide regrowth of tissue, leading to regeneration of a functional biological blood vessel:
Blocked blood vessels can quickly become dangerous. It is often necessary to replace a blood vessel - either by another vessel taken from the body or even by artificial vascular prostheses. Researchers have developed artificial blood vessels made from a special elastomer material, which has excellent mechanical properties. Over time, these artificial blood vessels are replaced by endogenous material. At the end of this restorative process, a natural, fully functional vessel is once again in place. The most important thing is to find a suitable material. The artificial materials that have been used so far are not ideally compatible with body tissue. The blood vessel can easily become blocked, especially if it is only small in diameter. Researchers have therefore developed new polymers. "These are so-called thermoplastic polyurethanes. By selecting very specific molecular building blocks we have succeeded in synthesizing a polymer with the desired properties."
To produce the vascular prostheses, polymer solutions were spun in an electrical field to form very fine threads and wound onto a spool. The wall of these artificial blood vessels is very similar to that of natural ones. The polymer fabric is slightly porous and so, initially, allows a small amount of blood to permeate through and this enriches the wall with growth factors. This encourages the migration of endogenous cells. The new method has already proved very successful in experiments with rats. "The rats' blood vessels were examined six months after insertion of the vascular prostheses. We did not find any aneurysms, thromboses or inflammation. Endogenous cells had colonized the vascular prostheses and turned the artificial constructs into natural body tissue." In fact, natural body tissue re-grew much faster than expected so that the degradation period of the plastic tubes can be made even shorter.
CALICO LIFE SCIENCES PARTNERS WITH THE BUCK INSTITUTE FOR RESEARCH ON AGING
Wednesday, April 29, 2015
This sort of notice should be expected given that the leadership at Google's Calico venture shows all the signs of intending to set up a very broad research infrastructure for the development of drugs to modestly slow aging. Sooner or later they are going to partner with all of the major laboratories and research groups in the field that share the same interests. This latest news is missing any interesting details on which technologies they might be interested in, but that is par for the course. I point it out to play the connections game in this small research community, noting that the SENS Research Foundation also partners with the Buck Institute on, for example, senescent cell clearance research. Near everything else the Institute does is of little relevance to the SENS approach to development of rejuvenation biotechnology, however - it is more in line with the mainstream approach of manipulation of the operation of metabolism so as to slow aging. This is slowing the accumulation of damage, not trying to repair that damage, and will probably be more challenging and produce far less impressive results.
The future for SENS-like rejuvenation therapies such as senescent cell clearance is to step by step take over the mainstream by consistently producing much better results at much lower costs at each stage of the early development process. So far this is the way things are going for senescent cell clearance, but there are a lot of other technologies making up the rejuvenation toolkit of the future that remain far from that stage of progress.
The Buck Institute for Research on Aging in Novato announced Tuesday that it has entered into a partnership agreement with Calico Life Sciences, a Google-backed life extension company based in South San Francisco. Chris Stewart, chairman and CEO of the North Bay Life Science Alliance, an effort to develop the North Bay into an economic hub for life-science companies, said, "We're very excited. You're seeing for the first time a significant amount of private sector money going into research on aging. I think it is a good marriage between the two organizations."
In September 2014, Calico announced it had entered into a five-year joint venture with AbbVie, a Chicago-based pharmaceutical company, to develop treatments for cancer and Alzheimer's. Both Calico and AbbVie committed to investing 250 million initially with the option to each add another 500 million at an unspecified later date. Since then, Calico has entered into partnership agreements with five different research laboratories, including the Buck Institute, but it has kept the financial terms of those agreements and most other details secret. Stewart said more and more pharmaceutical companies are "outsourcing their research and development by going to universities or institutes like the Buck Institute and partnering with them. Rather than buying companies, Calico is doing some strategic partnerships."
Announcing the deal with the Buck Institute, Calico's president of research and development, Hal Barron, said in a press release, "Given the Buck's exclusive focus on aging, we believe that there's great potential to increase our understanding of the biology of aging and to accelerate the translation of emerging insights into therapies to help patients with age-related diseases." Aside from that, Calico declined all comment. The only details supplied in the press release were that Calico will have the option to obtain exclusive rights to discoveries made under research it supports at the Buck Institute and will establish and maintain "certain" science operations there. One possible reason for Calico's reticence is that it hasn't decided on what areas of age-related illness it wants to focus, and it doesn't want to tip its hand to competitors.
PREDICTED FUTURE LIFE EXPECTANCY CONTINUES TO INCREASE
Thursday, April 30, 2015
Predicting human life expectancy in the decades ahead is a big business, as the vast pension and life insurance industries rely upon these forecasts. If the forecasts are dramatically wrong, and they will be just as soon as any significant advances in rejuvenation biotechnology reach the clinic, then financial upheaval lies ahead for all of the counterparties, insurers, and governments who bet against larger than expected increases in human life. The actuarial profession pays attention to the state of medical research aimed at intervention in the aging process, and the more mainstream treatment of age-related disease, and their estimates of life expectancy at a given future date have been rising in past years. This is the most recent example of this process at work:
A new study forecasting how life expectancy will change in England and Wales has predicted people will live longer than current estimates. The researchers say official forecasts underestimate how long people will live in the future, and therefore don't adequately anticipate the need for additional investments in health and social services and pensions for the elderly. Researchers developed statistical models using death records, including data on age, sex, and postcode, from 1981 to 2012 to forecast life expectancy at birth for 375 districts in England and Wales. They predict that life expectancy nationally will increase for men from 79.5 years in 2012 to 85.7 in 2030, and for women from 83.3 in 2012 to 87.6 in 2030. The longevity gap between men and women has been closing for nearly half a century and will continue to get narrower. The forecasts for 2030 are higher than those by the Office of National Statistics, by 2.4 years for men and 1.0 year for women.
People living in the longest-living areas in 2012 - found in southern England and well-off parts of London - are expected to live seven or eight years longer than those in parts of urban northern England, such as Blackpool, Liverpool and Manchester, and South Wales - equivalent to the difference in national life expectancy between the UK and Sri Lanka or Vietnam. By 2030, the gap is projected to grow to more than eight years. "The bigger gains in life expectancy we predict will mean pensions will have larger payouts, and health and social services will have to serve an older population than currently planned. We also forecast rising inequalities, with bigger increases in lifespan for people in affluent areas than those in disadvantaged areas. This means wealthy people will benefit more from health and social services than poor people, and therefore should be prepared to pay its costs through higher taxes."
VISCERAL FAT CORRELATES WITH BRAIN TISSUE DAMAGE
Thursday, April 30, 2015
Building and maintaining excess fat tissue, specifically the visceral fat clustered around internal organs, harms long-term health in numerous ways. It raises the risk of suffering from all of the most common age-related medical conditions, and raises lifetime medical expenditures even while lowering life expectancy. A primary mechanism here is thought to be greater levels of chronic inflammation spurred by this fat tissue, but visceral fat is metabolically active and prompts a wide range of changes throughout an individual's body. One of the end results is a greater level of physical damage to brain tissue over time, largely a result of breakage and failure in tiny blood vessels:
Obesity has been associated with microstructural brain tissue damage. Different fat compartments demonstrate different metabolic and endocrine behaviors. The aim was to investigate the individual associations between abdominal visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) and microstructural integrity in the brain. This study comprised 243 subjects aged 65.4 ± 6.7 years. The associations between abdominal VAT and SAT, assessed by CT, and magnetization transfer imaging markers of brain microstructure for gray and white matter were analyzed and adjusted for confounding factors.
Our data indicate that increasing visceral adipose tissue rather than subcutaneous adipose tissue is associated with microstructural brain tissue damage in elderly individuals. This association cannot be accounted for by BMI, which is an easily obtainable clinical measure of obesity but does not discriminate different fat compartments. Awareness of differences in the underlying mechanisms between body fat patterns and brain damage may offer more focused individual advice or treatment than considering BMI only. Further research in a general population with a wider age range is necessary to study whether the relationship between visceral adiposity and microstructural brain tissue damage is merely a result of ageing, or exists independently of age. Furthermore, cognition tests could be of additional value for evaluating the clinical consequences of these findings.
THE DOG AGING PROJECT
Friday, May 1, 2015
A group of researchers are advocating for clinical trials in household dogs to test methods of gently slowing aging that so far are largely studied in mice only. The high level goal here is to produce more rigorous data in longer-lived mammals, something that is presently lacking. If as a side-effect it helps to raise awareness of the potential to extend healthy human life spans through progress in medical science, then all to the good. At this point the researchers have turned in part to the public and philanthropy to raise funds for the project, and are going about it in a fairly organized way. It is good to see the scientific community developing these skills, as this form of fundraising coupled with greater involvement of donors will become increasingly important in the future:
For millions of people, pets are considered part of the family. Unfortunately, companion animals such as dogs age rapidly and have relatively short life expectancies. Scientists want to change this. Research in the biology of aging has made tremendous strides over the past several years, with a few interventions found capable of slowing aging and extending lifespan in small mammals such as mice and rats. These same interventions could provide dogs with two to five or even more years of additional healthy, youthful life.
The Dog Aging Project is a unique opportunity to advance scientific discovery while simultaneously providing enormous benefit for people and their pets. We believe that enhancing the longevity and healthspan - the healthy period of life - in peoples' pets will have a major impact on our lives. To accomplish this goal, we are creating a network of pet owners, veterinarians, and scientific partners that will facilitate enrolling and monitoring pets in the Project. The Dog Aging Project has two major aims: a longitudinal study of aging in dogs and an intervention trial to prevent disease and extend healthy longevity in middle-aged dogs.
The first phase of this study will enroll middle-aged dogs (6-9 years depending on breed) in a short-term (3-6 month), low-dose rapamycin regimen and follow age-related parameters such as heart function, immune function, activity, body weight, and cognitive measures. These animals will then be followed throughout life to determine whether there are significant improvements in healthy aging and lifespan. The next phase of the study will enroll a second cohort of middle-aged dogs into a longer-term, low-dose rapamycin regimen designed to optimize lifespan extension. As with phase one, several age-related parameters will be assessed before, during, and after the treatment period. Based on the mouse studies, we anticipate that rapamycin could increase healthy lifespan of middle-aged dogs by 2-5 years or more.
We believe that improving healthy lifespan in pet dogs is a worthy goal in and of itself. To be clear, our goal is to extend the period of life in which dogs are healthy, not prolong the already difficult older years. Imagine what you could do with an additional two to five years with your beloved pet in the prime of his or her life. This is within our reach today, with your help.
INVESTIGATING FACTORS RELATING TO SURVIVAL AFTER AGE 50
Friday, May 1, 2015
A fifty-year longitudinal study of human aging is wrapping up, and the results, as is usually the case, point to the importance of lifestyle choices in determining natural variations in human longevity. It also reinforces the point that you can't use good lifestyle choices to guarantee a path to an exceptional life span: the majority of people with the best lifestyles are still dead in their 80s, even though they on average do far better than their peers, with a lower level of pain and disease. The only way to reliably live far longer in good health is through progress in medical science, for the research community to produce rejuvenation therapies capable of repairing the cell and tissue damage that causes aging. The degree to which we all help to ensure those therapies are developed in time is the greatest determinant of our future health and longevity.
For the past 50 years, researchers have followed the health of 855 Gothenburg men born in 1913. Now that the study is being wrapped up, it turns out that ten of the subjects lived to 100 and conclusions can be drawn about the secrets of their longevity. Various surveys at the age of 54, 60, 65, 75, 80 and 100 permitted the researchers to consider the factors that appear to promote longevity. A total of 27% (232) of the original group lived to the age of 80 and 13% (111) to 90. All in all, 1.1% of the subjects made it to their 100th birthday. According to the study, 42% of deaths after the age of 80 were due to cardiovascular disease, 20% to infectious diseases, 8% to stroke, 8% to cancer, 6% to pneumonia and 16% to other causes. A total of 23% of the over-80 group were diagnosed with some type of dementia.
"The unique design has enabled us to identify the factors that influence survival after the age of 50. Our recommendation for people who aspire to centenarianism is to refrain from smoking, maintain healthy cholesterol levels and confine themselves to four cups of coffee a day." It also helps if you paid a high rent for a flat or owing a house at age 50 (indicating good socioeconomic standard), enjoy robust working capacity at a bicycle test when you are 54 and have a mother who lived for a long time. "Our findings that there is a correlation with maternal but not paternal longevity are fully consistent with a previous studies. Given that the same associations have been demonstrated in Hawaii, the genetic factor appears to be a strong one." But still we found that this "genetic factor" was weaker than the other factors. So factors that can be influenced are important for a long life.