FIGHT AGING! NEWSLETTER
March 16th 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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- Senolytic Drugs to Kill Off Senescent Cells and Thereby Slow the Progression of Degenerative Aging
- More Press Attention for Aspirations of Radical Life Extension
- A Cancer Researcher Discusses the State of Cancer Research
- A Few Articles on Lifestyle and Brain Aging
- On Age-Related Dysfunction of the Blood-Brain Barrier
- Latest Headlines from Fight Aging!
- Surveying Present Well-Known Initiatives in Longevity Science
- The 2015 Alcor Conference Will Be Held in October
- Discussing SKN-1 and the Extracellular Matrix in Aging
- Considering an Autoimmune Component to Alzheimer's Disease
- Theorizing on H3.3 and Heterochromin in Aging
- Assessing Proteostatic Mechanisms in Long-Lived Mice
- Ultrasound Treatment for Amyloid in Alzheimer's Disease
- A Proof of Concept for Repair of the Cerebral Cortex
- Looking Into Ways to Prevent Heart Calcification
- Overthinking Radical Life Extension
SENOLYTIC DRUGS TO KILL OFF SENESCENT CELLS AND THEREBY SLOW THE PROGRESSION OF DEGENERATIVE AGING
As we age, an increasing number of cells fall into a senescent state in which they cease dividing and begin to secrete all sorts of compounds that both harm surrounding tissue structure and raise the odds of nearby cells also becoming senescent. This seems to be a tool of embryonic development that now also acts to suppress cancer risk by removing the ability to divide from those cells most likely to become cancerous. Unfortunately it harms tissue function in doing so, and worse, only actually suppresses cancer risk when there are comparatively few senescent cells. Given a lot of these cells their activities cause chronic inflammation and other issues that in fact raise the risk of cancer, and help cancer cells to prosper where they do arise. By the time we reach old age, a high proportion of cells in many tissues are senescent.
The Strategies for Engineered Negligible Senescence, SENS, is a package of research programs based on repair of the known forms of cellular and molecular damage that cause aging. It is the path to true rejuvenation therapies, rather than merely slowing the progression of aging, and thus is worthy of far more attention and funding than it has at present. Some parts of the SENS research programs have gained more attention in recently years, however. It seems to me that I was on the ball a few years back when I suggested senescent cell clearance would be the first SENS technology to arrive. Since the 2011 demonstration of senescent cell clearance to slow down degenerative aging in a laboratory lineage of aging-accelerated mice, an increasing amount of attention has been given to removing senescent cells. A startup was funded early this year to work on one possible attempt, for example.
A few years ago I thought that meaningful progress here would be something along the lines of repurposing the targeted cell killing technologies under development in the cancer research community: identify a clear molecular signal for cellular senescence, assemble a treatment based on a sensor mechanism attached to a destructive payload, and introduce millions of them into the body. I still think that is the best way forward to obtain high degrees of cell clearance. However, the present research industry is very focused on drugs, and especially focused on the reuse of existing drugs even if the outcome is marginal. So it may very well be that the first senescent cell clearance therapies are (a) not all that great in terms of degree of clearance, and (b) based on drug candidates that already exist or are slight modifications of what already exists.
Still, as this news shows, senescent cell clearance is a part of the mainstream now. The people pursuing it are never going to mention SENS, but fifteen years of persistent advocacy and small-scale funding of early staging research for SENS goals has brought senescent cell clearance as a strategy to its present position. Let that not be forgotten. Let it also be noted that the effects of actually trying to repair some of the damage outlined in the SENS viewpoint are already more impressive than most of the efforts to slow aging over the past decade: drugs aiming to alter metabolism by targeting targeting sirtuins, mTOR, and so forth. This is what we should expect. Repair should always produce better results that simply tinkering with the mechanism to slightly slow the pace of damage. Full healthspan and lifespan studies in mice remain to be carried out for this approach, however, so the degree to which it affects the bottom line as well as other measures has yet to be determined.
Scripps Research, Mayo Clinic Scientists Find New Class of Drugs that Dramatically Increases Healthy Lifespan
The scientists coined the term "senolytics" for the new class of drugs. "We view this study as a big, first step toward developing treatments that can be given safely to patients to extend healthspan or to treat age-related diseases and disorders. When senolytic agents, like the combination we identified, are used clinically, the results could be transformative. The prototypes of these senolytic agents have more than proven their ability to alleviate multiple characteristics associated with aging. It may eventually become feasible to delay, prevent, alleviate or even reverse multiple chronic diseases and disabilities as a group, instead of just one at a time."
Senescent cells - cells that have stopped dividing - accumulate with age and accelerate the aging process. Since the "healthspan" (time free of disease) in mice is enhanced by killing off these cells, the scientists reasoned that finding treatments that accomplish this in humans could have tremendous potential. The scientists were faced with the question, though, of how to identify and target senescent cells without damaging other cells. The team suspected that senescent cells' resistance to death by stress and damage could provide a clue. Indeed, using transcript analysis, the researchers found that, like cancer cells, senescent cells have increased expression of "pro-survival networks" that help them resist apoptosis or programmed cell death. This finding provided key criteria to search for potential drug candidates.
Using these criteria, the team homed in on two available compounds - the cancer drug dasatinib and quercetin, a natural compound sold as a supplement that acts as an antihistamine and anti-inflammatory. Dasatinib eliminated senescent human fat cell progenitors, while quercetin was more effective against senescent human endothelial cells and mouse bone marrow stem cells. A combination of the two was most effective overall.
Next, the team looked at how these drugs affected health and aging in mice. "In animal models, the compounds improved cardiovascular function and exercise endurance, reduced osteoporosis and frailty, and extended healthspan. Remarkably, in some cases, these drugs did so with only a single course of treatment." In old mice, cardiovascular function was improved within five days of a single dose of the drugs. A single dose of a combination of the drugs led to improved exercise capacity in animals weakened by radiation therapy used for cancer. The effect lasted for at least seven months following treatment with the drugs. Periodic drug administration of mice with accelerated aging extended the healthspan in the animals, delaying age-related symptoms, spine degeneration and osteoporosis.
The authors caution that more testing is needed before use in humans. They also note both drugs in the study have possible side effects, at least with long-term treatment. The researchers, however, remain upbeat about their findings' potential. "Senescence is involved in a number of diseases and pathologies so there could be any number of applications for these and similar compounds. Also, we anticipate that treatment with senolytic drugs to clear damaged cells would be infrequent, reducing the chance of side effects."
The Achilles' Heel of Senescent Cells: From Transcriptome to Senolytic Drugs
The healthspan of mice is enhanced by killing senescent cells using a transgenic suicide gene. Achieving the same using small molecules would have a tremendous impact on quality of life and burden of age-related chronic diseases. Here, we describe the rationale for identification and validation of a new class of drugs termed senolytics, which selectively kill senescent cells. By transcript analysis, we discovered increased expression of pro-survival networks in senescent cells, consistent with their established resistance to apoptosis.
Using siRNA to silence expression of key nodes of this network, including ephrins (EFNB1 or 3), PI3Kδ, p21, BCL-xL, or plasminogen activated inhibitor-2, killed senescent cells, but not proliferating or quiescent, differentiated cells. Drugs targeting these factors selectively killed senescent cells. Dasatinib eliminated senescent human fat cell progenitors, while quercetin was more effective against senescent human endothelial cells and mouse BM-MSCs. The combination of dasatinib and quercetin was effective in eliminating senescent MEFs. In vivo, this combination reduced senescent cell burden in chronologically aged mice. In old mice, cardiac function and carotid vascular reactivity were improved 5 days after a single dose.
These results demonstrate the feasibility of selectively ablating senescent cells and the efficacy of senolytics for alleviating symptoms of frailty and extending healthspan.
MORE PRESS ATTENTION FOR ASPIRATIONS OF RADICAL LIFE EXTENSION
Adding decades or adding centuries of health and vigor to human life spans are in fact much the same thing: success in adding decades in an environment of rapid progress in biotechnology means that all those people have time to wait for new technologies that add yet further decades. As soon as future rejuvenation treatments reach that point of initial effectiveness, at which years are added more rapidly than the passing of time erodes them, then most recipients are on a trajectory towards indefinite healthy life. This is shocking for many people when they first think it through, but it is a very straightforward, logical outcome of progress in medicine. Aging is just a medical condition; it is not set in stone, nor is it so mysterious that researchers cannot today be working on ways to remove its causes. In fact there are groups now, such as the SENS Research Foundation and Methuselah Foundation, that have been advocating and funding scientific work in this area for more than a decade.
It always takes far too long to sell the mainstream of any field on a new idea, even when that idea is obviously excellent and obviously an improvement on present affairs. So it is with the goal of repairing the causes of aging, and even the very concept of treating aging as a medical condition. Interest in treating aging in the medical research community has lagged very far behind the bounds of the possible these past two decades, and it has required a great deal of advocacy to get to where we are today. Ten years ago talking about rejuvenation via an implementation of SENS biotechnologies that repair various forms of cellular and molecular damage thought by the consensus to be involved in aging was called fringe, laughed at, or rejected out of hand. Today we see the start of mainstream researchers working on exactly the projectsproposed by SENS and companies founded to build commercial treatments. It is good to be right, but much better when everyone else starts to agree with you and, more importantly, work what has to be done.
Further, now we're in a time where large organizations like Google Ventures are openly putting a lot of money towards the goal of radical life extension. As of the moment they are not actually funding any work that has a hope of achieving that goal, rather mainstream efforts likely only to produce therapies capable of marginally slowing aging, but it is an important step in the growing support and legitimacy granted to longevity research. It is hard for talking heads to laugh at this work now, and from here on out that means increased funding, while the lines of research with a good chance of success will slowly overtake the current mainstream by demonstrating their better prospects at each stage of development. As that happens organizations like Google Ventures will begin to pour funding into that work. The first steps in this process are happening right now for senescent cell clearance, and will happen for other repair based technologies from the SENS portfolio as they bootstrap their way to success - something that depends very much on people like you and I helping philanthropists to deliver the needed funding, by the way.
Google Ventures and the Search for Immortality
Bill Maris has hundreds of millions to invest this year, and the freedom to invest it however he wants. He's looking for companies that will slow aging, reverse disease, and extend life. "If you ask me today, is it possible to live to be 500? The answer is yes," Bill Maris says one January afternoon in Mountain View, California. The president and managing partner of Google Ventures just turned 40, but he looks more like a 19-year-old college kid at midterm. He's wearing sneakers and a gray denim shirt over a T-shirt; it looks like he hasn't shaved in a few days. "We actually have the tools in the life sciences to achieve anything that you have the audacity to envision," he says. "I just hope to live long enough not to die."
Google puts huge resources into looking for what's coming next. In 2014, it started Google Capital to invest in later-stage technology companies. Maris's views on the intersection of technology and medicine fit in well here: Google has spent hundreds of millions of dollars backing a research center, called Calico, to study how to reverse aging, and Google X is working on a pill that would insert nanoparticles into our bloodstream to detect disease and cancer mutations. "There are plenty of people, including us, that want to invest in consumer Internet, but we can do more than that," he says. He now has 36 percent of the fund's assets invested in life sciences, up from 6 percent in 2013. "There are a lot of billionaires in Silicon Valley, but in the end, we are all heading to the same place," Maris says. "If given the choice between making a lot of money or finding a way to make people live longer, what do you choose?"
I also recently noticed the online post for an NPR interview from late last year. You might have missed the first time around, so here it is again:
Achieving Immortality: How Science Seeks to End Aging
The dream to live forever has captivated mankind since the beginning. We see this in religion, literature, art, and present day pop-culture in a myriad of ways. But all along, the possibility that we'd actually achieve such a thing never quite seemed real. Now science, through a variety of medical and technological advances the likes of which seem as far fetched as immortality itself, is close to turning that dream into a reality. This hour, we talk with experts who are on the cutting edge of this research about the science and implications of ending aging:
Wendell Wallach - consultant, ethicist, and scholar at Yale's Center for Bioethics where he chairs the working research group on Technology and Ethics. His upcoming book, "A Dangerous Master: How To Keep Technology From Slipping Beyond Our Control," will be out May 12th of 2015.
Aubrey de Grey - leading expert on anti-aging medicine and technology as well as the Chief Science Officer of the SENS Research Foundation. He's the co-author of "Ending Aging: The Rejuvenation Breakthroughs That Could Reverse Human Aging in Our Lifetime"
Stephen Cave - Fellow of the Royal Society of Arts. He holds a PhD in Metaphysics from Cambridge, and has worked as a diplomat for The Queen of England. He's the author of "Immortality: The Quest to Live Forever and How It Drives Civilization"
A CANCER RESEARCHER DISCUSSES THE STATE OF CANCER RESEARCH
Risk of cancer is very important in aging; as we become older we accumulate mutations in nuclear DNA at an accelerating rate. Sooner or later the right combination occurs to create a cancerous cell, set to divide without limit, its safeguard mechanisms broken. If that cell is not caught and destroyed by the immune system then its progeny form a tumor and mutate further at an increased pace. The tumor eventually grows large enough to disrupt a nearby vital organ or spreads copies of itself to a place where that can happen, and that is the end of the story for you. Cancer can happen at any age, but it is predominantly an age-related disease because the odds are based on the level and pace of DNA damage.
Any future rejuvenation toolkit has to incorporate a robust cure for cancer. Some combination of mature next generation targeted therapies and advanced detection for early stage, more easily cured cancers should be good enough when we're talking about supporting the addition of a few decades of additional healthy life expectancy. Being able to control 95% of all cancers would probably buy that much runway for most people, provided all the other necessary components of rejuvenation were also present and available. Once we consider more time spent alive and accumulating DNA damage, something more effective will be needed. Perhaps this will prove to be along the lines of blocking all telomere lengthening mechanisms as needed, or perhaps the current genetic revolution will lead - a few decades from now - to nanomachinery or gene therapies capable of cell by cell reversion of genetic alterations to a known good base sequence.
If we believe that a robust cancer cure is good enough to cover a few decades of additional healthy life added to the present human life span, then we shouldn't be all that worried about the state of progress in cancer research. Or at least, there is little we can do as advocates for longevity science that isn't already being done a hundred times more loudly and effectively by the present cancer advocacy community. Cancer research is very well funded indeed, and largely moving in the right direction. A great deal of innovation is taking place in the laboratory, for all that the present state of regulation makes it very slow going indeed for any of that to arrive in the clinic. If, as is the case at the SENS Research Foundation, we think that more than merely robust cancer cures are needed, then there are other lines of work to support, based on the aforementioned blocking of telomere lengthening.
At the detail level, and in the mainstream of cancer research, success over the next decade or two is driven by the degree to which researchers can find and exploit commonalities in cancer. Producing a treatment that works for twenty types of cancer is much better than one that is restricted to a single type. There are so very many types of cancer that meaningful progress over the field as a whole will be overwhelmingly determined by success or failure to identify and exploit such commonalities. Not all that many people are willing to go the whole hog and work on turning off telomere lengthening, which is the one clear thing that all cancers require, but in recent years scientists have identified a number of different mechanisms that may work as therapeutic targets for fairly broad collections of cancers. It is still very early days when it comes to seeing what will work and what will not, however. The researcher quoted in the interview below is working on one such cancer commonality, but like most of the mainstream he is fairly pessimistic on whether or not these commonalities will be enough:
Will there be a cancer cure in our lifetimes?
In graduate school, Barrie Bode conducted research aimed at expanding knowledge of the biochemistry and metabolism of a normal human liver. He was particularly interested in how the liver regulated the transport and metabolism of an amino acid known as glutamine. A year after earning his Ph.D., he came across two lines of cells from a cancerous liver. On a whim, he measured the rate of glutamine import into those cancer cells - and was stunned to find it was about 10 times higher than normal. That observation changed the course of his life's work. It also led to the identification of two specific amino acid transporters that are elevated in a wide spectrum of primary human cancers and aid tumor growth. For the past two decades, Bode has been working to develop highly targeted therapies to slow the uptake of glutamine and other nutrients that feed cancer.
"I think my research group is working in one of the hot areas of cancer research - identifying unique metabolic changes in cancer and developing ways to slow, stop or exploit these changes. We're not alone in this pursuit. These are exciting times. The scientific knowledge emerging annually is staggering. And it's really revealing the complexity of these diseases that we collectively call cancer. We are light years ahead of where we were just 20 years ago and are learning new things about the biology of cancer literally each week. In fact, we're generating so much data now - including sequences of nucleic acids, sequences of expressed proteins within a tumor, the chemical signatures of metabolic systems - that there is a little bit of a bottleneck. It's not a dearth of data that's limiting medical researchers but the necessary analyses of the available and emerging data. Those analyses will ultimately reveal cancer's complex fabric and vulnerabilities.
"I do not think there will be a cure for cancer in our lifetimes. It's still going to be a long road, but there is good news for cancer patients. Cancer is just a catchall phrase for dozens of different diseases that have the same endpoint - uncontrolled growth of tissue driven by mutated cells. Each cancer is complex and different, and even within a tissue there are distinct forms or cancer - different kinds of colon, breast, liver and brain cancers, for example, all driven by unique mutations and behaviors. Some types of cancer might be cured - that's happened already. But new pharmaceutical cures are rare. Over the next century, I'd say the chance is very remote that we will find a single 'cure for cancer.' Instead, treatments will become more refined and targeted, informed by the science and technologies that are available so that cancer can be managed much like other diseases, such as heart disease and diabetes. The plasticity, or ability to change, of cancer cells will require that these treatments be modified over time.
"There is a lot of cancer research going on, but there could be much more. The National Cancer Institute receives about 11 percent of the National Institutes of Health budget. The NIH budget likewise is about 10 percent of the national defense budget. So by deduction, we're funding cancer research at a penny for every dollar of defense."
A FEW ARTICLES ON LIFESTYLE AND BRAIN AGING
There is a good deal of evidence to show that lifestyle choices such as lack of exercise and putting on excess weight accelerate the decline of the brain. Lack of exercise means a more rapid deterioration in blood vessel integrity, and that in turn causes a growing number of tiny lesions in the brain, damage that adds up year by year until the cognitive effects become noticeable. Excess visceral fat tissue does the same thing via other mechanisms, spurring chronic inflammation that corrodes blood vessel structure. It does a lot more besides - most age-related conditions are accelerated by greater levels of inflammation, and that is handily provided by a fat and sedentary life.
Better lifestyle choices can add years of health and life expectancy per the consensus epidemiological data. You can't exercise your way to reliably living to age 90 or 100, however, and you're still going to be severely impacted by degenerative aging when you get there. So why bother? Well, for one, because you'll likely undergo much less pain, suffering, and frailty along the way. Perhaps more importantly, however, this is an age of very rapid, accelerating progress in medical biotechnology. A few years counts when that is how long it takes to develop a prototype therapy, or for a well-supported set of clinical trials to run to completion, or for a medical business to start up and put its products into the global supply chain. A few years means the difference between today's technology and the next version. As we move into an era in which researchers are now trying to treat the causes of aging with increasing vigor, it becomes an ever better idea to improve your own personal odds of living to see the results.
Better midlife fitness may slow brain aging
People with poor physical fitness in their 40s may have lower brain volumes by the time they hit 60, an indicator of accelerated brain aging. "Many people don't start worrying about their brain health until later in life, but this study provides more evidence that certain behaviors and risk factors in midlife may have consequences for brain aging later on." A subset of 1,271 participants from the Framingham Offspring Study participated in exercise treadmill testing in the 1970s, when their average age was 41. Starting in 1999, when their average age was 60, they underwent magnetic resonance imaging (MRI) of their brains as well as cognitive tests. The participants did not have heart disease or cognitive problems at the beginning of the study, and none were taking medication that alters heart rate.
In individuals with low fitness levels, the blood pressure and heart rate responses to low levels of exercise are often much higher than in individuals with better fitness. The researchers found that people who had a lower fitness level or greater increase in diastolic blood pressure (bottom number) or heart rate a few minutes into the low-intensity treadmill test (2.5 miles an hour) had smaller brain tissue volume later in life. People who had a larger increase in diastolic blood pressure during low-intensity exercise also performed more poorly on a cognitive test for decision-making function later in life.
Poor heart function could be major risk for Alzheimer's disease
The study associates heart function with the development of dementia and Alzheimer's disease. Participants with decreased heart function, measured by cardiac index, were two to three times more likely to develop significant memory loss over the follow-up period. "Cardiac index is a measure of heart health. It reflects cardiac output or the amount of blood that leaves the heart and is pumped through the body taking into consideration a person's body size. A low cardiac index value means there is less blood leaving the heart."
"We thought heart disease might be driving the increased risk of dementia and Alzheimer's disease. When we excluded participants with heart disease and other heart conditions, we were surprised that the risk of dementia and Alzheimer's disease got even worse. The risk we found between lower cardiac index and the development of dementia may reflect a subtle but protracted process that occurs over decades - essentially a lifetime burden of subtle reductions in oxygen and nutrient delivery to the brain."
Nourishing the Aging Brain
Despite a wealth of research into why caloric restriction extends life, we are still rather far from pinpointing the mechanism behind the longevity effect of this dietary intervention. Of significant interest is how diets may affect aging in the brain, which is particularly sensitive to alterations in energy availability. Caloric restriction attenuates the progression of Alzheimer's disease in mouse models, for example, while diet-induced obesity exacerbates symptoms. By studying the influence of diet on aging in the brain, researchers have discovered a number of bioenergetic molecules and druggable targets that may serve as candidates for interventions to delay the onset of neurodegenerative disorders.
Calorie-restricted animals are smaller than their well-fed counterparts, perhaps corresponding to decreased cell proliferation, a phenomenon that occurs in response to energy deficits in both normal and cancer cells. Decreased cell proliferation may be important, as it also leads to slower division of stem cells, allowing these progenitor cell populations to supply the various cell types of the body for longer periods of time. This sparing of stem-cell pools could explain why dietary restriction is particularly effective in maintaining tissue homeostasis in rapidly proliferating tissues such as skin, hair, and bone marrow. Neural tissues, such as the brain and spinal cord, have a limited capacity to rejuvenate themselves through stem-cell renewal, however, perhaps explaining why dietary restriction may not impact these areas of the body as much as others.
ON AGE-RELATED DYSFUNCTION OF THE BLOOD-BRAIN BARRIER
Yesterday I pointed out a prospective treatment that briefly disrupts the blood-brain barrier and by doing so appears to provoke glia, the immune cells of the brain, into clearing up amyloid deposits. The visible outcome is an improved state of cognitive function in a mouse model of Alzheimer's disease wherein the mice are engineered to generate amyloid in large amounts and show accelerated cognitive decline. That is one interpretation of the results, in any case. It is interesting that the researchers produced measurable benefits by temporarily opening the blood-brain barrier, as, like all structures in the body, its function declines and falters with age, and this is thought to contribute to neurodegenerative conditions such as Alzheimer's disease.
What is the blood-brain barrier? It is a layer of cells that wraps capillary blood vessels in the brain, wherein neighboring cell membranes overlap in an arrangement known as a tight junction that forms a barrier to fluids. It isn't just a wall, however: it is also a collection of molecular mechanisms that very selectively transport various privileged molecules back and forth between the brain and the blood supply. Everything else is blocked. With advancing age this barrier begins to leak, but the causes and mechanisms involved are not entirely clear at the detailed level, and nor is it completely nailed down as to exactly what sort of further damage is caused as a consequence of this leakage.
This open access paper on the topic is presently only available as a PDF, but is a good illustration of the current state of knowledge regarding the blood-brain barrier in aging: the sorts of questions that remain open and the direction of present research. As is often the case in specific manifestations of age-related degeneration, rising levels of chronic inflammation appear to play an important role:
Blood-brain barrier dysfunction developed during normal aging is associated with inflammation and loss of tight junctions but not with leukocyte recruitment
An accumulating body of evidence suggests that disruption of blood-brain barrier (BBB) function followed by blood-to-brain extravasation of circulating neuroinflammatory molecules may increase risk for the onset and progress of cerebrovascular-based neurodegenerative disorders such as Alzheimer's disease (AD), vascular dementia (VaD) and multiple sclerosis. We recently reported in wild-type mice maintained on standard diets, progressive deterioration of capillary function with aging was concomitant with heightened neuroinflammation. However, the mice used in this study were relatively young (12 months of age) and potential mechanisms for loss of capillary integrity were not investigated per se. The current study therefore extended the previous finding to investigate the effect of aging on BBB integrity in aged mice at 24 months and its potential underlying molecular mechanisms.
A functional consequence of increased cerebral capillary permeability with aging is enhanced blood-to-brain delivery of circulating neuroinflammatory molecules. Disturbed BBB has been reported in mid-aged rodent models independent of co-morbidities or the provision of pro-inflammatory diets. The cerebrospinal fluid/serum ratio of albumin, a surrogate marker of increased capillary permeability, is significantly elevated with aging. In addition, recent studies suggest that increased BBB permeability in aged rodent brains is associated with reduced expression of BBB tight junction proteins.
Only a few studies have investigated potential mechanisms involved in BBB breakdown with normal aging and these suggest heightened inflammatory processes. In vitro and in vivo studies show that TNF-α potentiates the permeability of BBB by suppressing the expression of tight junction complexes, whilst inhibition of TNF-α results in restoration of the tight junction protein expression and normalized BBB integrity. Similarly, anti-TNF-α antibodies were shown to attenuate BBB permeability via restored expression of BBB tight junction proteins in rat model of acute liver failure. In this study, exaggerated endothelial TNF-α in aged mice was associated with reduced expression of the BBB tight junction proteins.
Collectively, the findings of this study suggest that the mechanisms of BBB dysfunction that occurs in normal aging may result from the loss of endothelial tight junctions, induced by pro-inflammatory TNF-α through heightened peripheral inflammation.
LATEST HEADLINES FROM FIGHT AGING!
SURVEYING PRESENT WELL-KNOWN INITIATIVES IN LONGEVITY SCIENCE
Monday, March 9, 2015
One of the frustrating and probably incurable aspects of the popular press is that when a journalist reviews a field of work, he or she tends to paint every initiative as equal. So when it comes to efforts to extend human life span, no distinction is made between projects that have a good chance of achieving radical life extension or rejuvenation and those that can at best produce a slight slowing of aging, or those that are practical and supported by the present state of scientific knowledge versus highly speculative goals that may not be possible to achieve for a lifetime yet. To the journalist, these are all the same thing. It is something to think about whenever you read an article on an area of research or business with which you have no familiarity. You might not be learning as much as you think you are:
Peter Thiel, the billionaire co-founder of PayPal, plans to live to be 120. Compared with some other tech billionaires, he doesn't seem particularly ambitious. Dmitry Itskov, the "godfather" of the Russian Internet, says his goal is to live to 10,000; Larry Ellison, co-founder of Oracle, finds the notion of accepting mortality "incomprehensible," and Sergey Brin, co-founder of Google, hopes to someday "cure death." These titans of tech aren't being ridiculous, or even vainglorious; their quests are based on real, emerging science that could fundamentally change what we know about life and about death. It's hard to believe, though, since the human quest for immortality is both ancient and littered with catastrophic failures.
But historical precedent hasn't dissuaded some of the biggest names in Silicon Valley. Thiel, for example, has given millions to the Methuselah Foundation. Aubrey de Grey, Methuselah's co-founder, says the nonprofit's main research initiative, Strategies for Engineered Negligible Senescence (SENS), is devoted to finding drugs that cure seven types of age-related damage: "Loss of cells, excessive cell division, inadequate cell death, garbage inside the cell, garbage outside the cell, mutations in the mitochondria, and crosslinking of the extracellular matrix.... The idea is that the human body, being a machine, has a structure that determines all aspects of its function, including its chance of falling apart any time soon, so if we can restore that structure - at the molecular and cellular level - then we will restore function too, so we will have comprehensively rejuvenated the body."
But SENS, which has an annual operating budget of five million, is puny compared with the Brin-led Project Calico, Google's attempt to "cure death," which is planning to pump billions into a partnership with pharmaceutical giant AbbVie. Google is notoriously secretive, but it's rumored to be building a drug to mimic foxo3, a gene associated with exceptional life span. Then there's the Glenn Foundation for Medical Research, the granddaddy of modern antiaging initiatives, started by venture capitalist Paul F. Glenn in 1965. Since 2007, the foundation has distributed annual "Glenn Awards," grants to independent researchers doing promising work on aging. The Glenn Foundation also works to kick-start antiaging initiatives within large institutions ("It began at Harvard, and then we sought out MIT and then the Salk Institute and then the Mayo Clinic," Mark R. Collins, spokesman for the Glenn Foundation, explains), and it puts more than a million per year toward grants by the American Federation for Aging Research, a charitable foundation dedicated to age-related disease.
THE 2015 ALCOR CONFERENCE WILL BE HELD IN OCTOBER
Monday, March 9, 2015
The cryonics industry conferences hosted by Alcor take place every three years. The last was in 2012, and if you take a look at the Alcor YouTube channel you'll find videos from the event. These conferences are well attended by scientists in various fields, and the presentations are always interesting. The next conference in the series will be held later this year: the date is October 9th and the place is Scottsdale, Arizona:
We hold the Alcor conferences only once every three years. We heard from many people who didn't make it to the 2012 conference who expressed regret after hearing about it from those who went. This will be a rare opportunity to network and hear about progress in numerous areas directly from those involved.
We will very soon start announcing speakers and topics. For now, we plan to cover repair and revival scenarios, rehabilitation, and reintegration; the evidence supporting cryonics; how a regular person can afford cryonics and best plan for funding it and their own post-revival life; legal challenges and progress; multiple approaches to eliminating fracturing and other forms of damage; and much more!
This conference should be the largest cryonics conference yet, and we want the videos of sessions to serve a powerful educational and inspirational purpose for years to follow. There is already a substantial list of possible speakers and sessions but it is not too late to suggest your own ideas! Get your thoughts and suggestions in soon though, because the program will fill up over the next few weeks.
DISCUSSING SKN-1 AND THE EXTRACELLULAR MATRIX IN AGING
Tuesday, March 10, 2015
Here is a brief look at one small slice of research efforts focused on aging as it pertains to the extracellular matrix, the intricate structure of proteins that surrounds and supports cells. The arrangement of extracellular matrix proteins determines the mechanical properties of a given tissue, such as elasticity or ability to bear load:
The Blackwell lab focuses on research in healthy aging and lifespan by studying the model organism C. elegans, which is a type of worm. The lab specifically focuses on understanding oxidative stress responses and collagen development profiles in relation to lifespan. A simplified way of thinking about how collagen and extracellular matrix relate to lifespan is that as one grows older, the collagen and extracellular matrix slowly breakdown and are not as quickly repaired when injured. This is seen most prominently in cartilage-based injuries. Cartilage is made of collagen and extracellular matrix. A knee injury affecting the cartilage will heal much faster in young individuals than older individuals.
In C. elegans the SKN-1 gene plays a key role in promoting longevity through various pathway regulation including proteasome maintenance, stress resistance, immunity and lipid metabolism. One of the more surprising findings from these studies was the observation that SKN-1 was also involved in regulation of extracellular matrix genes and the resulting collagen expression profiles that change as the organism ages. SKN-1 dependent extracellular matrix remodeling is critical for lifespan extension in C. elegans. Several longevity interventions that delay aging are, in part, successful due to enhancing the function of extracellular structures.
C. elegans is the simplest multicellular animal with tissues that can conceivably be compared to humans. It was originally chosen in the 1970s as a model organism. Some of its advantages are that it reproduces in a few days and it self-fertilizes, which can make genetic manipulation much easier. It is a great organism for studying aging, because you can do so much to it genetically, and you can see the effects of aging in a short amount of time. With respect to translatability, I think there is a tendency to always question that. But worms and humans share the most fundamental processes, and the most basic wiring is there. So for testing an idea or delving into the unknown, C. elegans is a great organism to start with.
Humans have a much more complex profile of collagens, so it is hard to draw direct comparisons literally. However, I think the remodeling of the extracellular matrix and collagen is important in human aging. As an example, collagen decreases in the skin with age, as does the elasticity, and as elasticity decreases this further drives a decrease in collagen levels. The extracellular matrix is certainly an area that could use further studies on the effects of aging on the matrices to evaluate what changes occur over time.
CONSIDERING AN AUTOIMMUNE COMPONENT TO ALZHEIMER'S DISEASE
Tuesday, March 10, 2015
The present consensus on Alzheimer's disease focuses on the accumulation of misfolded proteins into amyloid plaques as the crucial mechanism, and thus clearing amyloid is a major research focus. Turning this focus into working therapies is taking far longer than expected, however, with numerous disappointing outcomes along the way so far. This state of affairs leads to a research environment in which other theories and approaches are multiplying, in search of better results. The example noted below is one of a great many initiatives that incorporate a quite different way of looking at the mechanisms of Alzheimer's disease:
The lipid Ceramide is pervasive throughout the human body as well as other animal and plant species. Researchers have identified elevated ceramide levels as a risk factor for Alzheimer's and have shown that amyloid triggers excess production of the lipid, although precisely how and why remain a mystery. That synergy had the scientists expecting that generating antibodies against ceramide would hamper plaque formation. Instead they found that the excessive ceramide had already worked its way into the bloodstream, generating antibodies that supported disease progression, particularly in female mice. This appears to support the theory that Alzheimer's is an autoimmune disease, which tends to be more common in women and is characterized by the immune system producing antibodies against a patient's tissue.
It also has researchers thinking that measuring blood levels of the lipid or some of its byproducts could be an early test for Alzheimer's since ceramide levels were elevated well before mice showed signs of substantial plaque formation. "It's a chicken-egg situation. We don't know if the anti-ceramide antibodies that may develop naturally during disease might be a result or a cause of the disease." The researchers are now circling back to a previous approach of directly blocking ceramide, this time, using a genetically engineered mouse that from birth lacks an enzyme needed to make ceramide, then crossbreeding it with an Alzheimer's mouse model. They expect that the mice genetically programmed to get Alzheimer's will produce less ceramide and less amyloid.
THEORIZING ON H3.3 AND HETEROCHROMIN IN AGING
Wednesday, March 11, 2015
There are very many speculative theories on mechanisms of aging that await studies to prove or disprove their effects, as well as to demonstrate whether or not those effects are significant over a human life span. Here is one of them:
We propose to focus on cells that either do not replicate in adults or accomplish very few divisions during the lifespan of an organism - that is, far less than set by the Hayflick limit. For the purpose of this review, we will term these cells below Hayflick limit (BHL) cells. Below Hayflick limit cells include postmitotic cells such as terminally differentiated neurons and muscle cells, and female ova, which are formed during embryonic development and remain in a nonproliferating state for decades. Below Hayflick limit cells are interesting for the following reason: On the one hand, they are far from entering the replicative senescence state; on the other hand, due to the constant molecular turnover and active metabolism in these cells (even in the absence of replication), the lifespan of an adult organism should lead to accumulation of irreversible changes, which could contribute to organismal aging.
One principal carrier of epigenetic information is chromatin - a hierarchically organized complex of DNA, histones, and nonhistone proteins. Not surprisingly, the recent interest in 'all things epigenetic' begat new ideas on the role of chromatin in aging. It has been known since the 60s that DNA methylation is progressively lost with aging. Could epigenetic changes also irreversibly accumulate with time in BHL cells thus contributing to organismal, but not replicative, senescence?
We discuss the possibility that in nonreplicating cells, epigenetic modifications, and more specifically very particular changes in chromatin structure - the gradual replacement of canonical histones H3.1/H3.2 with variant histone H3.3 - could contribute to organismal aging by inducing aberrations in gene regulation and other functions in BHL cells. Although this hypothesis has not been directly supported by a plethora of experimental data as yet, the aggregation of existing claims and accumulating evidence leads almost inevitably to paradoxical conclusions about the role of H3.3 in BHL cells with tempting implications with regard to the aging process. The 'H3.3 dilemma', as we term this situation in the field, is both sufficiently intriguing and convincing to be worth-raising, in the hope that it will trigger new directions and efforts for research.
ASSESSING PROTEOSTATIC MECHANISMS IN LONG-LIVED MICE
Wednesday, March 11, 2015
Proteostasis is the continued normal balance of protein levels and uses in cells. Aging and age-related disease by definition involve loss of proteostasis, such as through cellular damage and reactions to that damage. A wide array of mechanisms work to maintain proteostasis, and the list should probably include near all of those involved in protein production, folding, and recycling. There are far more researchers focused on this aspect of aging than on damage repair after the SENS model, in which it is argued that we should focus on fixing underlying damage, at which point proteostasis mechanisms should be free to restore the normal balance of cellular operations:
Protein turnover decreases with age, resulting in a progressive accumulation of damaged proteins and propagation of the aging phenotype. Maintaining protein homeostasis (i.e., proteostasis) through coordination of mRNA translation, protein synthesis, protein folding, and protein breakdown may be a key component of slowed, or healthy aging. Therefore, models of slowed aging may provide valuable insight into the role of proteostasis and how proteostatic mechanisms are regulated during slowed aging. We have proposed that simultaneously assessing both protein and DNA synthesis through deuterium oxide incorporation (D2O) can provide insight into what proportion of new proteins is made in new versus existing cells.
Here, we present a tissue- and sex-specific assessment of proteostasis using DNA and protein synthesis in long-lived Snell dwarf mice. We demonstrate that proteostatic mechanisms, as assessed by the new protein to new DNA synthesis ratio, were increased by threefold in skeletal muscle and heart of Snell compared to normal controls. Mean lifespan in female Snell is increased by approximately 50% compared to normal controls, while male Snell dwarfs have an approximate 29% increase in mean lifespan compared to their respective sex-specific controls. With the exception of protein synthesis in skeletal muscle, there were no sex differences in protein or DNA synthesis. Although differences in proteostatic mechanisms do not explain subtle sex differences in lifespan extension, it is important to note that both sexes have increased proteostatic mechanisms as well as significant lifespan extension. Collectively, our data further suggest proteostasis is a shared characteristic of slowed aging.
ULTRASOUND TREATMENT FOR AMYLOID IN ALZHEIMER'S DISEASE
Thursday, March 12, 2015
Researchers are investigating the use of ultrasound to reduce levels of harmful amyloid in the brain. At this point it is showing benefits in mice, but there is a way to go yet before there can be any certainty that this strategy can also work in humans:
From imaging babies to blasting apart kidney stones, ultrasound has proved to be a versatile tool for physicians. Now, several research teams aim to unleash the technology on some of the most feared brain diseases. The blood-brain barrier, a tightly packed layer of cells that lines the brain's blood vessels, protects it from infections, toxins, and other threats but makes the organ frustratingly hard to treat. Safely and temporarily opening the blood-brain barrier is a long-sought goal in medicine. About a decade ago, researchers began exploring a strategy combining ultrasound and microbubbles. The premise is that ultrasound causes such bubbles to expand and contract, jostling the cells forming the blood-brain barrier and making it slightly leaky.
Researchers hypothesized that the brief leakage would rev up the brain's inflammatory response against β amyloid - the toxic protein that clumps outside neurons in Alzheimer's and may be responsible for killing them. Disposing of such debris is normally the role of the microglia, a type of brain cell. But previous studies have shown that when β amyloid forms clumps in the brain, it seems to overwhelm microglia. Exposing the cells to antibodies that leak in when the blood-brain barrier is breached could spur them to wake up and do their jobs. Some antibodies in blood may also bind directly to the β-amyloid protein and flag the clumps for destruction.
Researchers recently tested the ultrasound strategy in a mouse model of Alzheimer's. After injecting these animals with a solution of microscopic bubbles, they scanned an ultrasound beam in a zigzag pattern across each animal's entire skull, rather than focusing on discrete areas as others have done. After six to eight weekly treatments, the team tested the rodents on three different memory tasks. Alzheimer's mice in the control group, which received microbubble injections but no stimulation, showed no improvement. Mice whose blood-brain barriers had been made permeable, in contrast, saw full restoration of memory in all three tasks. The team also found a two- to fivefold reduction in different types of β-amyloid plaques in the brain tissue of the treated group. The attempt to stoke microglia's appetite appeared to work; researchers found much more β-amyloid protein within the trash-eating cells of treated animals.
A PROOF OF CONCEPT FOR REPAIR OF THE CEREBRAL CORTEX
Thursday, March 12, 2015
Regenerative medicine for the brain that enables periodic repair in situ is essential to the future of human longevity. This is the only tissue in the body that cannot be outright replaced as a last resort, as its structure defines the data of the mind. Scientists are making some progress towards this goal, applying the tools developed in stem cell research in an increasingly refined way:
Researchers have taken an important step in the area of cell therapy: repairing the cerebral cortex of the adult mouse using a graft of cortical neurons derived from embryonic stem cells. The cerebral cortex is one of the most complex structures in our brain. It is composed of about a hundred types of neurons organised into 6 layers and numerous distinct neuroanatomical and functional areas. Brain injuries, whether caused by trauma or neurodegeneration, lead to cell death accompanied by considerable functional impairment. In order to overcome the limited ability of the neurons of the adult nervous system to regenerate spontaneously, cell replacement strategies employing embryonic tissue transplantation show attractive potential.
A major challenge in repairing the brain is obtaining cortical neurons from the appropriate layer and area in order to restore the damaged cortical pathways in a specific manner. The results show, for the first time, using mice, that pluripotent stem cells differentiated into cortical neurons make it possible to reestablish damaged adult cortical circuits, both neuroanatomically and functionally. These results also suggest that damaged circuits can be restored only by using neurons of the same type as the damaged area. This study constitutes an important step in the development of cell therapy as applied to the cerebral cortex.
Much research will be needed before there is any clinical application in humans. Nonetheless, for the researchers, "The success of our cell engineering experiments, which make it possible to produce nerve cells in a controlled and unlimited manner, and to transplant them, is a world first. These studies open up new approaches for repairing the damaged brain, particularly following stroke or brain trauma."
LOOKING INTO WAYS TO PREVENT HEART CALCIFICATION
Friday, March 13, 2015
Many elastic tissues harden with age in part due to calcification, an increased deposition of calcium between cells. In the cardiovascular system this is eventually fatal, as elasticity in blood vessels and the heart are essential to proper function. The usual focus for discussion here is the stiffening of blood vessel walls through this and other mechanisms, causing hypertension and all its attendant consequences, but heart tissue also stiffens and calcifies:
Calcific aortic valve disease (CAVD) is the third leading cause of heart disease. In CAVD, which can develop with age, heart valves begin to produce calcium, causing them to harden like bone. Scientists have long known that blood flow in the heart plays a role in the calcification of valves and arteries, but they did not understand how. In a new study, investigators reveal the chain of events that cause healthy valves to become bone-like. The researchers had previously discovered that disruption of one of two copies of a master gene called NOTCH1 can cause valve birth defects and CAVD. In the current study, the researchers report that NOTCH1 acts like a sensor on the endothelial cell - the cells that line the valve and vessels - detecting blood flow outside of the cell and transmitting information to a network of genes inside the cell. Activation of NOTCH1 by blood flow causes a domino effect, triggering numerous other genes in the network to turn on or off, resulting in suppression of inflammation and calcification. However, if this process is disrupted by a decrease in NOTCH1, the cells become confused and start to act like bone cells, laying down calcium and leading to a deadly hardening of the valve.
The scientists used stem cell technology to make large amounts of endothelial cells from patients with CAVD, comparing them to healthy cells and mapping their genetic and epigenetic changes as they developed into valve cells. The researchers used the power of gene sequencing and clever computational methods to uncover the "source code" for human endothelial cells and learn how that code is disturbed in human disease. "By understanding the gene networks that get disrupted in CAVD, we can pinpoint what we need to fix and find new therapeutics to correct the disease process." Sifting through this mountain of data, the scientists found three key genes that were altered by the NOTCH1 mutation and also acted as master regulators, turning off the critical pathways that normally prevent inflammation and calcification. Remarkably, when the researchers manipulated the activity of these three genes, almost all of the other genes in the network were corrected, pointing to novel therapeutic targets for CAVD. The scientists are now screening for drugs that restore the gene network to its normal state.
OVERTHINKING RADICAL LIFE EXTENSION
Friday, March 13, 2015
Some people spent a fair amount of time debating philosophical points on what it would be like to live for centuries or longer, a prospect that will become an actual possibility before the end of the century, enabled by the development of rejuvenation biotechnologies. There is nothing wrong with that as a hobby, but the most disconnected, ridiculous arguments against a long life span have a way of finding their way back into discussions over today's funding for aging research. Even the polemics in favor of radical life extension drift away into points that have little to do with day to day experiences of life, such as this one in which the author considers that aging into different opinions and ideals a century from now is actually undesirable and a viable argument in favor of dying instead.
Yet that prospect is hardly terrible; we are all living with it comfortably already, after all. No-one really expects to be exactly the same person twenty years from now, let alone hundreds were they available. Life is change and motion. The best argument for radical life extension via the medical control of degenerative aging is the simple one: that today we'd like to be alive and active tomorrow, and that was the state of things in all of our past days.
In the future it is likely that advances in medicine will grant us the opportunity to prevent the process of ageing. The question of whether eternal life would be a good thing will then be of the utmost practical importance to humanity. In this essay, I claim that it would be. We need to begin by working out our answer to Lucretius' view that death is not a bad thing. Put another way, we first need to find out what it is that makes us think life is valuable and worth living, and then we can see if the beliefs we end up committed to in light of our answer to this question also commit us to believing that eternal life would be desirable.
The Lucretian shifts the scope of the argument to consideration of whether death is a bad thing for the person who dies. However, this separation of the interests and happiness of persons who have close relationships is problematic. While others conclude Lucretius is wrong merely because there must be at least something valuable in life, I want to draw attention to a specific good that I believe is, and we generally agree to be, valuable, namely having positive personal relationships with others. In arguing that death is not a bad thing or not a bad thing for the person who dies, Lucretius is forgetting that death is what all too often robs us of the opportunity of creating, continuing, and/or developing further, positive relationships with others.
If my body lived for another 200 years, but my beliefs, aims, and way of living were utterly different from what they are now by the end, would it really be me that was still alive? It would be extremely difficult to maintain one's personal identity, understood this way, over a long time. Other authors doubt that such a psychologically disjointed life, with mere bodily and no personal continuity, is desirable. In response, I suggest applying the idea that relationships with others are central to the meaning of life to the problem of personal identity. Though the existence of these sources may be finite, their influence need not be. While it would be difficult to keep these influences in mind as time passed, an immortal person could take measures to actively remind themselves of them in writing, visually (with photos etc.) or memory if she showed sufficient discipline.
Another concern about the prospect of immortality is that it may become boring and therefore meaningless. What pursuits could be so interesting they would never get boring? I do not think the dismissal of intellectual contemplation as a candidate is convincing. Further, we should not ignore that as time passes, radically new pursuits (and relationships) will become available that, at that present time, we may have no way of conceptualizing (just as a caveman would scarcely have been able to conceptualize a video game). Further, some pleasures do not have diminishing marginal returns, such as the enjoyment of fine food. This point can, again, be made more convincing if we consider the element of social relationships. It is no coincidence that a recurrent and problematic question that people frequently raise during discussion of this topic is whether one's loved ones would be immortal too. Eating nice food might eventually get boring, but would spending time enjoying life with loved ones?