FIGHT AGING! NEWSLETTER
November 23rd 2015
Fight Aging! provides a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress towards the medical control of aging in order to prevent age-related frailty, suffering, and disease, as well as improvements in the present understanding of what works and what doesn't work when it comes to extending healthy life. Expect to see summaries of recent advances in medical research, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more.
This content is published under the Creative Commons Attribution 3.0 license. You are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!
To subscribe or unsubscribe please visit: https://www.fightaging.org/newsletter/
- Halfway to Our SENS Research Fundraising Goal, and Giving Tuesday is Coming Up on December 1st
- The Immortals Among Us
- Declaring the Importance of Classifying Aging as a Disease
- JAK-STAT Inhibition and Consequent Reduction of SASP as a Mechanism to Lower Inflammation in Aging
- Transthyretin Amyloid May Contribute to the Progression of Cartilage Damage and Osteoarthritis
- Latest Headlines from Fight Aging!
- The Health Optimizer's Point of View
- Heat Shock Proteins and Hormesis as a Basis for Therapy
- Investigating the Removal of Stemness from Cancer Cells
- Another Call to Classify Aging as a Disease
- An Analysis of Social Media Life Extension Advocacy
- Google Life Sciences to Fund Heart Disease Program
- Regenerative Medicine for Infected Teeth
- Human ARF Gene Blocks Zebrafish Regeneration
- The Latest on DNA Methylation as a Biomarker of Aging
- A Demonstration of Engineered Vocal Cord Tissue
HALFWAY TO OUR SENS RESEARCH FUNDRAISING GOAL, AND GIVING TUESDAY IS COMING UP ON DECEMBER 1ST
This year's Fight Aging! matching fundraiser has a 125,000 fund provided by generous philanthropists, and we are seeking to raise a further 125,000 from the community to fund progress in longevity science. All charitable donations made before the end of 2015 will be matched, with the funds going to the SENS Research Foundation to support their work on rejuvenation biotechnology. This includes programs aimed the safe removal of senescent cells and glucosepane cross-links, both of which are counted among the root causes of degenerative aging. I'm pleased to note that we're half way to the goal, with a month a half left to go: more than 390 donors have collectively given 67,000 in the last six weeks. There is another 58,000 left to go to hit the target, and if we manage this before the end of the year then we'll have collectively given a cool quarter of a million this year to speed up the best approaches to human rejuvenation therapies.
With this in mind, remember that Giving Tuesday is coming up on December 1st. If you haven't yet donated - or know people who might be persuaded - then that will be a great time to jump in. Medical science doesn't emerge from nothing: it needs your support, and here is a chance for your donations to be matched by other funds as well. From the latest SENS Research Foundation newsletter:
SENS Research Foundation is getting ready to celebrate #GivingTuesday on December 1st. GivingTuesday is now a global event celebrated by supporters of various charities giving to their favorite causes. If you've been planning on contributing to the fight against age-related disease this year, GivingTuesday is a great opportunity to make a difference.
So far, SENS Research Foundation has 3 matching grants set up for GivingTuesday. The first is our FightAging! Challenge which will match every donation you make to us up to 125,000. On GivingTuesday, the first 5,000 we raise will not be doubled or even tripled - it will be quadrupled thanks to the generosity of the Croeni Foundation and Aubrey de Grey. Help us turn 5000 into 20,000 and accelerate the fight against age-related diseases! Donate at http://www.sens.org/donate on December 1st.
If there are any in the audience interested in adding their own 5,000 matching grant to this Giving Tuesday initiative, then by all means contact us with the offer of help, and we'll connect you with the SENS Research Foundation to arrange the details.
It is thanks to philanthropy that SENS research is making progress. Just take a look at the SENS Research Foundation's 2015 annual report: seed funding the US startup Oisin Biotechnology to work on senescent cell clearance; transferring lysosomal aggregate clearance technology to Human Rejuvenation Technologies for development; the French company Gensight is now devoting significant funding to to clinical development of the mitochondrial repair technologies whose early stage research was supported under the SENS banner; progress towards the toolkit needed for glucosepane cross-link clearance was published in the prestigious journal Science. All of these initiatives were funded in part by everyday philanthropists just like you and I, alongside people like Peter Thiel, Jason Hope, and Aubrey de Grey.
The wheel is turning, and meaningful progress towards rejuvenation treatments is taking place. Our donations continue to move SENS research closer to realization, and closer to becoming the mainstream of aging research. The more that we can help to fund the demonstrations of effectiveness at every stage of early research through to early clinical translation, the sooner that therapies to treat and control aging will arrive.
THE IMMORTALS AMONG US
Let us define immortality as being a state of agelessness, which seems a common colloquial usage these days. More precisely this means that the risk of death due to intrinsic causes such as wear and tear damage of vital organs remains the same over time, perhaps due to advanced medical interventions. Falling pianos are still going to kill you, and a hypothetical biologically young immortal in a hypothetical environment maintaining today's first world extrinsic mortality rate would have a half-life of 500 years or so, meaning that at any age, there is a 50% chance of evading a life-ending event for another 500 years. There are no human immortals by this criteria of a static intrinsic mortality rate, it seems, though for a while it looked like very old humans might have essentially flat but very high mortality rates in the same way as very old flies do. Immortality in a state of advanced frailty and coupled with a 90% or higher yearly mortality rate isn't the sort of circumstance that most people would aspire to, of course. It barely improves on the actual circumstance that the oldest of people find themselves in, all too briefly.
However, let us think beyond the box. Consider the small horde of children that you'll find playing and running in any junior schoolyard here and now. By the time the survivors of their cohorts reach a century of age, the 2100s will have arrived. If the current very slow trend in increasing adult life expectancy continues, adding a year of remaining life expectancy at 60 for every passing decade, then something like 25% of these present children will live to see that centenary. But I don't for one moment believe that this trend will continue as it has in the past. Past increases in life expectancy were an incidental side-effect of general improvements in medicine across the board, coupled with increasing wealth and all the benefits that brings. Across all of that time, no-one was seriously trying to intervene in the aging process, to address the causes of aging, or to bring aging under medical control. Times are changing, and now many groups aiming to build some of the foundations needed to create exactly this outcome. You may even have donated to support some of them, such as the SENS Research Foundation. The trend in longevity in an age in which researchers are trying to treat the causes of aging will be very different from the trend in longevity in an age in which no such efforts are taking place.
You don't have to dig very far into the state of the science to see that the first rejuvenation treatments are very close, their advent limited only by funding. If funding were no issue for senescent cell clearance, for example, it would absolutely, definitively be in clinics a decade from now. Other necessary technologies are more distant, but not that much more distant - the 2030s will be an exciting time for the medical sciences. For the occupants of today's junior playground, it seems foolish to imagine that by age 60 they will not have access to rejuvenation treatments after the SENS model at various stages of maturity, many having having been refined for more than 30 years, at the height of their technology cycle, and just giving way to whatever radical new improvement happens next.
Take a moment for a sober look at the sweeping differences and expanded technological capabilities that exist between today, the 1960s, and the 1910s. So very much has been achieved, and that pace of progress is accelerating. Those junior playground athletes of today will live to see a world even more radically different and advanced than our present time is in comparison to the First World War era. These are the immortals among us. The majority of them will have the opportunity to attain actuarial escape velocity, to keep on using ever-improving versions of rejuvenation treatments until they are gaining life expectancy at a faster rate than they are aging. Their cellular damage, the wear and tear created by the normal operation of metabolism, will be repaired as fast as it is is generated. It is the rest of us, those of us who are no longer spring chickens, who are faced with much more of a race to the goal. The degree to which we can successfully fund and advocate the necessary research is the determinant of whether we can scrape by into the age of rejuvenation treatments, or whether we will gain modest benefits but still age to death - because we were born too soon, and because the rest of the world didn't get its collective act together rapidly enough in what is now the very tractable matter of building a cure for aging.
DECLARING THE IMPORTANCE OF CLASSIFYING AGING AS A DISEASE
To follow on from a recently linked article on the present regulatory state of affairs for aging research, below find another recent call for regulators and administrators to classify aging as a disease. Numerous researchers have issued opinions and position papers on the topic in the past few years, and to understand why this is the case requires an understanding of how regulation impacts the research funding landscape. From a regulatory standpoint aging is not currently considered a medical condition per se. In some classifications, deviation from normality is one of the baseline criteria, and hence universal phenomena like aging are not included, no matter how ugly the end result. In the case of regulation tied to the legal matter of whether or not it is permitted to offer a particular treatment, and in the US the FDA adopts an "all that isn't listed is forbidden" position, the omission of aging as a treatable condition is a big deal. It means that there is no straightforward path to commercialization of potential therapies for aging within the current framework, and this greatly raises the difficulty of obtaining funding for that goal.
Attempts to change this state of affairs are slow, expensive, drawn out affairs of official and unofficial lobbying. You can see one of the approaches presently underway in the forthcoming clinical trial of metformin, a drug highly unlikely to produce meaningful results in my opinion, but which is the thin end of the wedge when it comes to the scientific community trying to force change on the FDA in the matter of aging. The recent increase in calls to classify aging as a disease should be considered in this context: the word "disease" is just shorthand for "something that I'm allowed to try to treat, and can thus raise funding for." Now that slowing aging and the medical control of aging are accepted as a plausible, possible near future goal by much larger fractions of the research community, the regulatory straitjacket is becoming ever more uncomfortable.
In the case of the World Health Organization's International Statistical Classification of Diseases and Related Health Problems the situation is still all about money, but in this case the benefits sought are a little more indirect. Adding aging to the WHO classification scheme is a way to induce various bureaucracies around the world to direct thought, funding, and verbiage to aging in the context of possible treatments. This falls somewhere between an attempt to amplify advocacy for the treatment of aging and an attempt to expand government research funding, such as the National Institute on Aging budget, via existing mechanisms requiring adherence to the WHO classifications.
For my part, I think that striving to change the regulatory system from within is just another way of implicitly endorsing its existence. None of the vast costs imposed on medical research and development by FDA bureaucrats will go away if aging officially becomes a disease. The better way forward would be for researchers in the US to develop relationships with developers elsewhere in the world, such as the more advanced Asia-Pacific nations in which medical regulation isn't so overbearing and costly: commercialize elsewhere, and deliver services and therapies to the market via medical tourism. The result will be more new treatments, delivered more rapidly, and at lower cost. If the FDA continues to pile on the costs and time for regulatory acceptance of new therapies, more than doubled in the past ten years, alternative commercial ecosystems will develop. Not before time, to my eyes, and it is a pity that this process is not further along now. The best path ahead is to make the FDA and its ilk irrelevant, to bypass the broken system and grasp greater freedom, not to support the present bureaucratic suppression of medical research by spending years to slightly change its parameters.
Why Classifying Aging As A Disease Is Of Crucial Importance To Humanity
Most people have probably heard many times the idea that one can "grow old gracefully" and in a healthy way. This message is perpetuated by the fitness and health industry and pension companies love to show the image of happy, relatively healthy 65-year-olds who can finally escape dreaded work and do what they enjoy in life, for at least a few years before a period of serious disability and death. It is true that some people live over a century and delay many specific pathologies. I also agree that it is a more desirable scenario to die frail at 100 than earlier, but the fact is that what we define as biological aging is in itself a pathological problem, a problem that still suffers from a lack of research. While not every age-related change is studied, the damages can be broadly classified into categories, and specific biomolecular problems can be directly targeted.
While there is a small decrease in function between 20 and 40, the human body still remains "very healthy" until mid 40s when disease correlated to the aging process overtakes accidents/suicides as most common cause of death. Keeping the human body biologically under 50 years old would take away the vast majority of all disease, and even if biologically young people were obese and smoked, there would likely only be a small number of cases where these "unhealthy" habits caused lethal health problems. The problem with WHO and governmental programs is that these systemic pathologies destroying the body and generating ill health in the elderly are not yet considered to be a disease. I have worked trying to change this paradigm. Earlier this year I coauthored "It is time to classify biological aging as a disease", and Alex Zhavoronkov and his company In Silico Medicine have recently published a paper on this issue, to persuade the World Health Organisation to classify aging as a disease as a part of the International Statistical Classification of Diseases and Related Health Problems (ICD-11).
When I was a child I was told wrinkles signified wisdom and life experience, but didn't impact one's health in any way. Nowadays my brain is wired to spot the pathologies behind them; skins laxity and jowls linked to blood sugar crosslinking and destruction of collagen, dysfunction of matrix metalloproteinases and subsequent extracellular matrix degradation. Wrinkled skin is not simply a cosmetic issue, as senile skin is failing to perform its duties properly, similar to burned and scarred skin. Many old people become easily dehydrated, are less able to cope with temperature fluctuations, and they injure and bruise themselves easily due to the loss of components making up the main skin layer, the dermis. Skin aging in itself is yet not classified as a disease, but lesions have pathological names, and photo-aging caused by sun exposure, which shares molecular pathologies with intrinsic skin aging, is considered a pathological condition. What is humanity gaining by this hypocrisy?
JAK-STAT INHIBITION AND CONSEQUENT REDUCTION OF SASP AS A MECHANISM TO LOWER INFLAMMATION IN AGING
Here I'll point out a paper in which researchers link the suddenly popular JAK-STAT signaling pathway with the harmful activities of senescent cells in old tissues and the rising level of chronic inflammation that contributes to the progression of most age-related diseases. The varied roles of the genes and proteins involved in the JAK-STAT signaling pathway have been studied by a number of research groups of late. There are four Janus kinases (JAK) and at least seven Signal Transducer and Activator of Transcription (STAT) proteins involved in this very small slice of cellular metabolism, and of course their activities influence and are influenced by scores of other mechanisms. Nothing ever happens in isolation inside a cell. The JAK-STAT pathway is of interest because inhibition of some of its components and activities appears to somewhat restore the activity of old stem cell populations, and has also been shown to reduce the growth in chronic inflammation that accompanies aging.
In the open access paper linked below, the authors propose that reductions in inflammation resulting from JAK inhibition occur because the intervention damps down the harmful output of senescent cells. Cellular senescence is a mechanism that removes cells from the cycle of replication in response to damage or stress. It may be an evolved adaptation of a tool of embryonic development that serves to suppress cancer risk, but it unfortunately also produces damage as these cells grow in number - and aging is nothing more than an accumulation of damage and reactions to that damage. Senescent cells generate a disruptive mix of signal molecules known as the senescence-associated secretory phenotype; this alters the behavior of surrounding cells, damages nearby tissue structures, and to the point of this paper, creates inflammation. When few senescent cells are present, as is the case in younger life, there is little harm done. Most are destroyed by the immune system or by their own programmed cell death processes, but over time an ever-increasing number of senescent cells evade these fates to linger indefinitely. In old age a substantial proportion of some tissues are made up of these dysfunctional cells, and tissue function declines as a direct result. Even the cancer suppression falters in the end, with the inflammatory and other effects of SASP promoting cancerous growth more effectively than the removal of cellular replication suppresses it.
The direct approach to cellular senescence is to periodically destroy senescent cells to keep their numbers low. It doesn't matter how exactly they are causing havoc if they can be safely removed. This is the best and fastest path to therapies, but is nonetheless very much a minority concern in the research community. Shortcuts carried out in advance of understanding, even when they work as this destructive approach does, go against the grain of scientific culture. The usual preferred approach is to gather full understanding of what is going on under the hood and then alter the operation of cellular metabolism in targeted ways to reduce undesirable outcomes. Never mind that this is far harder, slower, more expensive, and - for the foreseeable future - less effective. What is important to the research community is that it aligns with the goal of mapping cellular metabolism. Along these lines, it is interesting to note that the paper below, essentially advocating modulation of SASP via JAK inhibition as a desirable approach to therapies, is written by the very same researchers who recently demonstrated improved healthspan via partial elimination of senescent cells.
This is why we need philanthropy and advocacy and organizations like the SENS Research Foundation to get out there and push forward down the fast and effective path. No distractions, no mapping, just straight to the first generation therapies capable of meaningfully treating the causes of aging. It is far from an academic question as to how rapidly effective treatments can be created to address the effects of cellular senescence in aging. Countless lives depend upon this and the other necessary components of a toolkit of rejuvenation therapies. So I'd say that the point to take away from this particular research paper is that it provides one more set of evidence to confirm that, yes, destroying senescent cells to remove SASP as soon as possible is a great idea. In that I'm not in agreement with the authors' summary on possible ways forward:
JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age
A hallmark of aging is chronic, low-grade, "sterile" inflammation. Elevated proinflammatory cytokines and chemokines are closely associated with mortality and with a variety of age-related diseases, including atherosclerosis, depression, cancers, diabetes, and neurodegenerative diseases. Inflammation also is associated with frailty, a geriatric syndrome characterized by decreased strength and incapacity to respond to stress.
The underlying mechanisms of age-related chronic inflammation, tissue dysfunction, and frailty remain elusive. Cellular senescence, stable arrest of cell growth in replication-competent cells, is a plausible contributor. Senescence can be induced by a number of stimuli and stresses. Senescent cells accumulate with aging in the skin, liver, kidney, the cardiovascular system, and other tissues in various species. The senescence-associated secretory phenotype (SASP), largely comprised of proinflammatory cytokines and chemokines, links senescent cells to age-related inflammation and diseases. We found that elimination of senescent cells delayed the onset of age-related phenotypes and enhanced healthspan. Therefore, senescent cells and the SASP could play a role in age-related pathologies, particularly those that involve systemic inflammation.
The JAK/STAT pathway plays an important role in regulating cytokine production. We hypothesized that it may directly affect the SASP. We demonstrate here that senescent preadipocytes, fat cell progenitors, accumulate in adipose tissue with aging and can contribute to adipose tissue inflammation. We found that JAK inhibitors decrease the SASP in preadipocytes and human umbilical vein endothelial cells (HUVECs). They also decrease age-related adipose tissue and systemic inflammation as well as frailty. Our findings provide insights into the possible contribution of senescent cells to age-related inflammation and, in turn, to age-related pathologies, as well as potential therapeutic targets to alleviate age-related dysfunction.
There are three potential approaches for targeting senescent cells. One is to prevent them from arising by disabling p16- or p53-related processes or other upstream mechanisms that drive the generation of cellular senescence. This approach, however, is likely to induce cancer. The second is to eliminate senescent cells that already have formed. The third is to blunt the proinflammatory nature of the SASP. Mounting evidence suggests that senescent cells can have both harmful and beneficial effects. Therefore, partial suppression of the SASP seems to be a reasonable option, particularly when short-term alleviation of age-related dysfunction might be indicated.
TRANSTHYRETIN AMYLOID MAY CONTRIBUTE TO THE PROGRESSION OF CARTILAGE DAMAGE AND OSTEOARTHRITIS
Earlier this year researchers published evidence suggesting that rising levels of transthyretin (TTR) amyloid may contribute to age-related damage to cartilage tissue in joints and consequent development of osteoarthritis. Amyloids of various types accumulate in tissue with advancing age, each resulting from a different misfolded protein whose altered properties in that state cause it to form solid deposits. The biochemistry of this process is different in each case, and usually complex and incompletely understood. You don't have to look any further than the field of Alzheimer's research and the still dominant amyloid hypothesis to see that investigations of amyloid biochemistry are enough to keep most of a sizable scientific industry busy for decades. Knowledge of amyloid-β has grown in proportion to the funding and attention directed to the Alzheimer's research community, but for many of the other forms of amyloid it isn't entirely clear as to exactly how their presence contributes to the age-related conditions that correlate with the presence.
In some cases this is because the data is still arriving: researchers were not looking in the right place, or not paying enough attention, or lacked funding for the necessary investigations. TTR amyloidosis is an excellent example of this situation, as until fairly recently the majority of research interest focused on the rare inherited form of the condition, which is caused by genetic mutation and leads to an abnormally rapid accumulation of amyloid. Then it was discovered that a sizable fraction of supercentenarians die due to TTR amyloidosis, the condition called senile systemic amyloidosis in this case to distinguish it from the inherited form. In essence this form of amyloid builds up in the cardiovascular system of the most elderly people, attaining a large enough presence to choke proper function of the heart. Later, in the past couple of years, researchers have found signs of the damage done by TTR amyloid in a range of age-related conditions: as a contributing cause of spinal stenosis; as an unsuspected contribution to heart failure in a much wider group of old people; and now in the progressive destruction of cartilage.
The silver lining here is that promising therapies capable of breaking down TTR amyloid are under development. The more that we see this amyloid involved in age-related degeneration, the happier we should be given ongoing progress towards a basis for effective treatments. The SENS Research Foundation has funded work on catabodies that can degrade TTR amyloid, other groups have made inroads into disrupting amyloid formation, while earlier this year a human trial of small molecule drugs to clear TTR amyloid reported good results.
Transthyretin Deposition in Articular Cartilage: A Novel Mechanism in the Pathogenesis of Osteoarthritis
Amyloid deposits are prevalent in osteoarthritic joints. We undertook this study to define the dominant precursor and to determine whether the deposits affect chondrocyte functions. Amyloid deposition in human normal and osteoarthritic knee cartilage was determined by Congo red staining. Transthyretin (TTR) in cartilage and synovial fluid was analyzed by immunohistochemistry and Western blotting. The effects of recombinant amyloidogenic and nonamyloidogenic TTR variants were tested in human chondrocyte cultures.
Normal cartilage from young donors did not contain detectable amyloid deposits, but 7 of 12 aged normal cartilage samples (58%) and 12 of 12 osteoarthritic cartilage samples (100%) had Congo red staining with green birefringence under polarized light. TTR, which is located predominantly at the cartilage surfaces, was detected in all osteoarthritic cartilage samples and in a majority of aged normal cartilage samples, but not in normal cartilage samples from young donors. Chondrocytes and synoviocytes did not contain significant amounts of TTR messenger RNA. Synovial fluid TTR levels were similar in normal and osteoarthritic knees. In cultured chondrocytes, only an amyloidogenic TTR variant induced cell death as well as the expression of proinflammatory cytokines and extracellular matrix-degrading enzymes. The effects of amyloidogenic TTR on gene expression were mediated in part by Toll-like receptor 4, receptor for advanced glycation end products, and p38 MAPK.
These findings are the first to suggest that TTR amyloid deposition contributes to cell and extracellular matrix damage in articular cartilage in human osteoarthritis and that therapies designed to reduce TTR amyloid formation might be useful.
LATEST HEADLINES FROM FIGHT AGING!
THE HEALTH OPTIMIZER'S POINT OF VIEW
Monday, November 16, 2015
Below find linked a profile of one of a number of modest health optimization initiatives that are driven by the desire to raise the odds of living to see the arrival of real, working rejuvenation therapies, such as the anticipated results of the SENS research programs. There is a large marketplace to serve people who are convinced they can do better than the 80/20 of calorie restriction and regular moderate exercise in personal health and longevity. This seems like a valid hobby for someone with time and money to burn, but I don't believe that that it is in fact possible to know whether or not you are in fact doing better or worse than the 80/20 approach. At least not at the present time. The data is far too uncertain and the possible gains too small for near all possible optimizing action that people might take today beyond calorie restriction and exercise. You are better off taking that time and effort and directing it to support progress in SENS research.
Your risk of death each year doubles every eight years. I've got one in a thousand chances of dying of natural causes this year. In eight years' time, it's two in a thousand. In 16 years' time, it's four in a thousand. Today, we're just trying to find those extra few years. In 20 years time, finding an extra five years will be huge. Maybe in those extra five years, they can cure aging. The idea is that increasing your life expectancy every year so you can live a bit longer massively increases your chance of living forever.
Rule number one: Stop smoking. If you smoke, you give up half your chances of getting there. And there's normal things, like diet and exercise. There are things you can do at home, like reducing blood pressure and heart rate, that have a huge impact on your general health. But that's all science and research-based. I'm certainly hoping there will be more radical approaches as well. There's also going to be things like storing your stem cells. I'd like to investigate who's offering that service. I want to be storing stem cells today - before the outside starts aging - so when we develop the technology to grow my own parts, I don't have to get a replacement organ and I can actually repair my own heart or repair my own lungs using my own stem cells. I'll be doing it with my 40-year-old stem cells rather than my 60-year-old stem cells. There are definitely going to be clinics out there offering longevity solutions without any science basis at all. I want to weed those out and avoid those ones as well.
Plenty of people have that ethical debate about whether or not you should extend life. But do people want to live forever? I think the answer's no. The people who do, really do. You don't half-want to live forever. If you want to, you definitely want to. There's this online survey, where they ask that question every year, and around 35% of people say yes. I thought that was amazingly low. Imagine a 90-year-old - a bit in pain, not doing anything exciting. If we cure aging, then it'll be a few years after that when we can reverse aging. If you could have a 20-, 30-year-old body again, which is going to be far more useful for you and certainly pain free, then you'd want to live forever. Still, an awful lot of people think that death is a natural thing and we shouldn't fight it.
HEAT SHOCK PROTEINS AND HORMESIS AS A BASIS FOR THERAPY
Monday, November 16, 2015
As this open access paper demonstrates, researchers continue to discuss manipulation of heat shock proteins and the hormetic response to mild levels of cell damage or stress as a basis for possible therapies to slow some of the consequences of aging. These proteins are a crucial part of cellular housekeeping mechanisms, and increasing their activity has been fairly conclusively demonstrated to be beneficial in a variety of species. Despite more than a decade of intent to do something along these lines, and some recent signs of progress, there has been little to no concrete movement beyond the laboratory, however.
Modulation of endogenous cellular defense mechanisms via the stress response signaling represents an innovative approach to therapeutic intervention in diseases causing tissue damage, such as neurodegeneration, for example is reported how drugs that modulate proteostasis by inhibiting Hsp90 function or promoting Hsp70 function enhance the degradation of the critical aggregating proteins and ameliorate toxic symptoms in cell and animal disease models. Efficient functioning of maintenance and repair processes seems to be crucial for both survival and physical quality of life. This is accomplished by a complex network of the so-called longevity assurance processes, which are composed of several genes termed vitagenes. Consistently, by maintaining or recovering the activity of vitagenes can be possible to delay the aging process and decrease the occurrence of age-related diseases with resulting prolongation of a healthy life span.
There is now strong evidence to suggest that factors such as oxidative stress and disturbed protein metabolism and their interaction in a vicious cycle are central to Alzheimer's disease pathogenesis. Brain-accessible antioxidants, potentially, may provide the means of implementing this therapeutic strategy of delaying the onset of Alzheimer's disease, and more in general all degenerative diseases associated with oxidative stress. As one potentially successful approach, potentiation of endogenous secondary antioxidants systems can be achieved by interventions which target the heme oygenase/carbon monoxide and/or Hsp70 systems.
Reports exist of enhanced longevity via treatment with a large number of agents in a wide range of animal models displaying hormetic dose responses. The generality of the hormetic dose response, being independent of biological model, endpoint, inducing agent and mechanism and with its quantitative features being a measure of plasticity constrained biological performance, strongly suggests that attempts to extend normal lifespan via alteration of metabolism will be likewise limited to the 30-60% as has been typically reported. Thus, hormesis has a fundamental role in aging research, affecting both the quality and the length of life as well as affecting the research methods (e.g., study design, statistical power, etc.) by which such biological concepts are studied.
INVESTIGATING THE REMOVAL OF STEMNESS FROM CANCER CELLS
Tuesday, November 17, 2015
Most types of cancer are made dangerous by malignancy and metastasis, the ability to grow and spread rapidly. For many cancers these capabilities have been shown to be driven by a comparatively small population of cancer stem cells. One of the possibilities arising from the growing knowledge of stem cell biology is to turn off the stemness of cancer cells, reprogramming them to cease aggressive replication. As this paper indicates, however, efforts on this front are still in the very early stages of research:
Metastasis is the major factor responsible for the lethality of malignant breast cancer in human patients. Although various targeted and non-targeted therapies can occasionally control the progress of breast cancer, a significant portion of patients develop resistance to chemotherapy and experience metastatic recurrence. The epithelial to mesenchymal transition (EMT), a key developmental program in embryogenesis, has been found to be closely intertwined with the occurrence of metastasis in various human cancers. EMT can be prompted by the expression of multiple transcriptional factors and is controlled by several signaling pathways.
Towards the goal of understanding breast cancer metastasis, our group performed a cross-species expression profiling and identified Foxq1 as an EMT- and metastasis-promoting gene in breast cancer. Following this discovery, Foxq1 expression has been shown to promote EMT and metastasis in a wide array of human cancers. In line with the previously-mentioned link between EMT and stemness, we demonstrated that ectopic expression of FOXQ1 led to an increase in the stem-like phenotype. This increase in the stem cell population correlated with the induction of EMT. Mechanistically, we identified the receptor tyrosine kinases PDGFR α and β as downstream targets of FoxQ1.
Our study showed that knockdown of PDGFR α and β significantly decreased cell proliferation, migration and invasion. The effects were greatest when both α and β were knocked down. Knockdown of PDGFR α and β decreased lung metastases in vivo. These results strongly suggest that FoxQ1's role as a promoter of the cancer stem cell's phenotype is regulated in part by PDGFR activity. Our study demonstrates that EMT and stemness properties are not controlled by identical gene programs, at least in some cell lines. Inhibiting PDGFR α and β significantly reduced the stemness properties without impacting the mesenchymal-like phenotype of those cells. Since this inhibition correlated with a marked decrease in malignancy, our study suggests that the acquisition of stem-like properties may drive malignancy to a greater degree than EMT alone. Further studies must be done to identify other pharmacological targets that synergize with the stemness-promoting activity of PDGFRs. Reversing cancer stemness, together with conventional chemotherapy, could provide an ideal approach for prevent cancer recurrence and metastasis by eradicating both the bulk tumor cells and the cancer stem cells with self renewal capability.
ANOTHER CALL TO CLASSIFY AGING AS A DISEASE
Tuesday, November 17, 2015
In the stifling, costly regulatory systems surrounding medical research and commercial application of therapies, aging is not classified as a disease for which one can develop treatments. This is a good deal of the reason why it is hard to raise funding for potential interventions in the aging process, and it is why, now that those interventions are more broadly recognized as plausible, we are seeing a growing chorus of calls for change. For my part, I'd rather see the whole corrupt, backwards system of medical regulation torn down, or for the research and development community to make regulators irrelevant by carrying out their work in other jurisdictions, supplying the resulting therapies via medical tourism. But the mainstream will always want to work to adjust the system from within, leaving most of the harms and unnecessary costs intact, rather than take more radical steps to speed up progress:
Aging itself is the process of the human body deteriorating over time, and its effects are now attributed to a wide range of illnesses. People gradually lose their sight and vision, their organs suffer decreased function, and in some cases people's very minds change so much that they cease being who they used to be. Several diseases and conditions are labeled as the culprits of aging, with research and treatments being directed at each of them individually. This work is certainly important, but several scientists argue that this approach is too piecemeal. According to them, such ailments represent the side effects of a greater disease, one that in fact can be treated and prevented. That disease is aging itself.
The notion of aging as a disease is not an entirely revolutionary one, and several scientists have been pushing for such recognition. Scientists have recently called on the World Health Organization to classify aging as a disease in the 11th iteration of its International Statistical Classification of Diseases and Related Health Problems (ICD-11). The ICD is the standard tool for identifying and classifying diseases used by medical professional throughout the world. Our current biological understanding of aging is shifting along with societal attitudes towards what can be classified as a disease, and that the ICD-11 needs to be updated to reflect this.
A change in nomenclature may not sound like it has much effect, but it has great potential. History has shown that the classification of mental disorders, such as autism, as diseases has led to increased attention to the subject, the development of more accurate diagnostic methods, and increased involvement of the pharmaceutical industry and policy makers. It also provides the basis for clinical trials, which are critical in creating specific anti-aging treatments. A formal World Health Organization classification of aging as a disease would involve the creation of a dedicated task force, in a fashion similar to what is being done for chronic pain. It would also allow for the recognition of an "ideal norm" of a disease-free state of a specified age (such as 25), which would provide a clear goal for treatments to strive towards. If we consider aging a disease, it doesn't just represent a nomenclatural change in thinking but rather a paradigm shift. The first step in tackling a problem is to define it, and while people may not specifically consider aging a disease as of yet, we have always been striving for longer and healthier lives. It is, after all, the entire purpose of medicine, and this classification is a logical next step. Science and medicine only make progress once the problem is properly identified.
AN ANALYSIS OF SOCIAL MEDIA LIFE EXTENSION ADVOCACY
Wednesday, November 18, 2015
One of the younger initiatives here takes a look at discussions of longevity science and living longer on social media. While I don't disagree with the general thrust of the article, that social media is largely filled with less helpful chatter, I would argue that it is hard to demonstrate that the initial premise is correct, that there is any usefully direct link between social media and success in the sense of raising funding for the right lines of research and development. Money is the present key to progress in rejuvenation biotechnology, as funding is the present bottleneck, but we can debate the ways and degrees to which that is influenced by the flow of discussion. Following various initiatives for the past decade, one of the things that has stood out for me is the disconnect from month to month between how much discussion takes place in various forms of media and how much money is coming in via philanthropy. Only at longer time scales, comparing now with a few years ago, are there correlations between increased discussion and increased funding.
This research aims to evaluate the capacity of social media to support the development of science combating age related disease. The study will explore whether this particular area of science is benefiting from social media promotion and advocacy, or instead failing to inspire or achieve any of these things. Key to this is determining the percentage of facebook posts which offer legitimate information in relation to prolonging lifespan. The results were obtained by analysing a sample of 100 Facebook posts from each of the most popular (in terms of membership) facebook groups related specifically to life extension. Each post was categorised by purpose and topic, and then those intended to spread seemingly legitimate information were given a legitimacy ranking. From the results, it is clear that these posts, on the whole, are not acting to stimulate development or progress in this area of science. Of most concern was a lack of legitimacy and scientific evidence behind many posts on the subject of life extension. The research highlights a range of issues which, if not improved upon, represent a genuine obstacle for popularising and advancing science combating age-related disease.
14.71% of posts were raising awareness of a potential cure for aging or age-related disease, 2.55% were raising awareness of a potential cause for age-related disease, 17.59% were analysis/opinion on subjects related to life extension, 31.02% were general advocacy, 5.86% were related to fundraising, 1.06% promoted commercial ventures, and 27.18% had no identifiable purpose or were unrelated to life extension. Only 14.71% of all posts were related to potential cures, and 82.61% of these were suitable for the legitimacy scale. Of these, 0% were actual studies, 55.9% were links to an analysis of a study, and 22.81% were articles based on opinion rather than a scientific study. If we take a look at the overall picture of life extension on social media, taking into account all the data we have collected, only 26.4% of posts could be considered as scientifically informative. Of these, a tiny 1.21% could be considered as a top grade legitimate source.
This is concerning, as legitimate information about developments in science are integral to spreading awareness among the mainstream. Advocacy is clearly a double-edged sword, as even advocacy based on memes and images is positive for the overall picture. However, advocating posts based on memes, images, and promotion, seem to play a more self gratifying role, and offer little in terms of legitimising the cause, particularly to a mainstream audience. Above all else, although attempts to raise awareness and gain greater advocacy through social media are admirable, and absolutely essential to the cause, the results show that a great deal more caution, and in many cases vigilance needs to be exerted when sharing information.
GOOGLE LIFE SCIENCES TO FUND HEART DISEASE PROGRAM
Wednesday, November 18, 2015
An interesting next step from Google Life Sciences: they are putting forward 50 million in search of a laboratory to propose a program that pushes forward the state of the art in research and treatment of heart disease. Spent over ten years, that would produce an organization about the present size of the SENS Research Foundation, or a tenth of the Buck Institute, for purposes of comparison - and smaller than many of the research groups presently dedicated to the study of heart disease. So this is a sizable and welcome investment in medical research, but the significance is overhyped by the reporting organization here; no-one is going to cure heart disease with a 50 million project, since heart disease is caused by aging, and in the most general sense. This is an effort to change the funding landscape, stir things up, and make some progress.
If you walk through the list of forms of cell and tissue damage that causes degenerative aging, near every one of them contributes to structural failure of the cardiovascular system. The loss of stem cell activity and consequent decline in repair of tissues is only one of these: mitochondrial DNA damage produces oxidized lipids that contribute to atherosclerosis in blood vessel walls; extracellular cross-links stiffen blood vessel walls and cause hypertension and consequent structural weakening in the heart; senescent cells wreck havoc on all the tissues they accumulate in; transthyretin amyloids that accumulate with age are implicated in heart disease via their ability to clog the cardiovascular system; and the loss of lysosomal function in long-lived cells, including those of the heart, progressively damages their function. Curing heart disease, removing it from the picture, requires treatments that effectively address near all of the causes of aging.
Cardiovascular disease people on Earth than anything else - over 17 million a year, and the number keeps going up. Of those deaths, more than 40 percent is due to coronary heart disease. Medicine has drugs that can treat it and practices that can help prevent it, but nobody really knows what causes it or how to cure it. Now, Google and the American Heart Association aim to change that by dropping a 50 million funding bomb on the problem. And as you might expect from a Silicon Valley giant that believes in moving fast and breaking things - an approach that hasn't always transferred well to basic scientific research - the company isn't spreading the money around. Google Life Sciences and the AHA said the money would go to one team over five years. "Traditional research funding models are often incremental and piecemeal, making it difficult to study a long-term, multifaceted subject. AHA and Google Life Sciences have committed to a bold new approach."
The AHA, already the largest funder of cardiovascular research in the US outside of the federal government, says the program will be its most heavily funded initiative in nearly a century. Applications begin in January and if all goes according to plan, they'll be due by February 14th. (Valentine's Day. Get it?) If you want the 50 million, your idea has to fit on a single page. And Google won't take a financial or intellectual property stake in the results. The organizations hope that the program will accelerate the field of heart research much like Google's self-driving car eventually compelled the entire automobile industry to follow its lead.
REGENERATIVE MEDICINE FOR INFECTED TEETH
Thursday, November 19, 2015
This is an example of a comparatively straightforward approach to regenerative medicine, in which researchers mix existing drugs and promising signal molecules with a scaffold gel, aiming to spur regrowth that would not normally occur. In this case, this sort of approach has the potential to regenerate the pulp tissue damaged in infected teeth:
A researcher is developing an advanced nanogel formula that roots out endodontic infections and encourages the recovering tooth to rejuvenate itself. The most common treatment for endodontic infection is the dreaded root canal, which requires several clinic visits to complete. This new therapy would be a one-shot solution. The treatment consists of two antibiotics, ciprofloxacin and metronidazole, along with a dose of nitric oxide. These are encapsulated in an injectable, self-assembled "biomimetic" nanomatrix gel.
Nanogels are a hot area of research because they can be injected directly into a desired target and formulated to release medications over a specific timeframe. In this case, that allows the UAB team to defeat common endodontic infections with low concentrations of those two antibiotics and avoid a third antibiotic used in current therapies. That third antibiotic, minocycline, often stains teeth and causes other side effects. The gel also mimics the natural extracellular matrix (hence the term "biomimetic"), which encourages the formation of new blood vessels in formerly infected pulp tissue. "The reason a tooth dies is due to lack of blood vessels. By removing the infection and recruiting new blood vessels to the tooth, we believe we can rejuvenate it."
HUMAN ARF GENE BLOCKS ZEBRAFISH REGENERATION
Thursday, November 19, 2015
Usually it isn't worth noting that researchers have found a way to break a specific biological process; typically that is a very early stage in finding out how things work, pull out the pieces one by one and see what happens, taking place long before the emergence of a decent overall picture of the situation. Here, however, researchers have broken regeneration in a much more interesting way, a part of ongoing efforts to identify exactly why it is that zebrafish, like salamanders, can regrow entire limbs and organs while mammals cannot. The ultimate goal here is to find out whether the necessary machinery for adult organ regrowth exists at all in humans, a suppressed part of our evolutionary heritage, and if so, build a way to safely turn it on:
Insights from creatures like zebrafish and salamanders, which routinely regrow damaged tails, limbs, jaws and even hearts, may one day endow humans with heightened regenerative abilities. "In the last 10 to 15 years, as regenerative organisms like zebrafish have become genetically tractable to study in the lab, I became convinced that these animals might be able to teach us what is possible for human regeneration. Why can these vertebrates regenerate highly complex structures, while we can't?" Whether the regenerative powers of zebrafish and salamanders represent ancient abilities that mammals have lost, perhaps in exchange for advanced tumor-suppression systems remains an open question for biologists. Most tumor suppressor genes, being extremely useful for preventing cancer and for forming tissues during development, are broadly distributed and conserved across many different species. Recent studies, however, suggest that one, the ARF gene, arose more recently in the avian and mammalian lineage, and has no equivalent in the genomes of highly regenerative animals.
To explore whether this gene might play a role in preventing tissue regeneration in humans, the researchers added human ARF to the zebrafish genome and assessed how it affected the fishes' normal ability to regrow damaged fins after injury. They found that human ARF had no effect on the fishes' normal development or response to superficial injury, but when the researchers trimmed off the tip of a fish's tail fin, the gene became strongly activated and almost completely prevented fin regrowth by activating a conserved tumor-blocking pathway. "It's like the gene is mistaking the regenerating fin cells for aspiring cancer cells. And so it springs into action to block it. Humanizing a lower vertebrate species to study regeneration has not generally been used before, and to our surprise it turned out to be remarkably tractable. The gene fits right in very cleanly and completely alters the organism's response."
The discovery suggests that future efforts to promote regeneration in humans will likely require carefully balanced suppression of this anti-tumor system. The same pathway in humans theoretically could be blocked to enhance researchers' ability to grow model organs from stem cells in a laboratory dish, to enhance patients' recovery from injury. Since tumor suppressors are thought to play a role in aging by limiting the rejuvenating potential of stem cells, blocking this pathway could even be a part of future anti-aging therapies. However, any such interventions would come with significant risk of removing an important brake on the growth of tumors.
THE LATEST ON DNA METHYLATION AS A BIOMARKER OF AGING
Friday, November 20, 2015
Over the past few years, researchers have been working to construct and validate a biomarker of aging based on changes in DNA methylation patterns that occur over a lifetime. DNA methylation is constantly in flux, part of the complex system of epigenetic regulation that alters the output of proteins in response to circumstances in order to regulate cellular behavior. Some of these changes are driven by the accumulation of forms of cell and tissue damage that cause aging, and measurements of those should correlate well with biological age: how damaged you are, and thus how aged you are, and further how high your mortality risk is as a result.
A low-cost, quick, and reliable measure of the degree to which an individual is are damaged and aged will be a necessary tool for future research into aging and longevity. Currently the only way to assess whether or not a putative rejuvenation therapy works as intended to extend healthy life is to wait and see. That is very costly, even in studies that use short-lived species, and a therapy has to be tested in longer-lived mammals at some point on the road to clinical application. Given a reliable biomarker that measures biological age, it will be possible to rapidly assess many more potential therapies that treat the causes of aging, steering the community towards the most effective approaches, and reducing the time spent on dead ends or less effective research programs.
Several recent studies have made use of the age-related changes in methylation profiles to construct DNA methylation signatures, a DNA methylation age (DNAm age) or 'epigenetic clock', with impressively high correlations with chronological age, of about 0.7 or greater. Considering that methylation profiles are modifiable by lifestyle and other environmental influences, it has been proposed that DNAm age is a biomarker of aging, that is, that DNAm age provides a better estimate of biological age than chronological age and is associated with current and future health and mortality.
In this study, we estimated DNAm age using the frequently applied Horvath prediction model and confirmed it using the Hannum prediction model. The study sample consisted of 378 twins aged 30-82 years from the Danish Twin Registry. The oldest 86 twins (mean age 76.2 years at intake) were resampled in a 10-year follow-up study and had methylation age determined again at mean age 86.1 years. The mortality in this sample was subsequently followed for 8 years. The twin design enabled us to control partly for genetic and rearing environment in the mortality study.
We found that the DNAm age is highly correlated with chronological age across all age groups, but that the rate of change of DNAm age decreases with age. The results may in part be explained by selective mortality of those with a high DNAm age. This hypothesis was supported by a classical survival analysis showing a 35% (4-77%) increased mortality risk for each 5-year increase in the DNAm age vs. chronological age. Furthermore, the intrapair twin analysis revealed a more-than-double mortality risk for the DNAm oldest twin compared to the co-twin and a 'dose-response pattern' with the odds of dying first increasing 3.2 (1.05-10.1) times per 5-year DNAm age difference within twin pairs, thus showing a stronger association of DNAm age with mortality in the oldest-old when controlling for familial factors. In conclusion, our results support that DNAm age qualifies as a biomarker of aging.
A DEMONSTRATION OF ENGINEERED VOCAL CORD TISSUE
Friday, November 20, 2015
Here is news of a technology demonstration in which yet another part of the body has some of its component parts constructed in the laboratory and successfully tested for functionality:
Tissue engineers have for the first time made structures that not only resemble real vocal cords but also function like them. Impaired vocal cords make it hard or impossible for people to speak. There is currently no way to fix severe damage, which can result from surgery, traumatic injury, or diseases like cancer. The researchers implanted the engineered tissue into a larynx that had been taken from a dog and had one of its vocal cords removed. They demonstrated that the lab-made tissue vibrates and sounds like healthy tissue. Further tests in mice showed that the tissue elicited a minimal immune response, raising the researchers' hopes that such implants could eventually work in people.
Vocal cords are bands of tissue stretched horizontally on either side of the larynx, or voice box, just above the trachea, or windpipe. In recent years researchers have tried to re-create that structure in the lab, using polymer scaffolds to culture and grow stem cells in three dimensions - a well-established tissue engineering approach. But while they've made tissues that look the part, the engineered tissue has not vibrated effectively. Those previous attempts may have been limited because they didn't use cells from vocal cord tissue. This latest effort retrieved such cells from human cadavers and from donors who had healthy tissue removed during surgery. The researchers used a collagen scaffold to culture and grow the cells, and after a couple of weeks they had what resembled vocal cords. Subsequent protein analysis confirmed that it contained a large portion of the specific kinds of proteins found in the real tissue.
It will take at least several more years of development and testing before this process might be used in vocal cord transplants on people. But if further studies confirm the observation that tissue engineered from the cells of unrelated donors doesn't cause a harmful immune response, it should be possible to generate a large amount of vocal cord tissue from a small number of sources.