FIGHT AGING! NEWSLETTER
May 18th 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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- Considering the Rejuvenation of Muscle Satellite Cells
- An Intriguing Finding on Senescent Cells in Salamanders
- Putting Old Stem Cells Back to Work: Another Drug Target Emerges From Parabiosis Research
- Primate Study Evidence for the Harm Caused by CMV
- SENS Research Foundation in the Media
- Latest Headlines from Fight Aging!
- What is Aging? Can We Delay It?
- Posttraumatic Stress Disorder Associated With Shorter Telomeres, Greater Incidence of Age-Related Disease
- Working in the Cryonics Industry
- Do Smooth Muscle Cells Contribute to Arterial Stiffening?
- Progress in Removing the Cells From Cell Therapy
- An Approach to Disabling Telomeres in Cancer
- A Look at the State of Artificial Heart Design
- A Hypothesis on Damaged Mitochondrial RNA in Aging
- Targeted Engineered Cell Microfactories as a Cancer Therapy
- Hydrogels Improve Stem Cell Therapies
CONSIDERING THE REJUVENATION OF MUSCLE SATELLITE CELLS
Stem cell populations in the body are responsible for tissue maintenance, at the very least by keeping up a steady supply of new somatic cells to replace those that have reached their replication limits, but also via a range of other less well cataloged signaling processes. The latter category has become much more interesting to clinical researchers since the advent of the present generation of stem cell therapies, many of which produce benefits despite the fact that the transplanted stem cells don't actually contribute any meaningful number of daughter cells to the recipient. The boost to regeneration is all in the signals exchanged between cells, the levels of various proteins in the tissue environment.
Stem cell activity declines with advancing age, and the progressive failure tissue maintenance provides a strong contribution to the onset of dysfunction and age-related disease. At present this phenomenon is most closely studied in muscle tissue and the supporting population of stem cells known as satellite cells. This is where researchers have the most experience and greatest body of knowledge, and it is where most of the really interesting discoveries in stem cell aging have occurred in recent years. The picture building here may or may not also be the case in other tissues, but it is encouraging nonetheless. Insofar as muscle goes, the failure of stem cell activity consists of growing quiescence more than a depletion of numbers or some form of damage inherent to stem cells. This is a reaction to a changing balance of signals in the tissue environment, which in turn is a consequence of growing levels of the low-level cellular and tissue damage that is at root the cause of aging. Since signals are the proximate cause, changing the signals - and cell behavior - is well within the reach of present day biotechnology. The hardest part of this process is finding the relevant signals amid the vast complexity of an aging biochemistry.
So in recent years, researchers have focused on FGF-2, and GDF-11, and a range of other possible candidate signal molecules associated with various fundamental cell behaviors. The degree to which stem cell activity can be restored without immediate signs of harm due to damage is very encouraging, albeit surprising. The caution here has all along been the threat of cancer: the predominant hypothesis regarding the existence of stem cell decline with aging is that, like cellular senescence, it is the result of an evolved balance between cancer and regeneration - which are, after all, two sides of the same coin. Unrestrained growth versus controlled growth. So it has been something of a surprise to find that instructing old, damaged stem cells in old, damaged tissues to act as though young has not produced the immediate enormous risk of cancer that was expected. Still, researchers remain sensibly cautious, as they should given that these approaches to invigorate old cells don't directly address any of the underlying reasons why the cells became quiescent in the first place.
Here is a recent paper on the topic of muscle stem cell rejuvenation that looks at some of the targets and research topics that have been pushed a little way out of the limelight by GDF-11 and its ilk, some of which have interesting associations with cellular senescence in aging - itself a hot topic these days:
Forever young: rejuvenating muscle satellite cells
Extended lifespan raises the issue of handling age-related disorders, which profoundly affect the quality of life of an increasing number of people. At the physiological level, the most relevant feature of aging is the functional decline of tissue functions. In particular, in the elderly, muscle mass declines progressively by means of a process named sarcopenia, making skeletal muscle one of the more compromised tissues during aging. Beyond the protein breakdown associated with the loss of sarcomeric proteins, aged muscles display compromised regenerative capacity associated with altered environmental cues.
Muscle regeneration is achieved by the interplay between adult stem cells, named muscle satellite cells (MuSCs), and other cellular types (i.e. macrophages and muscle interstitial cells) that participate in the orchestration of regeneration. Muscle niche derived and systemic cues contribute to regulate muscle homeostasis and functionality. In order to ensure optimal performance, it is critical that several properties of MuSCs are finely regulated and coordinated. Amongst these properties are survival, self-renewal, fine-tuning between exit from quiescence and proliferative expansion, and eventually commitment toward myogenic differentiation. All these processes are altered in the elderly leading to compromised muscle functionality.
Beyond the notion provided by parabiosis experiments that circulating systemic factors are able to restore muscle regeneration in aged mice, recent evidence supports the hypothesis that MuSCs are intrinsically defective in aged muscles. These new findings open the possibility to target this stem cell compartment to counteract functional decline of muscle during aging.
Research has provided evidence that constitutive activation of the p38 MAPK in aged MuSCs leads to a decline in their self-renewal and regenerative capacity. Partial pharmacological inhibition of p38 is sufficient to restore the ability of MuSCs to participate efficiently in muscle regeneration and to maintain the stem cell pool. Interestingly, an alteration of the FGF-2/FGFR1 axis was identified as a feature of aged MuSC dysfunction. Earlier authors suggest that increased activity of FGFR1 results in the disruption of MuSC quiescence in aged muscles, but recent work supports the hypothesis that FGF-2 increase in the aged niche is a compensatory response to the loss of function of FGFR1 activity observed in aged MuSCs.
Other recent work has demonstrated that geriatric MuSCs fail to support muscle regeneration and display defective activation. Serial transplantation experiments supported the conclusion that this defect is a cell intrinsic feature of geriatric MuSCs. The authors identify the master regulator of senescence p16INK4a as a key determinant responsible for a quiescence-senescence switch (a process named geroconversion) operating in geriatric MuSCs in coincidence with their impaired regenerative potential. Indeed, genetic inactivation of p16INK4a locus was sufficient to recover the cells from the senescence-associated cell cycle arrest and restore their self-renewal capacity, leading to the reconstitution of the stem cell pool after muscle damage. The novelty of this study relies on the finding that geriatric stem cells are associated with the progressive accumulation of DNA damage and senescence-associated markers that in turn contribute to the loss of reversible quiescence mediated by p16INK4a.
These studies demonstrate that in addition to the regenerative environment that profoundly affects the niche and stem cell function, there is another level of tissue homeostasis regulation that is intrinsic to adult stem cells. The cell autonomous functionality declines in the elderly due to de-regulated p38 signaling and accumulation of DNA damage and senescence-associated features. This evidence suggests new avenues to reverse the dysfunctional status of MuSCs from aged tissues. For instance, constitutive FGFR1 signaling can restore MuSCs asymmetric division and self-renewal, and pharmacological blockade of p38 signaling can promote MuSCs self-renewal and engraftment by silencing p16INK4a, thus reversing geroconversion and allowing MuSCs to support muscle regeneration.
AN INTRIGUING FINDING ON SENESCENT CELLS IN SALAMANDERS
Salamander regeneration is becoming well studied. Researchers are mining the biochemistry of this and other proficient regenerator species such as zebrafish, as they would like to port over the ability to regrow limbs and internal organs into humans via the application of suitably designed medical biotechnology. At present it is an open question as to whether this a practical goal for the near future. While the past decade of investigation has uncovered a great deal of interesting new information on exactly how organ regeneration progresses in these species, it hasn't pulled out any one obvious manipulation that could be attempted in human biochemistry. So at this point making humans regrow lost limbs and organs in the same way that salamanders are capable of might prove be anything in between the extremes of (a) an enormously complicated reforging of our fundamental biochemistry better suited for the 2050s than the 2020s, and (b) something strikingly obvious in hindsight that could be implemented today were the details made clear. We just don't know yet.
On a completely separate topic, interest is picking up in senescent cells as a target for the treatment of aging. A demonstration of improved healthspan in mice through partial clearance of senescent cells was made public earlier this year, and that was the culmination of several years of murmurings following earlier, less compelling technology demonstrations. Several research teams are working on different methods of achieving the same end, at various very early stages on the road to readiness for clinical trials. Senescent cells contribute to aging in near every tissue: they accumulate over time in response to cell damage or a potentially damaging tissue environment, and not enough of them are destroyed by their own programmed cell death mechanisms or the watchful eye of the immune system, ever alert for errant cells that should be removed from the picture. Every senescent cell emits a cocktail of signal molecules that corrodes the nearby extracellular matrix and changes the behavior of surrounding cells for the worse. Enough of that and organ function declines into disease states.
Give these two contexts, this recent open access research is rather intriguing. It seems that salamander immune cells are exceedingly effective at destroying senescent cells during their regenerative process, and indeed at other times as well - which adds another mechanism that would be nice to port to humans if at all possible. Note that the full paper is PDF format only at this point, and so you'll have to click through to download and read it.
Recurrent turnover of senescent cells during regeneration of a complex structure
Cellular senescence has been recently linked to the promotion of age-related pathologies, including a decline in regenerative capacity. While such capacity deteriorates with age in mammals, it remains intact in species such as salamanders, which have an extensive repertoire of regeneration and can undergo multiple episodes through their lifespan. Here we show that, surprisingly, there is a significant induction of cellular senescence during salamander limb regeneration, but that rapid and effective mechanisms of senescent cell clearance operate in normal and regenerating tissues. Furthermore, the number of senescent cells does not increase upon repetitive amputation or ageing, in contrast to mammals.
It is clear that salamanders possess a rapid and efficient mechanism to recognise and clear senescent cells that either arise endogenously, or are introduced from culture. Our study demonstrates that a robust macrophage-dependent surveillance mechanism operates in normal and regenerating tissues of adult salamanders, and this allows them to circumvent the negative effects associated with the long-term accumulation of senescent cells, such as the disruption of tissue structure and function. These surveillance mechanisms are particularly significant for limb regeneration because there is a notable induction of cellular senescence during this process. Consistent with this, recent reports show that systemic macrophage depletion during salamander limb regeneration leads to defects in this process.
We propose that effective immunosurveillance of senescent cells in salamanders supports their ability to undergo regeneration throughout their lifespan. It has recently been suggested that targeting senescent cells could lead to therapeutic strategies for age-related pathologies. Here, we identify an animal with an efficient mechanism for surveillance of senescent cells operating through adulthood. Analysis of this mechanism could lead to the identification of novel therapeutic targets for the amelioration of age-related disorders and extension of healthspan.
There is a further interesting twist here. The occurrence of cellular senescence in aging may well be an evolutionary adaptation of its role in embryonic development, where it is thought to act as a guide in the development of tissue shape, such as at the tips of limbs and fingers. In this light, the greater presence of senescent cells during salamander regeneration might not be all that surprising: at the level of cellular organization regrowth of a limb acts in many ways like the embryonic development of that same limb. So is improved immune surveillance of senescent cells in salamander regeneration just the same thing that already happens in mammals during their embryonic development? Or is it something quite different, as indicated by the fact that it operates all the time and across a lifespan? These are not questions with definitive answers, and so, as for regeneration itself, further research is needed to understand whether or not greater immune clearance of senescent cells can be brought from salamander to human as a practical concern.
PUTTING OLD STEM CELLS BACK TO WORK: ANOTHER DRUG TARGET EMERGES FROM PARABIOSIS RESEARCH
Heterochronic parabiosis is one of the research success stories of recent years. By linking the circulatory systems of an old and a young individual, usually laboratory mice, researchers have learned that levels of signal proteins circulating in blood and tissue change with age, and that these signals are the proximate cause of a great deal of the characteristic decline in stem cell activity that occurs with aging. The full story likely involves reactions to low-level cell and tissue structure damage that in turn change the balance of proteins generated and circulated, and stem cells react to this information by damping down their activity.
The consensus view in the research community is that this and other similar changes over the course of aging exist because they reduce the risk of cancer. Cancer is a game of chance, awaiting the right combination of mutations and cell damage. The more that damaged cells undertake activity such as replication then the higher the odds of spawning the seeds of a tumor. But if cells, and stem cells in particular, are less active then tissues and organs malfunction and weaken. Life span then is an evolved balance between death by cancer on the one hand and death through loss of tissue maintenance on the other, with natural selection favoring a balance that achieves a life span that produces success for the species in its niche.
The stem cell and parabiosis fields of research have produced a range of ways to spur greater activity in old and damaged cell populations. Many forms of simple stem cell transplant appear to work because the transplanted cells deliver signals that instruct native cells to be more active, for example. Interestingly, these lines of work have largely shown much less of a cancer risk in the laboratory and the clinic than was expected at the outset. It may well be that the evolved balance in mammals can be favorably adjusted towards greater stem cell maintenance of tissues, and extended healthy life as a response, but it is still a little early to be more than modestly optimistic on this front, I think. A way to activate dormant stem cells doesn't do much at all to revert the levels of cellular and molecular damage that cause aging. It only partially solves one problem, the diminished numbers in useful and necessary cell populations. Beyond that there are metabolic wastes inside and outside cells, lingering senescent cells, high levels of stochastic DNA damage, cells taken over by malfunctioning mitochondria, and more. Aging is a lot more than just stem cell dysfunction.
There was considerable excitement over the last drug target to emerge from parabiosis research, GDF-11. Increased levels of GDF-11 in the bloodstream put stem cells back to work in old mice and produced meaningful benefits in measures of health. This latest research is similar in nature, but involves a very different mechanism, possibly connected to regulation of chronic inflammation and its effects on stem cell activity:
Drug perks up old muscles and aging brains
Aging is ascribed, in part, to the failure of adult stem cells to generate replacements for damaged cells and thus repair the body's tissues. Researchers have shown that this decreased stem cell activity is largely a result of inhibitory chemicals in the environment around the stem cell, some of them dumped there by the immune system as a result of chronic, low-level inflammation that is also a hallmark of aging.
In 2005, researchers infused old mice with blood from young mice - a process called parabiosis - reinvigorating stem cells in the muscle, liver and brain/hippocampus and showing that the chemicals in young blood can actually rejuvenate the chemical environment of aging stem cells. Last year, doctors began a small trial to determine whether blood plasma from young people can help reverse brain damage in elderly Alzheimer's patients. Such therapies are impractical if not dangerous, however, so researchers are trying to track down the specific chemicals that can be used safely and sustainably for maintaining the youthful environment for stem cells in many organs. One key chemical target for the multi-tissue rejuvenation is TGF-beta1, which tends to increase with age in all tissues of the body and which depresses stem cell activity when present at high levels.
Researchers showed that in old mice, the hippocampus has increased levels of TGF-beta1 similar to the levels in the bloodstream and other old tissue. Using a viral vector developed for gene therapy, the team inserted genetic blockers into the brains of old mice to knock down TGF-beta1 activity, and found that hippocampal stem cells began to act more youthful, generating new nerve cells. The team then injected into the blood a chemical known to block the TGF-beta1 receptor and thus reduce the effect of TGF-beta1. This small molecule, an Alk5 kinase inhibitor already undergoing trials as an anticancer agent, successfully renewed stem cell function in both brain and muscle tissue of the same old animal, potentially making it stronger and more clever. "The challenge ahead is to carefully retune the various signaling pathways in the stem cell environment, using a small number of chemicals, so that we end up recalibrating the environment to be youth-like. Dosage is going to be the key to rejuvenating the stem cell environment."
Systemic attenuation of the TGF-β pathway by a single drug simultaneously rejuvenates hippocampal neurogenesis and myogenesis in the same old mammal
Stem cell function declines with age largely due to the biochemical imbalances in their tissue niches, and this work demonstrates that aging imposes an elevation in transforming growth factor β (TGF-β) signaling in the neurogenic niche of the hippocampus, analogous to the previously demonstrated changes in the myogenic niche of skeletal muscle with age. Exploring the hypothesis that youthful calibration of key signaling pathways may enhance regeneration of multiple old tissues, we found that systemically attenuating TGF-β signaling with a single drug simultaneously enhanced neurogenesis and muscle regeneration in the same old mice, findings further substantiated via genetic perturbations.
At the levels of cellular mechanism, our results establish that the age-specific increase in TGF-β1 in the stem cell niches of aged hippocampus involves microglia and that such an increase is pro-inflammatory both in brain and muscle, as assayed by the elevated expression of β2 microglobulin (B2M), a component of MHC class I molecules. These findings suggest that at high levels typical of aged tissues, TGF-β1 promotes inflammation instead of its canonical role in attenuating immune responses. In agreement with this conclusion, inhibition of TGF-β1 signaling normalized B2M to young levels in both studied tissues.
PRIMATE STUDY EVIDENCE FOR THE HARM CAUSED BY CMV
Cytomegalovirus, CMV, is a prime suspect in one of the characteristic malfunctions seen in the aging human adaptive immune system. CMV is a very prevalent form of herpesvirus, and something like 90% of individuals test positive for exposure by the time old age rolls around. Most people have no noticeable symptoms of infection, and CMV is usually only a topic in clinical practice when it comes to immune compromised patients or transmission to unborn children, both situations in which infections largely harmless to everyone else can become a threat. While it is indeed largely harmless in the short term, like all herpesviruses CMV lingers latent in the body to emerge over and again to challenge the immune system.
The scenario suspected of CMV is that while its latent infection goes unnoticed in the vast majority of people, every time the virus emerges from hiding ever more T cells specialize as memory T cells that identify CMV. The immune system in adults has a low pace of replacement for T cells, and is effectively running in a capacity system: there are only so many cells to go around at any one time, and over the years ever more of that limited resource is devoted to CMV rather than to facing down new threats. At present this is a compelling hypothesis in the research community rather than a proven absolute. What is definitively observed in old people is an expansion of less useful T cells such as memory cells, a dysregulation of the immune system that occurs at the expensive of naive T cells and other types needed for a robust immune response. The immune system is complex and far from fully understood, and so there are competing explanations for this observation; pointing to the actions of CMV is one of the better supported hypotheses.
What to do about all of this? The engineering approach, which already has some backing from past animal studies, is to focus on selectively destroying the unwanted immune cells. They have a fairly distinctive surface chemistry, and the cancer research community is pouring a great deal of time and effort into the development of ways to safely and selectively destroy cells in living tissue based on these and other identifiable differences. If the misconfigured immune cells are cleared out, the hope is that they will be replaced with fresh copies that are not burdened by a lifetime of responding to CMV, and the immune system will be brought back into balance. The fastest way to quantify the effectiveness of this approach is to try it, given the technologies available today and the pace of discovery. Indeed, clearance of innate immune cells had this beneficial outcome in animal studies. Sadly there is all too little work on this front at the present time, as is the case for many of the more direct approaches to repairing the causes of age-related dysfunction and frailty.
Here is an interesting open access paper on a primate study of CMV, comparing two groups with and without exposure to the virus, that adds more supporting evidence for its role in immune system dysfunction in aging. The particular groups used perhaps offer a platform for further and more incisive investigations in the future:
The interplay between immune maturation, age, chronic viral infection and environment
The worldwide increase in life expectancy has been associated with an increase in age-related morbidities. The underlying mechanisms resulting in immunosenescence are only incompletely understood. Chronic viral infections, in particular infection with human cytomegalovirus (HCMV), have been suggested as a main driver in immunosenescence. Here, we propose that rhesus macaques could serve as a relevant model to define the impact of chronic viral infections on host immunity in the aging host. We evaluated whether chronic rhesus CMV (RhCMV) infection, similar to HCMV infection in humans, would modulate normal immunological changes in the aging individual by taking advantage of the unique resource of rhesus macaques that were bred and raised to be Specific Pathogen Free (SPF-2) for distinct viruses.
Our results demonstrate that normal age-related immunological changes in frequencies, activation, maturation, and function of peripheral blood cell lymphocytes in humans occur in a similar manner over the lifespan of rhesus macaques. The comparative analysis of age-matched SPF-2 and non-SPF macaques that were housed under identical conditions revealed distinct differences in certain immune parameters suggesting that chronic pathogen exposure modulated host immune responses. All non-SPF macaques were infected with RhCMV, suggesting that chronic RhCMV infection was a major contributor to altered immune function in non-SPF macaques, although a causative relationship was not established and outside the scope of these studies. Further, we showed that immunological differences between SPF-2 and non-SPF macaques were already apparent in adolescent macaques, potentially predisposing RhCMV-infected animals to age-related pathologies.
Our data validate rhesus macaques as a relevant animal model to study how chronic viral infections modulate host immunity and impact immunosenescence. Comparative studies in SPF-2 and non-SPF macaques could identify important mechanisms associated with inflammaging and thereby lead to new therapies promoting healthy aging in humans.
SENS RESEARCH FOUNDATION IN THE MEDIA
The SENS Research Foundation, alongside its parent organization the Methuselah Foundation, is one of the most important scientific non-profits in the world today. These organizations are undertaking seed research, engaging in persistent advocacy, and organizing conferences to steer the scientific and funding communities onto the best paths to produce the toolkit of therapies and biotechnologies needed to achieve human rejuvenation. This means building ways to repair the catalog of cell and tissue damage that causes age-related fraity and disease, and thus reverse its progression. The goal is old age without pain, without suffering, without any loss of health and vigor, and given the right strategies in research and development, this is a practical goal for the decades ahead.
The SENS Research Foundation has a tiny budget for an organization that seeks to profoundly change the world for the better: entirely funded by philanthropic donations at a few million each year. It is never the intent that the SRF staff and associated researchers do everything themselves, however. The point of the exercise is to steer other funds and other scientific groups towards the best possible lines of research by demonstrating their worth, and by making sure that everyone in the scientific community knows about past demonstrations carried out elsewhere. Does this really work at this sort of funding level, however? The answer is a resounding hell yes it works, even if more is always better.
If you have been paying attention for the past decade you'll notice that these days there are several lines of SENS research that are spreading out and being picked up by people with deeper pockets. Senescent cell clearance has had its arrival year this year, with a great technology demonstration of improved healthspan in aging mice. Similar the targeting of telomere extension as the common mechanism in all cancer is a SENS approach that now has some people in the mainstream research community working on a variety of initiatives, while the SENS Research Foundation in-house efforts are respectfully covered by the popular science media.
Ten years ago, the people who publicly proposed exactly this research were mocked, and all too many scientists avoided talking about extending healthy human life by treating the causes of aging. Now it is a very different story. All those community fundraisers in the past, all of the advocacy, all of the grassroots efforts? They pay off. Not immediately, because it takes years to make things happen. But we can clearly see the results arriving now. There are yet more areas of SENS research that need to have their day in the sun, however, which is why we must double down and keep on trucking. We're starting to win the game in earnest, the wheel is moving, the avalanche started, so why stop here?
The SENS Research Foundation in fact probably gets more media attention than your average non-profit of its size, and justifiably so. Nowhere near enough media attention, I'd say. Research into repairing the causes of aging needs to be right up there in the public conversation alongside cancer research, and the funding should be much the same. That is a thing to aim for, and the sooner we get there the better the prospects for a future that doesn't involve sickness and decline. Here are a couple of recent items covering the SENS Research Foundation and its staff:
New innovation to extend life expectancy
Tucked away in a small office in the heart of Silicon Valley, the SENS research foundation is engaged in the cutting-edge work of rejuvenation biotechnology. They experiment with preservation of the cell and, more specifically, the powerhouse of the cell: the mitochondria.
With donations primarily from philanthropists, SENS operates on an annual budget of a few million that founders consider a drop in the bucket compared to what is spent on healthcare. SENS's approach is still a long away from being used on people, as it would likely need testing on animals first before being incorporated in human gene therapy, a technique also still under study.
Front and Center: Singer, Composer, Pilot, Global Outreach Coordinator at SENS Research Foundation, Maria Entraigues-Abramson
WiMN: You're currently the Global Outreach Coordinator for SENS Research Foundation. How has your experience as a singer and composer helped you with this role?
MEA: As you can probably tell I can't stay on just one thing. I've always had this unstoppable curiosity since I was a little girl, and science has been one of my other big passions. SENS Research Foundation is a non-profit organization located in the Bay Area, working to develop new therapies to prevent, reverse and eradicate the diseases of aging. As we age we accumulate damage at a cellular and molecular level, that happens since we are born.
This damage or "junk" as we call it, doesn't bother us much until we start getting older. When the amount of waste crosses a certain threshold it starts affecting the functions in our body and we get sick. If we live long enough, in the way medicine is today, we will get at least one age related disease (cancer, Alzheimer's, cardiovascular disease, Parkinson's, etc) if not several, and if we don't die of something else before, this is what will eventually kill us.
At SRF we have a roadmap to get aging under medical control. These strategies (Strategies Engineered for Negligible Senescence) were designed by biogerontologist Dr. Aubrey de Grey, a very prominent scientist from Cambridge, U.K., who co-founded the organization and is our Chief Science Officer. He wrote the book Ending Aging where he explains the seven types of damage that make us age and how we can tackle them using regenerative medicine. This is what we work on.
My work as the Global Outreach Coordinator is mainly development and fund raising. I focus on creating new relationships, bringing high net worth Individuals onboard. I do celebrity outreach, organize events, and anything that will help create awareness and raise funds to push the research and the development of treatments forward. These cures will happen, it is just a matter of time, and the more funding we get the faster it will happen. The fact that I've been in the music/entertainment business for so long helped me build a huge network of people and this is how I can do my job doing outreach for the organization, it is all about making connections and expanding our network.
LATEST HEADLINES FROM FIGHT AGING!
WHAT IS AGING? CAN WE DELAY IT?
Monday, May 11, 2015
Here is a very accessible position paper from the Longevity Science Advisory Panel, a UK group interested in medical intervention in the aging process. You'll need to click through to download the full PDF version:
Understanding ageing is demanding. Within it is the paradox that all species, including humans, strive for survival but ageing and death are almost universal in the living world. In this paper we summarise a range of theories and mechanisms of ageing. There is little evidence that it is programmed into our genes and substantial evidence that it is malleable, in that lifespan has been lengthened by a variety of means in a variety of species. Just as important as the process itself is the fact that ageing is associated with an increased risk of many life-threatening diseases. If ageing can be delayed then it is likely that there will be a delay in the development of some or all of these diseases, leading to increased longevity.
Our goal for this project was to produce a report about the complex processes involved in ageing. We wanted it to be accessible to a wide spectrum of readers, not just those involved in academic study. We carried out an unusual research project which involved interviewing eight respected biogerontologists to identify current knowledge about the biology of ageing, which treatments may show promise in delaying the ageing process, and what they see as the future outcomes from scientific research on this topic. We supplemented these expert views with evidence from published studies on the effectiveness of the most promising new anti-ageing treatments, and developed a model to show what this might mean for the extension of human lifespan in the future.
From this research we have been able to build up a picture of the latest developments in this area. The experts tended to agree on which possible factors are important in understanding the biology of ageing. However, they did not necessarily agree on which are the most important components of the ageing process, or on which interventions might have the greatest potential for extending lifespan.
POSTTRAUMATIC STRESS DISORDER ASSOCIATED WITH SHORTER TELOMERES, GREATER INCIDENCE OF AGE-RELATED DISEASE
Monday, May 11, 2015
Researchers have in the past determined that psychological stress is associated with shorter telomere length as measured in immune cells from a blood sample, and greater ill health in general, but there remains considerable uncertainty over the mechanisms involved. There is also a fair degree of research demonstrating associations between personality traits such as conscientiousness and measures of aging. To what degree is this outcome biological versus being based on factors such as failing to take good care of your health? This review of data on posttraumatic stress disorder (PTSD) looks at much the same question:
PTSD is associated with number of psychological maladies, among them chronic depression, anger, insomnia, eating disorders and substance abuse. Now researchers suggest that people with PTSD may also be at risk for accelerated aging or premature senescence. "This is the first study of its type to link PTSD, a psychological disorder with no established genetic basis, which is caused by external, traumatic stress, with long-term, systemic effects on a basic biological process such as aging."
The majority of evidence fell into three categories: biological indicators or biomarkers, such as leukocyte telomere length (LTL), earlier occurrence or higher prevalence of medical conditions associated with advanced age and premature mortality. In their literature review, researchers identified 64 relevant studies; 22 were suitable for calculating overall effect sizes for biomarkers, 10 for mortality. All six studies looking specifically at LTL found reduced telomere length in persons with PTSD.
The scientists also found consistent evidence of increased pro-inflammatory markers, such as C-reactive protein and tumor necrosis factor alpha, associated with PTSD. A majority of reviewed studies found increased medical comorbidity of PTSD with several targeted conditions associated with normal aging, including cardiovascular disease, type 2 diabetes, gastrointestinal ulcer disease and dementia. Seven of 10 studies indicated a mild-to-moderate association of PTSD with earlier mortality, consistent with an early onset or acceleration of aging in PTSD.
WORKING IN THE CRYONICS INDUSTRY
Tuesday, May 12, 2015
The small cryonics industry provides a vital service that all too few people avail themselves of. Low temperature preservation after death via vitrification ensures a chance at life again in the future. Provided that the fine structure of the brain is maintained, a preserved individual can wait indefinitely for the arrival of biotechnologies and nanotechnologies needed for restoration to life: a new body, cellular and structural repair of the brain, undoing all of the chemistry introduced in the preservation process, and so forth. It is an unknown chance, but nonetheless the only option going for those who will not live long enough to benefit from the rejuvenation and radical life extension that lies ahead as a result of progress in the science of aging. Here is a lengthy medical insider's view of the industry and its procedures, and the challenges inherent in public attitudes towards cryonics:
For me, cryopreservation was an obvious mechanical problem. You've got molecules; why not lock them in place so that somebody can fix them later? All these things happening in our cells are just mechanical processes - they are just little machines, basically - and if you can stop them before they start to disintegrate, that seems like a good thing. Before that I was a physician, but I haven't practiced for about five years now. I still have my license. My participation in the cryonics field happened very gradually. There's a lot of different things that need to be done. It takes a lot of people. I am the leader and do the surgical procedures as well. I keep the instruments organized and I write out the procedures.
Each case can be very different. I'll pick a generic case. We might get notified that a member of ours is sick, maybe a few weeks from dying, and maybe they're located in a nearby state so we have to mobilize and get our equipment nearby to be ready for when they are pronounced legally dead. Let's say they're in a hospice situation in some sort of a care facility - that would be better than a hospital because in a hospital they don't like other people coming in with their own equipment. If we see that they're getting closer to death, like a day or two out, we might try to get the equipment even closer to their bed. When they finally stop breathing, the heart stops, and the doctor pronounces them dead, then we take over.
We are trying to preserve all the intricate branches, about 2000, on each neuron, as well as the specific shapes of each synapse. If we cool them, it lengthens the amount of time before the neurons actually die. So we try to keep these cells alive as long as we possibly can. We put the person in an ice-bath - it's kind of like a stretcher with walls on it that contains ice water. That's the fastest we can cool externally. We start cooling, we start moving them out of the facility, we try to give medications that will stop the blood from clotting and will help slow down the metabolism further. An important one would be an antibiotic: we don't want bacteria to grow while we're doing this. Another important one would be to prevent blood clotting, and we want to constrict the blood vessels on the extremities to concentrate the blood flow to the core.
We move them out of there to a different facility where we can perform surgical procedures.We would prefer to start surgical procedures immediately. If the setting allows it, that's actually our standard protocol. We drain the blood out and replace it gradually with a cryoprotectant, like an antifreeze. That takes hours: to do the cooling and to pump those other chemicals in. Then we start cooling sub-zero, taking them down below the freezing point of water. If we do it right, we won't get ice crystals in the brain. That's called vitrification. It's never 100% perfect. There's always going to be ice crystals somewhere so its a matter of degrees; it's a matter of how much we can prevent that. There are different ways of sub-zero cooling: we can use dry ice, we can use nitrogen gas, circulate cold air over them. At some point, we remove the head usually because we don't need the rest of the body. That's not where the brain is. Sometimes we remove the brain also before we start the sub-zero cooling so it kind of depends on the patient. Then we take them down to -196 Celsius and immerse them in liquid nitrogen, and there they'll sit.
DO SMOOTH MUSCLE CELLS CONTRIBUTE TO ARTERIAL STIFFENING?
Tuesday, May 12, 2015
Vascular stiffening is a major cause of cardiovascular aging. It alone is enough to explain the age-related onset of hypertension, for example, which in turn deforms blood vessels and the heart, and causes ongoing harm to the brain where small blood vessels fail under stress, among other issues. Much of the cause of loss of elasticity in blood vessels is thought to be caused by cross-linking and calcification in the extracellular matrix, processes that occur as a side-effect of the normal operation of metabolism, and which could be reversed with suitably designed drugs. Unfortunately there is still comparatively little research focused on these targets, certainly nowhere near as much as is merited by the consequences of these contributing causes of degenerative aging.
Here, researchers identify another potential causative agent in the stiffening of blood vessels, in changing behaviors and characteristics of the smooth muscle cells that surround blood vessels. Is this a primary cause or a reaction to primary causes, however? More research is needed on that topic, as is often the case:
Arterial and vascular stiffness occurs through the normal process of biological aging and is associated with an increased risk of heart attacks and strokes. As we age, the aorta, which normally acts as a shock absorber dampening the pulse associated with each heartbeat, tightens and becomes rigid, causing a host of problems including high blood pressure, increased risk of adverse cardiovascular events and even death. In the United States, the risk of developing hypertension due to aging is greater than 90 percent in both men and women. Recent studies have identified several mechanisms for arterial stiffness in humans. Research has focused on the structural matrix proteins, or non-living components that compose the outer walls of blood vessels, as well as endothelial cells which line the inner portion of the vascular walls.
Researchers have focused on a new potential source - smooth muscle cells that are a major component of the "middle" of the blood vessel wall. The team isolated aortic cells from normal and hypertensive rat models in both young and aged animals. Then, using atomic force microscopy, an advanced microscope that incorporates a tiny probe that can interact with single cells and molecules, the team measured the compression force of the needle against the specimen and how the tip adhered to or "stuck" to smooth muscle cells.
"We found that hypertension increased both vascular smooth cell stiffness and adhesion or stickiness, and that these changes were augmented by aging. Our results are adding to our understanding and taking studies in a different direction. Although all cells are contributing to arterial stiffness, it's important to identify the order in which they're adding to the problem. Identifying smooth muscle cells as a contributor can help identify possible preventatives and potential drugs to counteract and reverse the disease and keep vessels healthier as we age."
PROGRESS IN REMOVING THE CELLS FROM CELL THERAPY
Wednesday, May 13, 2015
Many stem cell therapies seem to work via cell signaling rather than any other activity of the transplanted cells, the signals spurring native cells to get back to work and regenerate tissues. Knowing this, the logical end goal of research is then a class of therapy that delivers the signal chemicals rather than cells. Progress on this front is really only limited by the present comparatively poor understanding of just which signals are important in various different circumstances:
Scientists have discovered a way to regrow bone tissue using the protein signals produced by stem cells. The new study is the first to extract the necessary bone-producing growth factors from stem cells and to show that these proteins are sufficient to create new bone. Instead of using stem cells themselves, the scientists extracted the proteins that the cells secrete - such as bone morphogenetic protein (BMP) - in order to harness their regenerative power. To do so, the researchers first treated stem cells with a chemical that helped coax them into early bone cells. Next, they mined the essential factors produced by the cells that send the signal to regenerate new tissue. Finally, the researchers delivered these proteins into mouse muscle tissue to facilitate new bone growth.
The stem cell-based approach was as effective as the current standard treatment in terms of the amount of bone created. This current standard method involves grinding up old bones in order to extract the proteins and growth factors needed to stimulate new bone growth - a substance dubbed demineralized bone matrix (DBM). However, this approach has significant restrictions as it relies on bones taken from cadavers, which can be highly variable in terms of tissue quality and how much of the necessary signals they still produce. Moreover, as is the problem in organ donation, cadaver tissue is not always available. "These limitations motivate the need for more consistent and reproducible source material for tissue regeneration. As a renewable resource that is both scalable and consistent in manufacturing, pluripotent stem cells are an ideal solution."
AN APPROACH TO DISABLING TELOMERES IN CANCER
Wednesday, May 13, 2015
The present swamp of slow and expensive progress in cancer research is a swamp because every type of cancer is biologically very different, and most research programs are thus applicably only to a narrow slice of the exceedingly broad spectrum of cancers. Even there it is frequently the case that individual tumors are so highly varied that a vulnerability in one individual's cancer of a specific type is not present in another. There are better ways forward, however: progress in cancer research can be greatly accelerated by finding and focusing on common mechanisms shared by many different cancers. This has long been the SENS approach to cancer, to strike at the one known common mechanism shared by all cancers, which is to say their need to extend telomeres. Telomeres shorten with each cell division, and when too short a cell will destroy itself. This limits the number of times any ordinary cell in the body can divide, and cancers must thus break this limiting function in order to retain their uncontrolled growth.
A decade ago it was sadly the case that, as for any bold new plan, the SENS research program as an approach to medicine to treat degenerative aging and its consequences - such as cancer - was mocked. Today, however, numerous research groups are attempting to disrupt telomere extension in cancer. Times have changed, and the world is finally catching up to the perspective of earlier visionaries in aging research. Present work on disruption of telomere lengthening in the broader scientific community is largely aimed at blocking the activity of telomerase, while the SENS Research Foundation cancer program nowadays focuses on the less well researched alternative lengthening of telomere mechanisms.
Here researchers are taking an entirely different approach by attacking the structure of telomeres directly, rather than interfering in lengthening mechanisms, thus stripping telomeres from chromosomes in target cells:
Researchers have discovered a new strategy to fight cancer, which is very different from those described to date. Their work shows for the first time that telomeres - the structures protecting the ends of the chromosomes - may represent an effective anti-cancer target: by blocking the TRF1 gene, which is essential for the telomeres, they have shown dramatic improvements in mice with lung cancer. "Telomere uncapping is emerging as a potential mechanism to develop new therapeutic targets for lung cancer."
Every time a cell divides, it must duplicate its genetic material, the DNA, which is packed inside the chromosomes. However, given how the mechanism of DNA replication works, the end of each chromosome cannot be replicated completely, and, as a result, telomeres shorten with each cell division. Excessively short telomeres are toxic to cells, which stop replicating, and eventually, the cells are eliminated by senescence or apoptosis. This phenomenon has been known for decades, as well as the fact that it usually does not occur in tumour cells. Cancer cells proliferate without any apparent limits, and therefore, they are constantly dividing, but their telomeres do not gradually become shorter; the key behind this mechanism is that the telomerase enzyme in cancer cells remains active, while in most healthy cells telomerase is turned off.
Telomeres are made up of repeating patterns of DNA sequences that are repeated hundreds of times - this is the structure that shortens with each cellular division. Telomere DNA is bound by a six-protein complex, called shelterin, which forms a protective covering. The research team strategy consisted of blocking one of the shelterins, namely TRF1, so that that the telomere shield was destroyed. The idea of targeting one of the shelterins has not been tried so far, due to the fear of encountering many toxic effects caused by acting on these proteins that are present in both healthy and tumour cells.
"Nobody had explored the idea of using one of the shelterins as an anti-cancer target. It is difficult to find drugs that interfere with protein binding to DNA, and the possibility exists that drugs targeting telomere caps could be very toxic. For these reasons, no one had explored this option before, although it makes a lot of sense. TRF1 removal induces an acute telomere uncapping, which results in cellular senescence or cell death. We have seen that this strategy kills cancer cells efficiently, stops tumour growth and has bearable toxic effects." Having established the effectiveness and low toxicity of the new target, the researchers searched for chemical compounds that could have activity against TRF1. Two types of compounds have been found. "We are now looking for partners in the pharmaceutical industry to bring this research into more advanced stages of drug development."
A LOOK AT THE STATE OF ARTIFICIAL HEART DESIGN
Thursday, May 14, 2015
The next few decades will see competition between regenerative medicine and prosthetic design in the construction of replacement organs. At some point in the future the two will merge, most likely after a molecular nanotechnology industry emerges and becomes capable of manufacturing designs as complex and reliable as evolved cell biology. There are attempts today to build bioartificial organ substitutes that combine tissue and machinery, but designing artificial organs remains an undertaking still in its infancy, beset with challenges:
One of the biggest problems with ventricular assist devices (VADs), as well as with existing artificial hearts, is that they can damage the blood. Through shear stress, delicate platelets - whose function is to stop bleeding in normal situations - can become "activated," causing thrombosis or clots, which can lead to stroke or heart attack. It's the reason why patients require comprehensive anti-coagulation medication, which can have problematic side effects as well. Red blood cells can also be damaged by the high shear stresses caused by pumps and leach hemoglobin, causing more problems.
So how should an artificial heart pump blood? Should it run continuously at a steady rate, or pulsate like a real heart? Should it be made of synthetics, organic materials, or a combination of both? Currently most VADs rely on centrifugal or axial flow pumps to circulate blood via a rotary impeller, much like a sump pump moves water out of a flooded basement. These pumps rotate at high speeds - 5,000 to 10,000 rpms - in order to circulate in a minute the approximately 5 liters of blood in a human body. But all that pressure can cause problems. "It's like the force that's coming out of a water hose, and these poor little, innocent platelets are very sensitive to turbulence."
Researchers came up with the idea of using a completely different kind of pump, one that uses a peristaltic pumping mechanism - a far more gentle way of moving fluid. Peristaltic pumps rely on a symmetrical contraction and relaxation motion to generate a wave down a tube. It's basically how your gastrointestinal system transports food through the intestines. Peristaltic pumps are already used in heart/lung blood machines to circulate blood in and out of a patient during open-heart surgeries, but they have never been used in VADs or in artificial hearts.
Another challenge for researchers is trying to map the brain-heart connection. When you're lying down and want to get up, your brain tells the heart to beat faster, to pump more blood. Your body simply reacts. But how will a person's nervous system involuntarily control an artificial heart? "The classic example is a baseball player at the plate who isn't really doing anything. But as soon as the pitcher throws the ball, a dozen different things occur automatically. Blood flow increases, there's a rush of adrenaline. It doesn't look like he's doing anything, but the body reacts to that stimulus in a way that's profoundly different than just sitting there. The mechanical heart wouldn't care that here comes a 90 mph pitch. But we want it to care. We want it to know the difference." If an artificial heart contained enough organic material, could the body's neurological pathways reconnect with it?
A HYPOTHESIS ON DAMAGED MITOCHONDRIAL RNA IN AGING
Thursday, May 14, 2015
Mitochondria are the power plants of the cell, every cell equipped with a herd of hundreds of them, constantly recycled by cell quality control mechanisms and the numbers kept up by division like bacteria. Damage to mitochondria is thought to be important in aging, specifically damage to the DNA that all mitochondria carry. Some forms of mitochondrial DNA damage can lead to dysfunctional mitochondria that evade cellular quality control mechanisms even though broken, and thus proliferate to take over their cell, causing it to malfunction and export damaging reactive molecules into surrounding tissues.
These researchers have a different take on this contribution to the aging process, theorizing in an open access paper that the RNA produced from damaged mitochondrial DNA is also a consideration:
Accumulations of mitochondrial DNA (mtDNA) mutations associated with aging are evident in multiple human tissues. The role of mtDNA mutations can be observed in an aging animal model such as homozygous knock-in PolgA mice, which have a large colonial expansion of mtDNA mutations. They develop reduced lifespan and premature onset of age-related phenotypes, that are also observed in clinical practice like mitochondrial aging acceleration with anti-retroviral therapy through clonal expansion of mtDNA mutations.
These clonally expanded mtDNA mutations maintain transcription ability which could result in an accumulation of abnormal mitochondrial RNA (mtRNA) in the affected cells. Compensation-effect doctrine states that accumulated mtDNA mutations in the cell must reach a set threshold before they have a negative effect on cell function due to compensation effects from normal cellular mtDNA. In contrast to this theory, we suggest that an accumulation of aberrant mtRNA transcribed from mtDNA mutations negatively influences cellular function through complex internal and external mitochondrial pathways, and might be an important cause of aging and aging-associated diseases.
TARGETED ENGINEERED CELL MICROFACTORIES AS A CANCER THERAPY
Friday, May 15, 2015
Approaches towards targeting cancer are becoming ever more sophisticated, even as the same basic goal remains unchanged: deliver far lower doses of cell-killing treatments to a far smaller area, even to individual cancer cells where possible, reducing side-effects and damage to everything except the targeted tumor or cancer cells. There are many possible ways to achieve this end, and this one has many potential applications beyond merely cancer treatment:
Attacking the perennial problem of systemic toxicity from typical chemotherapy treatments, researchers have engineered therapeutic cells encapsulated in nanoporous capsules to secrete antitumor molecules from within the tumor. "We have engineered cells that locally convert a nontoxic substance into an antitumor agent. We can encapsulate cells in nanoporous capsules, which ensures the cells are localized and immunoisolated. This immunoisolated micro-factory can remain in the tumor, providing a permanent and renewable source of therapeutic molecules for long-term cancer management."
Engineered bacterial cells that are designed to express therapeutic enzymes under the transcriptional control of remotely inducible promoters can mediate the de novo conversion of nontoxic prodrugs in their cytotoxic forms. In situ cellular expression of enzymes provides increased stability and control of enzyme activity as compared to isolated enzymes. The team engineered Escherichia coli (E. coli), which was designed to express cytosine deaminase at elevated temperatures under the transcriptional control of a thermo-regulatory promoter cassette. This constituted the thermal switch to trigger enzyme synthesis. They subsequently co-encapsulated the cells with magnetic iron oxide in immunoprotective alginate microcapsules and then remotely triggered cytosine deaminase expression by alternating magnetic field-induced hyperthermia.
The goal of localizing therapy to avoid systemic toxicity from chemotherapy is the impetus for the vision to ultimately encapsulate a library of therapeutic cells that will take cues from their microenvironment and secrete appropriate antitumor molecules. Looking forward, the work will focus on using these microencapsulated cells to stimulate the immune system to act against tumors, as well as activating drug synthesis.
HYDROGELS IMPROVE STEM CELL THERAPIES
Friday, May 15, 2015
Researchers here demonstrate the utility of incorporating a hydrogel into stem cell therapies, where it can improve survival of the transplanted cells and the outcome for the patient:
Stem cells hold great therapeutic promise because of their ability to turn into any cell type in the body, including their potential to generate replacement tissues and organs. While scientists are adept at growing stem cells in a lab dish, once these cells are on their own - transplanted into a desired spot in the body - they have trouble thriving. The new environment is complex and poorly understood, and implanted stem cells often die or don't integrate properly into the surrounding tissue. Researchers created a hydrogel several years ago as a kind of a bubble wrap to hold cells together during transport and delivery into a transplant site. "This study goes one step further, showing that the hydrogels do more than just hold stem cells together; they directly promote stem cell survival and integration. This brings stem-cell based therapy closer to reality."
In addition to examining how the stem cells benefit from life in hydrogels, the researchers also showed that these new cells could help restore function that was lost due to damage or disease. The team injecting hydrogel-encapsulated photoreceptors, grown from stem cells, into the eyes of blind mice. Photoreceptors are the light sensing cells responsible for vision in the eye. With increased cell survival and integration in the stem cells, they were able to partially restore vision. "After cell transplantation, our measurements showed that mice with previously no visual function regained approximately 15% of their pupillary response. Their eyes are beginning to detect light and respond appropriately."
In another part of the study, researchers injected the stem cells into the brains of mice who had recently suffered strokes. "After transplantation, within weeks we started seeing improvements in the mice's motor coordination." The team now wants to carry out similar experiments in larger animals, such as rats, who have larger brains that are better suited for behavioral tests, to further investigate how stem cell transplants can help heal a stroke injury.