Fight Aging! Newsletter, July 7th 2014 – Fight Aging!
Later this year I will be running a SENS research charitable fundraiser in collaboration with various allies in the community. At this time I am in search of a few good people and organizations to stand with me and others in assembling a matching fund to raise additional donations from the grassroots supporters of longevity science.
I am far from the only person to recognize that the Strategies for Engineered Negligible Senescence (SENS) is perhaps the most important early-stage research program in medicine today. SENS is so far the only coherent, well-planned vision for producing rejuvenation treatments that has managed to establish traction and growth in the research community, while gaining the support of noted researchers and philanthropists. The SENS Research Foundation exists to shepherd this research, and is the hub of an enthusiastic network of supporters and scientists.
If we want to see real progress towards an end to age-related disease in our lifetimes, and years from now benefit from treatments that reverse the degeneration and frailty of old age, then we must put our support behind SENS. In the world of research funding, all of the most novel and promising science is funded in its early years by philanthropy, by people of vision and modest means who step up by their thousands to show that they understand what it means to change the world one step at a time.
Who are those people? That would be us. The big organizations and high net worth folk with big checkbooks never show up until later, years after they would have been most useful, and they only turn up because they see that people like us are making noise and changing the world. Ultimately, we are responsible for seeding the future that we wish to see, guiding later large-scale investments by the light we shine on the best path forward.
As always I only ask no more than I can do myself: I will be putting $15,000 on the table, and each of the other members of the matching fund will be doing the same. This year I hope to be able to do better than last year, when I, Jason Hope, and the Methuselah Foundation joined forces to raise $60,000 for rejuvenation biotechnology research.
Do you already make sizable 501(c)(3) charitable donations to the SENS Research Foundation and would like to see your efforts attract more funding? Then you should join in and help us to build this matching fund. Please do contact me if this is the case.
Do you know someone who could make a difference by joining in and can put $15,000 towards breakthrough medical science? Then ask. Do you have connections to organizations that might be interested in funding SENS research? Then think about giving me an introduction. What is the worst that can happen? There are far more terrible things in this world of ours than gaining a reputation as an advocate who sometimes asks people to fund progress in medical science.
Every year a group of exceptional young scientists come to work on projects at the SENS Research Foundation in California and in allied laboratories around the country. Producing the rejuvenation therapies of tomorrow is a project that will last for decades: the researchers who will lead companies and academic laboratories into the final stretches to produce the first comprehensive rejuvenation toolkit are still undergraduates and postgraduates today, just starting their careers. It is a very exciting time to be in biotechnology.
It is of great importance that today's leaders in the field of aging research do better than their predecessors when it comes to presenting their field as the groundbreaking, revolutionary, exciting place that it will be over the next twenty years. The world is changing, biotechnology is advancing at a breakneck pace, and the medicine of ten or twenty years from now will look like science fiction already. Radical new possibilities are on the horizon, and doors are opening. Today's scientists must cultivate a next generation of researchers who see aging as the most important medical condition yet be treated in earnest, and who find the new tools for producing those future treatments to be exciting: worth devoting a career to. Hence advocacy and progress isn't just about getting the job done today and raising the funds for today's researchers, but it is also about creating the research community of tomorrow.
At the SENS Research Foundation, I work in the OncoSENS department with Dr. Haroldo Silva. My project will study a specific pathway used by cancer cells called the Alternative Lengthening of Telomeres (ALT) pathway with the use of the ALT-associated promyelocytic leukemia (PML) nuclear bodies (APB) assay.
I will be performing Dr. Silva's version of the APB assay on two specific cell lines: an ALT cell line, called U2OS, and a telomerase control cell line, called 143B. I will be treating each of these cell lines with four drugs provided to us by Dr. Robert J. Shmookler Reis of the University of Arkansas for Medical Sciences, which are all known inhibitors of different proteins in homologous recombination-mediated pathways. My project will assess the effect of these drugs on the ALT pathway. The results generated by the APB assay will provide new data to better assess the potential of these drugs for cancer therapy, particularly for tumors associated with the ALT mechanism.
This summer, at the Buck Institute For Research on Aging, I will be working on a project in the laboratory of Dr. Heinrich Jasper. I will be examining the effect of unfolded proteins in fruit fly mitochondria on stem cell maintenance. Previous studies have shown that fruit fly gut stem cells tend to divide and generate new cells more frequently in stressful environments. Coincidently, the stress of numerous unfolded proteins in the mitochondrion triggers the mitochondrial unfolded protein response.
Recently, the response to mitochondrial unfolded proteins has been shown to control the aging rate of various organisms and has been associated with many renowned aging modulators. We also know that activating the response in certain body parts can have global effects, and these effects could greatly impact the aging process. Yet, there remains uncertainty regarding which proteins initiate the active pathway that alters aging, as opposed to those that are just associated with the process, and also the exact difference between mitochondrial unfolded protein response and other stress responses that seem to have no influence on aging. Thus, this project aims to provide some clarity concerning these aspects of the response.
Cellular senescence is a state of irreversible growth arrest that serves to protect against cancer. Senescent cells are accumulated with age or induced by anti-cancer therapies, such as chemotherapy and irradiation, in the tissue microenvironment. Senescent cells experience deep morphological and functional changes, and they activate a secretory program known as the senescence-associated secretory phenotype (SASP). The SASP includes several pro-inflammatory factors for which levels are increased during aging and cancer treatment.
The secretory program is regulated by multiple molecular events. Among those, the transcription factor hypoxia-inducible factor (HIF)-1a has been linked to many pathways and factors involved during senescence. HIF-1a responds to oxygen levels to promote the formation of new blood vessels in hypoxic conditions. During my internship, I will address the following questions: 1) Which chemotherapy drug or irradiation dose currently used for treatment of cancer patients induces senescence in the tissue microenvironment? and 2) How does the phenotype of senescent cells respond to HIF-1a regulation and to different oxygen concentrations?
This summer I will be working with Dr. Mark McCormick in the laboratory of Dr. Brian Kennedy at the Buck Institute for Research on Aging. We are working in the budding yeast Saccharomyces cerevisiae and the nematode worm Caenorhabditis elegans. These model organisms live for only a few weeks, making it possible to quickly study changes in their lifespan. Because they have long been used to study many other biological processes, there are many existing tools available to us when working with these organisms, such as genome-wide deletion collections. Finally, it has been shown repeatedly in many diverse biological processes that fundamental mechanisms first uncovered in simple model organisms are often conserved in higher organisms, such as humans. In the case of aging, changes in yeast genes in the TOR (target of rapamycin) signaling pathway, including the yeast gene TOR1 itself, were shown to extend lifespan, and subsequent work has shown that treatment with the TOR targeting drug rapamycin extends lifespan when fed to middle-aged mice, leading us to hypothesize that this drug target or others we uncover may allow us to extend human lifespan as well.
Recent progress in whole organ engineering techniques based on decellularization of organs and recellularization of the resulting collagen-based matrix suggests that this method could eventually be used in transplantation. The Wake Forest Institute for Regenerative Medicine team has developed a combination cell seeding system for efficient and functional re-endothelialization of the entire vasculature of an acellular renal scaffold.
In their previous study, the team developed a surface modification method to reinforce endothelial cell attachment onto renal vasculature via CD31 antibody conjugation. CD31 antibody binds to an antigen found on endothelial cells. Encouraged by their promising results using an endothelial cell line, the WFIRM team has recently attempted to re-endothelialize the kidney scaffolds using autologous cell sources for long-term porcine kidney implantation. This approach could potentially be applied to a translational clinical trial.
For my project, I plan to isolate and characterize primary endothelial cells from pigs to determine if the conjugation of CD31 antibody on vasculatures of kidney scaffolds will enhance primary endothelial cell attachment.
This summer, I am working on a thymus regeneration project in Dr. John Jackson's lab at the Wake Forest Institute for Regenerative Medicine. The thymus is a specialized organ in the immune system, and it is involved in the maturation of T-cells. T-cells recognize and attack foreign substances, called antigens, thus protecting the body from developing infections. In old age, the thymus starts to lose its functional abilities, rendering the immune system ineffective. One approach to restore the immune system in aged individuals is the regeneration of the thymus. Thymic tissue regeneration and T-cell maturation also have application in the treatment of autoimmune diseases, immunodeficiencies, and transplant rejection.
During the summer, I will work on one part of this larger project. I plan to decellularize a small piece of pig thymus, which entails getting rid of all the cells in the thymus, leaving behind the extracellular structure called a scaffold. After decellularizing the thymus, I will reseed the thymus scaffold with thymus epithelial cells and bone marrow cells from mice, providing a 3-D environment to the cells that resembles their natural environment in the body. I will then analyze the proliferation of these cells in the scaffold and look for the production of mature T-cells. The success of this project will be an important step forward towards the overarching goal of whole thymus regeneration.
To a large degree the future of medicine is the future of control over cells. Plus some other stuff around the edges relating to clearing up after cells, removing some of the metabolic waste and misfolded proteins that they can't deal with. These items aside, near all of disease and aging might be tamed with a sufficiently good ability to repair and direct the behavior of our cells as they go about the business of life. That is the ultimate goal of medicine: to prevent all death, suffering, and disability, and provide the option of remaining alive and in good health for as long as you desire.
In some ways these are still the very earliest days in the control of cells, despite more than a century of serious work on the topic. The research community is barely starting on programming cells for specific activities or outcomes, and the technologies to do so have only existed for a handful of years. Yet progress in cell biotechnology is accelerating rapidly. Given the knowledge that researchers have today it is not unreasonable to look ahead to envisage very specific technologies that will enable sophisticated cellular control, not just over individual cells in the lab, but eventually for every cell in the body, all at once. This will happen a matter of a few decades from now. Tomorrow's researchers will mass-produce merged assemblies of novel protein nanomachines and natural cell components to improve, repair, and direct cells in very sophisticated ways.
In this study, researchers were able to use antibodies detecting ABCB5 to zero in on the stem cells in tissue from deceased human donors and use them to regrow anatomically correct, fully functional human corneas in mice. "Limbal stem cells are very rare, and successful transplants are dependent on these rare cells. This finding will now make it much easier to restore the corneal surface. It's a very good example of basic research moving quickly to a translational application."
Until now, no one had directly and closely compared the stem cells acquired using these two methods. The scientists found they produced measurably different results. "The nuclear transfer ES cells are much more similar to real ES cells than the iPS cells. They are more completely reprogrammed and have fewer alterations in gene expression and DNA methylation levels that are attributable to the reprogramming process itself."
"If you believe that gene expression and DNA methylation are important, which we do, then the closer you get to the patterns of embryonic stem cells, the better. Right now, nuclear transfer cells look closer to the embryonic stem cells than do the iPS cells. I think these results show that the SCNT method is a far superior candidate for cell replacement therapies. I truly believe that using this method of producing stem cells will someday help us cure and treat a wide range of diseases that are defeating us today."
Red blood cells (RBCs) are an attractive vehicle for potential therapeutic applications for a variety of reasons, including their abundance - they are more numerous than any other cell type in the body - and their long lifespan (up to 120 days in circulation). Perhaps most importantly, during RBC production, the progenitor cells that eventually mature to become RBCs jettison their nuclei and all DNA therein. Without a nucleus, a mature RBC lacks any genetic material or any signs of earlier genetic manipulation that could result in tumor formation or other adverse effects.
Exploiting this characteristic, [researchers] introduced genes coding for specific slightly modified normal red cell surface proteins into early-stage RBC progenitors. As the RBCs approach maturity and enucleate, the proteins remain on the cell surface, where they are modified. Referred to as "sortagging," the approach relies on the bacterial enzyme sortase A to establish a strong chemical bond between the surface protein and a substance of choice, be it a small-molecule therapeutic or an antibody capable of binding a toxin. The modifications leave the cells and their surfaces unharmed.
"Because the modified human red blood cells can circulate in the body for up to four months, one could envision a scenario in which the cells are used to introduce antibodies that neutralize a toxin. The result would be long-lasting reserves of antitoxin antibodies."
While it is true that it never crosses the mind of most folk to actually do anything personally to help along progress in medical science, there is an enormously greater level of grassroots support for working on any specific named age-related condition than there is for work on aging itself. Which is somewhat strange, as all of the former are caused by the latter. Yet the nominal and incoherent position of the average fellow in the street is that on the one hand he doesn't want to suffer cancer or heart disease or neurodegenerative conditions, and is generally pleased that there are people out there somewhere trying to build cures, but yet on the other hand he is perfectly fine with aging to death on the same schedule as his grandparents, and is even made a little uncomfortable by the idea that anyone out there is working to slow or reverse aging.
Even if we set aside politics and public funding, the philanthropic and for-profit resources directed towards research and development of treatments for late stage age-related conditions are enormous in comparison to funding for research into aging itself. At this stage the best thing that could happen for the future of all of this medical development is for a sizable and increasing fraction of this flow of funds to be directed towards rejuvenation research, work on repairing the causes of aging so as to prevent and reverse all of its consequences. It is a much more efficient and beneficial path forward than the continued efforts to patch over the consequences after they have happened, but it just doesn't have much support at the moment.
This sorry state of affairs will change for the better, and indeed is changing for the better even now, but progress here will continue far more slowly than it might unless some group figures out the key to the lock. We all know that advocacy can in the best of circumstances change the course of funding and attention for any given cause in medical science, producing a large growth in directed resources and real research in the labs and the clinics. Look at AIDS research for a comparatively recent example of great success in patient advocacy: from near nothing to very large investments in research and development in a very short span of time. It can be done.
The goal that must be accomplished for rejuvenation research is in theory a simpler one than producing support from nowhere for a new condition. It is to take the existing hope and approval for better treatments for age-related conditions and transfer some of that to the development of treatments for the root cause of those conditions, which is to say aging and the few forms of damage in and between our cells that cause us to suffer and die in so many varied ways. This seems simple and obvious, but people have been trying for a while to make this pitch to the public with limited success to show for it to date. It isn't easy, and bringing the world around to this way of looking at aging and ill health is taking time and effort.
The most important of the present generation of advocacy groups, which includes the Methuselah Foundation and SENS Research Foundation have for the past few years been talking far more about changing the approach to aging in the field and curing specific age-related conditions. Talk of extending life spans is far more muted nowadays, but it is still the case that successfully treating the causes of aging will have that outcome. We may well wind up ten or twenty years from now with an incoherent public position on medical research that supports SENS-like research while still being generally opposed to its inevitable outcome, which is to say much healthier, more robust older people who will live longer and are biologically much younger than their years thanks to rejuvenation treatments that actually work. If that comes to pass soon enough then we'll all be living longer as a side-effect of what people actually seem to want, which is not to have Alzheimer's or cancer or heart disease. The only reliable way to not have all these things is to repair the causes of aging: everything else is an expensive waste of time and effort by comparison.
Still, I fear that the incoherent beliefs regarding medical research into aging and the general lack of support for better approaches will drag us through potentially decades of persisting with failed and suboptimal approaches to the effective treatment of age-related disease before there is finally interest in trying something that works. Those decades of wasted time would put paid to the chances of my generation living long enough to benefit from working rejuvenation treatments. Which is something of an incentive to find the key to the lock. No bullet is quite so interesting as the one with your name on it.
There are a lot of papers on Alzheimer's disease that fall outside the mainstream focus on the formation of amyloid in the brain. This is perhaps in part a consequence of the challenges and delays that have beset efforts to produce practical treatments based on the amyloid view of the progression of Alzheimer's. As soon as any consensus in medical research and development fails to keep up its momentum, there are factions nibbling at its heels and trying out other ideas. The past few decades of the broader field of medical science are littered with promising approaches discarded in favor of others in the course of a few short years. Some of the alternative views of Alzheimer's disease are far out on the fringes, while others explore plausible contributions to the disease process wherein any debate must start with "yes, but is this a meaningful effect in comparison to others?" or "perhaps, but this is happening a long way in to the chain of consequences and dysfunction."
Here is an outline of an interesting view on the contribution of microbial populations to the progression of Alzheimer's disease, both the symbiotic gut microbiota that are considered to influence aging to some degree, and the impact of a lifetime of exposure to hostile pathogens. These may turn out to be proxies for the state of the immune system or metabolic dysfunction due to obesity and old age, both of which are important in the progression of degenerative aging. It makes for interesting reading, but it is worth asking questions such as those above when looking at this sort of thing.
1) Fungal infection of the central nervous system (CNS): Recently yeast and fungal proteins including (1,3)-β-glucan, high levels of fungal polysaccharides and disseminated and diffuse mycoses in the peripheral blood of AD patients suggests that chronic fungal infections may increase AD risk.
2) HSV-1 is associated with AD: Abundant evidence suggests that the herpes simplex virus-1 (HSV-1), can establish lifelong latency in CNS tissues and contribute to AD.
3) Prion diseases: driven by an unusual type of self-replicating "microbe," prion diseases are sporadic, inherited or acquired and ultimately fatal neurological disorders highly similar to AD. The recent discovery that prions can serve as Aβ receptors to relay amyloid neurotoxicity, and that peripherally administrated prions reach the brain, has engendered renewed interest in this self-replicating protein and its involvement in AD-like signaling processes that include neuroinflammation, synaptic degeneration and amyloidogenesis.
4) Chlamydophila pneumoniae, other pathogenic bacteria and AD: The association of the gram negative, obligate intracellular bacteria and pneumonia-causing C. pneumoniae of the family Chlamydiaceae with diseases such as coronary artery disease, arthritis, multiple sclerosis, meningoencephalitis, and AD has recently gained serious attention.
5) HIV-1 and AD: HIV-associated neurocognitive disorders (HAND) is a common manifestation of HIV infection and encompasses a variety of neurological disorders. Histopathologically HIV-infected brains exhibit atrophy of neurites and neuronal loss in anatomical areas identical to what is seen in AD.
6) Toxoplasma and neurodegeneration: Toxoplasma species such as Toxoplasma gondii are intracellular protozoan parasites that can cause encephalitis and neurological dysfunction by promoting chronic inflammation of the brain and CNS. Recently AD has been associated with significantly increased anti-T. gondii antibodies suggesting a possible mechanistic link between T. gondii infection and AD.
7) Viroids, miRNAs and AD: viroids are minimalist plant pathogens that consist of a viroid-specific ssRNA that are remarkably similar to miRNAs in their mode of generation, processing, structure and function, mobility and ability to spread disease within the host. We may be able to gain insight on the mechanism of AD neuropathology driven by miRNA from what is already known about plant viroids and their ability to spread systemic degenerative disease.
8) Hepatitis and AD: Hepatitis C virus infection has recently been shown to significantly increase the risk for AD, especially in the aged.
9) Cytomegalovirus and AD: A growing number of common viruses and latent viral infections involving Herpesviridae have been linked to the development of AD, and one of these is the human cytomegalovirus (HCMV).
10) GI tract and blood-brain barrier permeability: Lastly and importantly, the GI tract epithelial barrier and the blood brain barrier both become significantly more permeable over the course of aging. This may make the CNS more susceptible to potential neurotoxins generated by microbiome-resident or environmental pathogens.
Taken together, it is clear that the human CNS is under constant assault by a wide array of extrinsic and intrinsic neurotrophic microbes and pathogens including bacteria, virus, fungus, nucleic-acid free prions, or small non-coding RNAs found both in the environment and contained within the microbiome. Virtually every type of microbe known has been implicated in contributing to the susceptibility and pathogenesis of the AD process. This may be especially important over the course of aging because innate-immune and physiological barriers are often compromised with age, enabling microbes and/or their 'neurotoxic secretions' to gain easier access to CNS compartments. Because AD is clearly a multifactorial disease, and there are multiple biological pathways by which brain cells can dysfunction, perhaps it is not too surprising that multiple and complex microbial insults could contribute to AD, including the spreading of pathological signals throughout the CNS.
Analysis of sleep and cognitive (brain function) data from 3,968 men and 4,821 women who took part in the English Longitudinal Study of Ageing (ELSA), was conducted. Respondents reported on the quality and quantity of sleep over the period of a month. In adults aged between 50 and 64 years of age, short sleep (less than 6hrs per night) and long sleep (more than 8hrs per night) were associated with lower brain function scores. By contrast, in older adults (65-89 years) lower brain function scores were only observed in long sleepers.
In this study, we did not find any significant interaction with gender. We found a significant decrease in amnestic and non-amnestic cognitive function in long sleepers, but this only reached significance in the older group. In our younger group, amnestic scores were significantly lower in short sleepers, whereas non-amnestic scores were lower in long sleepers. Our results show that an inverted U-shaped relationship exists in younger adults, where the amnestic scores for short sleepers were significantly lower than those for optimal sleepers, and whilst the amnestic scores for the long sleepers were reduced, this difference was not statistically significant. These findings could be interpreted in the context of recent findings in mice, which suggest that sleep deprivation causes irreversible damage to the brain which could impair cognitive function, particularly alertness. However, if this is the case, it is not clear why the effect of short sleep is not evident in the older group. That is, in the older adults, there was no observed effect in short sleepers but the amnestic scores in long sleepers were significantly lower than those for optimal sleepers.
In a study in men only, [previously published researcher] suggested that disturbed sleep is strongly associated with decline in executive function (or non-amnestic function), and less so for global cognition, whereas we found the opposite to be true in older adults. Indeed in our older group, the highest cognitive function scores (both amnestic and non-amnestic) were seen in those individuals with the greatest reported disturbances in sleep. In younger individuals however, there was no significant association between cognition and sleep quality, indicating that until we reach the age of around 65 years, there may be no association between sleep quality and cognitive function. The reason for these differences is unclear and prospective analyses of the effects of sleep quality on the decline in cognition could help rule out possible influences of reverse causality due to pre-existing ill-health or other confounders.
The suggestion that cognitive function increases with increasing sleep disturbance in older individuals appears to be counterintuitive. It may reflect the fact that those individuals who are more cognitively able are better at recording sleep disturbance data. Alternatively, it may indicate that in an elderly population, individuals who are more cognitively active may process the day's events and/or experience more worry or anxiety than those who are less cognitively active, and hence this may lead to an associated increase in self-reported frequency of sleep disturbance. Confounding effects of medications may also be more important in an older group. Likewise, in those participants with memory problems, we cannot exclude the possibility that their responses might have been erroneous to some extent due to their memory impairment.
The thymus is a gateway for the production of new T cells, the immune cells responsible for destroying pathogens and precancerous or senescent cells. The thymus is highly active in childhood, churning out a large supply of these immune cells as it builds up and supports the immune system. But upon adulthood the thymus atrophies quickly, reducing that supply to a trickle, and effectively imposing a cap on the number of T cells present in the body at any one time. Unfortunately the evolved mechanisms of the immune system, while very effective in the destruction of most intruders, interact with the presence of persistent herpesviruses - largely cytomegalovirus - to gradually convert useful killer T cells into useless memory T cells fixated on these viruses. Over the years the immune system becomes ever more dysfunctional simply through trying to do its job.
T cell deficiency related to disease, medical treatment, or aging represents a major clinical challenge and is associated with significant morbidity and mortality in cancer and bone marrow transplantation recipients. This study describes several innovative and clinically relevant strategies to manipulate thymic function based on an interventional radiology technique for intrathymic injection of cells or drugs.
We show that intrathymic injection of multipotent hematopoietic stem/progenitor cells into irradiated syngeneic or allogeneic young or aged recipients resulted in efficient and long-lasting generation of functional donor T cells. Persistence of intrathymic donor cells was associated with intrathymic presence of cells resembling long-term hematopoietic stem cells, suggesting a self-renewal capacity of the intrathymically injected cells. Furthermore, our approach enabled the induction of long-term antigen-specific T cell-mediated anti-tumor immunity following intrathymic injection of progenitor cells harboring a transgenic T cell receptor gene.
The intrathymic injection of interleukin 7 prior to irradiation conferred radioprotection. In addition, thymopoiesis of aged mice improved with a single intrathymic administration of low-dose keratinocyte growth factor, an effect that was sustained even in the setting of radiation-induced injury. Taken together, we established a preclinical framework for the development of novel clinical protocols to establish life-long antigen-specific T cell immunity.
Nerves are sheathed in myelin. That sheathing deteriorates to some degree with age, and more dramatically in demyelinating conditions such as multiple sclerosis (MS). Some of the approaches taken by researchers working on conditions such as MS may prove applicable to reversal of the lesser deterioration of myelin in aging, a process that correlates with some forms of cognitive decline.
Stem cell therapy is seen as having dramatic potential for treating MS, but there are key obstacles, especially the length of time it takes for progenitor cells to turn into oligodendrocytes, the brain's myelin-making cells. Using currently available methods, it can take as long as a year to generate a sufficient number of human oligodendrocyte cells to treat a single MS patient. That's partly because there are so many steps: the skin or blood cell must be turned into induced pluripotent stem cells, which can differentiate into any other type of cell and from which neural progenitor cells can be produced. Those progenitor cells then must undergo differentiation to oligodendrocyte progenitors that are capable of ultimately producing the oligodendrocytes.
Using fetal brain stem cells, the researchers searched for transcription factors that are absent in neural progenitor cells and switched on in oligodendrocyte progenitor cells. While neural progenitor cells are capable of producing myelin, they do so very poorly and can cause undesirable outcomes in patients, so the only candidate for transplantation is the oligodendrocyte progenitor. "The question was, could we use one of these transcription factors to turn the neural progenitor cell into an oligodendrocyte progenitor cell?"
"We narrowed it down to a short list of 10 transcription factors that were made exclusively by oligodendrocyte progenitor cells. Among all 10 factors that we studied, only SOX10 was able to make the switch from neural progenitor to oligodendrocyte progenitor cell." In addition, the researchers found that SOX10 could expedite the transformation from oligodendrocyte progenitor cell to differentiation as an oligodendrocyte, the myelin-producing cell and the ultimate treatment goal for MS. "Ideally, we'd like to get directly to oligodendrocyte progenitors. The new results are a stepping stone to the overall goal of being able to take a patient's skin cells or blood cells and create from them oligodendrocyte progenitors."
[Scientists] have bio-printed artificial vascular networks mimicking the body's circulatory system that are necessary for growing large complex tissues. "Thousands of people die each year due to a lack of organs for transplantation. Many more are subjected to the surgical removal of tissues and organs due to cancer, or they're involved in accidents with large fractures and injuries. Imagine being able to walk into a hospital and have a full organ printed - or bio-printed, as we call it - with all the cells, proteins and blood vessels in the right place, simply by pushing the 'print' button in your computer screen. We are still far away from that, but our research is addressing exactly that. Our finding is an important new step towards achieving these goals. At the moment, we are pretty much printing 'prototypes' that, as we improve, will eventually be used to change the way we treat patients worldwide."
The research challenge - networking cells with a blood supply. Cells need ready access to nutrients, oxygen and an effective 'waste disposal' system to sustain life. This is why 'vascularisation' - a functional transportation system - is central to the engineering of biological tissues and organs. "One of the greatest challenges to the engineering of large tissues and organs is growing a network of blood vessels and capillaries. Cells die without an adequate blood supply because blood supplies oxygen that's necessary for cells to grow and perform a range of functions in the body. Replicating the complexity of these networks has been a stumbling block preventing tissue engineering from becoming a real world clinical application."
Lysosomes are recycling units inside cells responsible for breaking down damaged cellular components and unwanted proteins. Lysosomal function declines with age in important long-lived cells, such as those of the nervous system, as they accumulate metabolic waste products that they are unequipped by evolution to destroy. They become bloated and inefficient, and as a consequence garbage piles up in their cells harming the surrounding tissues. This is seen in diseases such as macular degeneration, in which cells of the retina are overwhelmed by certain types of metabolic waste.
Healthful cell maintenance requires the efficient degradative processing and removal of waste material. Retinal pigmented epithelial (RPE) cells have the onerous task of degrading both internal cellular debris generated through autophagy as well as phagocytosed photoreceptor outer segments. We propose that the inadequate processing material with the resulting accumulation of cellular waste contributes to the downstream pathologies characterized as age-related macular degeneration (AMD).
The lysosomal enzymes responsible for clearance function optimally over a narrow range of acidic pH values; elevation of lysosomal pH by compounds like chloroquine or A2E can impair degradative enzyme activity and lead to a lipofuscin-like autofluorescence. Restoring acidity to the lysosomes of RPE cells can enhance activity of multiple degradative enzymes and is therefore a logical target in early AMD.
We have identified several approaches to reacidify lysosomes of compromised RPE cells; stimulation of beta-adrenergic, A2A adenosine and D5 dopamine receptors each lowers lysosomal pH and improves degradation of outer segments. Activation of the CFTR chloride channel also reacidifies lysosomes and increases degradation. These approaches also restore the lysosomal pH of RPE cells from aged ABCA4−/− mice with chronically high levels of A2E, suggesting that functional signaling pathways to reacidify lysosomes are retained in aged cells like those in patients with AMD. Acidic nanoparticles transported to RPE lysosomes also lower pH and improve degradation of outer segments. In summary, the ability of diverse approaches to lower lysosomal pH and enhance outer segment degradation support the proposal that lysosomal acidification can prevent the accumulation of lipofuscin-like material in RPE cells.
There seems to be an infinite fund of resources for any epidemiological research that involves television. Here researchers are trying to get a handle on the degree to which sedentary behavior negatively influences health, but their data strongly suggests that the correlation between increased mortality rates and more time spent watching television is only a correlation, as other similar forms of sedentary behavior do not show the same relationship, or at least not in this group of younger study participants.
Thus we are left reaching for the web of other factors that correlate with fewer hours spent watching television, such as wealth, education, intelligence, and so on - all of which themselves correlate with greater life expectancy. This is the challenge inherent in this sort of study, where obtaining even simple answers to simple questions from the data can be a struggle. There is plenty of evidence from other studies to suggest that less exercise and more time spent sitting both increase mortality rates, but when different - but really very similar - sitting activities have widely divergent statistical relationships with health it seems necessary to ask harder questions about the underlying mechanisms.
Adults who watch TV for three hours or more each day may double their risk of premature death compared to those who watch less. "Television viewing is a major sedentary behavior and there is an increasing trend toward all types of sedentary behaviors. Our findings are consistent with a range of previous studies where time spent watching television was linked to mortality."
CISD2, an evolutionarily conserved novel gene, plays a crucial role in lifespan control and human disease. Mutations in human CISD2 cause type 2 Wolfram syndrome, a rare neurodegenerative and metabolic disorder associated with a shortened lifespan. Significantly, the CISD2 gene is located within a region on human chromosome 4q where a genetic component for human longevity has been mapped through a comparative genome analysis of centenarian siblings.
We created Cisd2 knockout (loss-of-function) and transgenic (gain-of-function) mice to study the role of Cisd2 in development and pathophysiology, and demonstrated that Cisd2 expression affects lifespan in mammals. In the Cisd2 knockout mice, Cisd2 deficiency shortens lifespan and drives a panel of premature aging phenotypes. Additionally, an age-dependent decrease of Cisd2 expression has been detected during normal aging in mice. Interestingly, in the Cisd2 transgenic mice, we demonstrated that a persistent level of Cisd2 expression over the different stages of life gives the mice a long-lived phenotype that is linked to an extension in healthy lifespan and a delay in age-associated diseases.
At the cellular level, Cisd2 deficiency leads to mitochondrial breakdown and dysfunction accompanied by cell death with autophagic features. Recent studies revealed that Cisd2 may function as an autophagy regulator involved in the Bcl-2 mediated regulation of autophagy. Furthermore, Cisd2 regulates Ca2+ homeostasis and Ca2+ has been proposed to have an important regulatory role in autophagy. Finally, it remains to be elucidated if and how the regulation in Ca2+ homeostasis, autophagy and lifespan are interconnected at the molecular, cellular and organism levels.
For some folk, every possible aspect of future progress in technology is a chance to wish for class war. There will always be great differences between the haves and the have nots, but our modern age is distinguished from the past by just how little of medical technology is out of the reach of those comparatively poor people who live in the wealthier regions of the world where one finds most class war enthusiasts. If you are a billionaire you can buy the services of more doctors and assistants to do the legwork of applying for clinical trials, but there is no type of medicine that you can obtain with your wealth today that remains completely unavailable to the masses. This is generally true of most widely used technologies: communications devices, computing, transport, and so on. It is a flat age in which wealth buys you influence but little more than that.
When it comes to disparities in access to medicine, the people who care about such things should focus on those communities in the poorer reaches of the world that have yet to bring themselves up to par with Europe and US. The best way to help them is in fact to support faster progress towards ever better, cheaper, and more effective medical technology in Europe and the US: improvements in availability elsewhere will happen as a matter of course when price drops. Consider that the future of rejuvenation treatments will largely consist of mass-produced infusions: bacterial enzymes and other similar substances to break down metabolic waste, gene therapy vectors for allotopic expression of mitochondrial genes, and so forth. This is a form of medicine that once mature will be durable, easily administered, easily stored, and easily transported. It will be cheap, and it will eliminate the vast majority of all medical conditions, since the vast majority of all medical conditions are caused by aging.
The disparity between top earners and everyone else is staggering in nations such as the United States, where 10 per cent of people accounted for 80 per cent of income growth since 1975. The life you can pay for as one of the anointed looks nothing like the lot tossed to everyone else: living in a home you own on some upscale cul-de-sac with your hybrid car and organic, grass-fed food sure beats renting (and driving) wrecks and subsisting on processed junk from supermarket shelves. But there's a related, looming inequity so brutal it could provoke violent class war: the growing gap between the longevity haves and have-nots.
The life expectancy gap between the affluent and the poor and working class in the US, for instance, now clocks in at 12.2 years. College-educated white men can expect to live to age 80, while counterparts without a high-school diploma die by age 67. White women with a college degree have a life expectancy of nearly 84, compared with uneducated women, who live to 73.
This is just a harbinger of things to come. What will happen when new scientific discoveries extend potential human lifespan and intensify these inequities on a more massive scale? It looks like the ultimate war between the haves and have-nots won't be fought over the issue of money, per se, but over living to age 60 versus living to 120 or more. Will anyone just accept that the haves get two lives while the have-nots barely get one? We should discuss the issue now, because we are close to delivering a true fountain of youth that could potentially extend our productive lifespan into our hundreds - it's no longer the stuff of science fiction.
Instead of allowing the wealth gap to turn into a longevity gap, perhaps we'll find a way to use everyone's talents and share the longevity dividend at all levels of income. This kind of sharing could leverage the wisdom of elders, forestall the economic collapse many have predicted when the grey tsunami picks up speed, and avoid an all-out revolt against the one or so per cent. We stand at the threshold of two distinct futures - one where we have a frail, rapidly ageing population that saps our economy, and another where everyone lives much longer and more productive lives.
Lysosomes are one type of recycling unit in the cell, responsible for breaking down damaged cellular components and some unwanted proteins. One of the causes of aging is that in long-lived cells types of metabolic waste that cannot be broken down accumulate in lysosomes. These compounds are collectively called lipofuscin, and their presence in large amounts renders lysosomes bloated and inefficient. Cellular housekeeping as a whole then deteriorates until cells die or fall into dysfunctional states that harm tissue function. Everyone has this to look forward to. There is much less work taking place on a solution to this issue than on the analogous problem of lyososmal storage diseases, however, a collection of rare genetic disorders in which the lysosome lacks some of the tools it needs to break down ordinary, common structures and unwanted molecules. These compounds build up inside the cell and it eventually dies. If you follow the field of aging research you will see this over and and again: the harms that happen to everyone at the end of life are largely ignored, but there is much more interest in tackling similar problems that happen to just a few people in younger years.
Researchers here are looking at lysosomal exocytosis, which is a fancy term for the process in which a lysosome docks at the interior of the cell surface and then throws its cargo of garbage outside the cell. The degree to which this normally happens can be increased greatly, and early indications are that this is a potentially beneficial approach to treating lysosomal storage diseases. Will this be useful in the lysosomal issues that accompany aging, however? The type of garbage at issue is totally different, and it may well be that this would just swap the one problem for another. We have no idea what large amounts of lipofuscin between long-lived cells in nerve tissue will do over the long-term, though this is certainly something that could be investigated. Overall I'd prefer the SENS approach of infusing the body with enzymes that can safely break down lipofuscin constituents, but all of these strategies are at least worth investigation.
Lysosomes are acidic compartments in mammalian cells that are primarily responsible for the breakdown of endocytic and autophagic substrates such as membranes, proteins, and lipids into their basic building blocks. Lysosomal storage diseases (LSDs) are a group of metabolic disorders caused by genetic mutations in lysosomal hydrolases required for catabolic degradation, mutations in lysosomal membrane proteins important for catabolite export or membrane trafficking, or mutations in nonlysosomal proteins indirectly affecting these lysosomal functions.
A hallmark feature of LSDs is the primary and secondary excessive accumulation of undigested lipids in the lysosome, which causes lysosomal dysfunction and cell death, and subsequently pathological symptoms in various tissues and organs. There are more than 60 types of LSDs, but an effective therapeutic strategy is still lacking for most of them. Several recent in vitro and in vivo studies suggest that induction of lysosomal exocytosis could effectively reduce the accumulation of the storage materials. Meanwhile, the molecular machinery and regulatory mechanisms for lysosomal exocytosis are beginning to be revealed. In this paper, we first discuss these recent developments with the focus on the functional interactions between lipid storage and lysosomal exocytosis. We then discuss whether lysosomal exocytosis can be manipulated to correct lysosomal and cellular dysfunction caused by excessive lipid storage, providing a potentially general therapeutic approach for LSDs.
There are a range of epidemiological studies showing that carrying excess weight for years is associated with a sizable raised risk of suffering all of the common age related diseases - even if you turn things around and lose that fat later. Keeping the fat is of course worse. Other studies show measurable benefits as a result of choosing to improve your health at near any age. Starting to exercise more rigorously or adopting calorie restriction in old age, for example, are both shown to be beneficial. It is of course more beneficial to have been doing it all along, but the point here is that it is silly to shrug your shoulders if you've been letting things go. You can always produce improvements in your future health prospects by choosing to do better.