Fight Aging! Newsletter, November 17th 2014

November 17th 2014

Herein find a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress on the road to bringing aging under medical control, the prevention of age-related disease, and present understanding of what works and what doesn't when it comes to extending healthy life. Expect to see summaries of recent advances in medicine, 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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  • The Seven Pillars of Aging
  • Recent Interviews with Aubrey de Grey
  • SENS Research Foundation Newsletter, November 2014
  • The Lung Can Regenerate
  • Old Stem Cells Not So Good at Repairing Heart Attack Damage
  • Latest Headlines from Fight Aging!
    • Use of Transdifferentiated Cells in Regenerative Therapy
    • Improved Synthetic Blood Platelets Spur Clotting
    • An Interview with Michael Fossel
    • Suppressing Mitochondrial Fission as a Potential Treatment for Parkinson's Disease
    • Another Look at Blood Groups and Longevity
    • No Benefit to Survival from Injections of Young Blood Plasma Provided to Old Mice
    • Whole-Genome Sequencing of Supercentenarians
    • Pascal's Wager as Applied to the Defeat of Aging
    • Selective Removal of FXR1P Enhances Memory
    • The Overlap Between Vascular Disease and Alzheimer's Disease


Aging research is still mostly a matter of investigation, gathering data and validating theories without a hint of any intent to build treatments to help the aged. This terrible state of affairs is changing, however, and the prospects look increasingly good for serious levels of funding to arrive over the next decade at established research programs aimed at intervening in the aging process. Hence a lot of researchers are now interested in establishing such programs, and the existing programs are solidifying their positions and networks. It is often thought that scientists have a poor instinct for finance and competition, but the people who think that have evidently never seen the long game of grant management in action. A great deal of planning, positioning, and forethought takes place among those who manage sizable research portfolios.

Most of today's longevity science programs with an aspiration to producing therapies are presently focused on very modestly slowing aging through metabolic manipulation of one kind or another, such as the development of calorie restriction mimetic drugs. This is unfortunate, but I suppose that there has to be a start somewhere. When those programs are raising funds at five or ten times their present level, despite the poor prospects for any sort of meaningful extension of healthy life to emerge from their work, the same multiplier in funding levels will be attainable for SENS rejuvenation research. SENS-style biotechnologies that can repair the underlying cellular and molecular damage that causes aging are the approaches that actually matter if what you care about is adding decades of healthy life and restoring the old to vigor and health. SENS is still the young, disruptive movement in the field, but a rising tide floats all boats.

That said, SENS has rather set the tone for how researchers are choosing to present their research strategies: plans of development leading towards specific therapies to treat the aging process itself. This is a departure from the present state of medicine, in which only the symptoms of aging are treated, the various age-related diseases. Pushing the research community towards a growing consensus that aging can and should be treated as a condition (or rather collection of identifiable conditions) is a great victory in and of itself: now it's just a matter of steering in the right direction, funding the best strategies. SENS is presented as a set of seven classes of damage that causes aging, each with its own attendant proposed paths to treatments. The influence of that vision can be seen in the noted Hallmarks of Aging polemic published last year, which followed the same model but with a different, overlapping emphasis on what in aging is thought to be cause versus consequence.

Now here again we have another new position statement on treating aging that echoes the SENS model. It is put forward by leading figures in the research community, with yet another another take on what is cause versus consequence, and which research strategies to pursue, also overlapping to some degree with the SENS vision - though less so, I think. It is no doubt completely coincidental that there are seven pillars of aging, perhaps a reference to Proverbs 9:1, and it is certainly the case that all of these strategic considerations of aging research could be differently divided if the fancy takes you. But seven is a magic number it seems, and so seven it is:

Leading scientists identify research strategy for highly intertwined "pillars of aging" as next step in supporting the trans-NIH Geroscience Interest Group's efforts to integrate aging into research on chronic diseases

Scientists who have been successful in delaying mammalian aging with genetic, dietary and pharmacological approaches have developed a research strategy to expand Geroscience research directed at extending human healthspan. The scientists took part in the first summit of the NIH Geroscience Interest Group (GSIG) held last year on the NIH campus. The National Institutes of Health is made up of 27 different components called Institutes and Centers. Each has its own specific research agenda. The GSIG is aimed at promoting new pathways for collaboration, both within the NIH and with its funded researchers, specifically within the context of aging.

The "Pillars of Aging" and research goals are detailed in the following table:

Adaptation to Stress

  • Bridge continuum from psychological to molecular stresses.
  • Differentiate hormesis from toxic stress.
  • Better align human and animal studies.


  • Biomarker development: chronological vs. biological aging.
  • Link age-related environmental inputs to epigenetic signatures.
  • Test small molecules that regulate enzymes controlling epigenetic events.


  • Differentiate adaptive and maladaptive inflammatory response.
  • Define age-related inflammatory sources and their system effects.
  • Determine how obesity and metabolic dysfunction alter inflammation with age.

Macromolecular Damage

  • Generate systems level understanding of the role of types of macromolecular damage and their roles in chronic disease states.
  • Understanding how stochastic damage influences the variability of aging.


  • Define role of signal transduction pathways linked to metabolism in aging processes.
  • Understand contribution of circadian clocks to aging and metabolism.
  • Connect metabolic dysfunction with tissue-specific decline in aging.


  • Identify proteostatic pathways that are overwhelmed in specific chronic disease states.
  • Examine crosstalk between proteostasis machineries.
  • Understand non-cell-autonomous signaling and activation of proteostasis pathways.

Stem Cells and Regeneration

  • Determine whether declining adult stem cell function drives aging and chronic disease.
  • Examine how aging and associated disease impair adult stem cell function.
  • Determine how macromolecular damage accumulates in adult stem cell pools.

"We have high hopes that our research strategy will help move collaborative efforts to the next level. What has come out of our work is a keen understanding that the factors driving aging are highly intertwined and that in order to extend healthspan we need an integrated approach to health and disease with the understanding that biological systems change with age. The trans-NIH GeroScience Interest Group (GSIG) and this Geroscience initiative hope to mobilize the research community about considering prevention of multiple age-related chronic conditions by targeting common mechanisms underlying these conditions, rather than improving the management of diseases one by one. Our current approach to researching and treating chronic diseases is inadequate and fragmentary. By the time chronic diseases are diagnosed, much damage is done and undoing it is difficult. Targeting aging may allow early intervention and allow us to maintain vigor and activity, while offsetting the economic burdens of a burgeoning aging population hampered by multiple chronic diseases."

I see much of this, such as the focus on epigenetics, metabolism, stress, and proteostasis, as being largely a case of looking at the consequences of damage and the detailed operation of damaged machine. It is vastly complex, and not a path to prevention or reversal of aging. Nonetheless, that is where the overwhelming majority of today's research takes place. Still, most of the research community does see aging as being the result of damage, even though you might not be able to discern as much from their research work, and so there are components of these pillars that are pointed in the right general direction.


Aubrey de Grey is originator of the SENS rejuvenation research programs and presently Chief Science Officer at the SENS Research Foundation, the umbrella organization dedicated to ensuring that therapies to treat and reverse degenerative aging are developed as soon as possible. The Foundation funds a range of research into the underlying biotechnologies needed to produce regenerative medicine for aging, and is supported by a number of noted philanthropists and luminaries in the scientific community.

Success here is as much a matter of convincing the broader medical research community as it is of proving the case via scientific research: like all sweeping changes in the making, this is a bootstrap process of growing the funding and the research results until SENS effectively becomes the mainstream of aging research. This will happen because SENS research programs will prove capable of delivering far better results than the present approaches to aging, and at a fraction of the cost. SENS is based on repair of damage, while today's mainstream is much more interested in finding ways to alter the operation of our metabolism to slightly slow down the accumulation of further damage. It doesn't take a scientist to understand that repair will always win out in terms of cost-effectiveness, and that repair is the only way to rejuvenate the old, those who will benefit very little from ways to slow down the damage of aging.

Yesterday de Grey appeared on CNBC in a short segment to summarize some of his views. It is always good to see a broader audience get a taste of these things, but I should note that in the past decade television has shown itself to be a terrible medium to convey the exciting prospects for longevity science. Even fairly involved treatments of the research and researchers involved produced very little in return: no great visitation of web sites, no donations, no follow up. No doubt we can all theorize as to why this is the case, but it is what it is.

Do you really want to live to 1,000?

At this year's Exponential Medicine conference, CNBC was present to probe faculty about some of the exciting developments within accelerating technologies. One of the most eye-opening speakers is Aubrey de Grey, cofounder and Chief Science Officer of the SENS Research Foundation, who was interviewed about longevity and the prospect of regenerative medicine extending our lives to 1,000 years or more.

By way of a contrast here is a longer audio podcast interview with de Grey from last month, in which he covers the established SENS vision and the long-term goal for the entire research community of eliminating degenerative aging from the human condition:

Eliminating aging (it's more obvious than it sounds) with Aubrey de Grey

It sound crazy when you put it into perspective but at the moment there is a 100% chance of death. I don't want to sound too morbid but this includes you, your friends and your family...

Aubrey de Grey joins me [to] discuss his work on resolving the issue of aging which at it's fundamental level is just a problem with our mechanics breaking down over time. We cover neurodegenerative diseases to mitochondrial damage and he gives us the 7 key targets his research as suggested will have the biggest impact on the aging process. The interview was a fascinating insight into Aubrey's work and he will be appearing again soon do to a show about cancer and the potential to solve it.


The SENS Research Foundation is perhaps the only group in the world to presently focus on organizing, advocating, and carrying out research into the biotechnologies required for treatments capable of reversing degenerative aging. The pains and frailties of aging are the consequence of unrepaired damage to cells and tissues. While it is true that the forms of damage are well understood and there are several clear paths to develop means to repair this damage, it is still the case that someone has to do the initial proof of concept work and persuade the rest of the research community to join in. Without bold steps there will be no progress.

The latest newsletter from the SENS Research Foundation arrived in my in-box today, along with a reminder that we're in at present right in the middle of the Fight Aging! 2014 matching fundraiser to support the Foundation's research programs, and all the help we can get to hit the target will be greatly appreciated:

Everyone at SENS Research Foundation would like to thank all our contributors who have helped us reach nearly 40% of our challenge goal already, with the deadline being December 31st. Fight Aging! has pledged to us that for every $1 you give they will add $2 - tripling your donation. So please join the more than 300 donors who have shown their support for SENS Research Foundation and our work and donate today.

We are also looking for additional challenge grant sponsors. If you are interested in offering up a challenge please contact us.

One of the important activities undertaken by the Foundation is to help build the rejuvenation research community of tomorrow. A generation of well-connected, organized researchers who see the treatment of aging as an exciting, cutting-edge field of science won't come about by accident. The defeat of age-related pain, suffering, and disease is a long-term project, and the people who will in years ahead, at the height of their careers, put the capstone on the first generation of rejuvenation treatments are still in college today, deciding which academic path to pursue:

SENS Research Foundation invites all qualifying students to apply for the 2015 Summer Scholars Program. The online application will be available starting December 1, 2014. Completed applications will be accepted through February 2, 2015. If you are an undergraduate interested in rejuvenation biotech, this is your chance to gain valuable experience in the field.

The first in a series videos profiling the students who participated in the 2014 SRF Summer Scholars Program is now available for viewing on the SRF website. This video features our 2014 scholars in action at the SRF Research Center (SRF-RC). View the video to meet Christine Wu, Summer Wang, and Karina Liker and learn about their experiences in the program.

As is usually the case, the question of the month section makes for interesting reading:

Question of the Month #7: What's Menopause Got To Do With It (Rejuvenation Biotechnology)?

Q: SENS Research Foundation Chief Science Officer Dr. Aubrey De Grey recently made a comment to the media suggesting that "rejuvenation biotechnology could eliminate menopause within twenty years." How does intervening in the process of menopause fit in with SRF's agenda to ameliorate age-related disease?

A: SENS Research Foundation works to catalyze the development of rejuvenation biotechnology: a new class of medicines that will keep us young and healthy and forestall the disease and debility that currently accompany a long life, by targeting the root causes of age-related ill health.

Menopause shares much in common with major age-related health problems, inasmuch as they all result from the accumulation of cellular and molecular damage in our tissues over time. Because this damage takes our tissues' microscopic functional units offline, aging damage gradually degrades each tissue's capacity to carry out its normal function with time. When enough of this damage accumulates in a particular tissue, specific diseases and disorders of aging characteristic of that tissue emerges, whether it's in the brain (Alzheimer's and Parkinson's disease), or the heart and circulatory system (atherosclerosis and heart failure), or the machinery controlling cellular growth (cancer) - or the ovaries (menopause). The corollary of this is that by removing and repairing this damage, rejuvenation biotechnology will restore the proper structure of the cellular machinery that keeps our tissues functioning, restoring their ability to keep us alive and with the good health that most of us enjoy at earlier ages.

So maintaining a woman's fertility and postponing or eliminating menopausal symptoms comes down to a mixture of repairing and replacing damaged cells (notably egg cells) and tissues (follicles) whose age-related degradation leads to menopause in the first place, bringing the whole system back to its youthful, functional norm. Today, researchers are pursuing several "damage-repair" approaches to realize this goal, and that's what we'll discuss in an article at the SEN Research Foundation website.


One of the ongoing themes in stem cell research is the discovery that numerous tissues thought to be static or poor at regeneration are in fact generating new cells, and can in fact naturally regenerate under some circumstances. If the rudiments of these regenerative mechanisms exist, then why not build therapies based on reliably activating and steering them? Or so the thinking goes. At the present time work hasn't progressed much past discovery and experimentation, even for nerve tissues where the crucial discoveries that neurogenesis occurs in adults were solidified and accepted fifteen years ago. Most of the progress in the broader field of regenerative medicine to date has been a case of improving on regenerative mechanisms that have long been well recognized and are consistently at work in ordinary adults. That will change soon enough, however, as improved technologies and capabilities in working with cells are leading to rapid progress in all areas of cell research. The equipment and knowledge present in the labs of today is far advanced over that of even a decade ago, and the pace is picking up.

Here is a great example of the sort of discoveries taking place in recent years regarding the regenerative capabilities of tissues that normally recover from damage only poorly. In this case the focus is on the lung. Like much of this work, it seems very promising - that there are mechanisms that could with just comparatively simple manipulations greatly enhance the normal state of tissue regeneration. "Comparatively simple" is usually still a major research project in any form of cell biology, unfortunately, but this and similar results in other tissues show the path ahead. Regenerative medicine will undergo a great deal of improvement in near future:

Lung regeneration mechanism discovered

The idea that the lung can regenerate has been slow to take hold in the biomedical research community, in part because of the steady decline that is seen in patients with severe lung diseases like chronic obstructive pulmonary disease (known as COPD) and pulmonary fibrosis. Nevertheless, there are examples in humans that point to the existence of a robust system for lung regeneration. Some survivors of acute respiratory distress syndrome, or ARDS, for example, are able to recover near-normal lung function following significant destruction of lung tissue.

Mice appear to share this capacity. Mice infected with the H1N1 influenza virus show progressive inflammation in the lung followed by outright loss of important lung cell types. Yet over several weeks, the lungs recover, revealing no signs of the previous lung injury. Using this mouse model system, [researchers] previously identified a type of adult lung stem cell known as p63+/Krt5+ in the distal airways. When grown in culture, these lung stem cells formed alveolar-like structures, similar to the alveoli found within the lung.

The research team reports that the p63+/Krt5+ lung stem cells proliferate upon damage to the lung caused by H1N1 infection. Following such damage, the cells go on to contribute to developing alveoli near sites of lung inflammation. To test whether these cells are required for lung regeneration, the researchers developed a novel system that leverages genetic tools to selectively remove these cells from the mouse lung. Mice lacking the p63+/Krt5+ lung stem cells cannot recover normally from H1N1 infection, and exhibit scarring of the lung and impaired oxygen exchange - demonstrating their key role in regenerating lung tissue. The research team also showed that when individual lung stem cells are isolated and subsequently transplanted into a damaged lung, they readily contribute to the formation of new alveoli, underscoring their capacity for regeneration.

p63+Krt5+ distal airway stem cells are essential for lung regeneration

Lung diseases such as chronic obstructive pulmonary disease and pulmonary fibrosis involve the progressive and inexorable destruction of oxygen exchange surfaces and airways, and have emerged as a leading cause of death worldwide. Mitigating therapies, aside from impractical organ transplantation, remain limited and the possibility of regenerative medicine has lacked empirical support. However, it is clinically known that patients who survive sudden, massive loss of lung tissue from necrotizing pneumonia or acute respiratory distress syndrome often recover full pulmonary function within six months.

Correspondingly, we recently demonstrated lung regeneration in mice following H1N1 influenza virus infection, and linked distal airway stem cells expressing Trp63 (p63) and keratin 5 (Krt5) to this process. Here we show that [these cells] undergo a proliferative expansion in response to influenza-induced lung damage, and assemble into nascent alveoli at sites of interstitial lung inflammation.


One of the areas in which stem cell therapies have shown promise right from the beginning is in the treatment of various forms of heart disease and the tissue damage caused by a heart attack, or myocardial infarction. Benefits have been evident enough for a broad clinical industry to flourish in many parts of the world well in advance of the exceedingly slow and largely unnecessary process of pushing treatments through the regulatory gauntlet in the US. A trend in the development of therapies has been from the use of transplanted stem cells obtained from donors to the use of stem cells isolated or reprogrammed from a patient's tissue samples, something that should produce a better class of result because it removes concerns regarding transplant rejection and other issues that can arise when the tissues from one person are used in another.

If using the patient's own cells in a regenerative therapy, the question of age immediately arises, however. Most people in need of regenerative treatments are in need exactly because they are old and suffering from age-related degenerative medical conditions. Their organs falter and fail, and the leading use case for present and future regenerative medicine is to at least partially compensate for or ideally turn back this downward spiral. We age because we become damaged, the machinery of cells and tissues degraded in various ways to the point of malfunction, and a part of that damage accrues to stem cell populations. Work on understanding why stem cell activity declines with aging has in recent years placed a great deal of emphasis on the state of the surrounding tissue environment rather than the cells themselves. The muscle stem cells known as satellite cells recover much of their ability to maintain tissues when moved from old tissue to young tissue, for example. This, of course, leads to more optimism for the near future of regenerative treatments for old people, provided that sizable benefits can indeed be obtained by coaxing stem cells into a more youthful and active behavior through altered levels of signal proteins such as GDF-11.

Not all types of stem cells do as well as aged satellite cells, however. Mesenchymal stem cells (MSCs), usually obtained from bone marrow or fat tissue in adults, are at present one of the most-used cell types in treatments under development as well as those available in clinics or trials. Unfortunately, there is fairly robust evidence to show that these cells don't work as well in regenerative therapies when obtained from older donors. The research group quoted below have investigated the mechanisms involved, which is the first step on the road to understanding whether or not there is a practical way to fix this problem in the near term, and thus make cells from old patients just as effective as those from young patients:

Aging Increases the Susceptivity of MSCs to Reactive Oxygen Species and Impairs Their Therapeutic Potency for Myocardial Infarction

In the last decade, great successes been achieved in transplanting MSCs to treat myocardial infarction (MI) in animal models as well as in clinical trials. Previously, lower efficacy of old MSCs than the young ones in myocardial repair has been confirmed by independent studies and furthermore different potential mechanisms have been proposed, such as deteriorated paracrine capacity and impared angiogenic capacity. However, the causes why the efficacy of MSCs on myocardial repair after ischemia was attenuated with aging were far from thoroughly demonstrated. In the current study, our purpose is to determine whether other causes existed in addition to the previous findings that aging influenced the therapeutic efficacies of MSCs. We show that aging increases the susceptivity of MSCs to reactive oxygen species (ROS) and impairs their therapeutic potency for myocardial infarction. To our knowledge, this is the first evidence that MSCs from old donors were more susceptible to ROS induced adhesion impairment and apoptosis, leading to a more rapidly decreased survival rate, and thus resulting in a dampened therapeutic effectiveness.

Back to 2001, two landmark studies showed transplantation of bone marrow cells could generate de novo myocardium. Thereafter, MSCs transplantation was carried out by several clinic trials, and a promising therapeutic potential was reported. However, as autologous MSCs transplantation was favoured in clinic, and most patients were over 60 years old, one question arises - are MSCs from old donors qualified to do the job? We found an impaired therapeutic efficiency of transplantation using MSCs from old donors. Furthermore, our data suggest that this impairment may be caused directly by a significantly decreased viability of old MSCs engrafted, in which the micro-environmental ROS in the MI region may play important roles.

The co-injection of MSCs with the free radical scavenger, NAC (N-acetyl-L-cysteine) has been shown to protect MSCs from ROS and enhanced their therapeutic efficiency. In our study, in order to investigate whether MSCs from old donors were more vulnerable to the micro-environmental ROS in the MI region in vivo, besides the old and young MSCs transplantation groups, we introduced a group in which 1 mM NAC was co-injected with the old MSCs. Interestingly, we found a similar number of NAC treated old MSCs and young MSCs remained one week after transplantation, whereas the number of survived MSCs from old donors was only about a half of that of survived MSCs from young donors. In addition, judging by the histology and function of heart, we found an impaired therapeutic efficiency transplanting MSCs from old donors. Since the NAC plays its role as a ROS scavenger but does not have a significant therapeutic effect in treating MI without MSCs, we may safely indicated that MSCs from old donors has lower viability in vivo in the MI region due to their increased susceptivity to the environmental ROS.

To survive, cells require an adequate interaction between them and the extracellular matrix, otherwise they will undergo apoptosis, known as anoikis. Thus, the viability of engrafted MSCs also depends on cell adhesion. However, the infarction of myocardium created a harsh micro-environment, including an accumulation of ROS, which has been reported to hinder cell adhesion. Therefore, we postulated that the low survival rate of MSCs from old donor may be caused by an enhanced susceptibility to environmental ROS. By adhesion assay and apoptosis assay, we found that ROS caused more damage in the adhesion of old MSCs than of the young ones, which further increase the old MSCs' apoptosis indirectly.


Monday, November 10, 2014

When creating patient-matched cells for use in regenerative therapies the present approach is to generate pluripotent cells, such as induced pluripotent stem cells, from an easily obtained sample, and then guide those cells to differentiate into the desired cell type. Researchers are finding it is possible in some cases to directly transform one cell type into another, however, a process called transdifferentiation. In theory this might prove more efficient and less costly, but at this point it is very early in the development of regenerative therapies that use transdifferentiated cells:

[Scientists] learned that fibroblasts - cells that causes scarring and are plentiful throughout the human body - can be coaxed into becoming endothelium, an entirely different type of adult cell that forms the lining of blood vessels. The new method [starts] with exposing fibroblasts to poly I:C (polyinosinic:polycytidylic acid), a small segment of double-stranded RNA that binds to the host cell receptor TLR3 (toll-like receptor 3), tricking the cells into reacting as if attacked by a virus. Fibroblasts' response to a viral attack - or, in this case, a fake viral attack - appears to be a vital step in diverting fibroblasts toward a new cell fate. After treatment with poly I:C, the researchers observed a reorganization of nuclear chromatin, allowing previously blocked-off genes to be expressed. The fibroblasts were then treated with factors, such as VEGF, that are known to compel less differentiated cells into becoming endothelial cells.

About 2 percent of the fibroblasts were transformed from fibroblasts into endothelial cells, a rate comparable to what other research groups have accomplished using viruses and gene therapy. Preliminary, as-yet-unpublished work [suggests] they may be able to achieve transformation rates as high as 15 percent. "That's about where we think the yield of transformed cells needs to be. You don't want all of the fibroblasts to be transformed - fibroblasts perform a number of important functions, including making proteins that hold tissue together. Our approach will transform some of the scar cells into blood vessel cells that will provide blood flow to heal the injury."

The scientists introduced the transformed human cells into immune-deficient mice that had poor blood flow to their hind limbs. The human blood vessel cells increased the number of vessels in the mouse limb, improving circulation. "The cells spontaneously form new blood vessels - they self assemble. Our transformed cells appear to form capillaries in vivo that join with the existing vessels in the animal, as we saw mouse red blood cells inside the vessels composed of human cells. One of the next steps will be to see if we can rescue an animal from an injury. We want to know if the therapy enhances healing by increasing blood flow to tissues that may have been damaged by a loss of blood because of ischemia."

Monday, November 10, 2014

Present work on artificial blood tends to focus on narrow areas of functionality in which short-term augmentation of the capabilities of natural blood are useful, such as oxygen transport and clotting. From these diverse paths a wholly artificial blood substitute will no doubt eventually arise, but bear in mind that this line of development faces stiff competition from the use of cell technologies to produce biological blood as needed. One way or another blood donation will be a thing of the past not so many years from now:

An additive nanoparticle manufacturing process has been used to design and realize a synthetic platelet for the first time. The platelets are "super mimics", matching the natural shape, size, flexibility, and surface biochemistry of real platelets unlike prior incarnations that match only one or two qualities. The synthetic plates are made by a layer-wise build-up of synthetic polymers and biological proteins, some of which include polystyrene, polyallylamine hydrochloride, and bovine serum protein (a generic protein). The surfaces are conjugated to natural clotting factors such as von Willebrand Factor binding peptide, and fibrinogen-mimetic peptide. The new nanoparticle-derived synthetic platelets have a natural, flexible "discoid" shape rather than a rigid spherical shape that overcame the margination problem. Nanoparticles have been developed previously for solving the same challenges but thus far have been hampered by deficiencies such as poor circulation in the blood stream, poor margination (the migration from central bloodstream to extremities), and poor targeting.

The synthetic platelets also display preferential attachment to injury sites because they are decorated on the exterior with the right proteins including von Willebrand Factor and collagen. In animal experiments, the synthetic platelets were introduced into the blood stream after injury to the tail of the model animal - mice. The platelets circulated broadly and then settled on the site of physical insult. In the animals that received the synthetic platelets with the biological mimic of the surface, the accumulation of platelets was three times higher than without for synthetic platelets with unmodified surfaces, accompanied by the same accelerated stopping of bleeding.

The immediate application is imagined for control of bleeding in people who have suffered traumatic injury, and patients who are undergoing surgery or suffer from a clotting disorder due to problems with platelets. But in addition, the new medical material is generating excitement for its potential as a therapeutic delivery vehicle for treating diseases that involve platelets, such as atherosclerosis (thickening of arterial wall leading to constriction of blood vessels) and thrombosis.

Tuesday, November 11, 2014

One of the roles of the enzyme telomerase is to extend the repeating telomere DNA sequences at the ends of chromosomes, thus lengthening the replicative life span of cells. Telomere length is a part of the clock mechanism limiting the life span of ordinary cells, and it decreases with each cell division. Telomerase is active in different tissues to different degrees, most notably in the stem cells that provide fresh cells with long telomeres to maintain tissues. The mix of these dynamics helps to determine the rate of cell turnover in any given tissue and the current average length of telomeres. This turnover rate varies greatly throughout the body, from a few days for the lining of the gut to essentially never for some of the central nervous system. The average length of telomeres tends to decline with aging or ill health, most likely due to a slowdown in the activity of stem cells and their delivery of new cells with long telomeres. As such these measures are probably a secondary aspect of aging, a marker rather than a root cause.

That said, increasing telomerase activity in mice has been shown to extend life, though there are several plausible reasons why this might be the case, only one of which involves enhanced tissue function due to longer-lived cells. The potential upside here has to be balanced with a concern over cancer: forcing cells into longer lives than evolution has settled on may or may not tip the balance in favor of much more cancer. This hasn't happened in the mouse studies, but mice have quite different telomere dynamics in comparison to humans.

Michael Fossel is one of the more noteworthy advocates for telomerase therapy as an important research direction for the treatment of aging. Here is an interview:

Michael Fossel's dream is to reverse human aging and since 1996 he has been a strong and vocal advocate of experimenting with telomerase therapy as a potential way of intervention in a wide variety of medical conditions related to aging. During our 1 hour discussion with Michael we cover a variety of interesting topics such as: his dream to reverse aging and the desirability and feasibility thereof; the Hayflick limit of cell division and Aubrey de Grey's concerns that telomerase therapy may cause cancer; the distinction between reversing aging and living forever; his "non-sexy" tips on healthy living; his take on cryonics and transhumanism.

"Ageing is dynamic, not static. Never mind the low-hanging fruit. [...] Go for the important one! The reason to [reverse aging] is not to double somebody's lifespan. The reason to do this is because people out there are hurting. They are frightened. They are terrified by the things that happen to them when they get disease. The reason to do this is because we are human and we should be working at this. It's not playing God, it is working at being human. It's compassion. It's not a matter of living longer, it is a matter of making people healthy again."

Tuesday, November 11, 2014

Mitochondria are bacteria-like organelles that swarm in their thousands in each of our cells, and they are important in aging because they can suffer forms of damage that negatively impact the functionality of their host cell. The mitochondrial population of any given cell is very dynamic: they swap protein machinery, fuse with one another, divide like bacteria, and are destroyed by cellular quality control mechanisms. Cells can even transfer mitochondria between one another, and all this takes place constantly at a very rapid pace. It has made it very challenging to prove exactly how damage to mitochondria occurs and propagates, which is one of the reasons why the SENS rejuvenation research approach is to jump over that question and focus on repair strategies that will work no matter how the damage is caused and spreads.

Mitochondrial dysfunction leading to higher rates of cell death or malfunction is implicated in a variety of specific age-related conditions, Parkinson's disease among them, and for reasons that may or may not run in parallel to the damage of aging. This has placed a spotlight on mitochondrial dynamics and the ability to manipulate their activities, as here. It is interesting to speculate on why less fission is beneficial; perhaps it allows mitochondrial quality control processes more chances to destroy damaged mitochondria before they replicate, or perhaps an increase in the rate of fusion over fission allows for more of the mitochondria in a cell to have all of the necessary proteins for complete function rather than just a damaged set:

The inhibition of a particular mitochondrial fission protein could hold the key to potential treatment for Parkinson's Disease (PD). The debilitating movement symptoms of the disease are primarily caused by the death of a type of brain cell that produces a chemical called dopamine. Understanding why these nerve cells die or do not work properly could lead to new therapies for PD.

Mitochondria are small structures within nerve cells that help keep the cells healthy and working properly - they are, in effect, the power generators of the cell. Mitochondria undergo frequent changes in shape, size, number and location either through mitochondrial fission (which leads to multiple, smaller mitochondria) or mitochondrial fusion (resulting in larger mitochondria). These processes are controlled mainly by their respective mitochondrial fission and fusion proteins. A balance of mitochondrial fission/fusion is critical to cell function and viability.

The research team found that when a particular mitochondrial fission protein (GTPase dynamin-related protein-1 - Drp1) was blocked using either gene-therapy or a chemical approach in experimental models of PD in mice, it reduced both cell death and the deficits in dopamine release - effectively reversing the PD process. The results suggest that finding a strategy to inhibit Drp1 could be a potential treatment for PD.

Wednesday, November 12, 2014

Evidence for blood group differences to be meaningfully involved in natural variations in longevity is nebulous at best. Nonetheless, papers emerge every so often on this topic to theorize and collect more evidence, but continue to reinforce the lack of compelling data:

ABO antigens have been known for a long time and yet their biological meaning is still largely obscure. Based on the available knowledge of the genes involved in their biosynthesis and their tissue distribution, their polymorphism has been suggested to provide intraspecies diversity allowing to cope with diverse and rapidly evolving pathogens. Accordingly, the different prevalence of ABO group genotypes among the populations has been demonstrated to be driven by malaria selection. In the similar manner, a particular ABO blood group may contribute to favour life-extension via biological mechanisms important for surviving or eluding serious disease.

There are only five reports suggesting a possible association between ABO blood groups and ageing/longevity features, among those only two performed on centenarians and only one performed by molecular methods. In the first one, a significant increase of A blood type was observed in the healthy elderly male population over 64 years of age from UK, but it is not possible to consider this study for the very low age taken into account. In a study carried out on a small sample of very longevous Turkish population, no association was found; however, the validity of age claims was very questionable because birth certificates were not available, so also this study cannot be considered.

A more recent study investigated the association between blood groups and life expectancy in the Japanese population. The authors compared frequencies of ABO blood groups in 269 centenarians living in Tokyo and those in 7153 regionally matched controls. Group B was observed more frequently in centenarians than in controls, suggesting that group B might be associated with exceptional longevity. The authors suggested that group B individuals are more likely to survive age-related diseases rather than escape them, since 33% of the centenarians were free of age-related diseases, but this did not correlate with the group B.

In a further study, to validate these results, [researchers] collected data on the ABO blood groups of patients who died in a United States tertiary care hospital over a 1-year period. If group B was a marker for a longer lifespan, it would be expected that the percentage of group B patients would rise with age at the time of death and those of other blood groups would decline. A total of 772 patients were included in the study and data were presented as ABO proportion stratified by age. The authors found that the percentage of group B patients declined with age, and this result was statistically significant. None of the other blood groups showed a statistically significant increase or decrease when plotted against decade of death. Overall, these results suggest that group B is not a marker for longevity, at least in US.

We have recently investigated the relationship between ABO group and longevity in a small sample of homogeneous Sicilian centenarians (n = 38) and young controls (n = 59). Our group of centenarians (age range 100-107) had no cardiac risk factors or other age-related diseases. The control group (age range 45-65) was recruited from blood donors and judged to be healthy on the basis of clinical history and blood tests. Samples were genotyped by molecular biology to determine ABO blood group and Chi Square analysis was used to determine the statistical significance of differences in ABO of centenarians and controls. Our pilot study shows a not-significant increase of A1 allele in Sicilian centenarians.

In the generation of centenarians under study, the control of cardiovascular disease, in fact plays a key role in the longevity attainment. So, the Sicilian results, that need to be confirmed in a larger sample of centenarians, also taking into account the gender due to its relevance in immune-inflammatory responses, are in line with the previous statements. So, people carrying A1 allele should be advantaged in attaining longevity because of the lower levels of the serum soluble inflammatory marker E-selectin linked to this blood group, so avoiding or delaying cardiovascular events.

Wednesday, November 12, 2014

The practice of heterochronic parabiosis, linking the circulatory systems of old and young mice and observing the results, produces measurable beneficial changes in the tissues of the old mice. Researchers have identified a few proteins such as GDF-11 where changes in the circulating levels occur with age, and artificially resetting these levels - such as via parabiosis - can alter the behavior of stem cells to make them more active in tissue maintenance. A range of other experiments are currently ongoing to try to better understand and catalog these results first identified via parabiosis studies. Some of these experiments are going to produce null or ambigious results, as is the case here, because nothing in biology is simple or straightforward. You'll probably want to skip ahead to the discussion section at the end of this open access paper, as that is where the interesting information can be found:

Aging is for now an irreversible process that affects multiple organs and is the leading cause of age-associated mortality and morbidity. The search for an efficient way to counter age-related changes in an organism is a task of high importance. Recently, scientific evidence of a rejuvenating effect of young blood on different tissue and organ functions was published. Among these studies, heterochronic parabiosis was particularly interesting: the model demonstrates the possibility of constant exchanges of cellular and humoral factors through the blood between animals of different ages.

Still, after such mostly positive reports, the question of the overall beneficial effect becomes extremely intriguing: Instead of looking at a specific parameter or a short period of time, is maintaining a young milieu globally beneficial over time? This can be asked through a simple measure: Does it increase lifespan? In previous experiments, we looked at the survival of mice following temporary isochronic and heterochronic parabiosis (unpublished data). It was found that aged mice tended to live longer after a period of heterochronic parabiosis than isochronic parabiosis, suggesting a globally beneficial effect of the young milieu. However, the difference was not statistically significant, and lifespans were not in the range of those of untreated animals, possibly due to the traumatic condition of parabiosis. Therefore, general conclusions were very uncertain regarding "anti-aging" effects, and another model for long-term effects was sought, namely, plasma injections.

To assess the anti-aging effect of young blood we tested the influence of repeated injections of plasma from young mice on the lifespan of aged mice. One group of 36 CBA/Ca female mice aged 10-12 months was treated by repeated injections of plasma from 2- to 4-month-old females. Their lifespan was compared to a control group that received saline injections. The median lifespan of mice from the control group was 27 months versus 26.4 months in plasma-treated group; the repeated injections of young plasma did not significantly impact either median or maximal lifespan.

Thursday, November 13, 2014

The search for longevity-associated genes continues, and the evidence taken as a whole suggests that the situation is very complex. It looks to be the case that potentially hundreds or thousands of genes each provide a tiny, environment- and lineage- specific contribution, and associations between single genes and natural variations in longevity are almost all either statistically weak or fail to replicate in different study populations. So the genetics of longevity looks like one of the many presently popular areas of study in which there is little to gain but knowledge of the details of our metabolism. The cellular and molecular damage that distinguishes old tissues from young tissues is well known and is the same in everyone. The best path towards treating aging is to repair this damage, not spend all our time figuring out how differences in the reaction to this damage causes some few very damaged people to live longer:

Supercentenarians (110 years or older) are the world's oldest people. Seventy four are alive worldwide, with twenty two in the United States. We performed whole-genome sequencing on 17 supercentenarians to explore the genetic basis underlying extreme human longevity. We found no significant evidence of enrichment for a single rare protein-altering variant or for a gene harboring different rare protein altering variants in supercentenarian compared to control genomes.

We followed up on the gene most enriched for rare protein-altering variants in our cohort of supercentenarians, TSHZ3, by sequencing it in a second cohort of 99 long-lived individuals but did not find a significant enrichment. The genome of one supercentenarian had a pathogenic mutation in DSC2, known to predispose to arrhythmogenic right ventricular cardiomyopathy, which is recommended to be reported to this individual as an incidental finding according to a recent position statement by the American College of Medical Genetics and Genomics. Even with this pathogenic mutation, [this supercentenarian] lived to over 110 years.

The entire list of rare protein-altering variants and DNA sequence of all 17 supercentenarian genomes is available as a resource to assist the discovery of the genetic basis of extreme longevity in future studies.

Thursday, November 13, 2014

There are two choices: do nothing and probably age to death, or support research into longevity science and live for much longer in good health if it is successful. Since you are here and reading this, the dice are already rolling for the rest of your life. Why not do what you can to improve the odds of a good outcome, a future in which effective rejuvenation treatments for age-related frailty and disease exist by the time you need them?

The choice comes down to doing nothing - except hoping that you have the right religious beliefs - or doing something - buying a cryonics policy and/or supporting scientific research. So what should you do? Perhaps the best way to illuminate the choice is to consider a previous choice human beings faced in their history. What should they do about disease? Should they pray to the gods and have faith that the gods will cure them, or should they use science and technology to find the cures themselves? In hindsight the answer is clear. Praying to the gods makes no difference, whereas using modern medicine has limited death and disease, and nearly doubled the human lifespan in the last century. Other examples also easily come to mind. What is the best way to predict weather, harness energy, communicate instantly over great distances, or fly to far off planets?

These examples highlight another advantage to making [the] wager - the incremental benefits that accrue as we live longer and better lives as we approach the holy grail of blissful immortality. Such benefits provide assurance that we are on the right path, which should increase our confidence that we are making the correct wager. In fact, the benefits already bestowed upon us by science and technology confirm that it is the best path toward a better future. As these benefits accumulate, and as we become aware of them, our existence will become increasingly indistinguishable from the most enchanting descriptions of any afterlife.

So we should throw off archaic superstitions and use our technology. Will we do this? Yes. I say with confidence that when an effective pill that stops or reverses aging becomes available at your local pharmacy - it will be popular. Or if, as you approach death, you are offered the opportunity to have your intact consciousness transferred to your younger cloned body, a genetically engineered body, a robotic body, or a virtual reality, most will use such technologies when they are demonstrated effective. By then almost everyone will prefer the real thing to a leap of faith.

Friday, November 14, 2014

As researchers make progress in understanding how memory works, they will also find ways to enhance its operation. A class of therapies that attempt to compensate for age-related memory impairment may arise as a result, but note that compensation is never a true replacement for addressing the actual causes of dysfunction. Still, even after the causes of memory issues with age are understood and prevented, there is still a place for options to enhance memory in healthy people. Who doesn't want better control over memory, even in youth?

This is an example of the sort of results currently emerging from studies of memory mechanisms in laboratory animals. Like all work at this early stage it is a long way from any practical implementation as an enhancement, but very interesting nonetheless:

[Researchers] used a mouse model to study how changes in brain cell connections produce new memories. They demonstrated that a protein, FXR1P (Fragile X Related Protein 1), was responsible for suppressing the production of molecules required for building new memories. When FXR1P was selectively removed from certain parts of the brain, these new molecules were produced that strengthened connections between brain cells and this correlated with improved memory and recall in the mice.

"The role of FXR1P was a surprising result. Previous to our work, no-one had identified a role for this regulator in the brain. Our findings have provided fundamental knowledge about how the brain processes information. We've identified a new pathway that directly regulates how information is handled and this could have relevance for understanding and treating brain diseases. Future research in this area could be very interesting. If we can identify compounds that control the braking potential of FXR1P, we may be able to alter the amount of brain activity or plasticity. For example, in autism, one may want to decrease certain brain activity and in Alzheimer's disease, we may want to enhance the activity. By manipulating FXR1P, we may eventually be able to adjust memory formation and retrieval, thus improving the quality of life of people suffering from brain diseases."

Friday, November 14, 2014

The flexibility and structural integrity of blood vessel networks declines with age. Metabolic waste products accumulate in blood vessel walls, and separately a combination of damaged cells, damaged proteins, and chronic inflammation leads to harmful restructuring. Other mechanisms are at work also, such as those involved in hypertension. This all means that ever more tiny blood vessels fail in one way or another, either bleeding into brain tissue or not delivering oxygen efficiently. The resulting damage builds up, a bit at a time. Thus there is every reason to consider a causal link between vascular issues and forms of dementia such as Alzheimer's: vascular problems eating away at the brain's integrity are going to worsen the effects of an emerging dementia even if it is caused by entirely different mechanisms. Further, there is the possibility that issues with blood flow in the brain can directly impact clearance of the misfolded proteins called amyloids implicated in the progression of Alzheimer's disease. Other links may yet be discovered.

The interaction between cerebrovascular disease (CVD) and Alzheimer's disease (AD) is a topic of considerable current interest. With age there is an increasing prevalence of coincident AD and CVD that is well recognized. Since 50% to 84% of the brains of persons who die aged 80 to 90+ show appreciable cerebrovascular lesions (CVL), a specific problem is their impact in relation to AD pathology. CVD frequently occurs in brains of both non-demented elderly and AD patients. The burden of vascular and AD-type pathologies are leading and independent causes of dementia in the elderly, suggesting additive or synergistic effects of both types of lesions on cognitive impairment.

The most frequent vascular pathologies in the aging brain and in AD are cerebral amyloid angiopathy and small vessel disease. AD brains with minor CVD, similar to pure vascular dementia, show subcortical vascular lesions in about two-thirds, while in mixed type dementia (AD plus vascular dementia), multiple larger infarcts are more frequent. Small infarcts in patients with full-blown AD have no impact on cognitive decline but are overwhelmed by the severity of Alzheimer pathology, while in early stages of AD, cerebrovascular lesions may influence and promote cognitive impairment, lowering the threshold for clinically overt dementia.


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