Fight Aging!

FIGHT AGING! NEWSLETTER
September 21st 2015

Fight Aging! provides a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress towards the medical control of aging in order to prevent age-related frailty, suffering, and disease, as well as improvements in the present understanding of what works and what doesn't work when it comes to extending healthy life. Expect to see summaries of recent advances in medical research, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more.

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CONTENTS

• Considering Klotho Delivery as a Means to Reduce Age-Related Stem Cell Decline
• A Selection of Recent Stem Cell Research
• Neuroscientists Are Also Capable of Incoherent Arguments Against Cryonics
• Failure of Asymmetric Cell Division Mechanisms May Contribute to Stem Cell Aging
• A Review of Work on Targeting α-synuclein Aggregates
• Latest Headlines from Fight Aging!
  • The Human Face of Cryonics
  • The Road to Mind Uploading
  • Engineering Vasculature in Decellularized Lungs
  • An Example of Phospholipid and Lifespan Data
  • On Negligibly Senescent and Long-Lived Species
  • Gut Bacteria and the Pace of Aging in Flies
  • Nir Barzilai and the Proposed Metformin Trial
  • An Argument for More Focus on the Oldest Old in Research
  • Improving Amyloid-Targeting Antibodies for Immunotherapy
  • Hypertension Causes Brain Damage

CONSIDERING KLOTHO DELIVERY AS A MEANS TO REDUCE AGE-RELATED STEM CELL DECLINE
https://www.fightaging.org/archives/2015/09/considering-klotho-delivery-as-a-means-to-reduce-age-related-stem-cell-decline.php

Today I'll point out an open access paper on the longevity-related gene klotho. Some researchers see therapies to adjust levels of the klotho protein produced from this genetic blueprint as a possible way to slow some of the effects of aging, particularly those connected to regeneration and stem cell activity. Work on this is slow-moving and painstaking, as for any similar approaches.

Yet a fairly large section of the medical research community is now devoted to at least partial and temporary restoration of tissue maintenance by stem cells in the old. A good fraction of the frailty and failure of aging results not just from direct damage such as cross-links in the extracellular matrix and broken mitochondria run amok, but also from the lack of repair of tissues, the faltering of the supply of new cells produced by stem cells in order to replace the old. Stem cell transplants are only the earliest and most direct way to try to temporarily boost regeneration and maintenance. In recent years many other possibilities have blossomed, these approaches involving the adjustment of specific biochemical signals so as to instruct native cells to return to work.

Where researchers have determined what happens to stem cell populations in the old, which is by no means a finished process given the wide range of tissue types still to be investigated fully, it seems that for the most part stem cells are neither missing nor critically impaired, but rather quiescent, simply inactive. This quiescence is thought to be an evolved response to the threat of cancer arising due to damaged DNA and cellular environments, with the present balance between activity and cancer on the one hand versus quiescence and failing organs on the other being the outcome of selection pressure for ever-longer human life spans. We are long-lived among mammals - and even primates - most likely because our intelligence and culture allowed the old to contribute to the success of their grandchildren.

So is it possible to gain meaningful benefits by ramping up a damaged engine, by signaling stem cells to get back to work without actually addressing any of the underlying cell and tissue damage that causes this evolved reaction of growing quiescence? Will this produce an excessive cancer risk, for example? It is of interest that so far there has been a surprising lack of cancer resulting from work in the laboratory and clinic, if anything. It may be that the characteristic stem cell decline with aging is not all that fine-tuned by evolution and that there is considerable wiggle room to produce therapies that can do better than today's medicine despite failing to address other important causes of degeneration. Either way, the stem cell issues ultimately need to be fixed as a part of any comprehensive toolkit of rejuvenation therapies. Damaged stem cells should be replaced or repaired, not just sent back to work.

Klotho, stem cells, and aging

Since klotho was serendipitously identified in 1997, our understanding of it as an aging suppressor has been continuously growing. Klotho protein has pleiotropic actions on many organs and tissues in mammals. However, very limited and premature data about klotho effects on stem cells are available. A better understanding of the effects of klotho on stem cells not only provides novel insights into the role of stem cells in antiaging processes but could also make a significant contribution to the advancement of regenerative medicine clinical practice.

Given that changes of functionality and a decreased number of stem cells contribute to or accelerate aging, implantation of stem cells to replenish new functional stem cells would be one means to attenuate age-associated disease by rebuilding the tissue or organ. This has been shown to be effective in preclinical and clinical trials in some diseases, including multiple sclerosis, myocardial infarction, ischemic stroke, and cancer. However, long-term side effects of stem cell implantation are not fully recognized, and should be a concern in most cases in which stem cells are permanently injected into patients. For example, recipients of genetically altered bone marrow transplants developed leukemia years after their allegedly successful transplants had cured their severe combined immunodeficiency. Despite potential side effects, recent advances in stem cell research and technology have shown promise.

On the other hand, activation or stimulation of endogenous or resident stem cells is another strategy to abate aging and age-associated disease. Current data from animal and in vitro cell-culture studies clearly demonstrated that klotho deficiency is associated with stem cell senescence and depletion. Furthermore, klotho deficiency may not only be a trigger for aging but also a pathogenic intermediate for accelerated aging and development of age-associated diseases, including Alzheimer's disease, hypertension, osteoporosis, cardiovascular disease, and chronic kidney disease (CKD). Conceivably, any therapy that restores or stimulates endogenous klotho or administration of exogenous klotho might provide a novel treatment strategy for aging and age-associated diseases.

To date, klotho gene delivery is shown to effectively rescue many phenotypes observed in klotho-deficient mice. Although gene therapy is effective in animal studies, its safety is still questionable, and clinical application is not in proximity. There are few clinical trials testing gene therapy in specific diseases. Compared to viral delivery of the klotho gene in animals, administration of exogenous klotho protein is a safer, easier, and more direct modality to restore endocrine klotho deficiency. Similarly to the use of erythropoietin or erythropoiesis-stimulating agents to correct anemia in CKD patients and insulin to maintain normal glucose metabolism in type I diabetes, the administration of exogenous klotho protein may be a viable and effective option in the near future to dwindle aging. Klotho protein can potentially reverse or retard stem cell depletion and abate age-associated pathological processes.

To date, no studies of klotho protein administration in humans have been reported. In contrast, animal studies have already provided convincing and encouraging data to support the proof of concept that soluble klotho protein administration is safe and effective. We showed that soluble klotho protein attenuates kidney damage and preserves kidney function in an ischemia-reperfusion injury model causing acute kidney injury, which is a state of acute klotho deficiency. Furthermore, klotho protein inhibited renal fibrosis in a unilateral ureteral obstruction kidney-injury model, which is also a state of low klotho expression in the kidney. Therefore, the preclinical data clearly support the therapeutic potential of soluble klotho protein for age-related disorders and klotho deficiency-associated diseases.

Thus far, animal experiments and in vitro cell-culture studies have shown the effects of soluble klotho protein on abating skin atrophy and skeletal muscle dystrophy during aging. It is anticipated that soluble klotho may play a pivotal role in regenerative medicine by preservation and activation of stem cells, particularly in heart tissue, where stem cells are very scarce or have low ability to replicate after injury. Therefore, if soluble klotho can activate stem cells or induce the replication of stem cells, klotho protein could be used as a promising therapeutic strategy for tissue repair and organ regeneration.

A SELECTION OF RECENT STEM CELL RESEARCH
https://www.fightaging.org/archives/2015/09/a-selection-of-recent-stem-cell-research.php

Research is ever slower than we would all like it to be, but the foundations of the next generation of stem cell therapies are being assembled at a comparatively rapid pace, thanks to a large and increasing level of funding and support. While it remains the case that as a society we collectively place a very low priority on medical research and development in comparison to the benefits it is capable of delivering, regenerative medicine based on the use and manipulation of stem cells is one of the most active fields within that constraint, rivaling the cancer research edifice. Would that the world wakes up as this age of biotechnology continues, realizing that health and longevity can be purchased at a falling price in time and money, and ever more people vote with their purses for research and medicine over circuses and war. One can hope.

Here is a selection of recent stem cell research, representative of the sort of work taking place in the field. Not a week goes by without the publication of an incremental advance that would have captured the headlines a decade ago, but is now just a matter of course. We'll be making the same comparisons ten years from now, looking back at today's grand advances, made small by progress.

Stem cells could help mend a broken heart, but they've got to mature

Currently, the only treatment options for damaged heart muscle are surgery, if possible, and for the worst cases, a whole heart transplantation. But there's a huge shortage of organs for transplantation, and for this reason, we need to find new strategies to treat heart disease. Stem cells have great potential to fill this void. They're a unique type of cell that starts out unspecialized but can multiply and turn into specialized cells of the adult body - for instance, brain cells or heart muscle cells, officially called cardiomyocytes.

This relies upon turning stem cells into heart muscle cells - but even once they differentiate, the heart cells remain immature. They're not fully developed, having characteristics you'd find in a fetus, not an adult. To advance these possible therapies, we need ways to take these heart muscle cells one step further, to maturity. I'm studying how the heart's natural environment affects that maturation process. I focus on how the extracellular matrix, or scaffold, of the heart affects maturation. The overall goal is to find a way to create from stem cells fully functioning, mature heart cells that can be safely and effectively used for transplantation therapies and drug screening applications.

Filling a void in stem cell therapy

Stem cell therapies have potential for repairing many tissues and bones, or even for replacing organs. Tissue-specific stem cells can now be generated in the laboratory. However, no matter how well they grow in the lab, stem cells must survive and function properly after transplantation. Getting them to do so has been a major challenge for researchers. Possible stem cell therapies often are limited by low survival of transplanted stem cells and the lack of precise control over their differentiation into the cell types needed to repair or replace injured tissues. A team has now developed a strategy that has experimentally improved bone repair by boosting the survival rate of transplanted stem cells and influencing their cell differentiation. The method embeds stem cells into porous, transplantable hydrogels.

Poststroke Cell Therapy of the Aged Brain

The efficacy of stem cell therapies for stroke so far is discouragingly low mainly because the time course of interactions between host neuroinflammatory response, the main obstacle to exogenous-mediated neuronal precursor cells, and exogenously administered stem cells is still unknown. Although mesenchymal stem cell transplantation into the brain has ascribed beneficial effects in preclinical studies of neurodegenerative or neuroinflammatory disorders, only some studies reported that stem cells can survive in a strong neuroinflammatory environment such as an ischemic area in stroke.

To conclude, these findings strongly suggest that UCB derived cells have significant neurogenic potential but this potential has to be used in a more efficient manner to treat neurological diseases like stroke in aged people. Antineuroinflammatory therapies are a potential target to promote regeneration and repair in diverse injury and neurodegenerative conditions by stem cell therapy. Therefore, the challenge now is to determine in detail the cross talk between different populations of immune cells and grafted neural stem progenitor cells at different phases after stroke in aged brain.

Mesenchymal stem cell therapy for osteoarthritis: current perspectives

Osteoarthritis is a prevalent chronic degenerative joint disease that will continue to impose an increasing burden on the aging population unless disease-modifying therapies are developed. The current standard of care with risk factor modification, pain management, and joint replacement will be inadequate to meet the needs of society moving forward. Mesenchymal stem cells (MSCs) offer a potential regenerative solution given their ability to differentiate to all tissues within a joint and modulate the local inflammatory response. Although these characteristics suggest they provide ideal building blocks to restore damaged joints, a strong body of evidence supports MSC-guided regeneration through paracrine stimulation of native tissue.

Further preclinical work will be mandatory to establish the mechanism by which MSCs have demonstrated a proof-of-concept to heal osteoarthritic lesions as this will have critical implications for clinical implementation strategies. Determining the ideal MSC source, processing, and delivery vehicle are further challenges that must be addressed to optimize biologics-based treatment of osteoarthritis. In 2015, the translation of MSCs to clinical therapy for osteoarthritis has been slow; however, signs of progress are evident and ongoing trials may show efficacy to indicate these products can serve as the disease-modifying therapy necessary to stem the tide of osteoarthritis.

Ex Vivo Expansion and In Vivo Self-Renewal of Human Muscle Stem Cells

In adult mammals, skeletal muscle is regenerated by a population of tissue-resident muscle stem cells, also known as satellite cells. Quiescent satellite cells in uninjured muscle are activated in response to injury or disease. Owing to a limited understanding of human satellite cell biology, it is still unclear as to what extent findings from mouse studies will translate to human cell-based therapies. A major barrier to the development of stem cell-based therapies is the inability to generate large numbers of transplantable stem cells with the potential to both self-renew and differentiate. In general, the contribution of donor satellite cells to muscle regeneration has been shown to correlate with the number of cells transplanted.

To further our understanding of human satellite biology, we used prospective cell isolation, RNA sequencing (RNA-seq) analyses, and cell transplantation to study a defined population of human myogenic progenitors with the potential to self-renew. This information was leveraged to identify changes in the molecular phenotype and self-renewal potential within the purified satellite cell population. Specifically, we mapped a core transcription factor regulatory network of self-renewal, and we established an essential role for p38 mitogen-activated protein kinase (MAPK) in the regulation of human satellite cell regenerative capacity akin to that observed in the mouse. Reversible pharmacologic inhibition of p38 in cultured human satellite cells resulted in a gene expression program consistent with the promotion of self-renewal, and it allowed for expansion of a population of satellite cells ex vivo with enhanced self-renewal and engraftment potential.

NEUROSCIENTISTS ARE ALSO CAPABLE OF INCOHERENT ARGUMENTS AGAINST CRYONICS
https://www.fightaging.org/archives/2015/09/neuroscientists-are-also-capable-of-incoherent-arguments-against-cryonics.php

In a recent published article a neurobiologist focused on the study of nematodes calls cryonics "impossible." He declares that the data of the mind is not being preserved and that people who are cryopreserved today cannot be restored. This is followed by another article in which a neuroscientist focused on brain mapping tells the former author that he is full of it and out of touch. It should be noted that the second fellow in this exchange doesn't think all that much of the cryonics industry as it is presently constituted, and favors the as yet commercially unavailable approach of plastination; there are always more than two sides in any argument.

Cryonics is the indefinite low-temperature storage of the brain as soon as possible following clinical death, and the small industry that has carried out this procedure since the 1970s has been in the news of late. The objective is to preserve the fine structure of neural tissue and nerve cell connections that encode the data of the mind. Provided that is stored successfully, then foreseeable forms of technology will in the future enable restoration and repair of this tissue. Early cryonics involved straight freezing, which wrecks tissue due to ice crystal formation. Modern cryonics aims for as-complete-as-possible vitrification via cryoprotectants, a process that suppresses ice crystal formation. There is ample evidence based on present theories of neural data encoding to believe that the necessary information is being preserved, albeit not the final absolute proof that many demand.

One has to be cautious of ascribing too much weight to the discussions of scientists who step beyond their fields; expertise in one area doesn't translate to the pronouncement of scripture for all areas. Indeed, if the error rates of scientific papers are anything to go by, one should think that a scientist's expertise enables them to be reasonably correct in their own specialty about half the time, and that after the expenditure of a great deal of work, collaboration, thought, and error-checking. Advancing the front lines of science is a challenging endeavor. For the purposes of the two articles I'll point out here, attacking and defending the scientific basis for cryonics, the boundaries of specialty and knowledge are such that a neurobiologist doesn't necessarily have the expertise in cryobiology to offer a fully informed opinion on the overlap between those two fields. The neurobiologist doesn't necessarily have the experience in the relevant areas of neurobiology for that matter - it is a very broad field with many deep and narrow specialties.

Anyone with a logical and inquisitive mind can make reasoned arguments, and those arguments are often worthy of engagement, but they should be taken for what they are. My objection here is not the matter of expertise, but the incoherence of the argument made against cryonics. Personally I'm all for arguing against mind uploading as the ultimate destination for cryopreserved individuals; it is possible and plausible, but a copy of you is not you, and only restoration of the original gives you continuity of existence. But if you are going to say that restoration of any sort is impossible then I expect to see a little more than "this is hard, the situation is complex, I don't see how it can be done, therefore it can't be done." At the very least I would expect the outline of a theory as to what it is that the method of preservation destroys. If you are not familiar with the current state of the intersection between cryobiology and neurobiology then fine, but don't write an article based on knowing something about that thin field of practice and theory without first stepping out into the unknown and learning what is going on and who is doing the cutting edge work. An intelligent individual can grasp the bones of a field close to his or her own specialty with a little study, and then say useful things, but that is not what is happening here.

The False Science of Cryonics

The cryonics industry offers to preserve people in liquid nitrogen immediately after death and store their bodies (or at least their heads) in hopes that they can be reanimated or digitally replicated in a technologically advanced future. Proponents have added a patina of scientific plausibility to this idea by citing the promise of new technologies in neuroscience, particularly recent work in "connectomics" - a field that maps the connections between neurons. The suggestion is that a detailed map of neural connections could be enough to restore a person's mind, memories, and personality by uploading it into a computer simulation.

I study a small roundworm, Caenorhabditis elegans, which is by far the best-described animal in all of biology. We know all of its genes and all of its cells (a little over 1,000). We know the identity and complete synaptic connectivity of its 302 neurons, and we have known it for 30 years. If we could "upload" or roughly simulate any brain, it should be that of C. elegans. Yet even with the full connectome in hand, a static model of this network of connections lacks most of the information necessary to simulate the mind of the worm. In short, brain activity cannot be inferred from synaptic neuroanatomy.

Synapses are the physical contacts between neurons where a special form of chemoelectric signaling - neurotransmission - occurs, and they come in many varieties. They are complex molecular machines made of thousands of proteins and specialized lipid structures. It is the precise molecular composition of synapses and the membranes they are embedded in that confers their properties. The presence or absence of a synapse, which is all that current connectomics methods tell us, suggests that a possible functional relationship between two neurons exists, but little or nothing about the nature of this relationship - precisely what you need to know to simulate it.

The features of your neurons (and other cells) and synapses that make you "you" are not generic. The vast array of subtle chemical modifications, states of gene regulation, and subcellular distributions of molecular complexes are all part of the dynamic flux of a living brain. These things are not details that average out in a large nervous system; rather, they are the very things that engrams (the physical constituents of memories) are made of. While it might be theoretically possible to preserve these features in dead tissue, that certainly is not happening now. The technology to do so, let alone the ability to read this information back out of such a specimen, does not yet exist even in principle. It is this purposeful conflation of what is theoretically conceivable with what is ever practically possible that exploits people's vulnerability.

No one who has experienced the disbelief of losing a loved one can help but sympathize with someone who pays 80,000 to freeze their brain. But reanimation or simulation is an abjectly false hope that is beyond the promise of technology and is certainly impossible with the frozen, dead tissue offered by the "cryonics" industry. Those who profit from this hope deserve our anger and contempt.

Ken Hayworth's Personal Response

As a neuroscientist I feel compelled to rebut some of your points. First off, please do not conflate what a small, highly-suspect company like Alcor is offering with what is possible in principle if the scientific and medical community were to start research in earnest. I started the Brain Preservation Prize as a challenge to Alcor and other such companies to 'put up or shut up', challenging them to show that their methods preserve the synaptic circuitry of the brain. After five years they have been unable to meet our prize requirements even when their methods were tested (by a third party) under ideal laboratory conditions. Out of respect for loved ones I will not comment on any particular case, but it is clear from online case reports that their actual results are often far worse than the laboratory prepared tissue we imaged. Speaking personally, I wish that all such companies would stop offering services until, at a minimum, they demonstrate in an animal model that their methods and procedures are effective at preserving ultrastructure across the entire brain. By offering unproven brain preservation methods for a fee they are effectively making it impossible for mainstream scientists to engage in civil discussion on the topic.

Unlike you however, I do think that cryonics and other brain preservation methods are worthy of serious scientific research today. First off, the cryobiology research laboratory 21st Century Medicine has published papers showing that half millimeter thick rat and rabbit hippocampal slices can be loaded with cryoprotectant, vitrified solid at -130 degrees C, stored for months, rewarmed, washed free of cryoprotectant, and still show electrophysiological viability and long term synaptic potentiation. They have so far been unable to demonstrate such results for an intact rodent brain - unlike the in vitro slice preparation, perfusing the cryoprotectant through the brain's vasculature results in osmotic dehydration of the tissue.

However, this same research group now has a paper in press showing that such osmotic dehydration can be avoided if the brain's vasculature is perfused with glutaraldehyde prior to cryoprotectant solution. Their paper reports high quality ultrastructure preservation across whole intact rabbit and pig brains even after being stored below -130 degrees C. I have personally acquired 10x10x10nm resolution FIB-SEM stacks from regions of these "Aldehyde Stabilized Cryopreserved" brains and have verified traceability of the neuronal processes and crispness of synaptic details. Considering these two results together, it seems at least plausible that further research might uncover a way to avoid osmotic dehydration without the need to resort to fixative perfusion, resulting in an intact brain as well preserved as the viable hippocampal slices. Even if glutaraldehyde remains a necessity, this Aldehyde Stabilized Cryopreservation process appears capable of preserving the structural details of synaptic connectivity (the connectome) of an entire large mammalian brain in a state (vitrified solid at -130 degrees C) that could last unchanged for centuries.

You state: "The presence or absence of a synapse, which is all that current connectomics methods tell us, suggests that a possible functional relationship between two neurons exists, but little or nothing about the nature of this relationship--precisely what you need to know to simulate it." Really? Little or nothing is known about the nature of the photoreceptor to bipolar cell synapse in the mammalian retina? Little or nothing is known about the bipolar to ganglion cell synapses? We may not know everything about these retinal cells and synapses but we know enough to have had "simulations" of retinas for two decades. Not based on the EM-level connectome directly but based on the statistics of connectivity as gleaned from coarser mappings. Do you really suspect that we would not be able to tell whether a particular retinal ganglion cell has an on-center or off-center receptive field based on the EM-level connectome alone? The textbooks and recent retinal connectomic studies argue otherwise.

I am certainly not saying that we now know everything about how the brain works, but I am saying that there is more than enough reason to suspect that the structural connectome may be sufficient to successfully simulate a brain given the depth of neuroscience knowledge we should possess by the year 2100 or 2200. Dismissing that as even a possibility hundreds of years in the future based on your failed attempts at understanding some particulars of C. elegans nervous system today seems very shortsighted. If you have real theoretical arguments then present them.

I personally agree, no one should pay 80,000 to freeze their brain without solid, open, scientifically rigorous evidence that at the very least the connectome is preserved. I would go further and say that regulated medical doctors are the only ones that should be allowed to perform such a procedure. But I do not agree that research in this area is doomed to failure. Instead the scientific and medical communities should embrace such research following up on the promising brain preservation results I mentioned above. Scientists should work to perfect ever better methods of brain preservation in animal models, and medical researchers should take these protocols and develop them into robust surgical procedures suitable for human patients.

I should say that Alcor under the leadership of Max More is open about how they preserve tissues, the present limitations and unknowns of the process, and the directions they are taking to improve the practice of cryopreservation under conditions of limited funding. Take a look through their extensive documentation and case studies presented at their website. I think it is far from fair to call that organization suspect. The perfect is the enemy of the good, and improvement in cryonics absolutely requires a practicing industry to drive that change. Within that framework, all challenges to prove effectiveness and improve towards an ideal are good and very welcome. This field, like all others related to preservation of life, is in great need of more funding, more support, and faster progress.

FAILURE OF ASYMMETRIC CELL DIVISION MECHANISMS MAY CONTRIBUTE TO STEM CELL AGING
https://www.fightaging.org/archives/2015/09/failure-of-asymmetric-cell-division-mechanisms-may-contribute-to-stem-cell-aging.php

Researchers have recently proposed that at least some stem cell populations make more subtle use of asymmetric division than thought, and that the mechanisms necessary to this process fail with age. Asymmetric cellular division has its origins deep in the evolutionary past, and it is entwined with the origins of aging. It is best cataloged in bacteria, a form of cellular replication in which the lineage maintains itself by segregating more of its waste and damaged components into one of the daughter cells with each division, leaving the other comparatively pristine. In this way bacteria can continually dilute the accumulation of damage that causes dysfunction and maintain a self-replicating lineage indefinitely, using division and one daughter cell as a form of disposal mechanism.

The situation is considerably more complex in multicellular organisms consisting of many specialized cell types with different replacement rates, but still much the same at the root of it all. Tissues lose cells constantly: old cells die and are replaced by new cells created by a population of stem cells dedicated to maintaining that tissue. The stem cells must maintain themselves in good condition, and asymmetric division appears to play a part in this self-renewal. It isn't just a way to ensure that when a stem cell divides the resulting pair consists of one new stem cell and one other type of cell destined to fill out nearby tissue, but it is also waste disposal for stem cells. It has been established that stem cells offload damaged mitochondria into the non-stem daughter cell when they divide, for example. The research linked below is more of the same, but looks at the partitioning of damaged proteins between the two daughter cells:

A barrier against brain stem cell aging

Neural stem cells generate new neurons throughout life in the mammalian brain. However, with advancing age the potential for regeneration in the brain dramatically declines. Researchers have shown that the stem cells of the adult mouse brain asymmetrically segregate aging factors between the mother and the daughter cells. Responsible for this is a diffusion barrier in the endoplasmic reticulum (a channel system within the cell that is for example important for protein synthesis and transport). The barrier prevents retention of damaged proteins in the stem cell daughter cell keeping the stem cells relatively clean. "Neural stem cell divisions appear to be much more asymmetric than we had previously anticipated."

In addition, researchers found that the strength of the barrier weakens with advancing age. This leads to reduced asymmetry of damaged protein segregation with increasing age of the stem cell. This could be one of the mechanisms responsible for the reduced regeneration capacity in the aged brain as stem cells that retain larger amounts of damaged proteins require longer for the next cell division. "This is an exciting new mechanism involved in stem cell division and aging. But as of now we are only just beginning to understand the molecular constituents and the true meaning of the barrier for stem cell division in the brain." One key question to be answered is whether the barrier is established in all somatic stem cells of the body. The answer to this question may open new routes to target age-dependent alterations of stem cell activity in human disease.

A mechanism for the segregation of age in mammalian neural stem cells

Throughout life, neural stem cells (NSCs) generate neurons in the mammalian brain. Using photobleaching experiments, we found that during cell division in vitro and within the developing mouse forebrain, NSCs generate a lateral diffusion barrier in the membrane of the endoplasmic reticulum, thereby promoting asymmetric segregation of cellular components. The diffusion barrier weakens with age and in response to impairment of lamin-associated nuclear envelope constituents. Weakening of the diffusion barrier disrupts asymmetric segregation of damaged proteins, a product of aging. Damaged proteins are asymmetrically inherited by the nonstem daughter cell in embryonic and young adult NSC divisions, whereas in the older adult brain, damaged proteins are more symmetrically distributed between progeny. Thus, these data identify a mechanism of how damage that accumulates with age is asymmetrically distributed during somatic stem cell division.

The endoplasmic reticulum is a complex structure with many roles, and if you look back in the Fight Aging! archives you'll find more information on other lines of research linking it to aging. Why does its behavior change? There is a question. It might be a consequence of fundamental cellular damage that causes aging, or it might be a direct or indirect reaction to that damage. As for so much of aging the lines of cause and consequence are yet to be filled in. The fastest path to drawing those lines is to work on repairing specific forms of damage known to contribute to aging and then see what happens as a result. That is also a path more likely to result in near-future treatments for degenerative aging than the approach of carefully cataloging everything, working backwards from the chaotic end stages of disease.

A REVIEW OF WORK ON TARGETING α-SYNUCLEIN AGGREGATES
https://www.fightaging.org/archives/2015/09/a-review-of-work-on-targeting-α-synuclein-aggregates.php

Here I'll point out a recent review of approaches to treat one of the more common synucleinopathies, conditions related to - and thought to be caused by - the abnormal accumulation of α-synuclein in tissues. The pathologies of numerous age-related diseases are linked to various different types of protein aggregate that are observed to build up with age: misfolded or simply overabundant proteins that precipitate to form solid clumps and fibrils. Amyloids are well known for their association with Alzheimer's disease, but there are many types of amyloid and many corresponding amyloidosis conditions. Similarly tau aggregates are linked to the tauopathies. The list goes on, and of course includes α-synuclein.

Why do these various different aggregates appear in old individuals but not young ones? Most of the evidence to support various theories comes out of Alzheimer's research, as that field has far more funding and far more scientists working on the problem. Amyloid levels in the brain are dynamic on a fairly short timescale, and the buildup of amyloid has the look of slowly failing clearance mechanisms. These might include general dysfunction in the choroid plexus filtration of cerebrospinal fluid, or in the drainage channels that carry away metabolic waste from the brain, or the mechanisms of the blood-brain barrier intended to shunt unwanted waste out of the brain and into the blood system. These and related forms of dysfunctions could plausibly arise from many of the forms of cell and tissue damage thought to cause aging, or from their consequences such as inflammation, loss of muscle strength, loss of tissue flexibility, and so forth.

The most promising near term approach to protein aggregates is to build treatments than can be periodically applied to clear out the buildup. Immunotherapies are so far the best of ongoing efforts, enlisting the immune system to attack and break down the aggregates, but there is still a way to go towards robust and reliably outcomes. Clinical trials have so far been disappointing, as is often the case in the first round of attempts in any area of medicine. Equally, other classes of rejuvenation therapy will be needed to repair the problems in clearance of aggregates that cause the buildup in the first place: just getting rid of the aggregrates themselves isn't a full solution, just a much better class of sustaining treatment than is presently available.

Work on clearing α-synuclein runs in parallel to work on amyloid-β, and with the same general pattern of progress, in that immunotherapies look to be the best path forward for now, yet only incremental benefits have been shown to date via this appreach. This review is focused on Lewy body dementia, but the approaches to clearing α-synuclein might be applied to any of the other synucleinopathies, such as Parkinson's disease.

Disease-modifying therapeutic directions for Lewy-Body dementias

Dementia with Lewy bodies (DLB) is the second most common pathologic diagnosis of dementia, following Alzheimer's disease (AD), comprising 25% of all dementias. The pathologic feature of DLB is the presence of Lewy bodies in the cortex and brainstem. Lewy-bodies are neuronal inclusions of abnormal filamentous assemblies of α-synuclein and ubiquitin. It is very difficult to distinguish DLB from dementia-associated with Parkinson's disease (PD), which shares many underlying clinical and pathological features with DLB. The major component of Lewy bodies in DLB and Parkinson's disease (PD) is misfolded α-synuclein. The normal α-synuclein is a soluble protein and is involved in presynaptic processing of neurotransmitters, mitochondrial function and proteasome processing. In DLB and PD, α-synuclein aggregates in Lewy bodies and causes neuronal death. Therefore, various strategies have been employed to reduce α-synuclein directly for the treatment of DLB and PD.

Secreted, extracellular α-synuclein might play a crucial role in the passage of misfolded α-synuclein from one cell to another. Therefore, immunotherapy targeting extracellular α-synuclein has been proposed, and it was found that immunization with recombinant human α-synuclein led to a reduction in α-synuclein accumulation and neurodegeneration without neuroinflammation. It was also found that administration of anti-α-synuclein antibody into the brains of PGDF-α-synuclein transgenic mice prevented cell-to-cell transmission of α-synuclein. The antibodies aid in clearance of extracellular α-synuclein proteins by microglia, thereby preventing their actions on neighboring cells. Misfolded extracellular α-synuclein might interact with antibodies to form antigen-antibody complexes, and these complexes are endocytosed and transferred to the lysosomal compartment for degradation through autophagy.

Recently, AFFiRiS AG, an Austria-based biotech company, developed a vaccine targeting PD and other synucleinopathies. The peptides used in the vaccine are designed to be too small to induce an α-synuclein-specific T cell response, thus avoiding T cell autoimmunity. The vaccine was tested in transgenic mouse models. Active vaccination resulted in decreased accumulation of α-synuclein oligomers in axons and synapses, reduced neurodegeneration, and improvements in motor and memory deficits in both models. Phase I clinical trials are currently ongoing.

Another strategy targeting α-synuclein is RNA interference (RNAi). Direct infusion of siRNA led to the reduction of α-synuclein. Recent studies have employed virally-mediated RNAi delivery, using lentivirus-mediated RNAi to successfully silence human α-synuclein expression in the rat substantia nigra. Other groups have employed AAV-mediated RNAi, but found that this approach caused neurotoxicity. They then tried AAV-mediated RNAi embedded in mircoRNA30 backbone, and they were able to reverse α-synuclein induced forelimb deficit and dopaminergic neuron loss. However, this approach induced inflammation. Transgene delivery using AAV was shown to be safe in previous studies and this technology has been used in human clinical trials in PD.

Other approaches employed to reduce α-synuclein include ribozymes, intracellular expression of single chain antibodies, endogenous microRNA, and mirtrons. A safe and effective approach to reduce the level of α-synuclein will likely slow down or even reverse the progression of DLB.

LATEST HEADLINES FROM FIGHT AGING!

THE HUMAN FACE OF CRYONICS
Monday, September 14, 2015
https://www.fightaging.org/archives/2015/09/the-human-face-of-cryonics.php

This lengthy human interest article looks at the cryonics industry through the lens of one person's end of life decisions and efforts to organize a good cryopreservation. Cryonics is the low-temperature storage of at least the brain immediately following clinical death, preserving the fine structure that encodes the data of the mind. It offers the only chance at a longer life in the future for those who will die before the advent of rejuvenation therapies, and it is a great pity that cryonics remains a niche industry while tens of millions go the grave and oblivion every year.

In the moments just before Kim Suozzi died of cancer at age 23, it fell to her boyfriend, Josh Schisler, to follow through with the plan to freeze her brain. As her pulse monitor sounded its alarm and her breath grew ragged, he fumbled for his phone. Fighting the emotion that threatened to paralyze him, he alerted the cryonics team waiting nearby and called the hospice nurses to come pronounce her dead. Any delay would jeopardize the chance to maybe, someday, resurrect her mind.

They knew how strange it sounded, the hope that Kim's brain could be preserved in subzero storage so that decades or centuries from now, if science advanced, her billions of interconnected neurons could be scanned, analyzed and converted into computer code that mimicked how they once worked. But Kim's terminal prognosis came at the start of a global push to understand the brain. And some of the tools and techniques emerging from neuroscience laboratories were beginning to bear some resemblance to those long envisioned in futurist fantasies. Might her actual brain be repaired so she could "wake up" one day, the dominant dream of cryonics for the last half-century? She did not rule it out. But they also imagined a different outcome, that she might rejoin the world in an artificial body or a computer-simulated environment, or perhaps both, feeling and sensing through a silicon chip rather than a brain.

She agreed to let a reporter speak to her family and friends and chart her remaining months and her bid for another chance at life, with one restriction: "I don't want you to think I have any idea what the future will be like," she wrote in a text message. "So I mean, don't portray it like I know." In a culture that places a premium on the graceful acceptance of death, the couple faced a wave of hostility, tempered by sympathy for Kim's desire, as she explained it, "not to miss it all." Family members and strangers alike told them they were wasting Kim's precious remaining time on a pipe dream. Kim herself would allow only that "if it does happen to work, it would be incredible." "Dying," her father admonished gently, "is a part of life." Yet as the brain preservation research that was just starting as Kim's life was ending begins to bear fruit, the questions the couple faced may ultimately confront more of us with implications that could be preposterously profound.

THE ROAD TO MIND UPLOADING
Monday, September 14, 2015
https://www.fightaging.org/archives/2015/09/the-road-to-mind-uploading.php

The mainstream press here has a go at summarizing some of the neurobiology and technologies that would lead to whole brain emulation, a copy of a human mind running in software. Many futurists believe that a copy of the mind running as an emulation is an acceptable continuation of the individual. Thus when they advocate brain preservation via cryonics or plastination it is for the purpose of recording the data for later use, not maintaining the actual tissue for later repair and restoration as a biological brain.

To me this seems a strange viewpoint; a copy of you is not you. Good for the copy and best of luck to him or her, but you yourself remain preserved and inactive. The essence of identity is physical continuity of both pattern and material that expresses that pattern, under a slow pace of change. If someone swapped out half of your brain all at once, you stop being you; you as an entity died in the initial removal, and a copy was created with the replacement operation. If half of the neurons in your brain are exchanged for machinery, one at a time, over a decade of active life, then you are still you - each replacement is incorporated into a working pattern and the change in data is little greater than those occurring due to the ongoing process of being alive. These are important differences, the two examples standing on either side of a large grey area.

The size of the futurist faction who advocate mind uploading for continuation of the individual is large enough that anyone undergoing cryopreservation would be wise to take with them some expression of their desires on the matter, perhaps an inscribed metal plate under the tongue or similar: "Please restore the original; do not copy, do not emulate."

Some neuroscientists believe it may be possible, within a century or so, for our minds to continue to function after death - in a computer or some other kind of simulation. Others say it's theoretically impossible, or impossibly far off in the future. A lot of pieces have to fall into place before we can even begin to start thinking about testing the idea. But new high-tech efforts to understand the brain are also generating methods that make those pieces seem, if not exactly imminent, then at least a bit more plausible. Here's a look at how close, and far, we are to some requirements for this version of "mind uploading."

The hope of mind uploading rests on the premise that much of the key information about who we are is stored in the unique pattern of connections between our neurons, the cells that carry electrical and chemical signals through living brains. You wouldn't know it from the outside, but there are more of those connections - individually called synapses, collectively known as the connectome - in a cubic centimeter of the human brain than there are stars in the Milky Way galaxy. The basic blueprint is dictated by our genes, but everything we do and experience alters it, creating a physical record of all the things that make us US - our habits, tastes, memories, and so on. It is exceedingly tricky to transition that pattern of connections into a state where it is both safe from decay and can be verified as intact. But in recent months, two sets of scientists said they had devised separate ways to do that for the brains of smaller mammals. If either is scaled up to work for human brains - still a big if - then theoretically your brain could sit on a shelf or in a freezer for centuries while scientists work on the rest of these steps.

The real challenge for aspiring mind uploaders will be figuring out how to create a fully functioning model of a human brain from a static snapshot of its connectome. To work, that model would have to include the molecular information in its neurons and synapses. Many neuroscientists think extracting that information would require another major step, others say structural details visible in the electron microscope might allow them to infer it. But some progress is being made - enough, anyway, so that the Obama administration signed off last year on a request by the National Institutes of Health for 4.5 billion to deliver a "comprehensive, mechanistic understanding of mental function" by 2025. Private foundations, like the Allen Institute for Brain Science and the Howard Hughes Medical Institute, have also announced major investments in basic brain research in recent years. And this summer, the blue-sky research arm of the United States intelligence agencies, Iarpa, distributed some 50 million in five-year grants to map the connectome in a cubic millimeter of mouse brain linked to learning behavior, record the corresponding neurons in live mouse brains and simulate the circuits in a computer.

ENGINEERING VASCULATURE IN DECELLULARIZED LUNGS
Tuesday, September 15, 2015
https://www.fightaging.org/archives/2015/09/engineering-vasculature-in-decellularized-lungs.php

Researchers here demonstrate the ability to regrow the blood vessel network in a decellularized lung, an important step in creating any sizable amount of engineered tissue. Decellularization is the process of stripping cells from donor tissue, leaving the intricate structure of the extracellular matrix and its chemical cues to guide cell growth. That matrix scaffold can be then be repopulated with a patient's cells to create an organ ready for transplant with minimal rejection risk. Since the scientific community still cannot recreate the full complexity of the extracellular matrix in artificial scaffolds, this remains the only way to create fully functional patient-matched organ tissue at the present time. Even so repopulation of decellularized organs has only been successfully carried out for a few organ and tissue types to date. It is a complicated process to deliver the right types of cells and coax them into recreating tissues correctly, especially when it comes to the all-important blood vessels that will supply the organ's cells:

Bioengineered lungs produced from patient-derived cells may one day provide an alternative to donor lungs for transplantation therapy. Here we report the regeneration of functional pulmonary vasculature by repopulating the vascular compartment of decellularized rat and human lung scaffolds with human cells, including endothelial and perivascular cells derived from induced pluripotent stem cells. We describe improved methods for delivering cells into the lung scaffold and for maturing newly formed endothelium through co-seeding of endothelial and perivascular cells and a two-phase culture protocol.

Using these methods we achieved ~75% endothelial coverage in the rat lung scaffold relative to that of native lung. The regenerated endothelium showed reduced vascular resistance and improved barrier function over the course of in vitro culture and remained patent for 3 days after orthotopic transplantation in rats. Finally, we scaled our approach to the human lung lobe and achieved efficient cell delivery, maintenance of cell viability and establishment of perfusable vascular lumens.

AN EXAMPLE OF PHOSPHOLIPID AND LIFESPAN DATA
Tuesday, September 15, 2015
https://www.fightaging.org/archives/2015/09/an-example-of-phospholipid-and-lifespan-data.php

One of the lines of evidence that points to mitochondrial damage as an important contribution to degenerative aging is that the life spans of mammalian species correlate well with varying composition of mitochondrial membranes. Differences in composition produce membranes that have more or less resistance to oxidative damage, such as that caused as a side-effect of the processes taking place inside mitochondria when they generate energy store molecules to power other cellular mechanisms. The membrane pacemaker theory of aging is associated with these details.

Learning more about membrane composition and the fine details of how it interacts with damage processes will not tell us how to fix mitochondrial damage and thus greatly improve matters in aging by reversing its course, however. That is already known: the biotechnologies needed to repair mitochondria or work around the damage are established visions, under development in a preliminary fashion, and emerging from entirely separate fields of research. What we should take away from the work linked here is a sense that there are multiple areas of evidence to suggest that repairing damaged mitochondria throughout the body will be of significant benefit, a form of rejuvenation, and thus worthy of greater investment.

The maximal lifespan (MLS) of mammals is inversely correlated with the peroxidation index, a measure of the proportion and level of unsaturation of polyunsaturated fatty acids (PUFA) in membranes. This relationship is likely related to the fact that PUFA are highly susceptible to damage by peroxidation. Previous comparative work has examined membrane composition at the level of fatty acids, and relatively little is known regarding the distribution of PUFA across phospholipid classes or phospholipid molecules. In addition, data for humans is extremely rare in this area.

Here we present the first shotgun lipidomics analysis of mitochondrial membranes and the peroxidation index of skeletal muscle, liver, and brain in three mammals that span the range of mammalian longevity. The species compared were mice (MLS of 4 years), pigs (MLS of 27 years), and humans (MLS of 122 years). Mouse mitochondria contained highly unsaturated PUFA in all phospholipid classes. Human mitochondria had lower PUFA content and a lower degree of unsaturation of PUFA. Pig mitochondria shared characteristics of both mice and humans. We found that membrane susceptibility to peroxidation was primarily determined by a limited number of phospholipid molecules that differed between both tissues and species.

ON NEGLIGIBLY SENESCENT AND LONG-LIVED SPECIES
Wednesday, September 16, 2015
https://www.fightaging.org/archives/2015/09/on-negligibly-senescent-and-long-lived-species.php

A number of researchers investigate aging and longevity by comparing the biochemistry of short-lived and long-lived species, as well as the few species that show little of the signs of aging until very late life. Some scientists believe that there are benefits that could be mined from the biochemistry of these species and used as the basis for therapies to modestly slow aging in humans by altering the operation of our metabolism. This popular press article looks at this field of research:

Just 30 years after the publication of Moby Dick, a group of Alaskan whalers attempted to tame their own ocean giant. Their target was a male bowhead whale, the second largest mammal on Earth. These whalers were armed with the latest technology, however - a "bomb lance", fired with gunpowder on impact to pierce through the thick whale blubber. Yet it was not enough to conquer the whale. The whale would continue to roam free for another 120 years, until 2007, when a group of Inupiat hunters finally caught the beast. They even found fragments of the original lance still embedded in the whale's blubber.

According to many estimates, these whales live at least 150 years, and perhaps as long as 210. Apart from slightly leathery skin, a bit of excess blubber, and its battle scars, they show remarkably few ill-effects of long life, however. And that has made them of keen interest to doctors studying ageing. "They live a lot longer than human beings, yet they are living in the wild, without going to the doctor or any of the perks of human society. So they must be naturally protected from age-related diseases." By studying these whales and other extraordinarily long-lived creatures, researchers hope we can find new medicines that will similarly slow down the human body's decay and delay death.

"Ageing is a mystery - we know relatively little about it compared other biological processes, and yet it's directly the greatest cause of suffering and death in the modern world. If we could retard it even a little, it would have unprecedented human benefit. This is the most important biological question, because the majority of chronic human diseases are the consequences of ageing. The way biomedical science is organised, it has mostly focused on particular diseases, like cancer, Alzheimer's, or diabetes. But if you delay ageing you could delay the incidence of all these diseases at once. We're not just extending the period of decrepitude. We want 70 year olds with the health of a 50 year old - that's the ultimate goal."

GUT BACTERIA AND THE PACE OF AGING IN FLIES
Wednesday, September 16, 2015
https://www.fightaging.org/archives/2015/09/gut-bacteria-and-the-pace-of-aging-in-flies.php

It is known that there are relationships between gut bacteria and aging in many species, though exploration of the details is still at a comparatively early stage. Even without delving into the literature one can imagine numerous possibilities by which these bacteria influence long-term health, such as by playing a role in the degree to which food is converted into nutrients useful for cells, or by interacting with the immune system. Here, researchers examine age-related changes in gut bacteria in flies. The health of the intestine is particularly important in fly aging, much more so than in higher species, so we should probably wait for similar experiments to be conducted in mammals before drawing conclusions:

Why do some people remain healthy into their 80s and beyond, while others age faster and suffer serious diseases decades earlier? A new study suggests that analyzing intestinal bacteria could be a promising way to predict health outcomes as we age. The researchers discovered changes within intestinal microbes that precede and predict the death of fruit flies. "Age-onset decline is very tightly linked to changes within the community of gut microbes. With age, the number of bacterial cells increase substantially and the composition of bacterial groups changes."

In a previous study, the researchers discovered that five or six days before flies died, their intestinal tracts became more permeable and started leaking. When a fruit fly's intestine begins to leak, its immune response increases substantially and chronically throughout its body. Chronic immune activation is linked with age-related diseases in people as well. In the latest research, which analyzed more than 10,000 female flies, the scientists found that they were able to detect bacterial changes in the intestine before the leaking began. As part of the study, some fruit flies were given antibiotics that significantly reduce bacterial levels in the intestine; the study found that the antibiotics prevented the age-related increase in bacteria levels and improved intestinal function during aging.

The biologists also showed that reducing bacterial levels in old flies can significantly prolong their life span. "When we prevented the changes in the intestinal microbiota that were linked to the flies' imminent death by feeding them antibiotics, we dramatically extended their lives and improved their health." Flies with leaky intestines that were given antibiotics lived an average of 20 days after the leaking began - a substantial part of the animal's life span. On average, flies with leaky intestines that did not receive antibiotics died within a week.

NIR BARZILAI AND THE PROPOSED METFORMIN TRIAL
Thursday, September 17, 2015
https://www.fightaging.org/archives/2015/09/nir-barzilai-and-the-proposed-metformin-trial.php

A group of researchers are attempting to gain approval to run a human trial of metformin with the aim of evaluating its ability to very slightly slow down the aging process. This is not ambitious at all from a technological perspective. It will make no real difference to aging, in comparison to what is plausible and possible via other methods, and the use of established drugs in this fashion is not a road to human rejuvenation. Instead this is an attempt to force change on the FDA from within the bounds of the system of regulation, which at present does not recognize aging as a medical condition amenable to treatment. By denying commercialization, funding for research and development is stifled all the back back down the chain, and this must change if we are to see faster progress in the future.

On a blazingly hot morning this past June, a half-dozen scientists convened in a hotel conference room in suburban Maryland for the dress rehearsal of what they saw as a landmark event in the history of aging research. In a few hours, the group would meet with officials at the U.S. Food and Drug Administration (FDA), a few kilometers away, to pitch an unprecedented clinical trial - nothing less than the first test of a drug to specifically target the process of human aging.

A scientist named Nir Barzilai tuned up his PowerPoint and launched into a practice run of the main presentation. His practice run kept hitting a historical speed bump. He had barely begun to explain the rationale for the trial when he mentioned, in passing, "lots of unproven, untested treatments under the category of anti-aging." His colleagues pounced. "Nir," interrupted S. Jay Olshansky, a biodemographer of aging from the University of Illinois, Chicago. The phrase "anti-aging ... has an association that is negative." "I wouldn't dignify them by calling them 'treatments,'" added Michael Pollak, director of cancer prevention at McGill University in Montreal, Canada. "They're products." Barzilai, a 59-year-old with a boyish mop of gray hair, wore a contrite grin. "We know the FDA is concerned about this," he conceded, and deleted the offensive phrase.

Then he proceeded to lay out the details of an ambitious clinical trial. The group wanted to conduct a double-blind study of roughly 3000 elderly people; half would get a placebo and half would get an old (indeed, ancient) drug for type 2 diabetes called metformin, which has been shown to modify aging in some animal studies. Because there is still no accepted biomarker for aging, the drug's success would be judged by an unusual standard - whether it could delay the development of several diseases whose incidence increases dramatically with age: cardiovascular disease, cancer, and cognitive decline, along with mortality. When it comes to these diseases, Barzilai is fond of saying, "aging is a bigger risk factor than all of the other factors combined." But the phrase "anti-aging" kept creeping into the rehearsal, and critics kept jumping in. "Okay," Barzilai said with a laugh when it came up again. "Third time, the death penalty."

The group's paranoia about the term "anti-aging" captured both the audacity of the proposed trial and the cultural challenge of venturing into medical territory historically associated with charlatans and quacks. The metformin initiative, which Barzilai is generally credited with spearheading, is unusual by almost any standard of drug development. The people pushing for the trial are all academics, none from industry (although Barzilai is co-founder of a biotech company, CohBar Inc., that is working to develop drugs targeting age-related diseases). The trial would be sponsored by the nonprofit AFAR, not a pharmaceutical company. No one stood to make money if the drug worked, the scientists all claimed; indeed, metformin is generic, costing just a few cents a dose. Patient safety was unlikely to be an issue; millions of diabetics have taken metformin since the 1960s, and its generally mild side effects are well-known.

Finally, the metformin group insisted they didn't need a cent of federal money to proceed (although they do intend to ask for some). Nor did they need formal approval from FDA to proceed. But they very much wanted the agency's blessing. By recognizing the merit of such a trial, Barzilai believes, FDA would make aging itself a legitimate target for drug development.

AN ARGUMENT FOR MORE FOCUS ON THE OLDEST OLD IN RESEARCH
Thursday, September 17, 2015
https://www.fightaging.org/archives/2015/09/an-argument-for-more-focus-on-the-oldest-old-in-research.php

Here an argument is made for more research into aging and its potential treatment to focus on the oldest segments of the population rather than the younger old. From the perspective of SENS and damage repair to achieve rejuvenation, I'm not sure this matters all that much: what needs to be done to treat aging under that model is well categorized and understood. The challenge is finding the funding and the will for implementation, not further delving into the unknown. From the perspective of investigating and deeply understanding the complex processes of aging, mapping the intricate chains of cause and consequence from initial damage to cells and tissues all the way through to end-stage disease, the concerns are probably more valid:

"Old people" are still being clumped together as one group, with an arbitrary cutoff of age 65. This causes several problems, for example the diseases of young elderly, less than 75-years-old, are often lifestyle-related. Diseases of young-old are primarily cancers, atherosclerotic heart diseases and diabetes. While it is laudable to spend resources ameliorating these conditions, we must face up to facts about aging research. Researching and treating diseases in the young-old constitutes a low-hanging fruit for medicine and pharmaceutical companies. This is in stark contrast to the complicated web of damages accumulated systemically, perpetuating the declining health of people aged over 80. The 85+ group have been historically ignored due to lack of research on aging itself. I refer to "aging itself" to mean the metabolic waste accumulation ultimately causing the systemic frailty syndrome seen in the old old.

A major problem is that aging has not historically been defined as a disease, warranting detailed scrutiny in order to constitute a target for medicine. The world is paying the price for it. It is still not known exactly what diversifies people aged 100+ on a molecular and cellular level, versus people dying of age-related diseases in their 80s. This is due to a significant lack of autopsies, quantifying the aging damage of the centenarians. Therefore it is not understood exactly how this age category succeed in avoiding lethal pathology for so long, and how their accumulated pathology might differ.

This is ultimately the only way forward to successfully get aging under control and truly change the late 80s mortality peak and prolong maximum human lifespan beyond 100. Currently the most common age of death in Sweden is 86 for men and 88 for women, for comparison the life expectancy is 80 and 83.5. From what we can deduce, risk avoidance, as well as avoidance of well known health issues like smoking and obesity, won't give much. These modifiable factors will only shift the life expectancy towards the most common age of death. The geriatric costs are staggering, we cannot afford more short-term thinking chasing low hanging fruits labelled diseases in the young-old. Quantifying the precise systemic tissue damages in the very old is paramount for developing concrete medical targets, targets composing the panel of upcoming therapies bringing aging under medical control.

IMPROVING AMYLOID-TARGETING ANTIBODIES FOR IMMUNOTHERAPY
Friday, September 18, 2015
https://www.fightaging.org/archives/2015/09/improving-amyloid-targeting-antibodies-for-immunotherapy.php

In this research, partly funded by the SENS Research Foundation, the authors investigate improvements to one type of immunotherapy aimed at clearance of amyloid. Amyloids of numerous types build up in tissues with aging to cause harm and disrupt normal function, including the amyloid β associated with Alzheimer's disease and the transthyretin amyloid implicated in heart failure. Efficient means of clearing amyloid must be a part of any future toolkit of rejuvenation therapies, as its presence is one of the noteworthy differences between old tissue and young tissue:

Alzheimer's disease (AD) is the most common of ~30 amyloid disorders that are currently incurable and often fatal. These diseases involve the extracellular self aggregation of a peptide or protein that forms amyloid deposits on organs. AD is a particularly complex disease since it involves the aberrant aggregation of amyloid β peptides (Aβ) and the microtuble-associated tau protein. Other debilitating amyloid disorders, are caused by mutant and wild-type forms of a blood transport protein transthyretin (TTR) that primarily deposit in the heart and/or nerves.

Passive vaccination with humanized anti-amyloid monoclonal antibodies (mAbs) is a primary immunotherapeutic approach for amyloid diseases. A recent novel therapeutic approach for AD has been to boost a patient's pool of amyloid-reactive IgGs using human intravenous immunoglobulin (IVIg). IVIg contains a diverse repertoire of pooled polyclonal human IgGs (pAbs), including anti-amyloid IgGs, from plasmas of thousands of normal individuals. Anti-amyloid pAbs isolated from normal human blood have demonstrated therapeutic potential not only for AD but for other amyloid diseases.

Recently, IVIg was tested in a 18-month phase 3 clinical trial for mild to moderate AD. The antibody did not meet its primary endpoints, but subgroup analysis indicated that IVIg had a slight beneficial effect for AD patients that were ApoE4 carriers and had moderate disease. Presumably, IVIg's ineffectiveness may have been because its anti-amyloid activity was not potent enough, and patients may have benefited more from an IVIg-like preparation that had enhanced activity. However, the development of a more viable and potent therapeutic reagent than IVIg has been hampered by our current poor understanding on its anti-amyloid activity.

We now report the following finding on pAb conformer's binding to amyloidogenic aggregates: pAb aggregates have greater activity than monomers (high molecular weight (HMW) species > dimers > monomers). Specifically, we show that HMW aggregates and dimeric pAbs present in commercial preparations of pAbs, intravenous immunoglobulin (IVIg) had up to ~200- and ~7-fold stronger binding to aggregates of Aβ and transthyretin (TTR) than the monomeric antibody. Notably, HMW aggregates were primarily responsible for the enhanced anti-amyloid activities of IVIg IgGs. Similar to pAbs, HMW and dimeric mAb conformers bound stronger than their monomeric forms to amyloidogenic aggregates. However, mAbs had lower maximum binding signals, indicating that pAbs were required to saturate a diverse collection of binding sites. Our findings strongly indicate that an IgG's anti-amyloid activity is enhanced when they aggregate (Dimers and HMW species), and is an intrinsic property that likely has physiological and clinical significance.

HYPERTENSION CAUSES BRAIN DAMAGE
Friday, September 18, 2015
https://www.fightaging.org/archives/2015/09/hypertension-causes-brain-damage.php

The stiffening of blood vessels due to cross-linking in the extracellular matrix and other factors such as calcification is known to cause hypertension, and the elevated blood pressure of hypertension causes progressive damage to brain tissue. The degree to which this damage occurs - and might be blamed for cognitive decline with aging - is becoming ever more clear as scanning technologies improve:

A new imaging technique found that some people with high blood pressure also have damage to nerve tracts connecting different parts of the brain. The area of brain damage detected is linked to difficulties in certain cognitive skills, decision-making, and the ability to regulate emotions. "We already have clear ways to explore the damage high blood pressure can cause to the kidneys, eyes, and heart. We wanted to find a way to assess brain damage that could predict the development of dementia associated with vascular diseases." While there has been a lot of research on hypertension-related brain changes in the grey matter, scientists proposed that a look into the brain's white matter could tell if high blood pressure was having an effect even earlier than what is known.

Researchers used diffusion tensor imaging (DTI), an enhancement of magnetic resonance imaging (MRI), to evaluate and compare the structural and functional properties of the main connections between different brain regions. Fifteen participants were on medication for moderate to severe high blood pressure and 15 participants had normal blood pressure. Participants were also given a cognitive assessment. The brain imaging found that, while none of the participants showed abnormalities on a standard MRI, the more advanced DTI revealed that participants with high blood pressure had damage to: 1) brain fibers that affect non-verbal functions; 2) nerve fibers that affect executive functioning and emotional regulation; and 3) limbic system fibers, which are involved in attention tasks. Researchers also found those with high blood pressure performed significantly worse on two different assessments of cognitive function and memory. However, there were no differences in tests evaluating verbal function or ability to perform daily activities.