Fight Aging!

FIGHT AGING! NEWSLETTER
September 22nd 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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CONTENTS

• Boosted Microglial Function as an Alzheimer's Therapy
• New Organ Liver Prize: First Contending Teams Announced
• Fetal Stem Cells and Muscle Regeneration
• Recent Infrastructure Advances for Stem Cell Research
• Our Cells Will Be Guided and Protected by Machines
• Latest Headlines from Fight Aging!
  • Attempts to Reduce Systematic Inflammation in Aging
  • Effects of Lifestyle or Effects of Aging?
  • A Glance at Silicon Valley Longevity Initiatives
  • Heat Shock Proteins and Neurodegeneration
  • AGE Levels Associate with Bone Fracture Risk in Aging
  • A Master Regulator of the Heat Shock Response
  • Connecting the Lab and the Clinic in Regenerative Medicine
  • A Look at a Future of Slowing Aging
  • How Neural Stem Cells Help to Repair Damage
  • A History of Life Extensionism in the Twentieth Century

BOOSTED MICROGLIAL FUNCTION AS AN ALZHEIMER'S THERAPY
https://www.fightaging.org/archives/2014/09/boosted-microglial-function-as-an-alzheimers-therapy.php

The immune system is a very efficient mechanism for certain types of task, if it can just be harnessed and put to work. Left to its own devices throughout most of a life span it can effectively destroy misbehaving cells, remove some types of harmful protein aggregates, and of course defend against self-replicating invaders of many different types. There is more besides, but if you want some biological line item in the body destroyed, then you could do worse than trying to use the immune system as your tool. Given this, it shouldn't be surprising to see that this dawning age of cell biology involves numerous efforts to produce immune therapies: ways to enhance and direct the immune system's actions to treat medical conditions. In the case of Alzheimer's disease immunotherapies gaining the most press in recent years have been those that aim to directly remove the amyloid beta deposits characteristic of the disease. There are a variety of ways in which that can goal might be achieved, such as through the use of a designed compound that is targeted by immune cells and happens to bind to amyloid beta, or by altering immune cells so that they target amyloid directly. The immune system is built around acquisition and management of recognition of protein fragments, so this sort of approach plays to its strengths.

There are other approaches, however. Microglia are specialized immune cells of the central nervous system and are already capable of attacking and removing amyloid beta. Like the rest of the immune system, their activity diminishes with age, however. There are groups working on the foundations of treatments based on the transplant of young microglia into old brains, a potential methodology that is becoming increasingly attractive given recent discoveries about aging and stem cells. Delivering young stem cells into old tissue can have the effect of reversing some of the responses to aging in native stem cells, restoring them to more youthful levels of activity as the environment of signals and proteins levels is temporarily shifted. Will this raise cancer risk due to more cellular activity in a damaged environment, and can that risk be well managed, as it has been in the cell therapy field to date? Time will tell, but I expect so.

Along these lines, the researchers quoted below are working on a way to skip the cell transplants and jump straight to the renewed cellular activity part of the treatment. Ultimately I expect much of the cell therapy field to evolve to use this sort of technique, in which the bulk of the work is direct manipulation or reprogramming of native cells, often by altering the levels of specific proteins present in the tissue environment. Currently such efforts are comparatively crude, but they will improve rapidly in years to come as cell biology becomes less of a jungle and more of a well-mapped city:

Targeted immune booster removes toxic proteins in mouse model of Alzheimer's disease

Using dementia-prone mice, the team gave monthly injections of an immune system booster known as a type B, CpG, oligodeoxynucleotide that specifically binds to Toll-like receptor 9, or TLR9 for short. Activation of TLR9 triggers an immune response. Tests in mice that received the immune system booster injections showed that amyloid plaque formation was 50 percent to 70 percent less than in mice that received no therapy. Reductions in amyloid beta were almost the same for mice treated early on, at age 7 months, and before disease onset, compared to mice treated at age 11 months, which already had mild dementia. Immunostaining tests on brain tissue in treated mice showed one to two times fewer damaged neurons containing disease-related tau aggregates than in untreated mice.

According to researchers, treated mice behaved "almost like normal" mice that never develop Alzheimer's-like symptoms. Unlike vaccines, which try to trigger an antibody-mediated stimulation of the body's immune system, [the] team's new approach attempts to "jump start and rejuvenate" the brain's natural microglial cell repair function. The breakdown of microglial repair - possibly from aging - has been linked for decades to the formation and removal of amyloid plaques and tau tangles in Alzheimer's disease.

Researchers say they selected TLR9 as the immune booster because it was a known stimulant for removing germs. A bacterial cytosine-guanosine sequence, or CpG, such as type B, CpG, oligodeoxynucleotide, was chosen to help activate TLR9 on brain cells because previous testing had shown it to be effective at triggering an immune response in both mice and humans, with very few side effects. "Now that we have shown that we can influence microglial function in Alzheimer's disease, to both prevent and repair tau-damaged brain tissue, then it is highly plausible that our treatment approach could also be applied to other neurodegenerative diseases tied to aging."

Amyloid beta and Tau Alzheimer's Disease Related Pathology is reduced by Toll-like Receptor 9 Stimulation

We have hypothesized that stimulation of the innate immune system via Toll-like receptor 9 (TLR9) agonists, such as type B CpG oligodeoxynucleotides (ODNs), might be an effective way to ameliorate AD related pathology. In the present study, we used the 3xTg-AD mice with both Aβ and tau related pathology. The mice were divided into 2 groups treated from 7 to 20 months of age, prior to onset of pathology and from 11 to 18 months of age, when pathology is already present. We demonstrated that immunomodulatory treatment with CpG ODN reduces both Aβ and tau pathologies, as well as levels of toxic oligomers, in the absence of any apparent inflammatory toxicity, in both animal groups. This pathology reduction is associated with a cognitive rescue in the 3xTg-AD mice.

NEW ORGAN LIVER PRIZE: FIRST CONTENDING TEAMS ANNOUNCED
https://www.fightaging.org/archives/2014/09/new-organ-liver-prize-first-contending-teams-announced.php

The New Organ initiative aims to greatly speed progress towards the tissue engineering of patient-matched organs as needed: a vision of no more waiting, no more transplant rejection, and a much lower cost of organ renewal, all leading to a far greater number of people who may benefit from these medical advances. The initiative is managed by the Methuselah Foundation, alongside the Mprize for longevity science, early stage investments in tissue engineering companies such as Organovo, and a range of other distinct projects such as sequencing the bowhead whale genome in search of greater insight as to why the range of mammalian longevity is so wide. The Methuselah Foundation was also at one point the home of SENS rejuvenation research programs before they spun off into their own organization, the SENS Research Foundation.

Late last year, the New Organ Liver Prize launched at the World Stem Cell Summit, a $1 million research prize to accelerate the creation of a functional bioengineered replacement liver. Today the Methuselah Foundation announced the first six contending teams. These researchers take a broad range of different approaches to organ tissue engineering, and one thing to bear in mind is that an engineered organ doesn't necessarily have to look like or be structured in the same way as the evolved organ it replaces or augments - it just has to do the same job. Can a patient benefit from scores of tiny liver-like tissue masses sheltered in lymph nodes that perform some of the functions of a damaged liver? Quite possibly.

Initial Six Teams to Compete for New Organ Liver Prize

Great news! Today, we're announcing a major milestone: the first six teams to officially compete for the New Organ Liver Prize. These teams represent scientists from Harvard Medical School, Massachusetts General Hospital, Northwick Park Institute for Medical Research, University College of London, University of Florida, University of Oxford, University of Pittsburgh, and Yokohama City University, and are being led by:

• Dr. Tahera Ansari (Team Hepavive): Pursuing the 'decell-recell' approach to bioengineering a liver.
• Dr. Stephen Badylak (Team Badylak): A pioneer in biologic scaffolds using extracellular matrix.
• Dr. Eric Lagasse (Team Ectogenesis): Grew mini-livers inside the lymph nodes of mice with liver disease.
• Dr. Bryon Petersen (Team Petersen): An authority on the role of hepatic stem cells in liver pathology.
• Dr. Takanori Takebe (Team Organ Creative): Created tiny 'liver buds' that grew and functioned in mice.
• Dr. Basak Uygun (Team HepaTx): First proof-of-principle transplantation of engineered liver grafts.

For full bios, please visit the team page and let us know what you think. Additional teams are also under review and will be announced in a future update. Good luck to all!

New Organ Founder and Methuselah CEO David Gobel: "We are gratified to see the initial interest in the Liver Prize. We are doing this because of the millions who need new organs. Organ disease, and the associated organ shortage, represents one of the greatest medical challenges that can be solved. A scientific foundation has been built over the last 15 years to pursue the vision of organs on demand. It's time for a significant societal commitment to that vision."

Representing distinguished leaders within regenerative medicine, the Founding Fellows of the Tissue Engineering and Regenerative Medicine International Society (TERMIS) remarked: "We strongly and enthusiastically endorse New Organ. Regenerative medicine has made significant advances in the past 15 years and the New Organ Liver Prize represents a golden opportunity for the next leap forward. The public and the medical community will realize a remarkable clinical benefit with the availability of 'off the shelf' whole livers obviating the need for donor organs, and the medical health care system will simultaneously benefit. We hope this forward-looking effort sets the standard that inspires other initiatives to focus all the resources of regenerative medicine on solving major health care challenges."

In a recent newsletter from the Methuselah Foundation there is further news on where things are going with the New Organ Alliance program: there is more of a focus on arms of the US government as a potential source of funds it seems, in addition to building relationships with other groups whose members are working to advance the state of the art in the organ transplant space.

On July 29th, New Organ facilitated a meeting hosted by the Department of Health and Human Services that brought together 10 federal agencies and other stakeholders to explore current efforts in tissue engineering and regenerative medicine (TERM) and the role that incentivized innovation can play in advancing specific challenge targets.

We've also submitted a proposal for a workshop entitled "Building a TERM Roadmap for Organ Disease" to several potential convening partners. The outline proposes a gathering of 75 scientific, government, industry, and philanthropic leaders committed to advancing biomedical engineering and regenerative medicine breakthrough technologies to address organ disease. Participants will define key challenges at the science and system level; identify enabling technologies and quantitative milestones that can be used to inform future research efforts and challenge prize targets; and examine tools and innovation models that can be applied to advance specific goals. Please contact us if you're interested in supporting this effort.

New Organ's close collaboration with the Organ Preservation Alliance (OPA) continues. OPA has proposed key ideas and facilitated input for several Small Business Innovation Research and Small Business Technology Transfer proposals on tissue and organ cryopreservation, currently under review. OPA also secured basic underwriting for the first global "Grand Challenges in Organ Banking" Summit, to be held in Palo Alto, CA in February of 2015. They've also updated draft rules for the proposed Organ Banking Prize: a challenge competition to demonstrate long-term storage of a solid organ and subsequent transplantation into a human or large animal.

Finally, New Organ is considering the possibility of a new Vasculature Prize to stimulate the vascularization of thick, functional tissue. Details on this effort, which is currently being explored in coordination with a federal agency, will be forthcoming as discussions progress.

FETAL STEM CELLS AND MUSCLE REGENERATION
https://www.fightaging.org/archives/2014/09/fetal-stem-cells-and-muscle-regeneration.php

The types of stem cell that can be extracted from accessible fetal tissues such as the umbilical cord and amniotic fluid are somewhat different to both adult stem cells and embryonic stem cells. Ultimately all of these various sources will go away in favor of cell reprogramming on the grounds that pretty much anything other than sourcing cells from a skin or blood sample from the patient in front of you is going to result in excessively costly treatments. It is simply too troublesome to manage the collection and preservation of fetal cells on an industrial scale unless it is the only useful alternative, which is not to mention that they cannot be patient-matched cells in any but the most rare of circumstances.

From a research perspective finding out what these various types of stem cell can achieve in terms of regenerative therapies is a necessary part of the process of guiding advances in cell programming. Embryonic and fetal stem cells provide aiming points and comparisons for cell reprogramming efforts, but that is only helpful if scientists know how to use these cells to produce therapies. Thus even as the production of induced pluripotent stem cells from ordinary skin cells is moving ahead, the first clinical trials are beginning, and researchers are becoming ever better at producing stem cells that are increasingly like those seen in various stages of embryonic development, it is still the case that various research groups are exploring what can be done with fetal and embryonic stem cells.

Here is an interesting review that notes fetal stem cells work in muscle regeneration in much the same way as other stem cell treatments have been shown to produce effects: they are not acting directly to restore tissue, but rather changing the signaling environment to alter the behavior of native cells. At some point the cell part of many cell therapies will fall away in favor of directly manipulating cell signaling, but there is still much to be discovered about which signals are needed and how to deliver them in a way that mimics the presence of stem cells.

Fetal stem cells and skeletal muscle regeneration: a therapeutic approach

More than 40% of the body mass is represented by muscle tissue, which possesses the innate ability to regenerate after damage through the activation of muscle-specific stem cells, namely satellite cells. Muscle diseases, in particular chronic degenerative states of skeletal muscle such as dystrophies, lead to a perturbation of the regenerative process, which causes the premature exhaustion of satellite cell reservoir due to continuous cycles of degeneration/regeneration. Nowadays, the research is focused on different therapeutic approaches, ranging from gene and cell to pharmacological therapy, but still there is no definitive cure in particular for genetic muscle disease. Keeping this in mind, in this article, we will give special consideration to muscle diseases and the use of fetal derived stem cells as a new approach for therapy. Cells of fetal origin, from cord blood to placenta and amniotic fluid, can be easily obtained without ethical concern, expanded and differentiated in culture, and possess immune-modulatory properties. The in vivo approach in animal models can be helpful to study the mechanism underneath the operating principle of the stem cell reservoir, namely the niche, which holds great potential to understand the onset of muscle pathologies.

Muscle pathologies are devastating diseases and nowadays researchers still make efforts to find a cure and not a therapy alone. It has been demonstrated that, after injection in injured or diseased muscle, fetal stem cells act through a mechanism that is mostly due to a bystander effect rather than a direct differentiation. The indirect action is mainly supposed to enhance the production of cytokines, such as VEGF, that stimulate the temporary restoring of the tissue function. To obtain a long lasting action due to efficient cell integration and tissue repopulation, fetal stem cells need to be genetically modified, forcing their differentiation in tissue-specific cells. Nevertheless, the development of safe genetic manipulation methods could make cells of fetal origin appealing for therapeutic application.

Conversely, the long-term positive effect observed using freshly isolated murine amniotic fluid stem (AFS) cells, highlights that they could have a decisive role in replenishing the muscle stem cell niche, which represent the reservoir of cells able to rescue the defect. Indeed, AFS cells are a safe and immune-privileged cell source prone to integrate in muscle tissue. This knowledge opens the challenge to improve the culture protocol for the AFS cells of human origin, which, so far, is still a limit to overcome for future clinical application to treat genetic and non-genetic muscle dysfunctions (dystrophies, skeletal muscle malformations, traumatic injuries).

RECENT INFRASTRUCTURE ADVANCES FOR STEM CELL RESEARCH
https://www.fightaging.org/archives/2014/09/recent-infrastructure-advances-for-stem-cell-research.php

Some of the most important work taking place in the stem cell research community is not in fact directly focused on producing treatments. Instead it consists of infrastructure improvements: creating ways to obtain more cells of a specific type, more reliably, more rapidly, and at a lower cost. This is important because falling costs accelerate further research and development, such as by broadening the number of laboratories that can budget projects in the field, and by expanding what can be accomplished within the budget of any given research group. Ultimately this will also make the resulting treatments cheaper and better, but at this point that is somewhat less important given where the field stands today. Cell therapies deployed to date have proved beneficial, but are just a first pass at the problem space, a fragment of what is possible. That initial success over the past decade has served to draw in enough money and interest for the next cycle to expand considerably. It will produce a panoply of far better, far more diverse approaches to the control of cells in medicine. It will be an explosion of variety and utility for patients, and the cheaper the tools the greater the result and the sooner it will arrive.

This is why it doesn't hurt to keep a weather eye on progress in enabling technologies and infrastructure in stem cell research. For those of us likely to need or benefit from regenerative treatments a decade or two from now, the pace of progress in tools today provides some insight as to the likely future landscape of therapies. Take these few items as illustrated of current work on the creation of reliable and low-cost sources of stem cells, for example:

Scientists Report Reliable and Highly Efficient Method for Making Stem Cells

Using the new technique in mice, the researchers increased the number of stem cells obtained from adult skin cells by more than 20-fold compared with the standard method. They say their technique is efficient and reliable, and thus should generally accelerate research aimed at using stem cells to generate virtually any tissue.

The standard method for reprogramming skin, blood, or other tissue-specific cell types into "induced pluripotent stem cells" (iPSCs) involves the artificial expression of four key genes dubbed OKSM (for Oct4, Klf4, Sox2 and myc) whose collective activity slowly prods cells into an immature state much like that of an early embryonic cell. Converting most cell types into stable iPSCs occurs at rates of 1 percent or less, and the process can take weeks. Researchers throughout the world have been searching for ways to boost this efficiency, and in some cases have reported significant gains. These procedures, however, often alter vital cellular genes, which may cause problems for potential therapies.

Adding to fibroblasts engineered to express OKSM either vitamin C, a compound to activate Wnt signaling, or a compound to inhibit TGF-β signaling increased iPSC-induction efficiency weakly to about 1% after a week of cell culture. Combining any two worked a bit better. But combining all three brought the efficiency to about 80 percent in the same period of time.

New molecule allows for up to 10-fold increase in stem cell transplants

Investigators have just published the announcement of the discovery of a new molecule, the first of its kind, which allows for the multiplication of stem cells in a unit of cord blood. Umbilical cord stem cells are used for transplants aimed at curing a number of blood-related diseases, including leukemia, myeloma and lymphoma. For many patients this therapy comprises a treatment of last resort. The research has the potential to multiply by 10 the number of cord blood units available for a transplant in humans. In addition, it will considerably reduce the complications associated with stem cell transplantation.

Pyrimidoindole derivatives are agonists of human hematopoietic stem cell self-renewal

The small number of hematopoietic stem and progenitor cells in cord blood units limits their widespread use in human transplant protocols. We identified a family of chemically related small molecules that stimulates the expansion ex vivo of human cord blood cells capable of reconstituting human hematopoiesis for at least 6 months in immunocompromised mice. The potent activity of these newly identified compounds, UM171 being the prototype, is independent of suppression of the aryl hydrocarbon receptor, which targets cells with more-limited regenerative potential. The properties of UM171 make it a potential candidate for hematopoietic stem cell transplantation and gene therapy.

OUR CELLS WILL BE GUIDED AND PROTECTED BY MACHINES
https://www.fightaging.org/archives/2014/09/our-cells-will-be-guided-and-protected-by-machines.php

A gulf presently lies between the nanoscale engineering of materials science on the one hand and the manipulation and understanding of evolved biological machinery on the other. In time that gulf will close: future industries will be capable of producing and controlling entirely artificial machines that integrate with, enhance, or replace our natural biological machines. Meanwhile biologists will be manufacturing ever more artificial and enhanced versions of cellular components, finding ways to make them better: evolution has rarely produced the best design possible for any given circumstance. Both sides will work towards one another and eventually meet in the middle.

Insofar as aging goes, a process of accumulating damage and malfunction in our biology, it is likely that this will first be successfully addressed and brought under medical control by producing various clearly envisaged ways to repair and maintain our cells just as they are: remove the damage, restore youthful function, and repeat as necessary. We stand much closer to that goal than the far more ambitious undertaking of building a better, more resilient, more easily repaired cell - a biology 2.0 if you like. That will happen, however. Our near descendants will be as much artificial as natural, and more capable and healthier for it.

The introduction of machinery to form a new human biology won't happen all at once, however, and it isn't entirely a far future prospect. There will be early gains and prototypes, the insertion of simpler types of machine into our cells for specific narrow purposes: sequestering specific proteins or wastes, or as drug factories to produce a compound in response to circumstances, or any one of a number of other similar tasks. If you want to consider nanoparticles or engineered assemblies of proteins capable of simple decision tree operations as machines then this has already happened in the lab:

Researchers Make Important Step Towards Creating Medical Nanorobots

Researchers [have] have made an important step towards creating medical nanorobots. They discovered a way of enabling nano- and microparticles to produce logical calculations using a variety of biochemical reactions. Many scientists believe logical operations inside cells or in artificial biomolecular systems to be a way of controlling biological processes and creating full-fledged micro-and nano-robots, which can, for example, deliver drugs on schedule to those tissues where they are needed.

Further, there is a whole branch of cell research that involves finding ways to safely introduce ever larger objects into living cells, such as micrometer-scale constructs. In an age in which the state of the art for engineering computational devices is the creation of 14 nanometer features, there is a lot that might be accomplished in the years ahead with the space contained within a 1000 nanometer diameter sphere.

Introducing Micrometer-Sized Artificial Objects into Live Cells: A Method for Cell-Giant Unilamellar Vesicle Electrofusion

Direct introduction of functional objects into living cells is a major topic in biology, medicine, and engineering studies, since such techniques facilitate manipulation of cells and allows one to change their functional properties arbitrarily. In order to introduce various objects into cells, several methods have been developed, for example, endocytosis and macropinocytosis. Nonetheless, the sizes of introducible objects are largely limited: up to several hundred nanometers and a few micrometers in diameter. In addition, the uptake of objects is dependent on cell type, and neither endocytosis nor macropinocytosis occur, for example, in lymphocytes. Even after successful endocytosis, incorporated objects are transported to the endosomes; they are then eventually transferred to the lysosome, in which acidic hydrolases degrade the materials. Hence, these two systems are not particularly suitable for introduction of functionally active molecules and objects.

To overcome these obstacles, novel delivery systems have been contrived, such as cationic liposomes and nanomicelles, that are used for gene transfer; yet, only nucleic acids that are limited to a few hundred nanometers in size can be introduced. By employing peptide vectors, comparatively larger materials can be introduced into cells, although the size limit of peptides and beads is approximately 50nm, which is again insufficient for delivery of objects, such as DNA origami and larger functional beads.

Here, we report a method for introducing large objects of up to a micrometer in diameter into cultured mammalian cells by electrofusion of giant unilamellar vesicles (GUVs). We prepared GUVs containing various artificial objects using a water-in-oil emulsion centrifugation method. GUVs and dispersed HeLa cells were exposed to an alternating current (AC) field to induce a linear cell-GUV alignment, and then a direct current (DC) pulse was applied to facilitate transient electrofusion.

With uniformly sized fluorescent beads as size indexes, we successfully and efficiently introduced beads of 1 µm in diameter into living cells along with a plasmid mammalian expression vector. Our electrofusion did not affect cell viability. After the electrofusion, cells proliferated normally until confluence was reached, and the introduced fluorescent beads were inherited during cell division. Analysis by both confocal microscopy and flow cytometry supported these findings. As an alternative approach, we also introduced a designed nanostructure (DNA origami) into live cells. The results we report here represent a milestone for designing artificial symbiosis of functionally active objects (such as micro-machines) in living cells. Moreover, our technique can be used for drug delivery, tissue engineering, and cell manipulation.

Cell machinery will be a burgeoning medical industry of the 2030s, I imagine. To my eyes the greatest challenge in all of this is less the mass production of useful machines per se, and more the coordination and control of a body full of tens of trillions of such machines, perhaps from varied manufacturers, introduced for different goals, and over timescales long in comparison to business cycles and technological progress. That isn't insurmountable, but it sounds like a much harder problem than those inherent in designing these machines and demonstrating them to be useful in cell cultures. It is a challenge on a scale of complexity that exceeds that of managing our present global communications network by many orders of magnitude. If you've been wondering what exactly it is we'll be doing with the vast computational power available to us in the decades ahead, given that this metric continues to double every 18 months or so, here is one candidate.

LATEST HEADLINES FROM FIGHT AGING!

ATTEMPTS TO REDUCE SYSTEMATIC INFLAMMATION IN AGING
Monday, September 15, 2014
https://www.fightaging.org/archives/2014/09/attempts-to-reduce-systematic-inflammation-in-aging.php

Chronic inflammation increases with aging due to a progressive dysfunction of the immune system: it is overactive but yet ineffective, like a failing engine running hot. Inflammation is a necessary part of the immune response, but if it is turned on all the time it causes all sorts of secondary forms of damage, and is associated with an increased risk of developing many of the common forms of age-related disease. Thus many research groups are interested in finding effective ways to reduce inflammation in aging, either by addressing the root causes of immune dysfunction, or more commonly, and as is the case here, by trying to alter biochemical signals and responses to those root causes:

Aging is associated with an overt inflammatory phenotype and physiological decline. Specialized proresolving lipid mediators (SPMs) are endogenous autacoids that actively promote resolution of inflammation. In this study, we investigated resolution of acute inflammation in aging and the roles of SPMs. Using a self-resolving peritonitis and resolution indices coupled with lipid mediator metabololipidomics, we found that aged mice had both delayed resolution and reduced SPMs.

The SPM precursor docosahexaenoic acid accelerated resolution via increased SPMs and promoted human monocyte reprogramming. In aged mice, novel nanoproresolving medicines carrying aspirin-triggered resolvins D1 and D3 reduced inflammation by promoting efferocytosis. These findings provide evidence for age-dependent resolution pathways in acute inflammation and novel means to activate resolution.

EFFECTS OF LIFESTYLE OR EFFECTS OF AGING?
Monday, September 15, 2014
https://www.fightaging.org/archives/2014/09/effects-of-lifestyle-or-effects-of-aging.php

There is a distinction to be drawn between primary and secondary aging, which at this time we might consider as the division between the things you can't yet do anything about on the one hand versus the things can you do something about on the other. Unfortunately the former are much more of a determinant of aging and age-related disease than the latter. Primary aging consists of damage-generating metabolic processes that we don't yet have the biotechnology to address, as described in the SENS view of aging. Secondary aging consists of the biochemical consequences of becoming fat and sedentary, or at least that is the bulk of it. We live in an age of comparative comfort in which becoming fat and sedentary is increasingly the norm, but that comes with a significant cost to long-term health.

Leptin is produced mainly in the white adipose tissue and emerged as one of the key catabolic regulators of food intake and energy expenditure. During the course of aging characteristic alterations in body weight and body composition in humans and mammals, i.e. middle-aged obesity and aging anorexia and cachexia, suggest age-related regulatory changes in energy balance in the background. Aging has been associated with increased fat mass, central and peripheral leptin resistance as indicated by its failure to reduce food intake, to increase metabolic rate and thereby to induce weight loss.

Leptin resistance is a common feature of aging and obesity (even in the young). The question arises whether aging or fat accumulation plays the primary role in the development of this resistance. The review focuses mainly on mechanisms and development of central leptin resistance. Age-related decline primarily affects the hypermetabolic component of central catabolic leptin actions, while the anorexigenic component is even growing stronger in the late phase of aging. Obesity enhances resistance to leptin at any age, particularly in old rats, calorie-restriction, on the other hand, increases responsiveness to leptin, especially in the oldest age-group. Thus, without obesity, leptin sensitivity appears not to decrease but to increase by old age. Interactions with other substances (e.g. insulin, cholecystokinin, endogenous cannabinoids) and life-style factors (e.g. exercise) in these age-related changes need to be investigated.

A GLANCE AT SILICON VALLEY LONGEVITY INITIATIVES
Tuesday, September 16, 2014
https://www.fightaging.org/archives/2014/09/a-glance-at-silicon-valley-longevity-initiatives.php

Here is a little more on some of the initiatives arising in the Bay Area venture and technology communities: the SENS Research Foundation, Calico Labs, and the Palo Alto Longevity Prize. As I pointed out a few days back, it's not just a matter of attracting money, however. The goal of bringing aging under medical control requires spending that money on the right research initiatives:

Some scientists in Palo Alto are offering a $1 million prize to anyone who can end aging. "Based on the rapid rate of biomedical breakthroughs, we believe the question is not if we can crack the aging code, but when will it happen." The Palo Alto Prize is also working with a number of angel investors, venture capital firms, corporate venture arms, institutions and private foundations within Silicon Valley to create health-related incentive prize competitions in the future.

It's a fantastical idea: curing the one thing we will all surely die of if nothing else gets us before that. I sat down with Aubrey de Grey, the chief science officer of the SENS Research Foundation and co-author of "Ending Aging," to discuss this very topic a few days back. According to him, ending aging comes with the promise to not just stop the hands of time, but to actually reverse the clock. We could, according to him, actually choose the age we'd like to exist at for the rest of our (unnatural?) lives. But we are far off from possibly seeing this happen in our lifetime, says de Grey. "With sufficient funding we have a 50/50 chance to getting this all working within the next 25 years, but it could also happen in the next 100," he says.

If you ask Ray Kurzweil, life extension expert, futurist and part-time adviser to Google's somewhat stealth Calico project, we're actually tip-toeing upon the cusp of living forever. "We'll get to a point about 15 years from now where we're adding more than a year every year to your life expectancy," he told the New York Times in early 2013. He also wrote in the book he co-authored with Terry Grossman, M.D., that "Immortality is within our grasp." That's a bit optimistic to de Grey (the two are good friends), but he's not surprised this prize is coming out of Silicon Valley. "Things are changing here first. We have a high density of visionaries who like to think high."

And he believes much of what Kurzweil says is true with the right funding. "Give me large amounts of money to get the research to happen faster," says de Grey. He then points out that Google's Calico funds are virtually unlimited. "Kurzweil asked Larry [Page] and Sergey [Brin] how much he had to work with and they said to let him know when he runs out of money and they'll send more," de Grey tells me.

HEAT SHOCK PROTEINS AND NEURODEGENERATION
Tuesday, September 16, 2014
https://www.fightaging.org/archives/2014/09/heat-shock-proteins-and-neurodegeneration.php

Heat shock proteins are one portion of an array of cellular housekeeping and repair mechanisms that swing into action in response to circumstances that cause elevated levels of damage to protein machinery: heat, exercise, toxins, and so forth. Some research groups are interested in building therapies based on inducing greater repair activity by raising the levels of heat shock proteins present in cells, but most researchers in the field are gathering data only:

Many members of the heat shock protein family act in unison to refold or degrade misfolded proteins. Some heat shock proteins also directly interfere with apoptosis. These homeostatic functions are especially important in proteinopathic neurodegenerative diseases, in which specific proteins misfold, aggregate, and kill cells through proteotoxic stress. Heat shock protein levels may be increased or decreased in these disorders, with the direction of the response depending on the individual heat shock protein, the disease, cell type, and brain region. Aging is also associated with an accrual of proteotoxic stress and modulates expression of several heat shock proteins.

We speculate that the increase in some heat shock proteins in neurodegenerative conditions may be partly responsible for the slow progression of these disorders, whereas the increase in some heat shock proteins with aging may help delay senescence. The protective nature of many heat shock proteins in experimental models of neurodegeneration supports these hypotheses. Furthermore, some heat shock proteins appear to be expressed at higher levels in longer-lived species. However, increases in heat shock proteins may be insufficient to override overwhelming proteotoxic stress or reverse the course of these conditions, because the expression of several other heat shock proteins and endogenous defense systems is lowered. In this review we describe a number of stress-induced changes in heat shock proteins as a function of age and neurodegenerative pathology, with an emphasis on the heat shock protein 70 (Hsp70) family and the two most common proteinopathic disorders of the brain, Alzheimer's and Parkinson's disease.

AGE LEVELS ASSOCIATE WITH BONE FRACTURE RISK IN AGING
Wednesday, September 17, 2014
https://www.fightaging.org/archives/2014/09/age-levels-associate-with-bone-fracture-risk-in-aging.php

Our bones become dangerously weak with advancing age. A lot of this stems from a growing failure of maintenance processes and an imbalance in the bone remodeling that constantly takes place - too much bone removal, and not enough creation. In addition, however, rising levels of the sugary metabolic wastes known as advanced glycation endproducts (AGEs) are also thought to play a role in weakening tissue structures like bone. There are many different types of AGE and not all are relevant to this type of dysfunction: some are short-lived and usually cleared out by the body, and thus their presence indicates a failure in clearance mechanisms or some form of metabolic dysfunction such as diabetes, while others are long-lived and hard for the body to break down, and these build up steadily over time. There is a wide range of current capabilities for measuring and manipulating AGEs: the basic toolkit for working with the most important long-lived human AGE glucosepane is only now being developed, for example.

Here researchers demonstrate an association between one common species of AGE and increasing bone frailty independent of the loss of bone density. Because of the points noted above this is a case of measuring what you can measure with the data to hand - it would be interesting to see this same data with glucosepane levels, as the measured form of AGE may be just a marker rather than a measure of the agent of harm:

Advanced glycation end products (AGE) in bone tissue are associated with impaired biomechanical properties and increased fracture risk. Here we examine whether serum levels of the AGE carboxy-methyl-lysine (CML) are associated with risk of hip fracture. We followed 3373 participants from the Cardiovascular Health Study (age 78 years; range, 68-102 years; 39.8% male) for a median of 9.22 years. Rates of incident hip fracture were calculated by quartiles of baseline CML levels, and hazard ratios were adjusted for covariates associated with hip fracture risk. A subcohort of 1315 participants had bone mineral density (BMD) measurement.

There were 348 hip fractures during follow-up, with incidence rates of hip fracture by CML quartiles of 0.94, 1.34, 1.18, and 1.69 per 100 participant-years. The unadjusted hazard ratio of hip fracture increased with each 1 standard deviation increase (189 ng/mL) of CML level (hazard ratio 1.27). Sequential adjustment for age, gender, race/ethnicity, body mass index (BMI), smoking, alcohol consumption, prevalent coronary heart disease (CHD), energy expenditure, and estimated glomerular filtration rate (based on cystatin C), moderately attenuated the hazard ratio for fracture to 1.17. In the cohort with BMD testing, total hip BMD was not significantly associated with CML levels. We conclude that increasing levels of CML are associated with hip fracture risk in older adults, independent of hip BMD. These results implicate AGE in the pathogenesis of hip fractures.

A MASTER REGULATOR OF THE HEAT SHOCK RESPONSE
Wednesday, September 17, 2014
https://www.fightaging.org/archives/2014/09/a-master-regulator-of-the-heat-shock-response.php

The heat shock response is an important process in cell maintenance, a coordinated set of mechanisms that recycle damaged proteins, activated by conditions likely to cause that damage. It is not only triggered by heat, but also by a variety of other potentially damaging circumstances such as raised levels of reactive oxygen species released by mitochondria during exercise, the presence of many types of toxic molecules, and so on. Increased heat shock response is involved in some of the methods demonstrated to slow aging in laboratory animals, and a few research teams are working towards ways to trigger it safely as a therapy - though as for the prospect of artificially inducing autophagy, another of the principal cell maintenance processes, there seems to be a lot of early stage research and little concrete progress towards this goal as yet.

Heat shock proteins protect the molecules in all human and animal cells with factors that regulate their production and work as thermostats. In new research [scientists] report for the first time that a protein called translation elongation factor eEF1A1 orchestrates the entire process of the heat shock response. By doing so, eEF1A1 supports overall protein homeostasis inside the cell, ensuring that it functions properly under various internal and external stress conditions. The researchers suggest that this finding could reveal a promising, new drug target for neurodegenerative diseases and cancer.

Heat shock proteins (HSPs) chaperone other proteins, helping them to fold properly and supporting their function. With neurodegenerative diseases, neurons lack enough protective HSPs that insulate them from protein-damaging stress. A hallmark of most neurodegenerative diseases is protein misfolding. If the heat shock response could be restored to its full capacity in aging neurons, then misfolded proteins might fold properly, potentially avoiding or halting progression of diseases such as Alzheimer's, Parkinson's, or amyotrophic lateral sclerosis (ALS). In contrast, many types of cancer cells rely on HSPs to survive. Because high levels of HSPs enable cancer cells to grow and proliferate, depleting these cells of HSPs could sensitize tumors to chemotherapy and radiation therapies. "It's a bit early, but we think that eventually we could design small-molecule activators and inhibitors that tweak the heat shock response. eEF1A1 controls every single step of the heat shock response simultaneously."

The eEF1A protein is expressed in two similar forms, 1 and 2, in different tissues. Motor neurons express form 2 (eEF1A2), which does not support the heat shock response. [Researchers] believe that this is the reason why these specialized cells cannot mount the heat shock response and therefore are particularly vulnerable to stress and diseases such as ALS. The challenge in drug development will be restoring the heat shock response in motor neurons by modulating the activity of eEF1A.

CONNECTING THE LAB AND THE CLINIC IN REGENERATIVE MEDICINE
Thursday, September 18, 2014
https://www.fightaging.org/archives/2014/09/connecting-the-lab-and-the-clinic-in-regenerative-medicine.php

An interview with the director of the Translational Tissue Engineering Center at Johns Hopkins University School of Medicine can be found at the Methuselah Foundation blog:

We named it the Translational Tissue Engineering Center because we're focused not just on the development of new technologies in regenerative medicine, but on addressing clinical challenges and developing new therapeutic outcomes for patients. In my lab, we're looking at a number of different applications in orthopedic surgery, rheumatology, and musculoskeletal repair. We're working on the regeneration of cartilage tissue, which lines the surfaces of joints. We're also looking at bone repair, which is important for joints and in craniofacial reconstruction, and exploring what can be done with muscle disease to repair tissues and treat the underlying disease. Then there are the plastic surgery applications - reconstruction of tissues and wound healing in the craniofacial region and soft tissue throughout the body. We're also in an ophthalmology building, so we're surrounded by a lot of clinicians focused on the eye, and we've begun projects looking at both corneal repair and retinal repair.

What's interesting right now is that there seems to be a renewed excitement for cell therapies and gene therapies, both among students and in the commercial sector. These types of industrial investment and commercial excitement tend to go through ups and downs, and I think there's a lot of excitement right now that we definitely want to get more and more connected with. One of the biggest gaps in my mind is what happens at the university versus what's feasible in commercial settings, and there are a number of these so-called valleys of death between the two. There's a valley of death in the laboratory of moving to proof of concept and actual efficacy in the most relevant pre-clinical models that the FDA will approve. Then there's another valley of death when you come out of the laboratory regarding how to manufacture and deliver whatever technology you're working with, and how to make it commercially viable.

Right now, I'm most encouraged by the interface between regenerative medicine and transplantation. There have been some exciting advances in transplantation and microsurgery, for example, with very complex grafts on the face, hands, and arms. And in order to take it beyond that, and make it less of a rare, boutique occurrence into something more widespread and accessible to a larger number of people, I think it could be very interesting to combine the latest work in cell therapy with the latest in both materials and immunomodulation. Also, I think some of the recent advancements in cancer immunology, which is really a type of regenerative medicine engineering - in other words, engineering the immune system to treat a disease - involve principles that are very promising and can be applied to many other things.

A LOOK AT A FUTURE OF SLOWING AGING
Thursday, September 18, 2014
https://www.fightaging.org/archives/2014/09/a-look-at-a-future-of-slowing-aging.php

This article is an example of the rising awareness of ongoing research into altering the pace of aging so as to extend healthy life. This is a good thing if you are thinking about raising funds for research on therapies for aging, as the more public attention the better, even if it is focused at first on a poor choice of scientific strategy. Working to slow aging is a course that will produce only marginal benefits and a slight change in the course of life and structure of society: people will live a little longer, and the present trend of adding a year to adult life expectancy each decade will continue or speed up a little. Everything will be essentially the same at the end of the day, however, and we will all still suffer horribly from age-related diseases and die because of aging.

Aging is an accumulation of damage at the level of cells and protein structures, and altering our metabolism to slightly slow down that process is both hard and not all that beneficial, since none of the prospective or envisaged treatments can slow it down all that much. The best of paths to actual therapies at this point in time are not as beneficial as the practice of regular exercise or calorie restriction, and that isn't something that is expected to change any time soon.

My hope is that the current enthusiasm for slowing aging will give way to work on reversing aging, producing actual rejuvenation by repairing the damage of aging rather than just slowing it down. For that to happen, the currently minority field of rejuvenation research needs enough funding to demonstrate that it can produce far better results and for far less investment - which should be the case just as soon as the first prototype treatments are deployed in mice. Repair of a failing system is obviously better than building a new system that fails more slowly: existing old machinery can be restored, and that repair process can be performed over and again to extend its healthy life indefinitely. Further, the causes of aging are very much simpler and more completely understood than the details of our metabolic machinery; building ways to repair these causes is a much easier prospect than reengineering metabolism.

Viewed globally, the lengthening of life spans seems independent of any single, specific event. It didn't accelerate much as antibiotics and vaccines became common. Nor did it retreat much during wars or disease outbreaks. A graph of global life expectancy over time looks like an escalator rising smoothly. The trend holds, in most years, in individual nations rich and poor; the whole world is riding the escalator. Projections of ever-longer life spans assume no incredible medical discoveries - rather, that the escalator ride simply continues. If anti-aging drugs or genetic therapies are found, the climb could accelerate. Centenarians may become the norm, rather than rarities who generate a headline in the local newspaper.

Pie in the sky? On a verdant hillside in Marin County, California - home to hipsters and towering redwoods, the place to which the Golden Gate Bridge leads - sits the Buck Institute, the first private, independent research facility dedicated to extending the human life span. Since 1999, scientists and postdocs there have studied ways to make organisms live much longer, and with better health, than they naturally would. Already, the institute's researchers have quintupled the life span of laboratory worms. Most Americans have never heard of the Buck Institute, but someday this place may be very well known.

Buck is not alone in its pursuit. The University of Michigan, the University of Texas, and the University of California at San Francisco are studying ways to slow aging, as is the Mayo Clinic. Should research find a life-span breakthrough, the proportion of the U.S. population that is elderly - fated to rise anyway, considering declining fertility rates, the retirement of the Baby Boomers, and the continuing uplift of the escalator - may climb even more. But the story might have a happy ending. If medical interventions to slow aging result in added years of reasonable fitness, life might extend in a sanguine manner, with most men and women living longer in good vigor, and also working longer, keeping pension and health-care subsidies under control. Indeed, the most-exciting work being done in longevity science concerns making the later years vibrant, as opposed to simply adding time at the end.

HOW NEURAL STEM CELLS HELP TO REPAIR DAMAGE
Friday, September 19, 2014
https://www.fightaging.org/archives/2014/09/how-neural-stem-cells-help-to-repair-damage.php

Researchers have identified a novel mechanism by which neural stem cells can help to repair and assist other brain cells:

Stem cells hold great promise as a means of repairing cells in conditions such as multiple sclerosis, stroke or injuries of the spinal cord because they have the ability to develop into almost any cell type. Now, new research shows that stem cell therapy can also work through a mechanism other than cell replacement. A team of researchers [has] shown that stem cells "communicate" with cells by transferring molecules via fluid filled bags called vesicles, helping other cells to modify the damaging immune response around them. "These tiny vesicles in stem cells contain molecules like proteins and nucleic acids that stimulate the target cells and help them to survive - they act like mini "first aid kits". Essentially, they mirror how the stem cells respond to an inflammatory environment like that seen during complex neural injuries and diseases, and they pass this ability on to the target cells. We think this helps injured brain cells to repair themselves."

Mice with damage to brain cells - such as the damage seen in multiple sclerosis - show a remarkable level of recovery when neural stem/precursor cells (NPCs) are injected into their circulatory system. PCs make vesicles when they are in the vicinity of an immune response, and especially in response to a small protein, or cytokine, called Interferon-g which is released by immune cells. A highly specific pathway of gene activation is triggered in NPCs by IFN-g, and that this protein also binds to a receptor on the surface of vesicles. When the vesicles are released by the NPCs, they adhere and are taken up by target cells. Not only does the target cell receive proteins and nucleic acids that can help them self-repair, but it also receives the IFN-g on the surface of the vesicles, which activates genes within the target cells.

A HISTORY OF LIFE EXTENSIONISM IN THE TWENTIETH CENTURY
Friday, September 19, 2014
https://www.fightaging.org/archives/2014/09/a-history-of-life-extensionism-in-the-twentieth-century.php

Subcultures and initiatives that support the extension of healthy life through medical research have grown considerably in the past twenty years, finding one another and merging with the spread of the internet, then raising funds and attracting attention in increasingly large cycles. Prior to this, however, these subcultures were thin threads indeed, tiny groups and single individuals out on the fringes of culture. Yet these roots of the present day life extension movements extend back a long way, and as is argued in the book "A History of Life Extensionism in the Twentieth Century" they were influential upon medicine even then. Here is an interesting review that touches upon the greater public support for extending healthy life that exists in Eastern Europe and Russia versus the West, something that has been noted in recent years with greater contact and collaboration between the English language and Russian language longevity science communities:

A History of Life-Extensionism in the Twentieth Century by Ilia Stambler is the most thorough treatment to date of the ideas of famous thinkers and scientists who attempted to prolong human lifespans. In this detailed and impressively documented work - spanning 540 pages - Dr. Stambler explores the works of life-extensionist thinkers and practitioners from a vast variety of ideological, national, and methodological backgrounds.

In substance, I agree with Dr. Stambler's central observation that life-extensionist thinkers tended to adapt to the political and ideological climates of the societies in which they lived. I do suspect that, in some regimes (e.g., communist and fascist ones), the adaptation was partly a form of protection from official persecution. Even then, Soviet life-extensionists were unable to avoid purges and denunciations if they fell out of favor with the dominant scientific establishment. My own thinking is that life-extensionism is a powerful enough human motive that it will attempt to thrive in any society and under any regime. However, some regimes are more dangerous for life-extensionism than others - especially if they explicitly persecute those who work on life extension.

Even so, I have been tremendously interested to delve into Dr. Stambler's discussion of the deep roots of life-extensionist thought in Russian society, where ideas favoring life prolongation have taken hold despite a long history of authoritarianism and more general human suffering. I even remember my own very early years in Minsk, where I found it easy to adopt an anti-death attitude the moment I learned about death - and where, even in childhood, I found my support for human life extension to be largely uncontroversial from an ethical standpoint. When I moved to the United States, I encountered far more resistance to this idea than I ever did in Belarus.

While most Americans are not opposed to advanced medicine and concerted efforts to fight specific diseases of old age, there does still seem to be a culturally ingrained perception of some "maximum lifespan" beyond which life extension is feared, even though it is considered acceptable up to that limit. I think, however, that the dynamics of a competitive economy with some degree of freedom of research will ultimately enable most Americans to accept longer lifespans in practice, even if there is no intellectual revolution in their minds.