Fight Aging! Newsletter, December 8th 2014

December 8th 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.

This content is published under the Creative Commons Attribution 3.0 license. You are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!

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  • A Perhaps Overdue Reality Check on the Utility of Immune Cell Telomere Length Measures
  • Today is Giving Tuesday and Aubrey de Grey is Matching Your SENS Rejuvenation Research Donations
  • Methuselah Foundation Helping to Put Bioprinters into the Hands of Researchers
  • Leading from the Front to the Last
  • Much More than Just Loss of Mass is Involved in the Age-Related Decline of Muscle Function
  • Latest Headlines from Fight Aging!
    • Cryonics, the Art of Not Dying
    • A Future of Cellular Programming
    • A Novel Approach to Chronic Kidney Disease
    • Targeting Microglia as a Potential Alzheimer's Treatment
    • Suppressing the Origins of Fibrosis
    • Human Induced Pluripotent Stem Cells Recall Their Origins
    • FOXO3A Variations and Measures of Aging
    • The Plasticity of Aging and Longevity Continues
    • The Present Mainstream of Longevity Science: Genetics, Drug Development, and Metabolic Manipulation
    • Another Measure of the Years of Life Lost to Excess Weight


Telomeres are the caps of repeating DNA sequences at the ends of chromosomes. A little of that length is lost with each cell division, and telomeres thus form a part of the limiting mechanism that prevents most cells in the body from simply proliferating forever. That is fairly important: when the limiting processes fail, we call the result cancer. There are mechanisms to lengthen telomeres, however, such as the activity of the enzyme telomerase for example. Stem cells must maintain themselves capable of replication so as to ensure a continual supply of new daughter cells with long telomeres to maintain tissue health, and telomerase allows that to happen. Telomeres and telomerase do various other things too, such as influence patterns of gene expression, as nothing in a cell ever acts in just one process. That would be far too easy.

Average telomere length is most commonly measured in the leukocytes, or white blood cells, from a blood sample. This can be correlated to age and health, though there are subtleties here and some ongoing discussion on the best way to construct these measures, as well as whether or not some of these measurement mothods are in fact useful at all. The shifts in average telomere length over time may be a reflection of the pace at which stem cells are active to introduce new long-telomere daughter cells into circulation, which in turn has some relation to aging because stem cell populations tend to decline in response to the rising levels of cellular damage that cause degenerative aging. This stem cell decline is most likely an evolved balance between cancer risk and tissue failure that arose to lengthen human life span in comparison to that of other primates, a consequence of our greater intelligence and culture that allowed older individuals to contribute meaningfully to the survival of their grandchildren and thus selected for greater longevity. This is all a simplified sketch of what remains a debated and more complex picture, however. The point to take away is that telomere length looks a lot more like a marker of aging than a cause.

That all said, telomere length as measured by today's young medical startup companies is not really a particularly good measure of aging or ill health, especially taken in isolation for one individual at a single point in time. It is a very blunt tool at this point, nowhere near as accurate as, say, the DNA methylation patterns that can indicate chronological age to within a few years. It is also open for debate as to what shorter average telomere lengths for white blood cells really actually indicate in any given situation, given how dynamic they are in response to transient illness - something that may have more to do with immune system state than anything else. So it is wise, I think, to pay attention to studies of this nature that point out further issues with the use of telomere length measures in any single tissue:

Comparison of the Relative Telomere Length Measured in Leukocytes and Eleven Different Human Tissues (PDF)

The relative length of telomeres measured in peripheral blood leukocytes is a commonly used system marker for biological aging and can also be used as a biomarker of cardiovascular aging. However, to what extent the telomere length in peripheral leukocytes reflects telomere length in different organ tissues is still unclear. Therefore, we have measured relative telomere length (rTL) in twelve different human tissues (peripheral blood leukocytes, liver, kidney, heart, spleen, brain, skin, triceps, tongue mucosa, intercostal skeletal muscle, subcutaneous fat, and abdominal fat) from twelve cadavers (age range of 29 week of gestation to 88 years old).

The highest rTL variability was observed in peripheral leukocytes, and the lowest variability was found in brain. We found a significant linear correlation between leukocyte rTL and both intercostal muscle and liver rTL only. High rTL variability was observed between different organs from one individual. Furthermore, we have shown that even slight DNA degradation leads to false rTL shortening. Despite the relatively low number of individuals analyzed and the large age span of the donors, we suggest that there is a very low correlation between the rTL within most tissues and the rTL in blood leukocytes. Thus, the use of leukocytes as a source of DNA for rTL analysis for the estimation of individual "tissue age" is questionable.

Since telomerase activity and cell turnover rates vary widely throughout the different tissue types of the body, it shouldn't be surprising at all to find that average telomere length in different tissues may or may not be meaningfully correlated with either age of the tissue or between different tissues of the same age. But as the authors point out, this isn't a large sample, and they are criticizing an already fairly weak correlative tool. As is often the case more data wouldn't hurt.


Giving Tuesday falls on December 2nd this year, today in fact, and I have to say that this is a far more admirable manufactured publicity event than the preceding Black Friday and Cyber Monday. In this case the motivation is to encourage more people to do good by helping charitable causes to meet their year end fundraising goals: a little mainstream social pressure to make the world a better place to add to that already present in many communities. We could all do more, of course, but the person without a charitable urge is, I think, no more than a person who hasn't yet found the way in which he or she wishes to change the world. When you do find a goal that speaks to you then generosity comes easily: there are always many fellow travelers to discover, and some of those people will be further ahead in the game, having organized to the point of setting up non-profit initiatives to advance the cause. If you want to get anything done in earnest there must be collaboration, networking, research, and sundry other projects, and to be effective in the long term all of that must be funded in some way, shape, or form. Hence the drive for donations.

There are many causes in the world for which the limiting factor on speed of progress is not money. Those are the truly hard jobs. For everything else, helping things along can become very simple: write a check, click the PayPal button, make a donation. Provided you've done the legwork to ensure you are donating to a sound charity performing proven good work, then congratulations - you are helping to make the world a better place. Funding the efforts needed to get the job done is a vital part of the bigger picture for any cause.

The charitable cause I favor above all others is the medical research needed to bring about the end of frailty, disease, and death as a result of aging. Aging is by far the greatest cause of human suffering in every part of the world, even those with other terrible problems. In a more reasonable world we wouldn't find ourselves in the position of having to persuade anyone that, yes, researching the means to treat and reverse aging is the most important goal in the world at present, the goal that will help the most people at the least cost. We are in that position, however, and progress in this research is absolutely limited by funding and little else. There are hundreds of researchers in the present life science community who, if given grants, would gleefully drop their present research in favor of working on ways to repair the cellular and molecular damage that causes aging. It is ever a challenge to bring funding into this community however: aging research is a small and comparatively unattended branch of medical science, and longevity science is a tiny field of that tiny branch. The public at large have not yet woken up to realize that the possibility of turning back the painful consequences of old age is, given sufficient funding, just a few decades away.

So it is Giving Tuesday, and you are sitting there with a few dollars in your pocket, and there is a PayPal button on the SENS Research Foundation donation page. Make a donation and it will be matched at $2 for every $1 you donate by the Fight Aging! matching fund founders, and also by a further $1 for today only by Aubrey de Grey personally. If you're here reading this, then there is perhaps a certain level of interest on your part in helping to assure a personal future that involves less disability, less pain, and less age-related disease. The only way that will happen is if the best and most promising research programs - such as those funded by the SENS Research Foundation - achieve more traction in the years to come. The way that starts is with more public interest and more grassroots donations: so it is up to you.

We know you share our conviction that a world without age-related disease is possible - and our commitment to making that world a reality.

So we would like to encourage everyone who is able to make a donation to SENS Research Foundation on #GivingTuesday and post, tweet, blog and let others know about how your are celebrating #GivingTuesday.

Today onl your donations will be quadrupled thanks to our ongoing Fight Aging! Challenge Grant and the generosity of Aubrey de Grey, who will match every donation made today.

Join us and be a part of a global celebration of a new tradition of generosity.


The Methuselah Foundation, the organization behind the New Organ initiative, places a strong emphasis on tissue engineering as one of the important pillars of the future of improved health and longevity. The Foundation invested in bioprinting company Organovo back when they were an early stage startup and maintains a strong relationship with that organization and its allies today.

The important thing to realize about much of the still young tissue engineering industry, bioprinting included, is that therapies involving constructed tissues are not yet a major concern for commercial development - although there is a lot of research taking place with that in mind. By necessity the initial products that provide revenue for the next phase of development must make use of small amounts of tissue, as the challenges in constructing scaffolds and blood vessel networks for larger structures are still a significant hurdle. At this point that largely means selling production line model tissues to research focused institutions in the pharmaceutical industry, where scientists can use them to conduct better and more consistent studies. There is a world of difference between cells in a flat petri dish and cells organized into a functional tissue. Many lines of research flounder on that difference, and given widely available model tissues these unfortunate projects might have been redirected or adjusted much more rapidly.

Here is an example of the sort of tissue product that is emerging from the industry at the moment, clearly aimed at research institutions as customers. This line of business is a logical stepping stone on the way to the eventual goal of building real, functional organs from scratch as needed. Each advance along the way has to be made profitable in order to support the next stage:

Organovo Announces Commercial Release of the exVive3D Human Liver Tissue

Organovo's exVive3D Liver Models are bioprinted, living 3D human liver tissues consisting of primary human hepatocytes, stellate, and endothelial cell types, which are found in native human liver. The exVive3D Liver Models are created using Organovo's proprietary 3D bioprinting technology that builds functional living tissues containing precise and reproducible architecture. The tissues are functional and stable for at least 42 days, which enables assessment of drug effects over study durations that well beyond those offered by industry-standard 2D liver cell culture systems.

Organovo has previously shown that exVive3D Liver Models produce important liver proteins including albumin, fibrinogen and transferrin, synthesize cholesterol, and possess inducible cytochrome P450 enzymatic activities. The exVive 3D Liver has successfully differentiated between structurally related compounds with known toxic and non-toxic profiles in human beings, and the model has also been employed successfully in the detection of metabolites at extended time points in vitro. Importantly, the configuration of the bioprinted liver tissues enables both biochemical and histologic data to be collected so that a customer can investigate compound responses at multiple levels.

Separately, the Methuselah Foundation is presently working with Organovo and a number of research institutions to put the latest in tissue printers into the hands of more researchers. This is another way to help speed things up in the laboratory: more tools for more workers.

Organovo Collaborates with Yale team to develop 3-D Organ Tissues for Surgical Transplantation Research

"We are excited to begin this collaboration with Organovo and are honored to be part of Methuselah's University 3D Bioprinter Program, which gives our key researchers access to cutting-edge 3D bioprinting technology," said Dr. John Geibel, Vice Chairman, Director of Surgical Research, and Professor of Surgery and Cellular and Molecular Physiology at Yale University. "This collaboration is a great way to bring the best minds of both worlds to solve a major research and medical goal - using bioprinting to produce transplantable tissues."

Under Methuselah's University 3D Bioprinter Program, Methuselah is donating at least half a million in direct funding to be divided among several institutions for Organovo bioprinter research projects. This funding will cover budgeted bioprinter costs, as well as other aspects of project execution. "Developing organs for surgical implantation will take meaningful efforts and focused partnerships. This collaboration with Yale, which combines their expertise and technology with our own, is one important step in progressing towards implantable, therapeutic tissues," said Keith Murphy, chairman and CEO of Organovo. "We are grateful to the Methuselah Foundation for their generous gift that gives those working towards significant breakthroughs in organ bioprinting an opportunity to use the NovoGen bioprinter and enable greater access to Organovo's powerful platform."


I rarely write obituaries, because once you start where do you stop? Perhaps a hundred and fifty thousand lives are lost every day, most due to aging and its consequences, and it isn't just the few people you happened to exchange emails with who are worthy of notice. Yet monuments are at root a selfish undertaking on behalf of the living, and we can easily bury ourselves in mourning and symbolism. Ultimately one has to ask: is this an initiative about death or is this an initiative about life? The world has too many thinly disguised death cults. Cruelly, even after yet another individual in one's personal circle of vision succumbs to the frailty of age all of our lives go on as before. We're still here with the same old to-do list in front of us - or at least we will be until we are not. But that is rather the point: we want to eliminate this part of the human condition, build the medical technologies to repair the breakages that cause aging and thus prevent all of its attendant suffering and death.

I've long admired the oldest people in this community. They participate with no hope at all of benefiting personally from the technologies they support: that is true altruism. It will be, I'd think, twenty years under even the best of circumstances before comparatively crude first generation rejuvenation treatments as envisaged in the SENS proposals become available. If you are in later life it is vanishingly unlikely that you will survive for long enough to benefit meaningfully from present research. Yet that research must happen. Someone must be first to benefit, and someone must be last to miss out.

So we get to this news from the Gerontology Research Group (GRG), providing notice of the death of their founder and organizer in chief Stephen Coles, a researcher and advocate for longevity science. This had been expected, I think, given the details of his ongoing public battle with cancer. He took full advantage of having a rough timeline at the end to ensure a good cryopreservation:

Dr. Stephen Coles passed away in Scottsdale on December 3 of complications of pancreatic cancer and was cryopreserved. He was 73. Scottsdale is where Alcor is, and Steve had traveled there last week to be close to the cryonics foundation.

He tracked the oldest people in the world for over 20 years, and published the most recent five years of his research in the journal PLoS ONE. Dr. Coles performed autopsies on 12 "supercentenarians," people who are 110 years old or older, more than any other pathologist, and determined TTR Amyloidosis as a predominant cause of death.

There is an obituary in the LA Times. For as long as I've been involved in advocacy, Coles has networked with fellow researchers and gathered data on late age survival. With his connections as a hub the GRG mailing list became a cosmopolitan watering hole at which gerontologists, other researchers, and advocates with many varied views on aging and medicine debated points and rubbed shoulders. In recent years Coles' own work helped to shape the SENS Research Foundation strategy of funding potential treatments for TTR amyloidosis, a condition in which misfolded transthyretin builds up in solid masses to clog blood vessels and organs. This condition may be a true final limiting factor on human life span, killing those who survive everything else. Or at least it will be until therapies exist, and the development of those therapies is presently underway - though, as always in matters related to aging, with too little funding for truly rapid progress.

Cryonics is the sensible choice for anyone finding themselves in Coles' position. It is the only presently available shot at making death a hiatus rather than oblivion, and it is one slice of the grand self-destructive tragedy of the modern human condition that next to nobody chooses this path. Preservation of the fine structure of the brain means preservation of the mind, and given continued storage a patient can wait for as long as needed for future molecular nanotechnologies capable of restoring a cryopreserved individual. That isn't impossible, just very hard. But instead all those lives, all those individuals, are lost.

To change this state of affairs many more respected people at the hub of their own networks of influence must make a very public choice to be cryopreserved. This is really no different than the sort of effective advocacy needed to change the present public disinterest in living longer lives through rejuvenation therapies. If we want to see a world without frailty and disease in aging then more people have to speak out and act accordingly: we don't lack the ability to get to this goal, but rather lack the widespread will to do the job. Each of us can only be the one person in this parade, of course, but congratulations and thanks should pass to Coles for choosing to be that one on both fronts.

And that must stand in place for the numerous obituaries and mentions I could have written in recent years. As the community grows there are ever more older members and so more people vanishing over time from the mailing lists and blogs. But what can you do? Fifty years ago you could do nothing but wish. Today, however, you can make a material difference: support the research, support the organizations, help to speed our progress towards the day on which people stop suffering and dying of old age.


It has been some years since sarcopenia was coined as a name for the characteristic loss of muscle mass and strength that occurs with aging, one of many attempts - some successful - to carve off an aspect of aging and obtain regulatory approval to work on treating it. It remains the case that making an official disease of sarcopenia is an ongoing process of lobbying with no end in sight, however. Without that blessing of the state there is no legal path to the translation of promising research into commercial clinical treatments, and thus far less incentive for the major funding sources to invest in any of the research needed to even get to the point at which commercial development is plausible.

In countries like the US only treatments for one of a list of defined diseases are considered for approval by the FDA, very much a case of all that is not permitted is forbidden. Even if sound and proven treatments exist and are widely used elsewhere in the world, people can be ruined financially and potentially go to jail for a long time for offering those treatments in the US. This was the case for first generation stem cell therapies for quite a number of years, for example. One of the large problems for the near future of longevity science as a whole is that aging itself is not considered a medical condition by the FDA and similar regulatory bodies. For so long as that is the case all meaningful early clinical development must occur in other regions of the world, and more importantly there will continue to be far less funding for research than might otherwise be the case.

Back to sarcopenia, however. There is indeed loss of muscle mass in aging, and this is a major cause of the frailty of later life. There is much more to the underlying processes than just a simple loss of mass, however. It is much more complex than that, as this review notes. The quoted portions are from the introduction and summary, and in between there is a more detailed overview of some of the mechanisms mentioned - it makes for interesting reading within the context that the practice of calorie restriction slows the progression of sarcopenia.

It is not just muscle mass: a review of muscle quality, composition and metabolism during ageing as determinants of muscle function and mobility in later life

Worldwide estimates predict 2 billion people will be aged over 65 years by 2050. A major current challenge is maintaining mobility and quality of life into old age. Impaired mobility is often a precursor of functional decline, disability and loss of independence. Sarcopenia which represents the age-related decline in muscle mass is a well-established factor associated with mobility limitations in older adults. However, there is now evidence that not only changes in muscle mass but other factors underpinning muscle quality including composition, metabolism, aerobic capacity, insulin resistance, fat infiltration, fibrosis and neural activation may also play a role in the decline in muscle function and impaired mobility associated with ageing. Importantly, changes in muscle quality may precede loss of muscle mass and therefore provide new opportunities for the assessment of muscle quality particularly in middle-aged adults who could benefit from interventions to improve muscle function.

Several longitudinal studies suggest that muscle mass alone cannot fully explain the loss of muscle strength and physical function in older adults. Estimates of the rate of change in muscle strength with age derived from a cross-sectional cohort have also been suggested to underestimate actual yearly changes in muscle strength. In the Health, Ageing, and Body Composition (Health ABC) study, the decline in muscle strength during ageing was reported to be two- to five fold greater than the loss of muscle mass in older adults aged 70-79 years over a 3-year follow-up period. Furthermore, there was wide inter-individual variability in changes in muscle cross-sectional area and muscle strength in older adults, such that muscle mass and muscle strength were well-preserved in some individuals but not others.

It will be important in future to better understand the main factors which underpin changes in muscle quality with age, which may well precede changes in muscle mass or be of greater functional significance in ageing muscles, with declining size. In addition, a universal consensus definition of muscle quality is necessary. Muscle quality is typically used to describe muscle strength or power per unit of muscle mass, therefore does not encompass muscle aerobic capacity which is closely associated with mobility and important for activities of daily living. Currently, there is a large gap in our knowledge on the primary determinants of muscle quality in middle-aged adults. The development of muscle quality assessment tools that encompass muscle quality and which are sensitive to small changes within muscle that precede a decline in muscle function would enable individuals to take preventative steps to maintain healthy muscle.


Monday, December 1, 2014

A great piece on the cryonics industry, with a focus on Alcor. Cryonics providers offer indefinite low-temperature storage for those who will die prior to the advent of effective rejuvenation therapies. This is the only shot at a longer life in the future available to those people, a demographic that may turn out to include all of us if things go poorly in medical research and advocacy over the next few decades. A cryopreserved individual has all the time in the world to wait for future restoration technologies to arise, as provided that the fine structure of the brain is maintained in the preservation process then the mind continues to exist, on hold:

In terms of the revival end of things, it's a long way off. [Alcor] isn't doing a whole lot of research there because it's too much of a cap on what we can do. There is a startup company that I can't really talk about that that's doing that, trying to grow tissues, grow organs. The whole field of regenerative medicine is really relevant to what we're doing. We benefit from a lot of other fields of research, like nanomedicine and the people trying to cryopreserve organs. They've actually managed to cryopreserve a rabbit kidney, keep it there for several months and then rewarm it, implant it in the rabbit and have it function. You can do it with all kinds of single tissues - it's very common now to cryopreserve corneas, sperm, eggs - there are dozens of tissue types that can be cryopreserved and then rewarmed. Going from a single tissue to a whole organ is much more difficult.

What we would imagine is that the brain would actually be repaired cell by cell, which is why we want to minimize the damage we do because there are a lot of neurons to be fixed. We do know that under good conditions we are preserving brains very well - we can look at vitrified brain tissue from animals under an electron microscope and it looks great. You can see the membranes are all intact, the neurons are all connected, it looks perfectly preserved.

Everything we know about personality tells us that it's stored in physical changes in the brain. Apart from very short term memory where the last few minutes is all electrical activity, anything longer than that is stored in changes in the neurotransmitter connections in the brain. That's what we're preserving under good circumstances. We're not just being speculative and taking a leap of faith. We've started a program of doing CT scans of our neuro patients. We can get really good readings of people's brains and see how we're doing.

It looks worse if we can't perfuse the brain [with cryoprotectants] and get ice crystal damage, but it doesn't mean it's destroyed. It's going to look bad to us, but in our view, we look at it like, the functional ability of the brain's been destroyed, but function is not really crucial. What really matters is that you're storing enough of the structure that some future technology can look at it and say "this membrane's been damaged really badly, but we know how to put it back together."

Monday, December 1, 2014

This is a revolutionary era in biology and biotechnology, one of the many consequences of it also being a revolutionary era in computation. Sustained and rapid progress is under way in hundreds of important fields of medicine in laboratories around the world, and this state of affairs is the reason why we have the opportunity to reach for the construction of rejuvenation treatments and the defeat of degenerative aging:

In the last two decades we have witnessed a paradigm shift in our understanding of cells so radical that it has rewritten the rules of biology. The study of cellular reprogramming has gone from little more than a hypothesis, to applied bioengineering, with the creation of a variety of important cell types. By way of metaphor, we can compare the discovery of reprogramming with the archeological discovery of the Rosetta stone. This stone slab made possible the initial decipherment of Egyptian hieroglyphics because it allowed us to see this language in a way that was previously impossible. We propose that cellular reprogramming will have an equally profound impact on understanding and curing human disease, because it allows us to perceive and study molecular biological processes such as differentiation, epigenetics, and chromatin in ways that were likewise previously impossible.

Stem cells could be called "cellular Rosetta stones" because they allow also us to perceive the connections between development, disease, cancer, aging, and regeneration in novel ways. Here we present a comprehensive historical review of stem cells and cellular reprogramming, and illustrate the developing synergy between many previously unconnected fields. We show how stem cells can be used to create in vitro models of human disease and provide examples of how reprogramming is being used to study and treat such diverse diseases as cancer, aging, and accelerated aging syndromes, infectious diseases such as AIDS, and epigenetic diseases such as polycystic ovary syndrome. While the technology of reprogramming is being developed and refined there have also been significant ongoing developments in other complementary technologies such as gene editing, progenitor cell production, and tissue engineering. These technologies are the foundations of what is becoming a fully-functional field of regenerative medicine and are converging to a point that will allow us to treat almost any disease.

Tuesday, December 2, 2014

Failing kidney function is a serious issue for many older people, and at this time comparatively little can be done about it:

Chronic kidney disease (CKD) affects at least one in four Americans who are older than 60 and can significantly shorten lifespan. Yet the few available drugs for CKD can only modestly delay the disease's progress towards kidney failure. [Researchers] focused on a central feature of CKD: the "fibrosis" process. This is a pathological response to chronic kidney stress that includes an abnormal buildup of fibrous collagen, a loss of capillaries a die-off of important kidney cells called tubular epithelial cells, and other changes that progressively reduce a kidney's ability to filter the blood properly.

The researchers compared the patterns of gene activity in fibrotic and normal human kidney tissue samples. They found abnormal patterns in gene networks linked to inflammation and sharp drops in activity in gene networks that support energy metabolism in the fibrotic samples. The fact that inflammation is a factor in CKD was already well known, so [researchers]] aimed their investigation at two types of energy metabolism - glucose oxidation and fatty acid oxidation - that seemed markedly reduced in the fibrotic samples. "What we found is that the tubular epithelial cells preferentially use fatty acid oxidation as their energy source in normal conditions. Even when fatty acid metabolism drops in the context of CKD, these cells don't switch to burning glucose for energy."

In human tubular epithelial cells, artificially reducing fatty acid metabolism quickly brought about fibrosis-like signs, including the buildup of fat molecules (unspent fuel) and the deaths of many affected cells. That fat buildup in kidney cells had been hypothesized to be a significant cause of cell death in CKD fibrosis, [but] the fat accumulation on its own had minimal impact. The more important factor in fibrosis was the loss of energy in the cells as fatty acid metabolism dropped. Researchers also found evidence that the shutdown of fatty acid metabolism in tubular epithelial cells is caused in large part by the growth factor TGFβ. This factor is known to promote fibrosis and has been linked to high blood glucose levels, high blood pressure, and inflammation - all triggers of CKD. "We hope to develop new compounds [that] boost enzymes more specifically related to fatty acid metabolism. In that way we might be able to greatly slow the progress of CKD."

Tuesday, December 2, 2014

Inflammation is an important component of Alzheimer's disease pathology. Therefore some researchers focus on possible ways to damp down this inflammation by developing more sophisticated ways to control the activities of varied types of neuroglia, the immune cells of the brain:

Activated microglia are associated with the progression of Alzheimer's disease (AD), as well as many other neurodegenerative diseases of aging. Microglia are therefore key targets for therapeutic intervention. β-amyloid (Aβ) deposits activate the complement system, which, in turn, stimulates microglia to release neurotoxic materials. Research has focused primarily on anti-inflammatory agents to temper this toxic effect. More recently there has been a focus on converting microglia from this M1 state to an M2 state in which the toxic effects are reduced and their phagocytic activity toward Aβ enhanced.

Studies in transgenic mice have suggested a number of possible anti-inflammatory approaches but they may not always be a good model. An example is vaccination with antibodies to Aβ, which is effective in mouse models, but has repeatedly failed in clinical trials. Biomarker studies indicate that AD commences many years prior to clinical onset. A hopeful approach to a disease-modifying treatment of AD is to administer agents that inhibit the inflammatory stimulation of microglia or successfully convert them to an M2 state. However, any such treatment must be started early in the disease.

Wednesday, December 3, 2014

Fibrosis is a type of scarring in which excessive connective tissue is created in response to damage. It plays an important role in the pathology of a range of age-related conditions, but does this process have its origins in a sufficiently narrow set of mechanisms that it could be selectively suppressed or disabled entirely in the near future?

[Researchers] have identified what they believe to be the cells responsible for fibrosis, the buildup of scar tissue. Fibrotic diseases, such as chronic kidney disease and failure, lung disease, heart failure and cirrhosis of the liver, are estimated to be responsible for up to 45 percent of deaths in the developed world. "Previous research indicated that myofibroblasts are the cells responsible for fibrosis. But there was controversy around the origin of this cell. Identifying the origin could lead to targeted therapies for these very common diseases."

With the knowledge that fibrosis appears to radiate from blood vessels, [researchers] examined the hedgehog signaling pathway, which normally regulates organ development but whose roles in the adult are less clear. They noticed that in adult mice, a hedgehog pathway gene called Gli1 was specifically expressed in a rare group of cells located around blood vessels in all solid organs. This pattern suggested that the cells might play a role in fibrosis. To test this hypothesis the researchers tagged this protein in tissue with varying forms of fibrosis, and found that these cells proliferated by almost 20-fold under chronic injury and turned into myofibroblasts. "We believe that this cell population is responsible for about 60 percent of all organ myofibroblasts. Most organs develop fibrosis as we age. Specifically, in the kidney we lose one percent of kidney function as a result of fibrosis for each year that we age."

Using a genetic strategy in mice, the researchers were able to ablate these Gli1 cells, while leaving other cells unharmed. In mice with kidney and cardiac fibrosis, the ablation of these cells resulted in reduction in fibrosis and rescued heart function. "We've found that these Gli1 progenitor cells differentiate into myofibroblasts, and in fibrotic disease, when they are ablated, we can rescue organs and organ function." Researchers note that the genetic strategy employed in the preclinical model is not feasible in humans. For this reason, future research involves the exploration of drugs that could specifically target and shut off these fibrosis-causing stem cells with the hope that either an existing drug or a new drug could translate to a potential therapy for humans.

Wednesday, December 3, 2014

Ordinary somatic cells can be reprogrammed into induced pluripotent stem cells (iPSCs) capable of generating any cell type in the body, provided that a methodology is established to reliably guide the cells down that path of differentiation. This reprogramming is sufficiently straightforward that near any lab can carry it out, which has led to rapid progress in this part of the field in recent years: a lot of effort has focused on developing the means to create specific cell types from pluripotent cells. Why so much interest in the research community? Because a key part of the infrastructure needed for the coming decades of cell therapies, regenerative medicine, and tissue engineering is a low-cost, reliable source of any cell type desired, rapidly created to order from an easily obtained patient tissue sample such as skin or blood.

Induced pluripotency is currently the leading contender technology for wholesale production of patient-matched cells by virtue of ease of use, but it is not without its complexities. Here, for example, researchers show that the reprogramming of human cells isn't producing as much of a clean slate as might be expected based on work in mice:

[Researchers] have discovered that human stem cells made from adult donor cells "remember" where they came from and that's what they prefer to become again. This means the type of cell obtained from an individual patient to make pluripotent stem cells, determines what can be best done with them. For example, to repair the lung of a patient with lung disease, it is best to start off with a lung cell to make the therapeutic stem cells to treat the disease, or a breast cell for the regeneration of tissue for breast cancer patients. By contrast, the iPSCs of mice, which are widely used in stem cell research, have no memory. "So, if you only studied the mouse alone, you'd never uncover this opportunity."

"We've shown that human induced pluripotent stem cells have a memory that is engraved at the molecular/genetic level of the cell type used to make them, which increases their ability to differentiate to the parent tissue type after being put in various stem cell states. So, not all human iPSCs are made equal. Moving forward, this means that iPSC generation from a specific tissue requiring regeneration is a better approach for future cellular therapies. Besides being faster and more cost-efficient in the development of stem cell therapy treatments, this provides a new opportunity for use of iPSCs in disease modeling and personalized drug discovery that was not appreciated before."

Thursday, December 4, 2014

FOXO3A is one of the very few genes where single nucleotide polymorphism variants are fairly reliably shown to correlate with statistical variations in human aging across populations. Generally genetic correlations with aging do not replicate between study groups, which implies that the effects of genetic variations on aging are individually very small and overall highly varied and complicated. As these researchers show, even in the case of FOXO3A variants it is hard to establish associations reliably:

In this study, we investigated the association of variation in the second consistently confirmed longevity-associated gene, FOXO3A, with aging-related phenotypes in the oldest-old. The Discovery sample was 1200 participants randomly drawn from 1651 eligible members of the Danish 1905 Birth Cohort Study. For replication of the findings observed in the Discovery sample, we used data on 1279 individuals from two additional population-based surveys of oldest-old Danes: the Danish 1910 and 1915 Birth Cohort Studies. We explored four phenotypes known to predict their survival, that is, cognitive function, self-reported health, hand grip strength, and activity of daily living (ADL). Moreover, we included data on five self-reported diseases: diabetes, cancer, cardiovascular disease, osteoporosis, and bone fracture, as these are either investigated in genetic association studies and/or are supported by foxo animal models.

We found FOXO3A variation to show nominal significant association with two of the investigated phenotypes; ADL and bone fracture. This does, however, not exclude relevance of FOXO3A variation for the remaining seven phenotypes or for the physiological processes behind these phenotypes; it is possible that more statistical power is needed to detect such associations, especially if these are of small effect size. Furthermore, as the foxo3a protein has a wide array of downstream targets, which themselves affect a wide range of cellular and physiological processes, it may simply be difficult to pinpoint the candidate phenotypes, which FOXO3A potentially affects. The association between FOXO3A variation and bone fracture was not accompanied by a concurrent association with osteoporosis. However, these two phenotypes cannot be expected to be completely interchangeable, as osteoporosis is often underdiagnosed and undertreated.

We could not formally replicate the associations of FOXO3A variation with ADL and bone fracture in another sample of Danish oldest-olds. There are a number of possible reasons for this. First of all, it may indicate that these were merely chance findings or that the Replication sample could be underpowered with respect to small effect sizes. However, another explanation could be that the individuals of the Replication sample were slightly older (94.7-100.9 years) than the individuals of the Discovery sample (92.2-93.8 years). This could potentially be of importance if the associations are not constant with age.

Thursday, December 4, 2014

When looking at most of the past extension of human life since the 1700s the major causes were better sanitation and control of infectious disease, with the largest effects on life expectancy at birth arising from lowered childhood mortality, even though there was also a steady increase in adult life expectancy. When looking back at the late 20th and early 21st century period from a safe distance of a century or so, the similar high level summary of the drivers of life extension will probably focus on greatly increased control over cardiovascular disease and the resulting steep decline in late life mortality due to this cause. There are many other improvements in medicine that have occurred in the past fifty years, but this is the one that stands out if you look at the data.

This period of medical strategy and development is coming to an end, however, and the summary of the next age in medicine with regard to its effects on human longevity will be that this was the time in which researchers started to directly address the processes of aging and, separately, brought cancer largely under medical control. Progress in the future of life expectancy at this point in time is overwhelmingly a matter of success in intervening in the aging process, building biotechnologies to repair the cellular and molecular damage that causes aging and thus prevent or turn back age-related frailty and disease.

If aging is purely a matter of damage we should expect all improvements in long term health to also extend life to some degree. If there is less damage then the machinery lasts longer - it really is that simple a concept, even though the machinery of our biology is very complex. Studies of changing life expectancy such as the one quoted below continue to find that aging appears to be plastic, and that present trends in reduced old age mortality are continuing in those regions with better access to medical technology. The only limits on life are imposed by a present inability to fix the problems that kill us, and that can be changed by funding the right research:

In high-income countries, life expectancy at age 60 years has increased in recent decades. Falling tobacco use (for men only) and cardiovascular disease mortality (for both men and women) are the main factors contributing to this rise. In high-income countries, avoidable male mortality has fallen since 1980 because of decreases in avoidable cardiovascular deaths. For men in Latin America, the Caribbean, Europe, and central Asia, and for women in all regions, avoidable mortality has changed little or increased since 1980. As yet, no evidence exists that the rate of improvement in older age mortality (60 years and older) is slowing down or that older age deaths are being compressed into a narrow age band as they approach a hypothesised upper limit to longevity.

Friday, December 5, 2014

This article talks generally about the current directions in aging research and recent developments while managing to entirely avoid mention of SENS-style rejuvenation research. Reading this you'd think that the only possible approach to aging involves altering our metabolism to work in a different way so as to slow down aging, and that periodic repair of damage without altering metabolism to reverse aging doesn't even exist as an idea.

The focus is on Calico Labs and Human Longevity, Inc., but a range of other topics are covered. With one or two exceptions this is essentially a list of technologies and approaches that I don't expect to produce either meaningful treatments to extend life or ways to reverse the consequences of aging in the old. It is new paint on the existing investigation of the fine details of exactly how young tissue becomes old tissue. Obtaining that knowledge is the scientific impulse, and should indeed be accomplished, but the applications of it in the near term won't result in ways to meaningfully move the needle on human longevity. Look at the much-hyped sirtuin research over the past fifteen years for a preview of the next decade of research into the genetics and metabolic changes of longevity: the generation of a mountain of data that probably helps to inform some areas of medical development, but no life extending treatments, and no reasonable expectation of producing anything except a very expensive way to slightly slow down the aging process even in the best possible success case.

The quest to end aging, rife with bizarre and doomed therapies, is perhaps as old as humanity itself. And even though researchers today have more sophisticated tools for studying aging, the hunt for drugs to prevent human decay has still seen many false leads. Now, the field hopes to improve its track record with the entrance of two new players, Calico, which launched in September 2013, and Human Longevity, which entered the stage six months later. South San Francisco-based Calico, founded by Google with an initial commitment of at least $250 million, boasts an all-star slate of biotechnology industry leaders. Human Longevity was founded by genome pioneer Craig Venter and hopes to use a big data approach to combat age-related disease.

The involvement of high-profile names from outside the aging field - and the deep pockets of a funder like Google - have inspired optimism among longevity researchers. "For Google to say, 'This is something I'm putting a lot of money into,' is a boost for the field. There's a tremendous amount of excitement. "We've made inroads over the past 20 years or so. But I think there's a long way to go."

Calico appears to be taking the approach that worked for Barron and Levinson at Genentech, the pioneering biotechnology company that has become among the more successful drug companies in the world by making targeted medicines - largely engineered proteins - that disrupt disease pathways in diseases such as cancer. The hallmark of Genentech's approach has been to dissect the pathways involved in disease and then target them with biotechnology drugs.

Such an approach is representative of one way to cure aging: targeting the diseases that become more prevalent as people grow older. This follows the argument that treating such diseases is itself treating aging. The opposing view is to see aging as an inherently pathological program that, if switched off or reprogrammed, could be halted. But because regulators don't consider the progression of life itself a disease, the semantic debate is moot to drug companies: they can only get drugs approved by targeting diseases that become more common with age, such as cancer, diabetes and neurodegenerative disorders.

"The way Calico has said they are approaching this is the right way, which is to understand some fundamental aspects of the aging process and see how intervening in them affects that process." But so far that approach has been difficult to translate successfully into interventions that delay aging or prevent age-related disease. But the legion of companies that have failed to commercialize these discoveries is large, and some in the field now think that further progress can be made only by studying human aging.

Friday, December 5, 2014

When considering the impact on life expectancy and long-term health the data tells us that obesity and smoking are in the same ballpark. Here is a recent research publication that puts some numbers to the very real costs of being overweight. The results are similar to those produced in past studies:

Researchers used data from the National Health and Nutrition Examination Survey (from years 2003 to 2010) to develop a model that estimates the annual risk of diabetes and cardiovascular disease in adults with different body weights. This data from almost 4,000 individuals was also used to analyze the contribution of excess body weight to years of life lost and healthy years of life lost.

Their findings estimated that individuals who were very obese could lose up to 8 years of life, obese individuals could lose up to 6 years, and those who were overweight could lose up to three years. In addition, healthy life-years lost were two to four times higher for overweight and obese individuals compared to those who had a healthy weight, defined as 18.5-25 body mass index (BMI). When one considers that these individuals may also develop diabetes or cardiovascular disease earlier in life, this excess weight can rob them of nearly two decades of healthy life. The age at which the excess weight accumulated was an important factor and the worst outcomes were in those who gained their weight at earlier ages. "The pattern is clear - the more an individual weighs and the younger their age, the greater the effect on their health. In terms of life-expectancy, we feel being overweight is as bad as cigarette smoking."


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