Fight Aging!

As noted this morning, Juvenescence is the new venture fund slash business development company created by investor Jim Mellon and allies as a part of his interest in the development of real, working anti-aging medicine. No-one is getting any younger, and that includes people with the resources to do something about this state of affairs, should they finally wake up to the ongoing revolution in biotechnology and put their shoulders to the wheel. This is the latest instance of a well-heeled group setting forth in earnest to achieve something in aging research and related biotechnology relevant to treating aging as a medical condition. Is it the most promising to date? Perhaps.

Past examples have included Larry Ellison's initiative, Paul Glenn's support of research, Peter Thiel's support of SENS, and Google's California Life Company, among others. In many cases, the rhetoric at the outset gave some hope that these large investments would be more visionary than a funding of the same old dead-end work on pharmaceutical alteration of metabolism to slightly slow aging that has characterized the mainstream for the past fifteen years. But in only one case was there in fact material support for the better, game-changing alternative, rejuvenation research of the sort exemplified by the SENS programs, the only plausible way to greatly extend lives and turn back aging in our lifetimes. If there is caution and a wait and see attitude related to Juvenescence and the rhetoric from its founders, it is because Lucy has snatched away the ball one too many times these past years. Still, this is promising rhetoric, I have to admit that much. It comes from a fellow who has raised talking up his position to something of an art form, so I'm sure we'll be hearing more of it:

Mellon on the Markets: New "highs" for early investors

On the subject of Juvenescence, I am off to San Francisco with my old best friend Anthony Baillieu to meet my new best friend Aubrey de Grey (Google him!) and my dear colleague Greg Bailey. We are all spending the day at the Buck Institute of Aging - not to be rejuvenated ourselves, but to understand more of the amazing science that is coming out of this institution.

One of the key senolytic drugs in development, being trialled by Unity Biotechnology, first emerged at the Buck. In a nutshell, senolytics are among the first of several compounds that will add significantly to human lifespan in the next ten or twenty years. While more fully described in the new book, these are drugs that clear so-called senescent cells from tissues. Senescent cells become more prevalent as we age, and are cells that are neither dead nor healthy, but which exist in a limbo like state. They contribute significantly to inflammatory disease and their removal, at least in part, is demonstrably life extending in animal models.

We are also visiting another company involved in senolytics, and will be looking to make an investment in it for our venture, Juvenescence Limited, which is jointly owned by Greg, Dec Doogan (formerly head of drug development at Pfizer, the world's biggest drug company) and myself. We have collectively recently invested a largish sum in a venture called Insilico Medicine, which uses deep neuronal networks (aka AI) to enhance medical discoveries, and we have capitalised a joint venture with Insilico called Juvenescence AI which will look to discover five new chemical entities a year for several years, using AI. These are exciting times in the field of longevity, and believe me, staying healthy today will allow you to cross a bridge to ultra-long life in the not too distant future.

Alex Zhavoronkov at Insilico Medicine will, I'm sure, forgive me when I say that I haven't been following the Juvenescence work all that closely because the early focus appeared to be fairly standard aging-related drug discovery in areas that I think have little potential. He knows my views on these matters. Should the staff at Insilico Medicine set their sights on senolytics and small molecule glucosepane breakers, I will be the first to laud their efforts, as that is a portion of the SENS rejuvenation research agenda wherein standard issue drug discovery processes, rational drug design, and improvements thereof can shine. But building more marginal geroprotectors that target mTOR or regulators of mitochondrial function or autophagy or other line items associated with the scores of ways to modestly slow aging in mice? Not so promising. We're twenty years in to that sort of work, and what do we have to show for it? More knowledge of the operation of metabolism, yes, but also a distinct absence of ways to add healthy years to life that are any more effectively than eating less and exercising more.

I think that the evidence to date gives us all good reason to think that there is a low ceiling to the utility of such mainstream work in terms of years of life gained at the end of the day, and that the ceiling isn't going to rise significantly with the input of far greater amounts of funding. It is a fundamental aspect of these mechanisms. Aging is damage, and if research doesn't aim to directly repair or remove that damage, then it will always be of low utility. Try keeping any damaged machine running without actually repairing it. Further, stand back for a moment and take an earnest look at calorie restriction mimetic development versus senolytic development. Fifteen years of the former has given us nothing to compare to the reliability and breadth of effects on aging and age-related diseases in animal studies resulting from a mere five years of earnest development in senolytics. This is because calorie restriction mimetics do not repair any form of damage that causes aging, whereas senolytic therapies to clear senescent cells do. It is that simple.

To return to Juvenescence, their clear interest in senolytics, and all of the obvious incentives to be involved in senolytic development now that the commercial side of the field has been validated by large investments in Unity Biotechnologies, makes me more cautiously optimistic for this initiative than I was when Calico launched. Even if the Juvenescence principals do no more than vocally and materially bolster the senolytics industry, that will still be a great good. Will they in fact do more than that for the development of SENS biotechnologies? We shall have to wait and see.

Not so long ago, researchers demonstrated that infusing tissues with nanoparticles could allow for safe and rapid thawing following low-temperature vitrification, avoiding damage that can occur due to ice crystal formation during a slower warming process. In the research noted here, a different scientific group is working on the nanoparticle approach as a way to cryopreserve fish embryos. They have achieved a proof of principle demonstration, but clearly have a way to go in terms of the quality of the result - it isn't yet as good as the earlier work on tissue sections. Taken as a whole the nanoparticle approach has the potential to help expand the use of vitrification for tissue storage, something that could greatly improve the logistics of organ donation, tissue engineering, and many areas of research by allowing indefinite storage of large sections of tissue. Greater use and development of tissue vitrification should in turn also help to advance the state of the art in human cryopreservation, the most important backup plan for those who will not survive to benefit from the rejuvenation therapies of decades to come, and a field in need of far greater investment and attention.

Zebrafish embryos have for the first time been frozen, thawed, and brought back to life. Researchers have been working on cryopreservation of zebrafish embryos for decades. It's never been done before. Over the past 60 years, scientists have had success preserving the sex cells and embryos of humans, cattle, mice, and many other animals. Trying to freeze and thaw fish embryos, however, has been more difficult because of their size and structure. The embryos are relatively large, bigger than a human egg. Fish embryos also have different compartments that freeze and thaw at different speeds. That can lead to the development of ice particles, which can damage the embryo.

Building on work by other scientists, researchers tweaked an existing cryopreservation method by injecting gold nanoparticles into zebrafish embryos, along with a cryoprotectant. The team froze the embryos in about one second using liquid nitrogen, then, after a few minutes, warmed them using a laser. The gold nanoparticles, which were distributed evenly throughout the embryos, absorbed the laser light and turned it into heat. The laser, which shown on the embryos for a millisecond, warmed developing fish so rapidly that they may have avoided being damaged by ice formation or other untoward effects of the quick-chill and thaw technique.

In the trials, only about 10 percent of the embryos survived to 24 hours. At this point, survivors started squirming and wiggling as their hearts, eyes, and nervous systems developed, proving their viability, yet none survived to day five, the final time point the team used. The advance is important for the field of genetics. Zebrafish have become an important model organism for studying the genetics of vertebrates and humans. Being able to preserve the different genetic lines of zebrafish generated in these studies means researchers wouldn't need to maintain live populations or run the risk losing irreplaceable research lines. It is also the most cost-effective method for this kind of research. The team is continuing to work on the technique to improve the viability of the embryos. Tweaks to the laser, gold nanoparticles, and even the cryoprotectant could make the method more suitable for embryos with a diameter of a millimeter or smaller. That would mean there would be one way of cryopreservation for all organisms with embryos of that size.

Link: http://www.the-scientist.com/?articles.view/articleNo/49986/title/Zebrafish-Embryos-Survive-Deep-Freeze-and-Quick-Thaw/

Jim Mellon is making a high profile investment in the development of therapeutics to treat aging, and this article offers a few more details on the company founded to carry this forward, Juvenescence. It is good to see new funding and vigor joining the field, but by the sound of it most of the proposed work is not actually all that interesting. It will be more of the standard drug development to try to slightly slow the aging process: consider the present panoply of work on calorie restriction mimetics, enhancement of autophagy, exercise mimetics, and so forth. Billions have been spent in this area in the past two decades with essentially nothing of practical use to show for it, because this approach to treating aging cannot possibly either produce significant rejuvenation or add decades to life spans. It fails to directly address the root causes of aging, does nothing more than tweak the operation of metabolism to slightly slow the consequences, and after twenty years of this work, the results still cannot even perform near as well as either actual calorie restriction or exercise.

Aside from the promise of investment in senolytic development, this initiative appears to be largely the Longevity Dividend approach so far; pour vast investment into perhaps adding a couple of years of life by 2030 or 2040. It is underwhelming, especially in comparison to the animal studies arising out of even just a few years of serious work on the alternative, which is to repair the forms of damage that cause aging. If Juvenescence focuses on senolytic drugs to clear senescent cells, it will be useful - the more the merrier in that part of the field. This is one of the few places where SENS rejuvenation research overlaps significantly with long-standing drug discovery practices, and not coincidentally it is also where results on aging and age-related disease in animal studies these past few years are both reliable and exciting in their magnitude - more has been achieved here in a few years than in the past two decades of work on calorie restriction, and at far less cost. Beyond these overlaps with SENS, all of the other usual suspects in the drug discovery agenda for slowing aging will, I predict, continue to produce little to no meaningful outcome no matter how much is invested in their development.

When British billionaire Jim Mellon wants to map out an investment strategy, he likes to write a book first. Out of that process came his most recent work - Juvenescence: Investing in the Age of Longevity. Now he and some close associates with some of the best connections in biotech are using the book as inspiration to launch a new company - also named Juvenescence - with plans to make a big splash in anti-aging research. "We are at an inflection point for the treatment of aging," says Greg Bailey, who likes to highlight some of the new cellular pathways that are pointing to new therapies that can counter the effects of aging. "I think this is going to be the biggest deal I've ever done. It will need repetitive financing. Five to $600 million was raised for Medivation. As we hit inflection points, we will need to raise a dramatic amount of money."

Bailey, the CEO of Juvenescence, was one of the early backers of Medivation, where he was a board director for 7 years - before Pfizer stepped in to buy the biotech for $14 billion. The primary game plan at Juvenescence is to come up with various operations engaged in developing new anti-aging drugs. Juvenescence AI is a joint venture they've just set up with Alex Zhavoronkov, who runs Insilico Medicine. Mellon met Zhavoronkov while he was researching his book, and believes that the tech the scientist developed can illuminate new programs with a better chance of success. "They are going to take up to 5 molecules from us every year for development," says Zhavoronkov, an enthusiastic advocate of AI in drug research who's also been working on some alliances with big pharma players. The group has invested about $7 million in the technology so far getting the joint venture set up. More will follow.

Aside from the cellular pathways that have attracted their attention, the biotech will look to effect change in the mitochondria, the cell's powerhouse, as well as clean up senescent cells that accumulate as the body grows older. And Bailey expects he'll be working some Biohaven-like deals to develop an advanced pipeline at a rapid pace. The principals chipped in the seed millions for the company and invested in the joint venture with Zhavoronkov. Bailey says you can expect to see $20 million to $50 million more from a friends-and-family raise before the end of the year. And it's expected to grow from there.

Link: https://endpts.com/british-billionaire-jim-mellon-and-high-profile-partners-roll-the-dice-on-an-anti-aging-upstart/

For years now, evidence has accumulated to suggest that Alzheimer's disease blocks memory retrieval rather than destroying memories, at least in the earlier stages prior to the onset of widespread destruction of neurons. Today's research is more of the same. This and related results raise the hope that success in any of the mainstream efforts to treat the causes of this disease should restore much of the cognitive function lost to the condition. Of course it is worth recalling that Alzheimer's patients rarely suffer Alzheimer's alone: it usually arrives alongside one or more other forms of neurodegeneration, each with distinct mechanisms that cause neurons to malfunction or be destroyed. This is in part because Alzheimer's disease is to some degree a lifestyle condition; not as greatly as is the case for type 2 diabetes, but being sedentary and overweight greatly raises the risk of both Alzheimer's and, separately, sufficiently accelerated vascular aging to cause vascular dementia or other forms of neurodegenerative condition. The brain has sizable energy demands, and is particularly vulnerable to the slow age-related failure in delivery of oxygen and nutrients.

It is worth noting that a lot of mouse breeding goes on behind the scenes in the sort of research noted here, very reliant as it is on genetic engineering. This work involved crossing three lineages. Many of the tools to investigate biochemistry in living beings take the form of genetic machinery that can be activated to tag specific cells or visualize a specific protein interaction. Each such tool is made manifest as a lineage of genetically altered mice; the change must be created early in or prior to embryonic development, as the research community still lacks a standardized toolkit for applying genetic changes to adults. If a research group wants to use multiple tools in a single experiment, then mice of the relevant lineages must be mated to obtain a cross-bred lineage. The same is true when applying a tool to a mouse model of a specific disease. Again, more cross-breeding. This is expensive and time-consuming. It is also one of the many things that will be replaced in the near future with some form of effective gene therapy platform - probably related to CRISPR - that can be deployed in adult mice, thus reducing costs and speeding progress. This is the point of the Maximally Modifiable Mice developed by the SENS Research Foundation, a program that aims to create mice equipped with a set of genetic machinery that can accept arbitrary updates in a sort of plug-and-play fashion.

Lasers reactivate 'lost' memories in mice with Alzheimer's

It has long been assumed that Alzheimer's disease completely erases memories. The condition involves clumps of proteins known as amyloid plaques and tau tangles accumulating in the brain, where they are thought to destroy the neurons that store our memories. But experiments suggest that memories may not be wiped by Alzheimer's disease, but instead become harder to access. What's more, these memories can be reawakened by artificially activating the neurons they are stored in.

To examine how memory is affected by Alzheimer's disease, the researchers developed a way of visualising individual memories in mouse brains. They genetically engineered mice with neurons that glow yellow when activated during memory storage, and red when activated during memory recall. Two sets of these mice were created - one set that was healthy, and one with a condition resembling human Alzheimer's disease. Both sets of mice took a memory test. First, they were exposed to a lemon scent and given an electric shock. Then, a week later, they were exposed to the same lemon scent. The healthy mice immediately froze in anticipation of being shocked again. But the mice with Alzheimer's disease froze almost half as much as the healthy mice, suggesting they did not remember the link between the smell and shock so strongly.

This behaviour matched what the team saw in the hippocampi of the mice - the brain regions that record memories. In healthy mice, the red and yellow neurons overlapped, showing that the mice were retrieving the lemon-shock memory from the same place it had been stored. But in the Alzheimer's mice, different cells glowed red during recall, suggesting that they were calling up the wrong memories. This might help explain why people with Alzheimer's disease commonly experience false memories.

Using a genetic engineering technique called optogenetics, the team went on to reactivate the lemon-shock memory in the Alzheimer's mice. By shining a blue laser down a fibre optic cable into the brain, they were able to stimulate the yellow memory-storing neurons, prompting the mice to freeze when they smelled the lemon scent. This shows that "lost" memories may still exist in the brain, and can be recovered. Optogenetics is not a technique that can be used in people yet, because it isn't yet safe or practical to tinker with our neurons or stick lasers in our brains. But in the future, targeted drugs or techniques like deep-brain stimulation may help people with Alzheimer's access their forgotten memories. The next step will be to confirm that the same memory storage and retrieval mechanisms exist in people with Alzheimer's disease, because mouse models do not perfectly reflect the condition in humans. In particular, the number of neurons that die in mouse models of Alzheimer's disease is far lower than in humans.

Optogenetic stimulation of dentate gyrus engrams restores memory in Alzheimer's disease mice

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by amyloid-beta (Aβ) plaques and tau neurofibrillary tangles. APPswe/PS1dE9 (APP/PS1) mice have been developed as an AD model and are characterized by plaque formation at 4-6 months of age. Here, we sought to better understand AD-related cognitive decline by characterizing various types of memory. In order to better understand how memory declines with AD, APP/PS1 mice were bred with ArcCreERT2 mice. In this line, neural ensembles activated during memory encoding can be indelibly tagged and directly compared with neural ensembles activated during memory retrieval (i.e., memory traces/engrams).

We first administered a battery of tests examining depressive- and anxiety-like behaviors, as well as spatial, social, and cognitive memory to APP/PS1 × ArcCreERT2 × channelrhodopsin (ChR2)-enhanced yellow fluorescent protein (EYFP) mice. Dentate gyrus (DG) neural ensembles were then optogenetically stimulated in these mice to improve memory impairment. AD mice had the most extensive differences in fear memory, as assessed by contextual fear conditioning (CFC), which was accompanied by impaired DG memory traces. Optogenetic stimulation of DG neural ensembles representing a CFC memory increased memory retrieval in the appropriate context in AD mice when compared with control mice. Moreover, optogenetic stimulation facilitated reactivation of the neural ensembles that were previously activated during memory encoding. These data suggest that activating previously learned DG memory traces can rescue cognitive impairments and point to DG manipulation as a potential target to treat memory loss commonly seen in AD.

This open access paper provides an introduction to the widespread use of mesenchymal stem cells (MSCs) in regenerative medicine and research. This is one of the better documented stem cell populations. The scientific and medical communities have more experience with these cells than is the case for most other stem cell types, the methodologies for use are more established, and as a consequence MSCs have been and continue to be used in many clinical trials, cell therapies available via medical tourism, and lines of ongoing research. That said, these cells are training wheels in a way, one present step on a longer road. The step is taken because it is convenient and should reliably lead to the next stage in the development of better cell therapies - not because it is the final stopping point.

Being first isolated in 1966 from bone marrow, mesenchymal stem cells (MSC) are adult stromal nonhematopoietic cells, well known for their potential to differentiate into osteoblasts and osteocytes. Although they are most known for their osteogenic differentiation potential, MSC have the ability to commit into all three lineages (osteogenic, chondrogenic, and adipogenic). MSC have been isolated and purified not only from bone marrow where they cooperate with hematopoietic stem cells (HSC) to form the niche, but also from various tissues, such as umbilical cord and umbilical cord blood, white adipose tissue, placenta, and the amniotic membrane of placenta. The capacity of MSC to differentiate into cell lineages and develop teratoma, a preserved tumor that contains normal three-germ layer tissue and organ parts, is a reason to consider them as multipotent progenitor cells suitable for regenerative therapy.

Beside their potential to differentiate into osteoblasts in the process of osteogenesis, there have been several other regenerative roles attributed to MSC. These cells can serve as pericytes wrapping around blood vessels to support their structure and stability. MSC have also shown the potential to integrate into the outer wall of the microvessels and arteries in many organs, such as spleen, liver, kidney, lung, pancreas, and brain. This led to the speculation that both bone marrow- and vascular wall-derived MSC as well as white adipose tissue-, umbilical cord blood-, and amniotic membrane-derived MSC could act as a cell source for regenerative therapy to treat various disorders such as osteoporosis, arthritis, and vessel regeneration after injury.

MSC may also be induced to differentiate into functional neurons, corneal epithelial cells, and cardiomyocytes under specific pretreatments ex vivo and in vivo that broaden the capacity of these cells in regenerative therapeutic interventions. In a previous study, umbilical cord matrix stem cells derived from human umbilical cord Wharton's Jelly were aimed to treat neurodegenerative disorders such as Parkinson's disease by transplantation into the brain of a rat model. The transplantation resulted in a significant reduction of symptoms for Parkinson's disease, thus suggesting an additional therapeutic role for umbilical cord matrix stem cells (MSC) in treating central nervous disorders. Further, MSCs exibit potent immunomodulatory and anti-inflammatory properties through cellular crosstalk and production of bioactive molecules.

These findings were enough evidence for scientists to speculate a promising role for MSC in regenerative therapy. In the past years, MSC have been used in clinical trials aiming for regeneration of tissues such as bone and cartilage as well as treatment of disorders such as spinal cord injury, multiple sclerosis (MS), Crohn's disease, and graft-versus-host disease (GvHD) due to their broad differentiation capacity and potential of hematopoietic cell recruitment. Several clinical trials are running to identify different aspects of MSC application in terms of safety and efficacy, and at the time of writing, a total number of 657 past clinical studies were found that involve mesenchymal stem cells for different clinical phases.

Link: https://doi.org/10.1155/2017/5173732

Hematopoietic stem cells (HSCs) reside it the bone marrow and produce all of the different types of blood and immune cell, via a cascade of various types of progenitor cell. Stem cell behavior changes in a number of ways with aging, most notably in a general reduction of activity that leads to inadequate tissue maintenance, but also in other possibly damaging ways. For example, HSCs tend to bias their production of progenitors more towards myeloid cell types and less towards lympoid cell types, which is thought to contribute to the growing disarray of the immune system. In this open access paper, researchers examine an aspect of this phenomenon.

Age-related phenotypes within the hematopoietic system can be influenced by cell-extrinsic alterations, such as changes in the bone marrow (BM) microenvironment. However, in mice, ample evidence points to intrinsic alterations in the hematopoietic stem cells (HSCs) themselves as the main drivers of hematological aging. These include functional, genetic, and epigenetic modifications. In mice, HSCs increase in frequency that however is paralleled by a decreased proliferative capacity on a per-cell basis. In several reports, aged murine HSCs have been characterized by an increased myeloid-to-lymphoid output, often referred to as a myeloid bias (My-bi), although also their myeloid cell forming ability is decreased on a per cell basis when compared to younger HSCs.

These observations are presumably coupled to an age-related clonal shift within the aged HSC compartment towards increased My-bi HSC frequency at the expense of lymphoid-biased (Ly-bi) HSCs. Regardless, the lineage skewing with murine HSC aging has been linked to an upregulation of myeloid-specific genes and a downregulation of lymphoid-specific genes, although many of previous transcriptome analyses were based on a selection and manual curation of lineage-associated genes. By contrast, recent global transcriptome analysis of single HSCs based on more objectively defined lineage-affiliated transcription programs revealed a molecular and functional platelet bias, rather than a My-bi, in aged murine HSC.

Human HSC and progenitor cell aging has not been characterized as extensively as within the murine system, but several parallels suggest that aging characteristics at least to some degree might be conserved across species. For instance, HSC proliferation and clonal diversity decline between cord blood (CB) and aged bone marrow (BM). In addition, donor age affects outcome of clinical BM transplantations, although this most likely cannot be solely attributed to reduced HSC performance. More direct evaluations of the frequencies and function of aged human hematopoietic stem and progenitor cells (HSPCs) from a limited number of individuals displayed similarities to previous findings in the mouse, including an increased myeloid-to-lymphoid output ratio and decreased reconstitution potential, although this is not undisputed. In the present study we characterize age-related changes of human HPSCs and compare these to similar studies in mice. By separating the myeloid lineage into megakaryocytic/erythroid and granulocyte/macrophage lineage, we could reveal a molecular underpinning of megakaryocytic/erythroid bias in aged HSC of both humans and mice.

Downstream of human HSCs, we observed decreasing levels of common lymphoid progenitors (CLPs), and increasing frequencies of megakaryocyte/erythrocyte progenitors (MEPs) with age, which could be linked to changes in lineage-affiliated gene expression patterns in aged human HSCs. These findings were paralleled in mice. Therefore, our data support the notion that age-related changes also in human hematopoiesis involve the HSC pool, with a prominent skewing towards the megakaryocytic/erythroid lineages, and suggests conserved mechanisms underlying aging of the blood cell system.

Our results support the notion that an increased HSC frequency with age may be a compensatory mechanism to sustain sufficient blood cell replenishment. However, these compensatory mechanisms do not fully maintain optimal functions of HSCs and progenitor cells in elderly humans, as evidenced by the frequency of age-related hematological defects, including anemia and reduced immune responses. A deeper understanding of the events underlying this functional decline may support interventional approaches to prevent or ameliorate the aging hematopoietic phenotype.

Link: https://doi.org/10.1371/journal.pone.0158369

This is a lightly edited update of an older article that I think merits its own post. There are more people writing on the topic of rejuvenation research these days. The goal of treating aging as a medical condition has gained more supporters. Some of those people are forming new organizations, thinking out loud on the nature of advocacy, what works and what does not. So perhaps it is time to revisit this older opinion on advocacy as a process of structured conveyance of information, of creating documentation where documentation is presently lacking.

Let us start by paraphrasing an old joke: did you know that we all express the symptoms of a fatal, inherited degenerative condition? It is called aging. It is a dark joke, but there is truth to be found in it, as is often the case in black humor. Unfortunately, all too few people think of themselves as patients suffering aging, and fewer still would call themselves patient advocates, agitating for research to lead towards therapies and cures for aging. This is a sorry state of affairs; given that our time is limited and ticking away, the tasks upon the table should always include some consideration of aging. What can we do about it? How can we engineer a research community, funding and support to make real progress within our lifetimes? If you don't spend at least some of your time on this issue, then you are fiddling while Rome burns. Time is the most precious thing we have, and we live on the cusp of technologies that will allow us to gain more time - but those advances in medicine won't happen soon enough unless we work at it.

Working to create progress in longevity science doesn't have to mean working in a laboratory. Most of the modest efforts I have made to help matters along take the form of written advocacy at Fight Aging! and elsewhere: sharing events, passing on news, putting scientific publications in context, explaining where we stand in research and development, encouraging fundraising, and so on. In effect this is a sort of loose documentation, a way to demonstrate the existence of a community of people interested in rejuvenation research, and a way to provide direction and grounding to newcomers: how to become involved, how to benefit from becoming involved, and how to help advance the science of human longevity. A body of documentation is a necessary foundation for later phases of development in longevity science, but will also help broaden the community of people who are both aware of this work and understand what it might be used to achieve.

Not everyone agrees that this is useful, however. One of the challenging attitudes I've encountered over the years is the idea that documentation of longevity science in this manner is largely worthless - that time and funds spent trying to make science clear to developers and laypeople should go towards other, more direct activities like further research. This sort of criticism is, I think, symptomatic of a failure to understand the necessary role of advocacy and education in the broader scope of technological progress. This article, then, is an answer of sorts: what is the role of documentation, and why is it so important that we should strive to build organizations that do this well?

The Challenge of Complex Ideas

Most important topics relating to the future of advanced technological development are very complex: the basis for rejuvenation therapies, strong artificial intelligence, molecular manufacturing, and so forth. Even the general concepts (such as "why is this important?", "why is this plausible?", or "why should I support it?") are made up of many moving parts and conditional arguments that the broader public generally hasn't thought about yet. Thus we advocates can't just jump in and start persuading people that radical life extension is a great idea: instead, when it comes time to try to explain why this goal is important - and how best to proceed with research and development - we must first walk through a whole squadron of supporting concepts that are unfamiliar to the audience. Each must be explained, and only then can they be assembled into the final persuasive conclusion.

In the area of healthy life extension and biotechnologies to repair aging, an array of foundational ideas might include the following:

• This is a time of radical progress in biotechnology, far more so than even just a decade ago.
• Scientists can extend life in a score of different ways in laboratory animals.
• But you don't see the results of this work in the clinic because the FDA is needlessly obstructive.
• Aging is just damage, and that damage is well enough understood for work on practical repair biotechnologies to proceed.
• A large-scale research program could plausibly produce decades of life extension by 2040.
• Any effective longevity therapy will give people more time of life and health to wait for even better new therapies.
• Overpopulation is a myth, and longer lives won't greatly increase population in any case.
• Ethical objections to engineered longevity are all weak in comparison to the massive and ongoing harm caused by aging.

Each of these is no small thing in and of itself, and worthy of longer treatment. So presenting all of the concepts that lead up to thinking about rejuvenation biotechnologies is time-consuming, hard to do well, and requires a willing and interested audience. Unfortunately few people in the broader public are in fact willing put in the effort to follow you, me, or anyone else with a complicated idea all the way from square one to the end point. That takes time and attention, both of which are precious commodities, hard to obtain at the best of times. Thus the ideas that do gain traction in our culture are those that can be successfully communicated in a short period of time, because they build directly upon what is already known.

The Example of Hotmail

The recent past provides many good examples of ideas that could be quickly communicated to the public at large, and as a result rapidly gained interest and support. Hotmail is one such example: when the company was founded in 1996, it was the first service to offer email over the web. The founders were petrified that they would be beaten to the punch because the idea was absolutely obvious in hindsight: take email, take websites, and merge the two. Anyone in the internet-using world could easily grasp that concept, and the service took off like wildfire when it launched.

But let's stop to think about that for a moment. Both email and the way in which most people experience the web are in and of themselves very complicated concepts. Imagine that some visionary fellow gave you the task of explaining to the public an email service used via a web site in 1970: you would be right back to having to explain many foundational, unfamiliar concepts to an audience unwilling to give you sufficient time and attention. What is a network? How do ordinary people connect to or even use a network? What is a web browser? How does an ecosystem of websites and hosting services arise? Why would I need email, or some sort of patchwork visual information service? And so forth. Nonetheless, in 1996 Hotmail was an idea that could be conveyed and understood in a single sentence. "Email via a website." When we consider this and other similar examples, we see that there must be an ongoing process by which complex, unfamiliar, and challenging ideas become simple, familiar, and easily communicated ideas.

Layers of Knowledge, Attention, and Expertise

You might envisage the broad field of longevity science as a series of concentric circles. The innermost circle is made up of a small number of people who pay a great deal of attention to the field, and who possess the most knowledge and expertise: researchers who work on cutting edge science, for example. The outermost circle consists of a large number of people who pay just a little attention to the field, and who possess the least knowledge and expertise - such as casual advocates and interested members of the public. The progression of circles from innermost to outermost reflects an increasing number of people, but lesser expertise and attention. I'd loosely categorize the circles from inner to outer as follows:

• Cutting edge researchers.
• Other researchers, postgraduates, and scientists in related fields.
• Dedicated patient advocates.
• Medical technology developers, funding sources.
• Physicians, clinicians and medical technicians.
• Interested members of the public.

In this model of human endeavor, knowledge flows outward while funds and newly participating members of the community flow inward - or at least, that is the ideal. In practice, managing this flow of knowledge is a big and thorny problem: many of the most important movements in technology over the last few decades have focused on how to best move knowledge from inner circles to outer circles. Consider the open science movements, fights over closed journal business models, and the many efforts to try to adopt open source practices in the scientific community, to consider but a few examples.

Let me advance a definition for the purposes of this article: documentation is the name given to explanations and tutorials produced by the members of one circle that are intended for the next outermost circle. For example, review papers written by scientists present an overview of progress in one area of research rather than new data or results. These review papers are a form of documentation for the next outermost circle of researchers - scientists in other fields, or postgraduates, or other academics with less experience in the topic at hand.

To take another example, what I do at Fight Aging! is a form of documentation by this definition: ongoing efforts to explain the ins and outs of longevity science to people who are less familiar with the field, and who have less time to devote to understanding the work of researchers. Academic publicity services at the major universities also perform a similar task, producing explanations for the outer circles of doctors, interested members of the public, and the like.

Documentation thus moves raggedly and through many hands, as each circle learns from the inward circles and then in turn explains its knowledge, understanding, and work to the outer circles. That there are so many layers involved goes a long way towards explaining how science so often becomes garbled and misinterpreted on the way from researchers to the interested public. The process works over time, however, as the example of Hotmail well illustrates. The level of knowledge in the outer circles does increase, and the efforts of people involved in producing documentation make it easier for new ideas to gain traction.

Researchers, Like Most Communities, Document Poorly and Reluctantly

Anyone who spends time working in a technical field eventually forms a cynical attitude towards documentation: it is never what it might be, and the next innermost circle never does a good enough job of explaining themselves. This is simply the way of the world: most people in a given circle spend the majority of their time and effort in communicating with each other, not with the members of the next outermost circle. In the sciences, researchers write papers for one another as a part of the business of research, and this publishing of results is not intended to educate anyone other than peers at a similar level of expertise in the same field.

The process of producing documentation for outer circles is nonetheless very important, despite being undertaken by only a minority in any field. It is only through documentation that there can exist a roadway of information to connect researchers who produce new science with developers who build clinical applications of that science. If documentation is lacking, then so is the pace of development: developers work on what they know, what can be understood, and what can be sold to their investors. Ultimately, that knowledge must come from efforts made by researchers to explain their work.

Across the years I've spent following work on longevity-related research as an interested observer, I've seen a score of techniques demonstrated to significantly extend healthy life in mice, or reverse a narrowly specific manifestation of the damage of aging. Many of these results are languishing undeveloped, as the FDA still forbids clinical application of biotechnologies for the treatment of aging, for all that there are signs that this might eventually change. There is little writing on these research results, and no good sources other than the original papers - most of which are behind journal paywalls. Thankfully those paywalls are beginning to crumble too. Yet this change is painfully slow: what hope is there for the proper transmission of knowledge from the circle of researchers to the circle of clinical developers when the researchers have little direct incentive to explain their work, due to the FDA roadblock and consequent lack of investment, and when no other group seems to be picking up the slack? Potentially viable medical technologies are lying near fallow, buried in the output of the scientific community, and left unexplained for the rest of us.

The Solution: Produce Documentation to Take up the Slack

Addressing the challenges of documentation and transmission of knowledge is an area in where a volunteer organization can make a real difference to the future of longevity science - and for a comparatively small amount of effort and money. The flow of knowledge from the research community is vital, in order to raise the level of understanding over the longer term, but also in the shorter term to make developers aware of what exists to be developed into new and potentially promising therapies.

As described above there exists a clearly identifiable gap in this process, however: science that might lead to therapies for aging exists in many different forms, but there is little to no documentation of it. The inner circles are not explaining themselves sufficiently. Thus there is little in the way of a roadway to systematically bring this knowledge out to the circles of life science students, entrepreneurs, clinical developers, and other interested parties. Those groups, in turn, have nothing to work with when it comes to educating the medical community and public at large. So as a consequence little funding flows back into the field, and few people know what is taking place, or how promising scientific progress might be. This, in a nutshell, is the problem. The US may be closed by regulatory fiat to commercial development of therapies to directly treat aging, but much of the rest of the developed world remains open for business in this field - if the developers in those countries knew more about the work that has taken place and presently lies largely buried.

The irony of the situation is that documentation isn't expensive in the grand scheme of things, and certainly not in comparison to earnest clinical development. It doesn't require more than a few weeks of part-time work for a life scientist, a graphic artist, and an editor to produce a long document that explains exactly how to replicate a demonstrated research result in longevity science - a way to extend life in mice, for example. That document will explain the research in plain English, at length, and in a way clearly comprehensible to people who are not cutting edge scientists: exactly what is needed open the door to a far wider audience for that research. More rather than less of this should be the normal state of affairs, but at present it is not the case.

In conclusion, documentation is important, a critical part of advocacy and the development process at the larger scale. It isn't just words, but rather a vital structural flow of information from one part of the larger community to another, necessary to sustain progress in any complex field. We would all do well to remember this - and to see that building this documentation is an activity in which we can all pitch in to help.

The dominant approach to Alzheimer's research and the development of potential therapies involves finding ways to clear out aggregates of amyloid and tau that build up in the brain. This has proven challenging, however. It is too early to say in certainty whether lack of tangible progress on this front is because it is a hard problem, or because this isn't the most effective direction. The weight of evidence strongly suggests the former is the case, but that hasn't stopped delayed progress from spurring the development of a great many alternative hypotheses as to the cause of Alzheimer's disease. One line of thinking suggests that pathogens are more important than presently accepted to be the case, and paints Alzheimer's disease as a consequence of the progressive age-related failure of the immune system to deal with specific types of invading microbe. The paper here is one example of the type.

The infectious nature of Alzheimer's disease (AD) was revealed when spirochetes (both dental and Lyme) were shown to be present in the brains of affected patients. The dental microbes travel from the oral cavity during times of disruption of the dental plaque and subsequent bacteremia following dental procedures. Lyme borrelia travel to the brain via the blood stream during the secondary stage of that disease. The spirochetes have an affinity for neural tissue and pass through the blood-brain barrier easily. Once the spirochetes are in the brain, they attach, divide (albeit very, very slowly), and multiply. When they reach a quorum, they begin to spin out a biofilm. Because of the exceedingly slow division, it takes approximately 2 years to accumulate sufficient organisms to make one biofilm. At some point after attachment and formation of the biofilms, the innate immune system becomes activated and attempts to destroy them.

The innate immune system first responder, Toll-like receptor 2, generates both NF-κB and TNF-α which try to kill the spirochetes in the biofilm, but cannot penetrate the "slime". NF-κB is also responsible for the generation of amyloid-β (Aβ) which itself is anti-microbial. Aβ cannot penetrate the biofilm either, and its accumulation leads to destruction of the cerebral neurocircuitry. Where spirochetes have been found in the brains of Alzheimer's disease (AD), it may be considered an infectious disease. Treatment with a bactericidal antibiotic with a concomitant biofilm disperser seems most reasonable; but any neurologic damage is irreversible. It is therefore of the utmost importance to treat early in the course of this disease.

Link: https://dx.doi.org/10.3233%2FJAD-160388

Researchers have discovered a way to provoke generation of new retinal cells in mice, based on investigation of the way in which regeneration functions in zebrafish, a species capable of regrowing lost organs. If we are fortunate, there will be something here that can be generalized and applied to other nervous system tissues, but even if restricted to the retina this is a good step forward for the field. It is promising to see that research into the biochemistry of species capable of proficient regeneration, such as zebrafish and salamanders, is starting to bear fruit.

Many tissues of our bodies, such as our skin, can heal because they contain stem cells that can divide and differentiate into the type of cells needed to repair damaged tissue. The cells of our retinas, however, lack this ability to regenerate. As a consequence, injury to the retina often leads to permanent vision loss. This is not the case, however, in zebrafish, which have a remarkable ability to regenerate damaged tissue, including neural tissue like the retina. This is possible because the zebrafish retina contains cells called Müller glia that harbor a gene that allows them to regenerate. When these cells sense that the retina has been injured, they turn on this gene, called Ascl1. The gene codes for a type of protein called a transcription factor. It can affect the activity of many other genes and, therefore, have a major effect on cell function. In the case of the zebrafish, activation of Ascl1 essentially reprograms the glia into stem cells that can change to become all the cell types needed to repair the retina and restore sight.

Researchers wanted see whether it was possible to use this gene to reprogram Müller glia in adult mice. The researchers hoped to prompt a regeneration that doesn't happen naturally in mammal's retina. Like humans, mice cannot repair their retinas. They created a mouse that had a version of the Ascl1 gene in its Müller glia that was turned on with an injection of the drug tamoxifen. Earlier studies by the team had shown that when they activated the gene, the Müller glia would differentiate into retinal cells known as interneurons after an injury to the retina of these mice. These cells play a vital role in sight. They receive and process signals from the retina's light-detecting cells, the rods and the cones, and transmit them to another set of cells that, in turn, transfer the information to the brain.

In their earlier research, however, the researchers found that activating the gene worked only during the first two weeks after birth. Any later, and the mice could no longer repair their retinas. The researchers determined that genes critical to the Müller glia regeneration were being blocked by molecules that bind to chromosomes. This is one way cells "lock up" genes to keep them from being activated. It is a form of epigenetic regulation - the control of how and when parts of the genome operate. In their new paper, the researchers show that by using a drug that blocks epigenetic regulation called a histone deacetylase inhibitor, activation of Ascl1 allows the Müller glia in adult mice to differentiate into functioning interneurons. The researchers demonstrated that these new interneurons integrate into the existing retina, establish connections with other retinal cells, and react normally to signals from the light-detecting retinal cells.

Link: http://hsnewsbeat.uw.edu/story/scientists-regenerate-retinal-cells-mice

A few years back, researchers found that manipulating levels of NF-κB in the hypothalamus influenced the pace of aging in mice. That work was several steps removed from any idea as to what exactly was going on under the hood; changing the amount of a specific protein in circulation can have any number of effects, both direct and subtle. NF-κB is already an area of interest in the study of aging and metabolism, and so there are many mechanisms to speculate on in this context. There was indeed speculation at the time. Other indirect evidence suggests that the quality of cellular function in the hypothalamus is connected to the pace of aging, such as results arising from investigations of autophagy and its relevance in this part of the brain. Other researchers have made some inroads into mapping possible ways in which the hypothalamus might influence the operation of metabolism throughout the body in order to modestly speed or slow aging. It is well known that the hypothalamus regulates all sorts of aspects of metabolism, but the open question is which of these relationships are relevant to the matter at hand.

The team that investigated NF-κB in the hypothalamus has since been hard at work, seeking a better understanding as to why this part of the brain is important in the way in which metabolic processes determine individual variations in aging and longevity. In a recently published paper, the team now points to one particular small population of stem cells in the hypothalamus that diminishes with age; losing these cells more rapidly appears to speed processes of aging throughout the body. The researchers believe that signals generated by these cells are the mechanism of action, and a closer investigation of these signals is the next step in this line of research. It has to be said that this sounds quite similar to the situation for Parkinson's disease, at least at the high level, in which one small but critical population of cells in the brain is diminished at a different pace in different individuals, and where autophagy - and disruption of autophagy in aging - might be important in determining the rate of loss. It also clearly parallels what is known of the age-related decline of stem cell populations in all tissues. We become damaged, and stem cell loss and inactivity is a downstream consequence of that damage.

Either way, this might make an interesting target for cell therapy: certainly, replacement of stem cell populations is on the rejuvenation research checklist. Whether it is a priority in this case rather depends on the size of the effect, however, which in this study looks like a ~10% gain in life expectancy resulting from a single cell therapy treatment carried out in middle-aged mice. Unfortunately, significant changes in longevity in mice on the basis of altered metabolism so far do not translate to significant changes in longevity in humans, at least in the few areas where the data exists for comparison. The life spans of short-lived mammals are far more plastic in response to circumstances and interventions than those of long-lived mammals. In the case of stem cell replacement as a way to reverse declines, however, it is hard to say how the comparisons will turn out - the data just isn't there yet. It is the fond hope of many in our community that approaches based on repairing loss and damage, very different from approaches based on altering metabolism to modestly slow damage accumulation or resist the consequences of damage, will turn out to have similarly scaled effects on life span in mice and humans. Maybe so, maybe not. As I said, the data isn't there. In order to find out, rejuvenation therapies based on repair must be rigorously tested in humans, and that hasn't yet happened in any useful way, even in the stem cell field.

Brain Cells Found to Control Aging

The hypothalamus was known to regulate important processes including growth, development, reproduction and metabolism. In a 2013 paper, researchers made the surprising finding that the hypothalamus also regulates aging throughout the body. Now, the scientists have pinpointed the cells in the hypothalamus that control aging: a tiny population of adult neural stem cells, which were known to be responsible for forming new brain neurons. "Our research shows that the number of hypothalamic neural stem cells naturally declines over the life of the animal, and this decline accelerates aging. But we also found that the effects of this loss are not irreversible. By replenishing these stem cells or the molecules they produce, it's possible to slow and even reverse various aspects of aging throughout the body."

In studying whether stem cells in the hypothalamus held the key to aging, the researchers first looked at the fate of those cells as healthy mice got older. The number of hypothalamic stem cells began to diminish when the animals reached about 10 months, which is several months before the usual signs of aging start appearing. "By old age - about two years of age in mice - most of those cells were gone." The researchers next wanted to learn whether this progressive loss of stem cells was actually causing aging and was not just associated with it. So they observed what happened when they selectively disrupted the hypothalamic stem cells in middle-aged mice. "This disruption greatly accelerated aging compared with control mice, and those animals with disrupted stem cells died earlier than normal." Could adding stem cells to the hypothalamus counteract aging? To answer that question, the researchers injected hypothalamic stem cells into the brains of middle-aged mice whose stem cells had been destroyed as well as into the brains of normal old mice. In both groups of animals, the treatment slowed or reversed various measures of aging.

The researchers found that the hypothalamic stem cells appear to exert their anti-aging effects by releasing molecules called microRNAs (miRNAs). They are not involved in protein synthesis but instead play key roles in regulating gene expression. miRNAs are packaged inside tiny particles called exosomes, which hypothalamic stem cells release into the cerebrospinal fluid of mice. The researchers extracted miRNA-containing exosomes from hypothalamic stem cells and injected them into the cerebrospinal fluid of two groups of mice: middle-aged mice whose hypothalamic stem cells had been destroyed and normal middle-aged mice. This treatment significantly slowed aging in both groups of animals as measured by tissue analysis and behavioral testing.

Hypothalamic stem cells control ageing speed partly through exosomal miRNAs

Although the nervous system clearly has a role in ageing, and research has demonstrated that the hypothalamus is particularly important, the cellular mechanism responsible for ageing is still unknown. It has been shown that adult neural stem/progenitor cells (NSCs) reside in a few brain regions that mediate local ­neurogenesis and therefore several aspects of brain functioning. Studies on adult neurogenesis have focused on the hippocampus and the sub-ventricular zone of the lateral ventricle in the brain. Decreased neurogenesis in these regions often correlates with the advent of related ageing-­associated disorders. More recently, it has been shown that adult NSCs are present in the hypothalamus, in particular in the mediobasal hypothalamic region (MBH), which is crucial for the neuroendocrine regulation of the physiological homeostasis of the whole body. We have previously shown that the hypothalamus has a programmatic role in causing systemic ageing. In this context, we investigated whether these hypothalamic NSCs (htNSCs) might be mechanistically responsible for this process.

We show that loss of htNSCs is an important cause of ageing in the whole body. This understanding aligns with our previous research showing that the hypothalamus has a programmatic role in systemic ageing. The underlying basis could be related to two functions of these cells: endocrine secretion and neurogenesis. Here we report that the modulation of ageing by htNSCs was achieved in a relatively short period, which should not have a major contribution from neurogenesis, while an endocrine function of these cells provided a neurogenesis-independent mechanism. In this context, we show that the anti-ageing effect of htNSCs is partially mediated by exosomal miRNAs secreted from these cells. Therefore, besides the classical endocrine function of the hypothalamus in secreting peptidyl hormones, htNSCs have a new type of endocrine function by secreting exosomal miRNAs.

Given this finding, we still predict that neuropeptide secretion by htNSCs, although not addressed in this work, also participates in the regulation of systemic ageing. This is partly because we previously found that GnRH is involved in the hypothalamic control of ageing and we observed here that some implanted htNSCs gave rise to GnRH-expressing cells. Thus, neuropeptide-based endocrine functions of htNSCs and their differentiated offsprings can contribute to the anti-ageing effects of these cells from other perspectives. Despite these outstanding questions, the overall findings in this work support that htNSCs are essential for the control of ageing speed.

Chronic inflammation in nervous system tissue is a common theme in age-related neurodegenerative diseases, including those that affect the retina. One source of this inflammation is the activities of microglia, a class of immune cell resident in the central nervous system. Microglia have a number of important roles to play in nervous system function beyond those of clearing debris and destroying errant cells. As immune function and tissue integrity become disarrayed with age, microglia grow overactive and inflammatory to the point of causing harm rather than helping to resolve issues. Due to the complexity of cellular metabolism, it is at present a challenge to draw a clear line of cause and consequence between the fundamental types of cell and tissue damage that cause aging and late stage consequences such as badly behaving microglia. As therapies to remove or repair portions of this damage emerge, the situation will become less confusing, however. This is a case in which the fastest way forward is to try approaches to the repair of old tissue and see what happens as a result to the system as a whole.

Microglia, the immunocompetent cells of the central nervous system (CNS), act as neuropathology sensors and are neuroprotective under physiological conditions. Microglia react to injury and degeneration with immune-phenotypic and morphological changes, proliferation, migration, and inflammatory cytokine production. An uncontrolled microglial response secondary to sustained CNS damage can put neuronal survival at risk due to excessive inflammation. A neuroinflammatory response is considered among the etiological factors of the major aged-related neurodegenerative diseases of the CNS, and microglial cells are key players in these neurodegenerative lesions.

The retina is an extension of the brain and therefore the inflammatory response in the brain can occur in the retina. The brain and retina are affected in several neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and glaucoma. AD is an age-related neurodegeneration of the CNS characterized by neuronal and synaptic loss in the cerebral cortex, resulting in cognitive deficit and dementia. The extracellular deposits of beta-amyloid (Aβ) and intraneuronal accumulations of hyperphosphorylated tau protein (pTau) are the hallmarks of this disease. These deposits are also found in the retina and optic nerve. PD is a neurodegenerative locomotor disorder with the progressive loss of dopaminergic neurons in the substantia nigra. This is accompanied by Lewy body inclusion composed of α-synuclein (α-syn) aggregates. PD also involves retinal dopaminergic cell degeneration. Glaucoma is a multifactorial neurodegenerative disease of the optic nerve, characterized by retinal ganglion cell loss. In this pathology, deposition of Aβ, synuclein, and pTau has also been detected in retina.

These neurodegenerative diseases share a common pathogenic mechanism, neuroinflammation, in which microglia play an important role. Microglial activation has been reported in AD, PD, and glaucoma in relation to protein aggregates and degenerated neurons. The activated microglia can release pro-inflammatory cytokines which can aggravate and propagate neuroinflammation, thereby degenerating neurons and impairing brain as well as retinal function. The differential activation of microglial M1 or M2 phenotypes can produce a neurotoxic or neuroprotective environment, and could constitute a key in neuroinflammation regulation. In the search for a new strategy to control neuroinflammation, it might be more effective to change the M1 phenotype to the M2 phenotype than to block microglial activation completely. In the regulation of microglial activation, several cell types including, neurons, astrocytes, and T-cells are involved. When the neuroinflammatory process is triggered by protein aggregates (Aß, α-syn, pTau etc.), peripheral immune cells infiltrate CNS and prompt more activation on resident microglia, favoring neuroinflammatory processes.

Link: https://doi.org/10.3389/fnagi.2017.00214

Tissue engineers heve demonstrate the ability to implant a seed consisting of a scaffold and liver cells into mice, and have it expand considerably into new tissue resembling natural liver tissue. This is an interesting hybrid approach between the two distinct strategies of growing tissue outside the body for transplantation and steering cell behavior to produce regrowth inside the body. Given the wide variety of technical initiatives aimed at organ regrowth, most of which are just as promising, it is hard to say at this point which of them will first break through into widespread use in human medicine.

Engineering human livers is a lofty goal. Human liver cells, hepatocytes, are particularly difficult to grow in the laboratory as they lose liver functions quickly in a dish. Now, researchers show that a "seed" of human hepatocytes and supporting cells assembled and patterned within a scaffold can grow out to 50 times its original size when implanted into mice. These engineered livers, which begin to resemble the natural structure of the organ, offer an approach to study organ development and as a potential strategy for organ engineering. "When we implant these tissues into a mouse with liver injury, the tissue seeds just blossom. Nature takes over and self-assembles a structure that looks like a human liver and has many liver-associated functions."

In 2011, the researchers showed that human liver-cell aggregates could be grown in mice. They assembled human hepatocytes and supportive stromal cells within a polymer scaffold, demonstrating that this dime-size artificial human liver tissue could grow stably for weeks in immune-compromised mice that had their own normal livers. The liver implant fused with the mouse circulatory system and received blood to perform a few liver functions. In the new work, the lab wanted to expand the size of the human liver graft beyond the 1 million cells used in the prior model. The team assembled different geometries of human primary hepatocytes, human umbilical vein endothelial cells, and fibroblasts, placed them within a degradable hydrogel, and implanted the tissue seed into a fat pad within a liver-injury mouse model.

To recapitulate liver damage, the animals are missing a key amino acid metabolism gene that results in toxic metabolite build up and progressive liver failure, which can be rescued by a drug used to treat individuals with a similar genetic disorder. The group chose this model because it they expected it to foster the liver seeds' growth. "The hypothesis is that mouse liver injury will produce factors that will travel through the blood stream and tell the human liver tissue to regenerate." The team found that the human liver tissue grew less in animals that were continuously treated with the drug compared to animals that were given intermittent cycles of the drug.

The human liver seed tissue grew best when they assembled endothelial cells into rope-like structures on top of the hepatocytes, rather than when the tissue was a spherical aggregate of all three cell types. The patterned tissue formed new structures in vivo, including ones that resembled bile ducts, and contained pockets of red blood cells, suggesting the presence of vascular structures within the tissue. The organ-like structures also produced appropriate human proteins such as albumin and transferrin.

Link: http://www.the-scientist.com/?articles.view/articleNo/49927/title/Engineered-Human-Liver-Tissue-Grows-in-Mice/

It starts with the death of companion animals. Not when you are young and comparatively resilient, but later in adult life when you are personally responsible for all of the decisions and costs, the management of a slow and painful decline. The futile delaying actions, the ugly realizations, the fading away, the lost capacity, the indignities and the pain, and all in an individual fully capable of feeling, but who lacks the ability to comprehend what is happening, or to help resist it. One slowly realizes that this is just a practice run for what will happen to everyone you know, later, and then to you. Ultimately it comes to euthanasia, and one sits there looking down at an animal who is a shadow of his or her previous self, second guessing oneself on degree of suffering, degree of spark and verve remaining. It is rarely a clear-cut choice, as in most companion animals the body fails before the mind. When it is clear, and your companion is dying in front of you, you will rush, and later chew it over for a long time afterwards; did you wait too long, could you have done better?

At some point you will ask yourself: why am I trying to maximize this life span? Why am I playing at balancing capacity against suffering? Why have I not just drawn an end to it? Why does it matter if a dog, a cat, another animal exists until tomorrow? Next year the animal will be gone without trace. In ten thousand years, it is most likely that you will be gone without trace. In a billion years, nothing recognizable will remain of the present state of humanity, regardless of whether there is continuation of intelligence or not. The great span of time before and after cares nothing for a dying companion animal. There is no meaning beyond whatever meaning you give to any of this, and there is a very thin line between that and the belief that there is no meaning at all, the belief that there is no point. If the animal you lived with will be gone, what was the point of it all? If you will be gone, why are you so fixated on being alive now, or tomorrow, or some arbitrary length of time from now?

It starts with companion animals, and it gnaws at you. The first of the cats and dogs you live with as the responsible party, the thinking party, the one motivated to find some meaning in it all, arrive and age to death between your twenties and your forties. That is traumatic at the end, but you find it was only practice, because by the end of that span of time, the first of the people closest to you start to die, in accidents and in the earlier manifestations of age-related disease. The death by aging of companion animals teaches you grief and the search for rationales - meaningless or otherwise - and you will go on to apply those lessons. To your parents, to mentors, to all of those a generation older who suddenly crumple with age, withering into a hospital or last years in a nursing facility. You are drawn into the sorry details of the pain and the futile attempts to hold on for the ones closest to you, a responsible party again. You are left thinking: why all this suffering? Why do we do this? What does it matter that we are alive? The span of a billion years ahead looms large, made stark and empty by the absence of those dying now, no matter how bustling it might in fact prove to be.

Grief and exposure to the slow collapse of aging in others: these are toxins. These are forms of damage. They eat at you. They diminish you, diminish your willingness to engage, to be alive, to go on. I think that this burden, as much as the physical degeneration of age, is why near all people are accepting of an end. The tiredness is in the mind, the weight of unwanted experiences of death by aging and what those experiences have come to mean to the individual. Human nature just doesn't work well under this load. It becomes easy to flip the switch in your view of the world: on the one side there is earnest work to end future suffering by building incrementally better medical technology, while on the other side lies some form of agreement with those who say that sadness and suffering can be cured by ending all life upon this world. Oh, you might recoil from it put so bluntly, but if you accept that existence doesn't matter, then the gentle, kind, persuasive ending of all entities who suffer or might suffer lies at the logical end of that road. It is just a matter of how far along you are today in your considerations of euthanasia and pain. This is the fall into nihilism, driven by the urge to flee from suffering, and the conviction that your own assemblies of meaning are weak and empty in the face of the grief that is past, and the grief that you know lies ahead.

Not all of the costs of the present human condition are visible as lines upon the face.

The authors of this article express a representative version of the geroscience perspective on aging research and its application in medicine. It is similar to that of the Longevity Dividend initiative of the past decade, which is to say that if a large amount of time and funding is invested, perhaps calorie restriction mimetic and similar marginally effective drugs can be brought to the clinic in order to modestly slow the progression of aging and add a few years of healthy life expectancy sometime prior to 2030. I believe I'm not the only one to be entirely underwhelmed by this strategy. This is not the future of aging research that we should either want or support.

Yes, it is a good thing that a sizable fraction of the research community is now prepared to work towards treating aging as a medical condition, and to advocate for that work in public. It wasn't always this way, and it took considerable effort to bring about the present renaissance. Yet if the research community aims low, consuming funding and careers to make progress towards goals for human longevity that are only a tiny bit removed from doing nothing at all, what is the point? If we want to instead see meaningful progress towards rejuvenation therapies capable of achieving a far greater impact on aging and the health of older people, we should look to groups like the SENS Research Foundation and its allies in the research community, or the companies developing senolytic therapies to clear senescent cells. The goal should be to repair the causes of aging, aiming to put a stop to aging, to bring it under control, not merely slow it down a little.

Over the past decades, the compression of morbidity was a basic strategy in gerontology. This strategy is aimed at limiting morbidity to a short time period near the end of life, thereby reducing the burden of diseases and disabilities through delay in the age at onset of the most common aging-related pathological conditions. A few years ago, a new direction in geriatric medicine, geroscience, began to develop. This interdisciplinary field of research is aimed at understanding the mechanistic links between aging and aging-associated diseases and centered primarily on extension of healthspan. According to the "geroscience hypothesis", aging could be manipulated in such a way that will in parallel allow delay the onset of all age-associated chronic disorders, because these pathologies share the same primary underlying risk factor, age.

Healthspan extension is a central component of activities aimed at achievement of 'optimal longevity', a condition defined as 'living long, but with good health and quality of life' including improved productivity, functioning and independence. Currently, the research attempted to enhance healthspan are focused primarily on slowing the biological processes underlying aging such as dysfunctions of mitochondria, impaired proteostasis and stem cell function and maintenance, deregulated sensing of cell energy status and growth pathways, cellular senescence, age-related decrease in stress resistance, as well as oxidative and inflammatory stress. These processes interact, influencing each other in order to maintain the normal pathways of cellular signaling and to support organismal homeostasis. The compensatory mechanisms mediating these processes, however, became exhausted when reaching a certain age and various aging aspects are manifested, enhancing as a consequence the risk of functional declines and progression of age-associated chronic pathologies.

Aging is traditionally regarded as 'natural' and consequently unpreventable process. However, in the opinion of many field experts, the idea that aging is inevitable part of human nature is rather questionable. Indeed, most present-day evolutionary theories postulate that aging has arisen as a by-product of fundamental evolutionary processes and does not have any specific function. If aging is in fact not an inadmissible component of life, then it might be manipulated like other processes that are commonly believed to be pathological or unnatural. The basic supposition underlying anti-aging research is that age-associated senescence may be regarded as a complex of pathophysiological processes that could be prevented, delayed, or even reversed.

The further elaboration of pharmaceuticals (both supplements and clinically approved drugs) specifically targeted at age-related pathologies is one of the most rapidly developing fields in modern biogerontology. An important point is, however, that most substances with potential anti-aging properties are apparently multifunctional and targeted at various molecular pathways that mediate aging. Furthermore, there is only limited evidence to demonstrate overall health benefits of using such substances so far. Findings from epidemiological studies reporting the long-term health impacts of these agents are rather inconsistent.

Another reasonable approach in anti-aging pharmacology is evaluation of the geroprotective potential of medications already approved by regulatory authorities for treating various pathological conditions related to aging. Among them, metformin, statins, beta-blockers, thiazolidinediones, newer generation β-adrenergic receptor inhibitors, renin-angiotensin-aldosterone system inhibitors, as well as anti-inflammatory medications appear to be the most promising drug candidates in this respect. The safety of these drugs has been confirmed in a number of clinical trials. This is also compelling evidence that they may improve health, well-being and physiological functioning in elderly patients suffering from chronic pathologies. One problem is that these substances are not used currently for treating age-related pathological conditions in the absence of clinical manifestations of particular illness. There are, however, good reasons to suggest that these agents could theoretically be redirected to preventing or treating other syndromes or conditions commonly associated with aging.

Despite an extraordinary rapid technological progress in pharmacology, there are few new preparations in the development pipeline now. Thereby, drugs generated on the basis of new knowledge gained from biogerontological research that can delay or prevent most age-associated disorders would apparently become "blockbusters" of modern pharmaceutical industry and market. That follows the idea that the extension of the healthy life expectancy by slowing aging process is the most efficient way to combat aging-related chronic illnesses and disabling conditions representing serious medical, social and economic issue in modern societies. This idea is referred to as the "longevity dividend" in the contemporary literature. Discovery and development of anti-aging drugs could likely provide an opportunity for revitalization of the drug development pipeline. Indeed, if it would be possible to slow down the aging process per se, then that would allow delay or prevent most aging-related disorders rather than combating them one by one, which is the conventional approach in the present-day disease-based paradigm of drug development.

Link: https://doi.org/10.1186/s12967-017-1259-8

As I might have mentioned once or twice, you can only get so far powered by zealotry. All movements start with the zealots and the visionaries and the earnest volunteers, but to grow to take over the mainstream, there must be funding sufficient to employ the much larger group of advocates who take a wage and go home at the end of the day. One of the growing pains of the longevity science community lies in finding this funding. In this day and age meaningful early stage medical research is comparatively cheap, and most people choose to support research programs such as those of the SENS Research Foundation rather than expanded advocacy. At some point this community has to become larger than a few volunteer efforts and a few small non-profits: infrastructure and staff must come from somewhere for greater advocacy and fundraising efforts, for conferences and outreach, and for all the other necessary tasks. It is certainly true that bootstrapping on the advocacy side of the fence is just as tough as bootstrapping on the research side of the fence.

There is a persistent view that life extension advocacy is something that does not require any investment and can be done in your spare time. Fundraising for overheads is like an elephant in the room: it is hard not to notice it is there, but people try to avoid talking about it. Without a doubt, talking to friends about the promise of rejuvenation technologies or reposting research news on your Facebook feed is useful and it can be done for free. But what if the goal is more ambitious - to change local legislation to make it more longevity-friendly, to convert decision makers of the state grant system to allocate more money to rejuvenation research, or to reach out to wealthy individuals able to fund more studies? These activities require money.

Every member of our community hopes for rejuvenation therapies to be developed, implemented and delivered at an affordable price as soon as possible. Preferably in their and their relatives' lifetime. And even though there is a steady progress, it would be good to see it speed up. How? Mostly by removing things that are holding us back. The list of bottlenecks include the following aspects: insufficient research funding due to rejuvenation projects being innovative and not well understood by the decisionmakers in different funding bodies; flaws within the grant system: unnecessarily detailed grant applications and reports, making the scientists spend time on them, rigid rules on how money should be disposed during the project, delays in funding delivery; young scientists turning to mainstream topics like single diseases instead of rejuvenation to avoid reputational risks and problems with funding; lack of public awareness on the promise of rejuvenation technologies and the positive aspects of their massive implementation for our society; and many more. One could call life extension advocate successful if he or she is removing or mitigating some of these bottlenecks so the overall situation in the field measurably improves.

To write one popular but accurate article about aging research progress in a specific field, the activist has to spend 2-3 hours to familiarise himself with the latest publications on the topic. Writing 2-3 pages with scientific references can also take several hours. So one article usually takes a half of the working day. If the writer is also involved in social media development (which requires posting new original materials every day) this can no longer be considered a hobby: it becomes at the least a part-time job and that should be paid. Have a look at the level of salaries of scientific writers for financial reference.

The usual places to promote rejuvenation research and corresponding policies are scientific conferences, public events and meetings of working groups discussing necessary changes in a law. In addition to the conference fee, going to a conference implies travel expenditures and booking a hotel, which can stand for from several hundred to a few thousand dollars per person, depending on the region where the conference takes place, and its duration. Promotion of a cause on a regular basis means an organization has to be represented at 10-20 events per year and often even more. Even if half of them do not have a registration fee, it means spending around $10k on the registration and up to $20k on travel and accommodation per person per year. Costs aside, going to a conference for advocacy reasons is a significant workload. In the case of lobbying for changes in the law (which can take several years), the activist has to attend from 5 to 20 meetings of the working group per year, to ensure the proposed changes are still being considered and keep being included in the new version of the law. Each meeting can take a half of a working day and implies some follow-up analytical and networking activities. You can view estimates of salaries of professional lobbyists or government relations managers for comparison.

Life extension advocacy groups are constantly seeking grant opportunities to cover their administrative needs. But all the same reasons that impede the scientists trying to receive a grant for rejuvenation research, also impede advocacy projects in our field. Due to the novelty of the idea of aging prevention, not many grant givers are keen to provide resources for its promotion. So before you ignore the "Donate" button that you see on the site of a life extension advocacy group, and before frowning at the line with administrative costs in their report, consider this: you and other members of our community are so far the only part of population who dislikes aging strongly enough to invest in the solution. And the best time to step in is always the same: now.

Link: http://www.leafscience.org/cost-of-advocacy/

If the successes in technological development achieved over the past few hundred years teach us anything, perhaps it should be that individual members of a species that evolved in an environment of pervasive scarcity and intermittent famine are not well equipped for an environment of consistent plenty. Our biochemistry and our instincts lead us astray: eat too many calories and life expectancy and long-term health will suffer for it. This is not new. We are no different from our ancestors in this aspect of the human condition. The change lies in the fact that we now live in an age so wealthy and capable that consistent overeating is affordable for a majority of the global population. Since people, on average, tend to follow their incentives in the short term rather than in the long term, the result is a very rapid growth in lifestyle diseases.

Visceral fat tissue doesn't care that you think it is hard to avoid. Maybe it is hard. But that doesn't change the choice, or the fact that it is a choice: choose to eat less, or choose to suffer the consequences resulting from the visceral fat tissue that you gain. That means greater lifetime medical expenditures, more years of chronic age-related disease, more disability, and a younger death than those who did managed to stay slim. Visceral fat tissue interacts with the immune system to generate chronic inflammation, and may increase the burden of senescent cells that also contribute to inflammation. Inflammation accelerates the development and progression all of the common age-related diseases, particularly cardiovascular disease. Issues in the vascular system in turn accelerate the decline into dementia. There is no such thing as being both healthy and overweight. Excess visceral fat tissue at any age is a bad thing.

What lies ahead in the matter of cheap calories and consequent declines in personal health? Most likely a future of continued issues and an increasingly overweight population, at least until someone comes up with a low-cost technological fix that work well enough to gain widespread adoption. Zero calorie food bases, maybe, or an implementation for human medicine of one of the various ways in which mice can be engineered to resist fat deposition. For the individual, it will for a while yet remain a matter of willpower and choice. It is risky to let things go in the hope that medical science will rescue you from the consequences of poor choices. The future of rejuvenation therapies will not happen as rapidly as we'd like: it will be piecemeal, and roll out incrementally over decades. That is plenty of time for even the younger members of the audience to dig a deep hole of ill health through becoming overweight and sedentary.

Study finds 90 percent of American men overfat

Does your waist measure more than half your height? In developed countries up to 90 percent of adult males and 50 percent of children may suffer from this condition. In the top overfat countries, 80 percent of women fall into this category. The term overfat refers to the presence of excess body fat that can impair health, and may include even normal-weight non-obese individuals. Excess body fat, especially abdominal fat, is associated with increased risk of chronic diseases, increased morbidity and mortality, and reduced quality of life. Researchers reported earlier this year that up to 76 percent of the world's population may be overfat. Now these same researchers have focused their efforts on data from 30 of the top developed countries, with even more alarming findings.

The relationship between the overfat condition and poor health is a spectrum or progression in which the vicious cycle of excess body fat, insulin resistance and chronic inflammation lie at one end, causing abnormal blood fats (cholesterol and triglycerides) and glucose, and elevated blood pressure, which then produces a variety of common diseases at the other end. Being overfat is linked to hypertension, dyslipidemia, coronary heart disease, stroke, cancer, type 2 diabetes, gallbladder disease, osteoarthritis and gout, pulmonary diseases, sleep apnea and others. Traditional means of assessment, such as stepping on a scale or calculating Body Mass Index (BMI), are ineffective at determining whether someone is overfat. Instead, researchers recommend taking a measure of the waistline (at the level of the belly button) and comparing it to height.

Overfat Adults and Children in Developed Countries: The Public Health Importance of Identifying Excess Body Fat

It was recently estimated that between 62% and 76% of the world's population have reached body fat levels that can impair health. This condition, which can now be labeled a pandemic, was described by the catch-all term overfat. It is well-recognized that the overweight and obese conditions represent a continuing threat to world health, replacing more traditional problems of undernutrition and infectious diseases. Indeed, being overfat shares direct links to insulin resistance and chronic inflammation, and to hypertension, dyslipidemia, coronary heart disease, stroke, cancer, Type 2 diabetes, gallbladder disease, osteoarthritis and gout, pulmonary diseases, sleep apnea, and others. Global rates of these conditions in adults and children (including adolescents) have risen significantly over the past ~40 years, paralleling significant increases in the numbers classified as being overweight and obese, and considerably affecting people of all ages and incomes in both developed and developing countries.

While the prevalence of being overweight and obese is well known, many normal-weight and non-obese individuals exhibit excess levels of body fat that can adversely affect their health. Indeed, reliance of body mass index (BMI) for determination of being overweight and obese may misclassify up to 50% or more of patients with excess body fat who may have increased health risks. The notion of a metabolically obese normal weight (MONW) individual is based on the finding that obesity-associated disorders such as high circulating insulin levels in people with cardiovascular disease or Type 2 diabetes can occur in those with normal BMI. Many at-risk individuals have been identified in a BMI range of 23-25 or lower. Overfat individuals who are not overweight and obese include MONW individuals, those with sarcopenic obesity, and many who have increased abdominal fat stores. Abdominal and visceral fat accumulation, regardless of weight status, has been found to increase risk of cardiovascular and metabolic (cardiometabolic) disease to the greatest degree.

Based on BMI evaluations, there appears to be a leveling off of the trend in rising obesity rates in some developed nations. However, the incidence of central adiposity - the excess accumulation of visceral fat in the abdominal region, sometimes called abdominal obesity - is increasing. This form of overfat is concerning because the potential health risks of central adiposity are more pronounced than those for increased subcutaneous fat in other regions of the body. The continued increase in abdominal obesity includes those who are normal weight and non-obese, with US population averages of 54.2%, and an increased prevalence in women (up to 68.3%). The estimate of overfat in the world's 30 top developed nations is substantially higher than the prevalence of overweight and obese adults and children worldwide. Regardless of BMI values, overfat individuals have excess body fat, a high degree of cardiometabolic dysregulation that can promote disease risk factors and chronic disease, increased morbidity and mortality, reduced quality of life, and pose a rising economic burden.

The economic fallout from the overfat pandemic has raised a serious global challenge. In 2011, the WHO estimated that the economic burden of preventable, non-communicable disease (in particular cardiovascular disease, cancer, and diabetes) is expected to create a cumulative output loss of US$47 trillion over the next two decades. In 2010, this represented 75% of global GDP (US$ 63 trillion) - enough capital to lift the 2.5 billion people currently below the poverty line, out of poverty for more than half a century. While it is difficult to determine the absolute burden of the overfat pandemic, it is clearly a strong causal factor in the development of a significant portion of chronic disease and reduced quality of life.

In this open access paper, the authors present their view of the role of the immune system in age-related disease. Chronic inflammation is the primary focus of many considerations of immune aging, but there are arguably many other areas of disarray and dysfunction in the aging immune system that are just as relevant to the progression of age-related disease. Like other researchers, the authors here divide the complexity of immune aging into two broad categories: inflammaging, changes that increase chronic inflammation and inappropriate immune activation, and immunosenescence, changes that weaken the efforts of immune cells to destroy pathogens and harmful cells, such as those that have become cancerous or senescent.

The proportion of elderly people is rising worldwide, especial in the developed countries. Aging-related changes in the immune system contribute to the increased susceptibility of the elderly to infectious diseases, cardiovascular disease and stroke caused by atherosclerosis, autoimmune disease such as rheumatoid arthritis, cancer, and degenerative diseases including Alzheimer's disease. Further, metabolic syndrome, which is caused by obesity, occurs from middle age, and proceeds to tissue failure such as renal failure in advanced age, is tightly related to the immune system. Chronic infections such as hepatitis induce tissue damage, which arouses immune responses and wound repair responses. Chronic inflammation follows tissue fibrosis in advanced age proceeding to tissue failure such as chronic obstructive pulmonary disease.

The most prominent cause of age-related immune dysfunction is T cell immunosenescence. There are three causes of T cell immunosenescence. One is the age-related hematopoietic stem cells (HSCs) deviation from lymphoid lineage to myeloid lineage. Second is the shrinkage of thymus. Third is expansion of T cell clones to cytomegalovirus (CMV). Changes of HSCs also affect immunosenescence. HSCs deviate to myeloid lineage by aging. Both in mice and humans the myeloid-lymphoid ratio elevates by aging, which induces the decline of lymphoid cells (T and B cells) and erythrocytes, and contributes to decline of adaptive immunity. The number of aged B cells decline and affinity and diversity of antibodies are low. Ageing related myeloid deviation increases the number of myeloid cells. However, the oxidative burst and phagocytosis of both neutrophils and macrophages are decreased. The antigen presentation of aged dendritic cells and the cytolysis of natural killer cells are low.

Pro-inflammatory cytokines such as interleukin-6 (IL-6), tumor necrosis factor α (TNF-α) and IL-1β are elevated in elderly people, a state that is called inflammaging, and in conjunction with obesity induce metabolic syndrome, type II diabetes, atherosclerosis, cardiac diseases. However, other reports have shown that pro-inflammatory (M1) macrophages are replaced by anti-inflammatory (M2) macrophages by aging. Here to solve this discrepancy we propose to classify age-related immune changes as follows. Age-related pathological changes are classified as firstly immune cell intrinsic changes caused by aging and secondly as the involvement of immune cells in age-related pathological changes. Increased susceptibility of the elderly to infectious diseases is mainly caused by age-related immune cell intrinsic changes, and is usually called immunosenescence. Metabolic syndrome and other related diseases, which occur at aged people, are mainly caused by immune cell attack in response to age-related tissue changes. Age-related tissue failure is then caused by repeated immune cell attack.

Link: https://doi.org/10.4331/wjbc.v8.i2.129

Many arguments have been deployed in support of greater investment in the development of rejuvenation therapies capable of treating aging as a medical condition, and ultimately bringing an end to age-related disease and mortality. Personally, I'm in favor of rationales based on individual freedom, as "we can try and we want to try" is entirely sufficient, and utilitarian concerns based on reducing the amount of suffering and death in the world. Since aging is by far the greatest cause of human suffering and death, and since the estimated cost of developing working rejuvenation therapies based on the SENS vision is compares very favorably what is spent every year on trying and failing to cope with the harms caused by aging, it only makes sense to forge ahead. Would that everyone saw things so clearly, but of course we don't live in that world yet. Advocacy for rejuvenation research and medicine to control aging is still very much needed, as most people simply don't care, and many are even opposed to this grand project when it is first presented to them.

Biogerontologist Aubrey de Grey, the father of SENS, a plan for the development of rejuvenation therapies based on repair of cell and tissue damage, always likes to answer to all objections and concerns regarding rejuvenation with two general arguments. The core of the first argument can be expressed quite succinctly: are any of the potential problems that might be caused by rejuvenation in the future worse than the actual problem of ageing we have today? By and large, the yardstick by which we measure a problem's magnitude is typically the amount of suffering, misery, and death it inflicts on people. For example, when war breaks out we do regret the destruction of landmarks and infrastructure, but that's hardly how we measure how bad the war was - rather, we speak of how many lives it has claimed or how many people it has maimed. Around 100,000 people die every day of ageing - that is, of the pathologies of old age and their complications. This is a huge number, and it is a whopping 2/3 of the deaths that occur every day (around 150,000). In a year, that adds up to around 36,500,000 deaths. According to the most conservative estimates, around 50,000,000 people died in World War II (1939-1945); on average, that is about 8,400,000 people a year. Thus, in a year, ageing kills about four times as many people as WWII did in the same timespan.

By this measure, the problem of ageing is really bad, killing every day more people than all the other causes of death put together, and causing enormous suffering as well. If we successfully implemented a comprehensive rejuvenation platform, the problem of ageing, and all the misery it causes, would disappear altogether. Do we think that the potential side effects of defeating ageing may be so bad that we would be better off not doing it at all? For each problem that you think the defeat of ageing might cause, you can ask yourself if it would be worse than the problem we have today - the misery, suffering, and death caused by ageing, not to mention the socio-economical problems it causes as well.

The second argument is that we should not presume to know better than the people of the future. There are many objections concerning potential future problems. However, the truth is we know very little about the future, especially compared to what will be known by the people who live in that future. It would be arrogant to assume that a problem today will necessarily be a problem in the future as well. Just imagine if our forefathers two hundred years ago had reasoned: "Vaccines could cause the population to spiral out of control! They would save a lot of lives, but those very lives would go on increasing our numbers, in a way or another, and in a couple of centuries billions of people would be walking the Earth! How could we possibly feed so many mouths? Better to forget about vaccines and let nature take its course. It's a necessary evil."

Today, we are in the same situation as our ancestors in the example above. If we say 'no' to creating rejuvenation today, we would be condemning not only ourselves, but the people of the future as well, to the diseases of ageing; worse still, we would be doing so on the questionable assumption that we know enough about the world of the future to decide rejuvenation would do it more bad than good. If we develop rejuvenation, we will give our descendants (and possibly ourselves) the option to use it; if we don't, we will deny them this option and force them to suffer from aging. One day, our descendants may either be thankful that we gave them a choice between health and disease, or regret that their arrogant and unimaginative forefathers didn't think the matter through before deciding on behalf of humanity of the future.

Link: https://rejuvenaction.wordpress.com/reasons-for-rejuvenation/aubreys-trump-cards/

In just a few short years, the study of cellular senescence has grown enormously. It has become an area of intense interest and funding in comparison to its prior status as a thin sideline of cancer research and a yet another of the backwaters of aging research. Sadly, aging research considered as a whole is still a neglected, poorly funded field of medical science in comparison to its importance to all of our futures, but this will hopefully change soon. The 2011 demonstration of a slowing of degeneration in an accelerated aging lineage of mice via removal of senescent cells opened a great many eyes. A growing number of studies since then have shown reversal of many specific aspects of aging through clearance of senescent cells, and the potential for removal of senescent cells to form the basis for the effective treatment of many age-related diseases. These studies are accompanied by varied approaches to the selective destruction of these unwanted, harmful cells in aged tissues, including several classes of drug compound, gene therapies, and antibody therapies. This is an important transition for the study of aging as a medical condition: the first legitimate, working rejuvenation therapies now exist in their earliest stages. They have become a reality. From here the field will only become ever more promising.

The July issue of EBioMedicine gathers together papers from recent months to focus on aging and metabolism. Prominent in this collection are papers on the biology of senescent cells, the contribution of senescent cells to aging, and methods of selectively destroying senescent cells. I pointed out a few of these when they were first published online earlier this year, but I think it worth looking through the collection as it is presented here. This is the future: the stream that will become a flood, a huge new industry of medicine. It is impossible to work in the medical life sciences without having heard something of this newly important area of research and development. Senolytic therapies capable of safely clearing a large fraction of the burden of senescent cells in old individuals may well do more for health in later life than all of the heralded advances of the past thirty years, statins and early stem cell therapies included. These are exciting times that we live in - and then, I would hope, not too many years from now, we'll be able to say all of this again as glucosepane cross-link breakers become a reality as well, another line of rejuvenation research that should be just as influential, at the very least for cardiovascular health.

Aging and Metabolism: Two Sides of the Same Coin

The mounting challenges healthcare systems face with an aging population are largely due to increased prevalence of noncommunicable diseases (NCDs). In 2015, NCDs accounted for 70% of all deaths globally. 80% of NCD-related deaths are attributed to cardiovascular disease, cancer, respiratory diseases, and diabetes. In this issue find a series of articles discussing diverse aspects of geroscience - the relatively new field of understanding the biology of aging and age-related disease. At the core of geroscience research is the dogma that aging is not simply an immutable outcome of life, but that its biological underpinnings, once understood, can be manipulated to improve health. From the series of pieces presented in this issue, it becomes apparent that aging and age-related disease are intimately entangled with metabolic function, both at the molecular/cellular and organismal levels. The etiology of cardiovascular disease, cancer, lung, liver, and kidney dysfunction, and diabetes can be at least in part attributed to metabolic defects associated with increasing age.

Cellular senescence describes the phenomenon where somatic cells cease to divide, become resistant to apoptosis, and develop a senescence-associated secretory phenotype (SASP) that can have deleterious effects on surrounding tissues and throughout the body. One article discusses the role of mitochondrial dysfunction in cellular senescence and how breakdown of mitochondrial components (mitophagy) is likely involved in senescence and aging. How telomeres - irrespective of length, contrary to the previous notion that shortened telomeres were simply a readout of a cell's age - can both protect against and effect cellular senescence programs is discussed in another article. Translational approaches to targeting the biological basis of aging is a rapidly-developing field. A third article discusses targeting cellular senescence programs to improve fitness. Among these approaches are so-called senolytic agents, which selectively clear senescent cells and relieve the associated pathophysiology they confer.

Telomeres and Cell Senescence - Size Matters Not

So far, the best explanation for replicative senescence is the shortening of telomeres, regions composed of DNA repeats associated with proteins, found at the ends of chromosomes. In the 1990s, it was shown that telomere regions gradually shorten with cell division and that this correlates with the induction of cellular senescence. Importantly, it was demonstrated that ectopic expression of the enzyme telomerase, which is capable of elongating telomeres, counteracts telomere shortening driven by cell division and bypasses the senescence arrest. This experiment demonstrated that telomere length was the limiting factor in the senescence arrest and therefore played a causal role in the process. Since then, great advances have been made in the understanding of how telomeres are able to signal the senescence arrest. These mechanisms are of particular importance in the field of ageing, since cellular senescence, driven by telomere dysfunction, has been shown to be a causal driver of ageing and age-related pathology.

In recent years, important conceptual advances have been made in terms of our understanding of the role of senescent cells in vivo. It is now clear that the impact of senescence in vivo is not restricted to the loss of proliferative capacity. Apart from the cell-cycle arrest, senescent cells have been shown to experience dramatic changes in terms of gene expression, metabolism, epigenome and importantly, have been shown to have a distinct secretome profile, known as the Senescence-Associated Secretory Phenotype (SASP), which mediates the interactions between senescent and neighboring cells. The SASP includes pro-inflammatory cytokines as well as growth factors and extracellular matrix degrading proteins and is thought to have evolved as a way for senescent cells to communicate with the immune system (potentially to facilitate their own clearance), but also as an extracellular signal to promote the regeneration of tissues through the stimulation of nearby progenitor cells. Nonetheless, it has been shown that a "chronic" SASP is able to induce senescence in adjacent young cells, contributing to tissue dysfunction.

Recent data indicates that senescent cells play a variety of beneficial roles during processes such as embryonic development, tumor suppression, wound healing and tissue repair. On the other hand, senescent cells have been detected in multiple age-related diseases and in a variety of different tissues during ageing. The positive and negative effects of senescence in different physiological contexts may be a reflection of the ability of the immune system to effectively clear senescent cells. It has been speculated that an "acute" type of senescence plays generally beneficial roles in processes such as embryonic development and wound-healing, while a "chronic" type of senescence may contribute to ageing and age-related disease. The role of telomeres in the induction of these two types of senescence is still unclear. In this review, we will first describe evidence suggesting a key role for senescence in the ageing process and elaborate on some of the mechanisms by which telomeres can induce cellular senescence. Furthermore, we will present multiple lines of evidence suggesting that telomeres can act as sensors of both intrinsic and extrinsic stress as well as recent data indicating that telomere-induced senescence may occur irrespectively of the length of telomeres.

Mitochondria in cell senescence: Is mitophagy the weakest link?

Cell senescence is increasingly recognized as a major contributor to the loss of health and fitness associated with aging. Senescent cells accumulate dysfunctional mitochondria; oxidative phosphorylation efficiency is decreased and reactive oxygen species production is increased. In this review we will discuss how the turnover of mitochondria (a term referred to as mitophagy) is perturbed in senescence contributing to mitochondrial accumulation and Senescence-Associated Mitochondrial Dysfunction (SAMD). We will further explore the subsequent cellular consequences; in particular SAMD appears to be necessary for at least part of the specific Senescence-Associated Secretory Phenotype (SASP) and may be responsible for tissue-level metabolic dysfunction that is associated with aging and obesity. Understanding the complex interplay between these major senescence-associated phenotypes will help to select and improve interventions that prolong healthy life in humans.

Cellular Senescence: A Translational Perspective

There is a possibility that senolytics and SASP inhibitors could be transformative, substantially benefiting the large numbers on patients with chronic diseases and enhancing healthspan. That said, as this is a very new treatment paradigm, there are many obstacles to overcome. At least one reassuring advantage of targeting cellular senescence is the conservation of fundamental aging mechanisms such as senescence across mammalian species, however, reducing the risk of results in mice failing to translate to humans. Furthermore, unlike the situation for developing drugs to eliminate infectious agents or cancer cells, not every senescent cell needs to be eliminated to have beneficial effects. Unlike microbes or cancer cells, senescent cells do not divide, decreasing risk of developing drug resistance and, possibly, speed of recurrence. With respect to risk of side-effects, single or intermittent doses of senolytics appear to alleviate at least some age- or senescence-related conditions in mice. This suggests that intermittent treatment may eventually be feasible in humans, perhaps given during periods of good health. If so, this would reduce risk of side-effects. Progression from the discovery of the first senolytics to being at the point of initiating proof-of-concept clinical trials has been remarkably fast. With sustained effort and a lot of luck, these agents could be transformative.

Risk of neurodegenerative disease is strongly connected to the health of the cardiovascular system. Lack of exercise and putting on excess weight significantly increase the risk of both cardiovascular disease and forms of dementia. You can't use lifestyle choices to hold back aging entirely; the only way forward towards that goal is the research and development of therapies that can repair the cell and tissue damage that causes age-related degeneration. You can, however, at least make the choice to avoid self-sabotage, even if most other people do not do so in this sedentary age of cheap calories. How greatly can you benefit from a good lifestyle alone? Researchers here examine epidemiological data and estimate that about a third of dementia cases might be preventable, though I think the tone is a little self-congratulatory given the present poor state of treatment options and outcomes.

"There's been a great deal of focus on developing medicines to prevent dementia, including Alzheimer's disease. But we can't lose sight of the real major advances we've already made in treating dementia, including preventive approaches." A recent commission brought together international experts to systematically review existing research and provide evidence-based recommendations for treating and preventing dementia. About 47 million people have dementia worldwide and that number is expected to climb as high as 66 million by 2030 and 115 million by 2050.

The commission's report identifies nine risk factors in early, mid- and late life that increase the likelihood of developing dementia. About 35 percent of dementia - one in three cases - is attributable to these risk factors, the report says. By increasing education in early life and addressing hearing loss, hypertension and obesity in midlife, the incidence of dementia could be reduced by as much as 20 percent, combined. In late life, stopping smoking, treating depression, increasing physical activity, increasing social contact and managing diabetes could reduce the incidence of dementia by another 15 percent. "The potential magnitude of the effect on dementia of reducing these risk factors is larger than we could ever imagine the effect that current, experimental medications could have. Mitigating risk factors provides us a powerful way to reduce the global burden of dementia."

The commission also examined the effect of nonpharmacologic interventions for people with dementia and concluded that they had an important role in treatment, especially when trying to address agitation and aggression. "Antipsychotic drugs are commonly used to treat agitation and aggression, but there is substantial concern about these drugs because of an increased risk of death, cardiovascular adverse events, and infections." The evidence showed that psychological, social and environmental interventions such as social contact and activities were superior to antipsychotic medications for treating dementia-related agitation and aggression. The commission also found that nonpharmacologic interventions like group cognitive stimulation therapy and exercise conferred some benefit in cognition as well.

Link: https://www.eurekalert.org/pub_releases/2017-07/uosc-e1i071717.php

In this research, it is shown that centenarians have a lower burden of disease than people who die at earlier ages. You might compare it with very similar results noted last month. Aging is the accumulation of molecular damage and its consequences; the only way to reach later ages is to be less damaged or more resilient to the consequences of damage. It would be very surprising to find that the longest-lived people are more damaged, rather than less, so the results here are the expected outcome for such a study. Nonetheless, centenarians are still frail and greatly impacted by aging - their state of being is not a goal to aim for via medical technology. Instead we should be looking at ways to turn back the causes of aging for everyone, to produce outright rejuvenation, not merely a slightly slower decline.

Researchers have been studying illness trajectories in centenarians during the final years of their lives. According to their findings, people who died aged 100 or older suffered fewer diseases than those who died aged 90 to 99, or 80 to 89. Forty years ago, life expectancy was such that, in the industrialized world, only (approximately) one in 10,000 people were expected to reach the age of 100 or more. Today's estimates suggest that half of all children born in the developed world during this century will live to at least 100. Therefore, the question that poses itself is whether extreme old age is necessarily associated with increased morbidity. There is evidence to suggest that centenarians develop fewer diseases than younger cohorts of extreme old people. In discussions surrounding the issues associated with aging populations, this is referred to as the 'compression of morbidity' hypothesis - a term which describes the phenomenon of the onset of disability and age-related diseases being increasingly being well into old age, resulting in a shortening (or compression) of this phase.

Using diagnoses and health care utilization data routinely collected by the German statutory health insurance company Knappschaft, the researchers studied relevant events during the final six years of life of approximately 1,400 of the oldest old. For the purposes of analysis, this cohort was then divided into three groups. Data on persons who had died aged 100 or older were compared with random samples of persons who had died in their eighties or nineties. The analysis, which included data on very old persons living in their own homes as well as data on those living in residential care, focused on comorbid conditions classified by the Elixhauser Comorbidity Index as being usually associated with in-hospital mortality. "According to the data, centenarians suffered from an average of 3.3 such conditions during the three months prior to their deaths, compared with an average of 4.6 conditions for those who had died in their eighties."

If one includes disorders commonly associated with extreme old age, such as different types of dementia and musculoskeletal disorders, approximately half of all centenarians recorded a total of five or more comorbid conditions. The same number of comorbid conditions was found in 60 percent of persons who had died in their nineties and 66 percent of persons who had died in their eighties. While different types of dementia and heart failure were found to be more common among centenarians than among the younger cohorts, high blood pressure, cardiac arrhythmia, renal failure, and chronic diseases were less common in those who had died after reaching 100 years of age. The incidence of musculoskeletal disorders was found to be similar in all three age groups.

Link: https://www.charite.de/en/service/press_reports/artikel/detail/gesellschaft_im_wandel_100_ist_die_neue_80/

The immune system is highly influential in the processes of regeneration. Inflammation is a key marker of the types of immune cell involved and the sort of activities they are undertaking, either helping or hindering regeneration, and greater levels of inflammation are usually a bad thing. Researchers have demonstrated enhanced healing by ensuring that fewer of the more aggressive and inflammatory class of macrophage cell are present in injured tissue, for example. Further, it is known that aspects of aging such as immune system dysfunction and the growth in number of senescent cells can disrupt regeneration, and inflammation appears to be an important component there also. Is inflammation a direct cause of failing regeneration, or is it more of a signal that other processes are at work, and those processes happen to coincide with greater inflammation?

In the paper here, researchers investigate this question in a subset of the broader problem. They are interested in the development of stem cell therapies as a treatment to accelerate wound healing. Wounds are inflammatory environments, however, and this isn't helpful when it comes to the survival of transplanted cells. The researchers find that one approach to suppressing inflammation can be beneficial in this scenario; this extends the common theme of inflammation as a hindrance to healing found in other areas of research relevant to enhancing existing regenerative processes. We are probably going to see much more on this topic in the next few years, especially if other research groups can find ways to improve the outcome of cell therapies via similar methodologies. In the long run, however, more sophisticated means of suppressing inflammation may be of greater important when it comes to adjusting native cell behaviors and capacity for regeneration. This is very much needed in older individuals.

Reducing inflammation protects stem cells during wound repair

Inflammation is normal in wound healing. As wounds heal, white blood cells, such as those called macrophages, are attracted to the wound site and release substances called cytokines that cause an inflammatory response. At the wound site, enzymes such as cyclooxygenase-2 (COX-2) also become more active and contribute to the inflammation. This inflammation is important in the normal healing process, affecting tissue growth and blood flow changes that allow the tissue to heal; when the inflammation subsides, skin cells start growing to cover the wound and help the tissue knit together. In chronic wounds, however, inflammation can be more extensive and prolonged. This is bad news for any stem cells that might be injected into a chronic wound to help heal it. Stem cells are not like typical drugs - they are alive, and like all life forms, they can die in a hostile environment. The harsh inflammation in chronic wounds kills many of the injected cells, and this is one of the reasons why, so far, stem cells have not worked as a treatment for chronic wounds.

Researchers hypothesized that celecoxib, a common anti-inflammatory drug that selectively inhibits the pro-inflammatory enzyme COX-2, would improve stem cell survival and treatment outcomes for chronic wound therapy. To test their hypothesis, the group used an experimental wound model in mice. The researchers split the mice into four groups. They left a control group completely untreated and treated the second group using mouse stem cells from bone marrow, which they injected into the skin near the wound. They treated a third group orally using celecoxib, and the final group received celecoxib orally, as well as a stem cell injection into the skin near the wound. After a week, the scientists examined the wound tissue for healing and inflammation, and checked if the stem cells had survived.

As expected, the wounds showed an inflammatory response over the duration of the experiment. However, the mice treated using both celecoxib and stem cells showed better wound healing and more tissue growth a week later, compared with untreated mice or mice treated using stem cells or celecoxib alone. A significantly higher amount of stem cells had survived and integrated into the wound tissue in mice that had received celecoxib. So far so good, but did celecoxib have any direct effects on the stem cells themselves? The scientists found that celecoxib directly increased stem cell differentiation into keratinocytes - skin cells required for wound healing. By helping the stem cells to survive and encouraging them to differentiate into skin cells, celecoxib produced a two-pronged healing effect.

Cox-2 inhibition potentiates mouse bone marrow stem cell engraftment and differentiation-mediated wound repair

Engraftment of transplanted stem cells is often limited by cytokine and noncytokine proinflammatory mediators at the injury site. We examined the role of Cyclooxygenase-2 (Cox-2)-induced cytokine-mediated inflammation on engraftment of transplanted bone marrow stem cells (BMSCs) at the wound site. BMSCs isolated from male C57/BL6J mice were transplanted onto excisional splinting wounds in presence or absence of celecoxib, a Cox-2 specific inhibitor, to evaluate engraftment and wound closure. Celecoxib administration led to a significantly high percent of wound closure, cellular proliferation, collagen deposition, BMSCs engraftment and re-epithelialization at the wound site. Thus celecoxib protects transplanted BMSCs from Cox-2/IL-17-induced inflammation and increases their engraftment, differentiation into keratinocytes and re-epithelialization thereby potentiating wound tissue repair.

Macrophages are one of the types of immune cell responsible for destroying potentially dangerous cells, such as those that have become cancerous. Unfortunately cancerous cells tend to circumvent the immune system by displaying molecules on their outer surface that cause macrophages to leave them alone. This is an abuse of recognition mechanisms that exist to protect other cell types. Researchers here show that producing engineered macrophages that ignore this signal can be a viable approach to cancer therapy, even though past attempts have proven too harmful to normal cells to proceed towards the clinic. Their new methodology manages to avoid the destruction of non-cancerous cells to any significant degree, which is a promising step forward for the use of macrophages in cancer immunotherapy.

One reason cancer is so difficult to treat is that it avoids detection by the body. Agents of the immune system are constantly checking the surfaces of cells for chemical signals that say they belong, but cancer cells express the same chemical signals as healthy ones. Without a way for the immune system to tell the difference, little stands in the way of cancer taking over. Now, researchers have learned how to re-engineer macrophages, the "first responders" of the immune system, so that they can distinguish between healthy and cancerous cells. Armed with this ability, the engineered cells were able to circulate through the body of a mouse, invade solid tumors and specifically engulf human cancer cells therein.

​​​​​​​"Our new approach takes young and aggressive macrophages from the bone marrow of a human donor and removes a key safeguard that cancer cells have co-opted to prevent them from being engulfed. Combined with cancer-specific targeting antibodies, these engineered macrophages swarm into solid tumors and rapidly drive regression of human tumors without any measurable toxicity." Immune cell therapies using engineered T-cells have recently emerged as successful treatments for some blood cancers, which are referred to as "liquid" tumors. Tumors in other tissues are generally more solid, which can physically impede the ability of T-cells to penetrate into the mass of the tumor. Macrophages readily infiltrate diseased and damaged tissues, including tumors. As such, macrophage-based cancer therapies were investigated decades ago. While they were found to be safe in patients, they were not effective in destroying cancerous cells. It is now understood that such macrophages received the same "don't eat me" signal from both healthy and cancerous cells.

It was since shown that a protein on human cells called CD47 functions as a "marker of self" by interacting with a protein on the surface of macrophages called SIRPA. When SIRPA contacts CD47 on any other cell, it serves as a safeguard that prevents the macrophage from engulfing the other cell, even if it's cancerous. With that in mind, the researchers thought that controlling this protein might revitalize macrophage-based cell therapies. Injections of antibody molecules that block CD47 from interacting with SIRPA are already being tried in the clinic based on observations of some reduction in the sizes of tumors in mouse models. However, such molecular treatments reproducibly cause rapid loss of many circulating blood cells, as macrophages now attack some healthy cells as well. In addition to causing anemia, some mice with depleted CD47 die from autoimmune disease.

To get around these safety concerns and to potentially maximize therapeutic effects on tumors, researchers took fresh, young macrophages from human donors as well as mouse donors and directly blocked their SIRPA. They also injected various antibodies that bind to cancer cells, which help to activate macrophages that might enter the tumor. "The big surprise is that injected macrophages circulate all around the body but accumulate only within the tumors where they engorge on cancer cells." After two injections, cancer cells were depleted 100-fold from tumors the size of a dime, and tumors regressed 80 percent in size. Importantly, blood cells were unaffected by the treatments, which suggests that this approach is safe.

Link: https://news.upenn.edu/news/penn-researchers-engineer-macrophages-engulf-cancer-cells-solid-tumors

The latest Lifespan.io crowdfunding campaign is in support of AgeMeter development, an infrastructure technology used to assemble the data needed for compound biomarkers of aging built from existing simple health measures. The development of a reliable, accurate, and low-cost biomarker of biological age, that reflects an individual's burden of molecular damage, and thus risk of disease and mortality, is an important topic. Without such a measure, it is very time-consuming to test potential rejuvenation therapies, as the only practical approach is to wait and see what happens over the life span of the test subjects. That is a formidable expense even for mouse studies. With such a measure, most of that work could be replaced with a quick set of tests before and after the use of a potential therapy.

While a great deal of attention is given to biomarker development that is based on patterns of DNA methylation, there is a school of thought that suggests researchers could build something just as useful by suitably combining existing simple measures such as heart rate, blood pressure, grip strength, and so on. The greatest challenge in the development of such a biomarker lies in ensuring accuracy and reliability at the point of data collection, while still allowing large numbers of people to be tested cost-effectively. This initiative seeks to modernize and improve existing approaches, now a more pressing concern given the advent of potential rejuvenation therapies such as clearance of senescent cells.

Centers for Age Control has launched a fundraising campaign on Lifespan.io in support of the AgeMeter, a diagnostic system to measure human functional age. The device is meant to assist in the assessment of therapeutics that address the aging processes during clinical trials, as well as being a useful tool for the general practitioner. As research efforts intensify towards developing effective rejuvenation therapies, the need for cost-effective ways of measuring the rate of aging becomes all the more urgent. An effective functional age test would be a very useful tool in determining this, complementing the data from biochemical tests.

The list of biomarkers AgeMeter will assess includes auditory and visual reaction time, lung capacity, muscle coordination, decision-making time, memory, and a few others, which are reliable predictors of functional age in previous studies. AgeMeter will be used by physicians for the health assessment of patients and to help highlight areas of concern. This will allow a doctor to work with the patient to develop an effective personalised healthcare strategy and could be of great value in helping people to maintain health.

"AgeMeter is a modernized successor to the H-SCAN functional age test that was originally developed in 1990 to assess physical biomarkers of aging. We have gathered an impressive experience in measuring functional age with H-Scan. Now we can make it serve humanity even better. AgeMeter will be a low-cost, modular touch screen device with special peripherals for integrating multiple cognitive and biometric assessment technologies. We hope to not only make a functional prototype suitable for research needs, but also to create software for a user account system for each test participant. This will enable individual users to store and access multiple test results, and therefore analyze the progression of one's metrics over time and in response to potential anti-aging interventions. We believe this is the most valuable part of the project for people who care about their health and want to be sure their lifestyle is good for them."

Link: http://www.leafscience.org/introducing-agemeter/

Considering the whole of the past thirty years, it is fairly safe to say that studies showing improved longevity in animal models have a terrible track record when it comes to the reproduction of findings. Small gains in life expectancy in one study promptly evaporate when it is attempted by other groups. Very few approaches to slowing aging can be reliably reproduced, and the most well-studied of those, calorie restriction, is probably the cause of many of the early failures. It used to be the case that all too few researchers controlled for the effects of calorie restriction: it is easy to make animals eat more or less as a consequence of pharmaceutical interventions, and the results due to changed calorie intake are larger than the results due to most of the interventions tested. The Interventions Testing Program has spent much of the last fifteen years demonstrating that most prior mouse studies of interventions thought to modestly slow aging should be taken with a grain of salt. The same is also true of studies in lower animals, in species with much shorter life spans, but where length of life is affected to a greater proportional degree by environmental influences.

The authors of the open access paper below try to put some numbers to the difficulties involved in picking out small changes in the aging process due to an experimental intervention. The animals involved tend to have quite variable life spans, and are very prone to life expectancy changes based on the details of their environment. This state of affairs requires larger numbers of animals and better statistical approaches to have any confidence in sifting out useful data. But the wrong conclusions are drawn, I think. The point of view of these researchers is that the way forward is to keep on chasing small effects on aging, and to improve the state of experimental design in order to make it more practical to find those small effects.

This is a ridiculous position. What should in fact happen is for the research community to put aside the lines of work that produce only small and erratic effects, stop digging into the biochemistry of exercise and calorie restriction as a gateway to mediocre therapies, and focus instead on biotechnologies with results that are reliable, reproducible, and large enough to be clearly identified even given the challenges. Today that means senolytics capable of clearing senescent cells, cell therapies, amyloid clearance, other line items resulting from the SENS approach of damage repair, and little beyond that short list. If the last few decades has taught us anything, it should be that attempts to tinker with the operation of metabolism in order to slightly slow aging by recapturing some of the effects of calorie restriction are expensive, unreliable, and produce only small gains. Why then is this metabolic tinkering with poor outcomes still the primary choice for most of the research community? It makes little sense, at least to those of us interested in the development of working, effective therapies that can produce rejuvenation in old humans.

Computational Analysis of Lifespan Experiment Reproducibility

Over the last few years, science has been plagued by a reproducibility crisis. This crisis has also taken root in the aging research community, with several high-profile controversies regarding lifespan extensions. Frequently cited reasons for the failure of a result to reproduce are substandard technical ability, lack of attention to detail, failure to control environmental factors or that the initial positive result was a statistical outlier that was never real in the first place. One way to address these reproducibility problems would be to list the numerous controversies and to attempt to identify the individual underlying causes and to provide a possible explanation. This would be a long and arduous task resulting in largely speculative explanation and provide little in terms to resolve future controversies. An alternative way would be to assume that these controversies arise mostly through honest disputes of scientists standing by their results. If so, their frequency would suggest an underlying technical problem with standard practices in the field that foster such disputes. We decided to take the alternative way and to ask how reproducible lifespan experiments are under ideal conditions, in silico, allowing to control every environmental and technical aspect.

One important experimental consideration to minimize both false positive and false negative results is the power of detection (POD), or statistical power of a given experimental design. POD is defined as the probability to appropriately reject the null hypothesis in favor of the alternate hypothesis. For lifespan experiments, where the null hypothesis is that there is no effect on lifespan, the POD is the probability to correctly detect a true lifespan extension. Power calculations are a statistical tool to determine whether the experimental design is sufficient to detect the expected effects size. Power calculations are widely used in long term expensive mouse experiments or in clinical trials to ensure that the planned experiments have the necessary power to detect the expected effect. However, power calculations are rarely employed in experiments to measure the effects of genetic or environmental perturbations that could affect lifespan in invertebrate model organisms such as C. elegans.

In this study, we asked how POD is influenced by different experimental practices and how likely it is that underpowered experiments lead to scientific disputes between two groups conducting identical experiments. To address these questions, we generated a parametric model based on the Gompertz equation using lifespan data of 5,026 C. elegans. We then used this model to simulate lifespan experiments with different conditions to determine how experimental parameters affect the ability to detect lifespan increases of certain sizes. We considered two important experimental features that contribute to the workload of lifespan experiments: frequency of scoring and number of animals in each cohort. Our data show that the POD is greatly affected by the number of animals in each group, but less so by scoring frequency. We further show how inappropriately powered experiments negatively affect reproducibility. Our results make clear that current standard practices are unlikely to produce consistently reproducible results for real longevity effects below 20%, even under ideal conditions.

TDP-43 is known to increase with age, and also forms aggregates observed in ALS and frontemporal dementia, among other conditions. The increased amount of TDP-43 alone, even without aggregates, appears to diminish the cellular housekeeping process of autophagy, with detrimental long term consequences. Artificially reducing the levels of TDP-43 too far will produce other issues, however, as this disrupts correct microglial function in the brain, making the microglia too aggressive when it comes to dismantling synaptic connections between brain cells. Thus building a therapy that targets TDP-43 isn't as straightforward as it might be. Here, researchers look at breaking down the aggregates rather than targeting TDP-43 indiscriminately, an approach that may result in a therapy for TDP-43-related conditions.

Scientists have long known that a protein called TDP-43 clumps together in brain cells of people with amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's Disease, and is associated with neuron death. This same protein is thought to cause muscle degeneration in patients with sporadic inclusion body myositis (sIBM), leading many researchers to think that TDP-43 is one of the causative factors. Now, researchers found that a specific chemical modification called acetylation promotes TDP-43 clumping in animals. Using a natural anti-clumping method in mouse models, the scientists reversed protein clumping in muscle cells and prevented the sIBM-related muscle weakness. "We suspect that getting rid of this abnormal TDP-43 clumping could be a potential therapy for these diseases. In principle, we think this reversal of clumping could be achieved by taking an injectable or oral medication. Though, we caution, that's still a long way off. The research community still has much more work to do."

TDP-43 normally works in the cell nucleus. It binds to DNA and to the RNA molecules transcribed from DNA. The protein appears to have many important functions in regulating how genes are expressed. Somehow - in people with sIBM, ALS, and a few other degenerative diseases - TDP-43 moves out of the nucleus and into the main volume of the cell, or cytoplasm, and then clumps together. The loss of TDP-43 from the nucleus leads to the failure of normal gene expression regulation. Many scientists suspect that this is the major reason why affected cells die. For many years, no one knew how TDP-43 moved out of its normal workspace in the cell nucleus, but a 2015 study identified one possible factor: a chemical modification known as acetylation.

Cells commonly use acetylation to switch the activity of proteins on or off. Acetylation at two spots on TDP-43 caused the protein to detach from RNA. The protein then drifted into the cytoplasm and started to aggregate. This research was done in cells grown in lab dishes. To underscore the potential relevance to human disease, the scientists examined spinal motor neurons from ALS patients and identified aggregates of TDP-43 that had been acetylated in the same way. For the new study, the researchers examined the effect of acetylated TDP-43 in living animals. In this case, they sought to mimic sIBM in mice, in which TDP-43 clumps in muscle cells. "We tend to see sIBM and ALS as resulting from essentially the same TDP-43-related pathological process - the clumping effect - but in different cell types. The advantage of studying sIBM is that muscle cells are much more accessible than are motor neurons, which are affected in ALS."

The team used a special method to inject acetylated TDP-43 proteins directly into mouse muscle cells. In contrast to ordinary TDP-43 proteins, these acetylated proteins quickly aggregated outside the nucleus. The aggregate-burdened cells showed multiple features that are also seen in human sIBM. The researchers observed cellular markers indicating that the muscle cells were actively trying to get rid of the TDP-43 aggregates. The team found that they could boost these cell defense mechanisms and swiftly remove most of the aggregates by adding heat shock factor 1 (HSF1), a naturally occurring protein that is known to work as a master switch for anti-aggregation processes in cells. The researchers now hope to identify compounds suitable for use in oral drugs that have the same anti-clumping effect.

Link: https://www.eurekalert.org/pub_releases/2017-07/uonc-anc071417.php

Despite an enormous amount of effort, researchers have discovered very few human gene variants with reliable effects on longevity across multiple study populations, and even those effects are small. FOXO3 is one of these genes. The current consensus in the face of this data is that variants in thousands of genes contribute to natural differences in human longevity, interacting strongly with one another and with environmental differences, such that the picture is somewhat different in every individual. The usual situation is for any genetic study of longevity to find a few correlations, but those correlations then fail to appear in any other study, even of people in the same region and community. Researchers here suggest that even for FOXO3, the picture is more complicated than thought, and it has less influence on aging than thought.

People who live into their 90s or 100s - beyond the typical life expectancy near 80 for adults - can offer important lessons about healthy aging. Centenarians experience slower aging throughout their lives; live independently well into their 90s and spend only the last relatively few years of their exceptionally long lives with significant diseases or disabilities. Unlike average aging, in the case of people who live into their late 90s and even into their 100s, centenarians appear to benefit from combinations of longevity-enabling genes that likely protect against aging and age-related diseases and disability. FOXO3 could be playing such a role for people who live into their early to mid-90s. The gene had gained quite a bit of attention over the last 10 years as a possible contributor to longevity, but despite a lot of study, the mechanism by which FOXO3 helps people remains murky. The goal of the new study was to better understand the gene's role in survival to not just the 90s but beyond to even more exceptional ages.

The researchers examined genetic data from blood samples of 2,072 extremely old subjects from four centenarian studies: the New England Centenarian Study; the Southern Italian Centenarian Study; the Longevity Genes Project; and the Long Life Family Study. Researchers conducting centenarian studies such as these are working together to discover the biological mechanisms that enable remarkable aging. The researchers found that while FOXO3 did seem to play a role in longevity to a degree, that role did not generally affect living to ages 96 or older for men, or 100 for women - the oldest one percent of the population. "We attended presentations and read scientific papers claiming associations between FOXO3 variants and longevity, yet when we tested for these associations among centenarians, we were unable to reproduce the findings. We suspect that part of the reason may be because these earlier claims were coming from studies made up mostly of people in their 80s and 90s, and not those in their 100s."

Link: http://oregonstate.edu/ua/ncs/archives/2017/jul/new-findings-suggest-genetic-influence-aging-90s-not-beyond

Today, I'll point out a few recent papers relevant to the decline of muscle mass and strength that takes place with aging. The research community is somewhere in the midst of the long process of formally defining this process as a disease called sarcopenia. Formally defined or not, sarcopenia is a significant contribution to the frailty of later aging: the weakness, the risk of falling, the loss of vigor. The papers below are one small part of a large body of work that suggests a fair degree of the total burden of sarcopenia is actually self-inflicted: we live in an age of lethargy, within the embrace of comparative wealth and new technologies of ease and transport. As a consequence some aspects of our decline into old age are faster than they might be, even though we benefit greatly from advances in medical technology in all other facets of health in later life. In short, muscle requires maintenance, and most people are far too quick to give up on that work at the first opportunity.

Beyond a lack of exercise, the remaining portion of sarcopenia is not one of the more simple consequence of aging, however. Rather, it is a twining, partially explored mess of interacting mechanisms. Various studies provide compelling evidence for the role of inflammation, stem cell decline, cellular senescence, neurological decline in the links between muscle and nervous system, reduced protein intake in the typical diet of older individuals, an age-related failure to process dietary amino acids, and many more. They are probably all correct, insofar as they each examine only one narrow portion of the progressive disarray of very complex systems. The parable of the blind men and the elephant is frequently invoked in relation to aging research, and with good cause.

I would say that the best approach to the treatment of sarcopenia, as for many portions of the whole of age-related degeneration, is to pursue efforts to repair the known forms of fundamental damage that cause aging. Even if we cannot yet fully trace the consequences of this damage from start to end, the research community should still attempt to reverse it. It is faster to fix the damage and see what happens as a result than it is to map the changing biochemistry of aging at the detail level. If both courses of action proceed in parallel, we can have our cake and eat it, first striking at the root of the problem and then going on to untangle the foliage at our leisure.

Epidemiology of Sarcopenia: Determinants Throughout the Lifecourse

This review of the epidemiology of sarcopenia documents evidence of the differential peak and rate of decline for three components linked to the disorder: muscle mass, strength, and physical function. Differences are also apparent in relation to the peak level and subsequent loss rate of these characteristics between men and women; between ethnic groups and over time. The data suggest that the rate of decline in muscle mass is much less rapid than that in muscle strength. This, in turn, is much less pronounced than the rate of decline in physical function. Men have significantly higher levels of muscle mass, strength and function at any given age than women. In contrast, rates of decline seem similar between the genders, for each of the three characteristics.

Environmental risk factors for all three components of sarcopenia include sedentary lifestyles, adiposity, and multi morbidity. The role of cigarette smoking and alcohol consumption are much less apparent than have been observed in studies of osteoporosis or cardiovascular disease. Nutrition has been identified as having an important influence on the development of sarcopenia; in particular, protein intake has the potential to slow the loss of muscle mass, but does not appear to be as influential as in maintaining muscle strength or physical function. Physical activity, in particular resistance training, when performed at higher intensities appears beneficial for muscle strength and functioning. Trials combining protein supplementation and physical activity show promising results in reducing the decline in muscle strength and function with advancing age.

Changes in health-related quality of life in elderly men after 12 weeks of strength training

Muscular strength is associated with functional ability in elderly, and older adults are recommended to perform muscle-strengthening exercise. Understanding how improved muscle strength and -mass influence general and specific domains of quality of life is important when planning health promotion efforts targeting older adults. The aims of the present study were to describe changes in health-related quality of life (HRQOL) in older men participating in 12 weeks of systematic strength training, and to investigate whether improvements in muscle strength and muscle mass are associated with enhancements in HRQOL.

We recruited 49 men aged 60-81 years to participate in an intervention study with pre-post assessment. The participants completed a 12-week strength training program consisting of three sessions per week. Tests and measurements aimed at assessing change in HRQOL, and changes in physical performance (maximal strength) and physiological characteristics. Muscle mass was assessed based on changes in lean mass (leg, trunk, arm, and total), and strength was measured as one-repetition maximum in leg extension, leg press, and biceps curl. Two of the eight HRQOL scores, role physical and general health, and the physical component summary scores, increased significantly during the intervention period. Small significant positive correlations were identified between improvements in muscle strength, and better physical and social function. Moreover, a significant increase in total muscle mass was seen during the intervention period.

Impact of Aging and Exercise on Mitochondrial Quality Control in Skeletal Muscle

Skeletal muscle accounts for approximately 40% of total body mass, and it plays an indispensable role in locomotion and metabolism. Skeletal muscle undergoes a gradual loss of fat-free mass, size, and function in the aging process, called sarcopenia. The etiology of sarcopenia is complex and involves the interplay of various factors such as oxidative stress, physical inactivity, imbalanced protein homeostasis, apoptosis, inflammation, malnutrition, and/or mitochondrial dysregulation. Mitochondria play an essential role in the aging-related muscle deterioration because of their importance in the production of energy and reactive oxygen species (ROS), apoptotic signaling, and calcium (Ca2+) handling. Thus, the natural aging process, along with coincident inactivity, progressively impairs mitochondrial integrity which might be a leading factor for sarcopenia.

Mitochondrial quality control in aging skeletal muscle is regulated via mitochondrial biogenesis and mitochondrial turnover; however, the regulation of these processes seems to be less sensitive to the effects of exercise compared to that in young, healthy muscle. Regulation of mitochondrial quality in skeletal muscle can be also accomplished by other cellular systems including ubiquitin proteasomal degradation, lysosomal regulation, and apoptosis. In particular, the lysosomal system has been recently suggested as a key player for regulating autophagy/mitophagy, as well as mitochondrial energy balance. Indeed, a key component of lysosomal biogenesis, the transcription factor TFEB, appears to determine exercise capacity, and we have suggested a coordinated function between TFEB and PGC-1α during both denervation- and CCA-induced skeletal muscle remodeling, suggesting an importance of maintaining a balance between mitochondrial biogenesis and lysosomal system for the muscle quality control. Therefore, it will be interesting for future studies to examine aging-related alterations in the lysosomal system in skeletal muscle, as well as to study how endurance and/or resistance exercise regulates lysosomal capacity in aging muscle. These findings will suggest a possible pharmaceutical target for improving aging-related mitochondrial dysregulation in skeletal muscle.

This open access review looks over present opinions on whether or not alternative splicing is important in aging, and in the creation and harmful activities of senescent cells in particular. Alternative splicing refers to the fact that a single gene can code for different proteins. Changes in the ratio of production for these alternative proteins for any specific gene might be either a form of disarray caused by molecular damage or a reaction to rising levels of cell and tissue damage - essentially another form of genetic regulation that, like epigenetic decorations to DNA, changes with age.

The summary in this paper is that the picture is very complicated and poorly understood at present, as is the case for much of the detail level of cellular metabolism and the ways in which it changes over the course of aging. Fortunately we don't need a full understanding in order to produce significant benefits by selectively destroying the lingering senescent cells found in old tissues; this is the great advantage of therapeutic approaches that target the known root causes of aging. A full accounting of the way in which these causes contribute to aging, in detail, over time, is unnecessary for first generation therapies, making this a much faster and cheaper road to treating aging as a medical condition.

At the cellular and molecular levels, the aging phenotype varies between tissues but can include common hallmarks such as genomic and epigenetic instability, mitochondrial dysfunction, telomere attrition, and the accumulation of senescent cells. Considered as one of the causes of age-related tissue degeneration, cellular senescence is an irreversible and programmed cell-cycle arrest that occurs in most diploid cell types. Senescence is associated with large-scale changes affecting a variety of processes such as cytokine secretion through the senescence-associated secretory phenotypes (SASPs), alterations in gene expression, and alternative splicing, as well as chromatin remodeling that includes senescence-associated heterochromatin foci (SAHF).

Although replicative senescence is linked to telomere attrition, telomere shortening is not necessarily required for the onset of senescence, implying the existence of different senescent programs. Consistent with this view, telomere-independent senescence can be controlled by pathways triggered by insults (stress-induced senescence), as well as by other intrinsic signals that occur during embryonic development and tissue repair. Notably, senescence can also be engaged by the hyperactivation of factors, such as RAS, that promote cell growth, a process known as oncogene-induced senescence that may be linked to telomere dysfunction. While the exact connection between senescence and organismal aging is still much debated, it has become increasingly clear that cellular senescence plays a role in some age-related diseases and in tissue degeneration associated with aging.

As senescence and aging are characterized by global cellular and molecular changes, it is fair to expect that splicing control will also be subjected to alterations. The challenge is to determine whether these changes are collateral or direct effects, and how they contribute to senescence and aging. Several reviews have recently presented splicing defects linked to age-associated diseases, such as neurodegenerative disorders and cancer. Given the challenges associated with maintaining homeostasis in cells and tissues subjected to constant internal and external insults, we can anticipate that a subset of mutations and epigenetic changes may alter the expression or activity of spliceosome components and splicing regulatory factors. These changes may, in turn, alter the splicing profile in several transcripts, resulting in a cascade of alterations that may either activate senescence, promote apoptosis, or elicit tumor formation. Although senescence and apoptosis may protect against tumor formation, the gradual accumulation of senescent cells will elicit tissue degeneration and organ dysfunction. While progressive age-related disturbances in homeostasis do indeed correlate with a broad range of alterations in alternative splicing, the current challenge is to determine whether a specific splicing change contributes to the aging phenotype or is simply a consequence with little or no functional impact.

Although we reviewed the impact of selected splice variants on aging, regulatory networks likely coordinate the production of splice variants from different genes to maximize functional outcomes that determine cell fate, and ultimately the aging phenotype. Consistent with this proposition, the activity of p53 in senescence and apoptosis can be modulated by SIRT1 and ING1, in turn affecting ING1 signaling and SIRT1 activity. Extending these relationships to the full repertoire of splice variants for all the components of the extended p53 regulatory network may be required to determine how important is the level of coordination and feedback involved in the production of splice variants contributing to aging. Already, the splicing regulatory proteins SRSF1, SRSF2, SRSF3, and SRSF6 are emerging as central players coordinating multiple splicing decisions in age-relevant and senescent transcripts. To help clarify the contribution of an expanding list of splice variants and regulators associated with aging, it would be useful to combine expression assays with the monitoring of phenotypes like cell growth and the production of senescent markers. Likewise, it would be informative to determine whether and how SASP components produced by senescent cells reprogram the splicing profiles of neighboring cells.

Link: https://doi.org/10.1111/acel.12646

Here, researchers provide evidence for a correlation between the rate of errors in translation, a step in the process by which proteins are produced from their genetic blueprints, and species longevity. Infrequent errors in the creation of proteins may be only a short-lived form of damage, as a low level of defective proteins should be recycled rapidly. It is quite possible that a higher error rate is an evolutionary consequence of short life spans, rather than vice versa. If a species is short-lived because it fills an environmental niche characterized by aggressive predation, for example, then evolution will not tend to produce a large investment in repair and systems integrity. Where such systems did exist in ancestors, they are lost in the absence of selection pressure to maintain them in the face of random mutational change. Still, the correlation is there to consider.

The error catastrophe theory of aging was proposed in the 1960s. According to this model, the aging process results from errors in mRNA translation that reduce the fidelity of the protein-translating enzymes leading to increasingly inaccurate protein synthesis, terminating in functional decline, and, ultimately, the death of the organism. This theory, for the first time, proposed that translation fidelity plays a major role in aging. The error catastrophe theory has been challenged by a number of studies in the 1980s. A major caveat of these studies, however, is that many of them were conducted in vitro following ribosome isolation. As the aging process affects entire cellular networks, isolated proteins or other cellular components may not fully recapitulate this in vivo process.

Experimental models where translation fidelity was experimentally perturbed displayed shortened lifespan and susceptibility to disease. For example, mutations in tRNA genes and tRNA processing enzymes have been linked to various human diseases. These studies underscore the importance of translation fidelity for maintaining organismal health. However, to prove that a process controls aging and longevity, ideally one would have to improve this process and show that it leads to lifespan extension. In the last decade, it was established that modulating the translational machinery can extend lifespan in a variety of organisms. Inhibition of the highly conserved target of rapamycin (TOR) pathway by mutations or chemical inhibitors such as rapamycin results in downregulation of protein synthesis and lifespan extension. The mechanisms explaining the life-extending effects of TOR inhibition are not fully understood, but most evidence points toward preferential translation of specific transcripts involved in stress response, rather than improved fidelity of translation. This leaves an open question whether translation fidelity plays a role in aging, and whether it is possible to improve translation fidelity.

A study by our group showed that the longest lived rodent, the naked mole rat (NMR) has significantly increased translational fidelity in comparison to a short-lived mouse. To examine the role of translational fidelity in aging, we tested whether translational fidelity co-evolved with species maximum lifespan. We examined translation fidelity in rodent species with diverse maximum lifespan ranged from 4 to 32 years. We found a strong correlation between the frequency of mistranslating the first and second codon positions and the maximum lifespan in 16 rodent species. This correlation remained significant after phylogenetic correction by the method of independent contrast, indicating that translation fidelity co-evolved with longevity. The fidelity of mistranslation at the third position and the misreading of a stop codon did not correlate with maximum lifespan, possibly due to the wobble effect at the third codon position, and to extremely low frequency of misreading the stop codon in all species. These results provide evidence that translation fidelity is an important factor in determining species lifespan.

Link: https://doi.org/10.1111/acel.12628

Aubrey de Grey, advocate for radical life extension and originator of the Strategies for Engineered Negligible Senescence (SENS) research programs, has derived a great deal of mileage from his assessment that it is possible to achieve life spans of 1000 years or longer, as illustrated in the brief interview below. Life spans of centuries and longer can be achieved by progress in biotechnology sufficient to bring aging under medical control, but the important point is that this progress doesn't have to happen all at once. For so long as the early rejuvenation therapies are good enough to add a decade or two of healthy life, that gives additional time to improve those therapies and obtain access to greater and more efficient means of rejuvenation. A tipping point of actuarial escape velocity is reached and remaining healthy life spans increase at a faster pace than one year of additional life expectancy with every passing calendar year. For there onwards, life expectancy is no longer limited by aging and disease.

Could Human Beings Live For 1,000 Years?

What have been the major advances at SENS and why haven't life-extension programmes gone mainstream yet?

Over the past two years we've had a slew of breakthrough publications in journals such as Science, Nature Communications and Nucleic Acids Research that reported key advances against the most intractable components of aging. It's no exaggeration to say that in at least a couple of cases we have broken through logjams that have stalled key areas for over 15 years. You may feel that eight years is a long time to be only making such preliminary, step-one breakthroughs, but you'd be wrong - step one is always the hardest, and that is why nearly all research, whether in academia or in industry, is immensely biased towards the low-hanging fruit and against the high-risk high-reward work that is so essential for long-term progress. We exist as an independent foundation for precisely that reason. But, saying that, I must also stress that we are already showing great success in taking enough steps so that our programmes become investable. The atherosclerosis one was the first of, at this point, five start-ups that have emerged from our projects - covering conditions as diverse as macular degeneration, senescent cells, amyloid in the heart, and organ transplantation.

What are the key therapies that will create a 1,000-year-old human?

It's critical to understand, and yet it's almost universally overlooked, that my prediction of such long lifespans for people who are already alive divides into two phases. The first phase consists of the therapies that SENS Research Foundation is working on right now, along with parallel initiatives that have achieved sufficient traction that we don't need to be their engine room anymore; most importantly, a variety of stem-cell therapies. The other ones are also one or another kind of damage repair or obviation - removing waste products, rendering mutations harmless, restoring elasticity. They combine to restore the molecular, cellular structure and composition of the middle-aged (or older) body, and thereby its function (both mental and physical), to how it was as a young adult.

But that's only the first phase and I have always stressed that I don't anticipate more than about 30 years of additional life arising from it. That's a lot when compared to anything we can do today, but it's not four digits. My prediction of four digits comes from the second phase, which arises from the critical fact that phase one buys time. If you're 60 and you get a therapy that makes you biologically 30, then, yes, you will be biologically 60 again by the time you're chronologically 90. Sure enough, the therapies won't really work any more, because the damage that has made you biologically 60 again is, by definition, the more difficult damage, the damage that the therapies don't repair. But this is 30 years on, and that's an insanely long time in any technology, including medical technology. So, when you're 90 you will have access not just to the same therapies that you had 30 years ago, but to improved ones that can repair a whole bunch of the damage that the first-generation ones couldn't. So they will work. They still won't be 100 percent perfect, but they won't need to be; they will just need to be good enough to 're-rejuvenate' you so that you won't be biologically 60 for the third time until you're chronologically 150 or whatever. And so on.

What is more important in reducing aging: medical therapies, drugs, or lifestyle changes?

I'm all for lifestyle optimisation, but you have phrased your question as a comparison and, for sure, the answer is that lifestyle optimisation can only, ever, make a very small difference - a year or two - to how long we stay healthy and thereby to how long we live. Now, medicines and drugs that we have today are equally modest in their effects, and that's why people die today at ages only slightly older than their parents. But within the next couple of decades we have, I believe, a very good chance to change that scenario completely.

Is anyone testing your therapies at the moment on humans?

Sure, but only a subset of them. Some of the easiest components of SENS are already in clinical trials, such as stem cells for Parkinson's disease. Others, including ones spun out from SENS Research Foundation's research, may get there within a year or two. But some are probably 10-15 years out still. Those ones are just as critical as the easier ones, so we are working as hard as we can to accelerate them, but we're devastatingly limited in that regard by shortage of funds.

Since the aging research community was quite hostile towards discussions of life extension up until comparatively recently, it took an outsider to point out the obvious: that it seemed plausible to achieve rejuvenation by repairing the molecular damage that appears to cause aging, and given even initially modest rejuvenation, the inevitable outcome would be actuarial escape velocity and life spans that stretched off into the far distance. It has to be said that there are advocates in the community these days who are quite uncomfortable with discussions of radical life extension of decades and centuries: but it is very, very important to put it on the table. Many of the strongest supporters in the early days of rejuvenation research were drawn to SENS by the prospect of greatly extending life spans, and by the first reasonable, plausible program that offered the potential to achieve this goal.

Further, consider that the aging research community now includes a great many people willing to argue for and work on approaches that might add a couple of years of additional life. Like the Longevity Dividend folk, they put forward grand proposals for large-scale funding, but only aim to extend human life expectancy by 5 or 10 years by 2030 or 2040, and explicitly deny any interest in extending maximum life spans. These unambitious goals are to be achieved through approaches such as calorie restriction mimetics, autophagy enhancement, or other metabolic tinkering. This is weak medicine, and if it is the only argument being put forward to the public, then we have already lost. There is no real difference between achieving nothing and achieving the Longevity Dividend; we all still age and die on roughly the same schedule.

If billions are to be spent and the careers of thousands of researchers devoted to this field, then let it be in pursuit of technologies that have the chance of bringing an end to aging. Let the goal be to build rejuvenation therapies that can in principle prevent and reverse the causes of degeneration, not just slow it down a little. The bottom line is that we must advocate for rejuvenation research and radical life extension if we want to benefit from meaningful results in our lifetimes. If we don't carry this flag forward, then we either end up with the Longevity Dividend or nothing, and our lives end in pain and decline in the same way and on the same schedule as those of our ancestors, with the sole difference being that we turned our backs on the opportunity that they never had.

Prior to a few years ago, senescent cells were a research backwater, and this state of affairs persisted for far too long given the evidence for their importance in degenerative aging. As a result, the standard assays for the presence of cellular senescence are going on twenty years old, an eternity in biotechnology development. The current thinking on senescent cells in the now revitalized field is that these methods are too crude, and that there are likely many varieties of senescence with significant differences from one another. While it is perfectly possible to build viable senolytic therapies today, producing benefits to health and longevity by selectively destroying at least some of the burden of senescent cells in old individuals, better and more comprehensive second generation therapies will require a correspondingly improved understanding of cellular senescence as a phenomenon - and certainly better assays for quantifying the presence of these cells.

Senescent cells accumulate with age, and can cause or contribute to several degenerative diseases of aging. These effects might stem from the fact that senescent cells cannot divide and therefore cannot create new cells to maintain tissue homeostasis. However, as senescent cells generally comprise a minority of cells within even very old tissues, it is more likely that senescent cells drive age-related disease cells via signaling effects. Indeed, senescent cells secrete a myriad of inflammatory cytokines, chemokines, proteases, and growth factors, the senescence-associated secretory phenotype (SASP), that can have potent effects on tissue microenvironments and thus drive age-related pathologies by mechanisms that extend beyond the loss of proliferative potential.

Traditional gene expression analyses that compare transcriptional profiles of cell populations are limited because they measure average of gene expression levels across the entire population. For example, two populations of 5000 cells each might show a twofold difference in the mRNA level of a particular gene, but this change could result from every cell expressing twice as much mRNA, or from a single cell expressing 5000 times more of that mRNA. The difference between these possibilities could have enormous phenotypic consequences in the context of a tissue. Single-cell approaches offer advantages over population studies because they can distinguish between these types of scenarios. Single-cell analyses also require fewer cells and therefore can be used to interrogate the phenotypes of rare cells, such as senescent cells produced during organismal aging.

To assess the contributions of individual senescent cells to known senescent phenotypes, we conducted quantitative PCR analyses of single quiescent and senescent cells from cultured populations of human fibroblasts. From these analyses, we find that (i) virtually all senescent cells display a gene expression signature that distinguishes them from their quiescent counterparts; (ii) nonetheless, the expression of most genes is more variable in senescent cells compared to quiescent cells; and (iii) there are correlations among genes expressed by senescent cells, including those encoding SASP factors, that localize in genomic clusters. Together, the data demonstrate that senescent phenotypes are more variable than the transcriptional profiles of cell populations previously suggested.

Identifying senescent cells at the single-cell level is an important technological step for future studies, especially in human tissues. While transgenic mouse models now allow senescent cells to be identified and isolated from mouse tissues, identifying senescent cells in human tissues remains difficult. Our findings emphasize the risk of using a single biomarker to identify senescent cells, whether in culture or in vivo. We recommend using several markers - in our own studies, for example, we tend to use combinations of SA-Bgal activity, loss of LMNB1 expression, HMGB1 relocalization, p16INK4a and/or p21WAF1 expressions, and the expression of strongly upregulated SASP factors. As many inducers of senescence (e.g., telomere attrition, ionizing radiation, bleomycin, and oncogene activation) ultimately induce a DNA damage response, it is likely that many of the factors identified in this study are common to several senescence inducers.

Link: https://doi.org/10.1111/acel.12632

It is becoming clear that the behavior of varieties of macrophage immune cells (including the microglia resident in the central nervous system) is important in regeneration, and may be one of the key distinguishing differences between mammalian species with limited regenerative capacity and proficient regenerators such as salamanders and zebrafish, capable of regrowing lost organs. It is too early to say whether it is possible or plausible in the near future to produce salamander-like regenerative in humans, but adjusting macrophage behavior appears quite promising based on the human research to date. The results noted here tie this macrophage-based approach to enhanced regeneration in mammals to the mechanisms of regeneration in zebrafish, adding more evidence to suggest that it is a good direction for continued research and development.

Researchers report evidence that zebrafishes' natural ability to regenerate their eyes' retinal tissue can be accelerated by controlling the fishes' immune systems. Because evolution likely conserved this mechanism of regenerative potential in other animals, the new findings may one day advance efforts to combat degenerative eye disease damage in humans. Both human and zebrafish eyes contain Müller glia, an 'inducible' stem cell type that gives zebrafish their remarkable regenerative abilities. The researchers found evidence that microglia, a cell type found in most vertebrae innate immune systems, affect the Müller glia's regenerative response and can be harnessed to accelerate the growth of new tissue in the retina. For the study, researchers created a model of the human degenerative retinal disease, retinitis pigmentosa, in zebrafish by incorporating a gene for a specialized enzyme into the rod cells of the fish retina. The enzyme has the novel ability to convert a chemical, metronidazole, into a toxin, which allows researchers to selectively kill the cells expressing it.

After initiating photoreceptor loss in the fish retinas, the researchers monitored the immune system's response by tracking the activity of three types of fluorescently labeled immune cells in and around the eye: neutrophils, microglia and peripheral macrophages. They found that neutrophils, the type of immune cells that are typically the first responders to tissue injury, were largely unresponsive to photoreceptor death. They also observed that the peripheral macrophages sensed the injury, but were unable to penetrate the blood-retinal barrier to access the dying cells. Microglia were the only cells the researchers saw that were able to both respond to the injury and reach the injured cells.

Building on the evidence that microglia were in play during injury, the researchers conducted tests in zebrafish with the specialized enzyme incorporated into both rod cells and microglial cells, removing both cell types to ask what role microglia play during regeneration. They found that when microglia were also lost, Müller glia showed almost no regenerative activity after three days of recovery, compared with approximately 75 percent regeneration in the control population. They then used an anti-inflammatory drug, dexamethasone to see if they could speed up regeneration in the zebrafish retinal tissue. Microglia come in two forms - M1, which is associated with inflammation; and M2, which is associated with repair. The researchers believed that by triggering the microglia to transition from phase 1 to phase 2 more quickly by using the drug, they could improve the zebrafishes' regenerative capabilities.

After using the enzyme to cause rod cell death in the fish, the researchers added the anti-inflammatory drug to the water to reduce microglia reactivity. The researchers saw a 30 percent increase in retinal regeneration at day 4 of recovery compared with controls. The researchers hope that by harnessing the ability to improve regeneration in zebrafish, they can better understand how to induce regeneration in human eyes, which share many of the same mechanisms for controlling regenerative potential.

Link: http://www.hopkinsmedicine.org/news/media/releases/immune_system_found_to_control_eye_tissue_renewal_in_zebrafish

Today, I thought I'd point out a few varied publications from the epidemiology research community. They have nothing much in common beyond being interesting and of relevance to the broader understanding of how aging progresses at the present time. The first addresses a common theme in recent years, which is to provide arguments against the misconception that excess weight is in any way beneficial in older age; the second adds data to the debate over whether there is in fact a physical, genetic basis for the correlation observed between intelligence and life expectancy; the third might be taken as an essay-length complaint about the state of the data and methodologies used to assess the degree to which longevity is inherited.

Epidemiology has a long history: if you trace back a great deal of today's aging research far enough, you'll eventually arrive at a starting point consisting of observations of large numbers of humans. Only in more recent decades has it become the case that lines of medical research relevant to aging can spring forth from examining the biochemistry of a few individuals, or of other species. Prior to the development of the tools of modern biotechnology, researchers had to start with the search for patterns in the demographics of life, disease, and death. That approach to medicine still continues today, of course, but it is slowly becoming divorced from those parts of the field that will make the greatest difference to the future of health and longevity.

Epidemiology can tell us things about how aging progresses in the absence of effective means to treat it. It can help to identify the difference between better and worse lifestyle choices, or find bearers of common genetic variants that somewhat improve resistance to the consequences of age-related cell and tissue damage. But epidemiology has nothing to say about the future of rejuvenation therapies: as a field it looks backwards, not forwards. It is the construction of a description of things as they are and were, not as they will be. Treatments capable of repairing the damage that causes aging will change the whole of the picture, and tomorrow will look nothing like today.

Central adiposity and the overweight risk paradox in aging: follow-up of 130,473 UK Biobank participants

For older groups, being overweight [body mass index (BMI): 25 to 30] is reportedly associated with a lower or similar risk of mortality than being normal weight (BMI: 18.5 to 25). However, this "risk paradox" is partly explained by smoking and disease-associated weight loss. This paradox may also arise from BMI failing to measure fat redistribution to a centralized position in later life. This study aimed to estimate associations between combined measurements of BMI and waist-to-hip ratio (WHR) with mortality and incident coronary artery disease (CAD). This study followed 130,473 UK Biobank participants aged 60-69 years (baseline 2006-2010) for 8.3 years (n = 2974 deaths). Current smokers and individuals with recent or disease-associated (e.g., from dementia, heart failure, or cancer) weight loss were excluded, yielding a "healthier agers" group.

Ignoring WHR, the risk of mortality for overweight subjects was similar to that for normal-weight subjects. However, among normal-weight subjects, mortality increased for those with a higher WHR (hazard ratio: 1.33) compared with a lower WHR. Being overweight with a higher WHR was associated with substantial excess mortality (hazard ratio: 1.41) and greatly increased CAD incidence compared with being normal weight with a lower WHR. Thus for healthier agers (i.e., nonsmokers without disease-associated weight loss), having central adiposity and a BMI corresponding to normal weight or overweight is associated with substantial excess mortality. The claimed BMI-defined overweight risk paradox may result in part from failing to account for central adiposity, rather than reflecting a protective physiologic effect of higher body-fat content in later life.

Childhood intelligence in relation to major causes of death in 68 year follow-up: prospective population study

Findings from prospective cohort studies based on populations from Australia, Sweden, Denmark, the US, and the UK indicate that higher cognitive ability (intelligence) measured with standard tests in childhood or early adulthood is related to a lower risk of total mortality by mid to late adulthood. The association is evident in men and women; is incremental across the full range of ability scores; and does not seem to be confounded by socioeconomic status of origin or perinatal factors.

Several hypotheses have been proposed to explain associations between intelligence and later risk of mortality. The suggested causal mechanisms put forward, in which cognitive ability is the exposure and disease or death the outcome, include mediation by adverse or protective health behaviours in adulthood (such as smoking, physical activity), disease management and health literacy, and adult socioeconomic status (which could, for example, indicate occupational hazards). Recent evidence of a genetic contribution to the association between general cognitive ability and longevity, however, might support a system integrity theory that posits a "latent trait of optimal bodily functioning" proximally indicated by both cognitive test performance and disease biomarkers. None of these possibilities are mutually exclusive.

We investigated the magnitudes of the association between childhood intelligence and all major causes of death, using a whole year of birth population followed up to older age, therefore capturing sufficient numbers of cases for each outcome. All individuals born in Scotland in 1936 and registered at school in Scotland in 1947 were targeted for tracing and subsequent data linkage to death certificates. For most endpoints, higher childhood intelligence was associated with a lower risk of cause specific death. Risk of death related to lifetime respiratory disease was two thirds lower in the top performing 10th for childhood intelligence versus the bottom 10th. Furthermore for deaths from coronary heart disease, stroke, smoking related cancers, digestive diseases, and external causes, risk of mortality was halved for those in the highest versus lowest 10th of intelligence. The risk of dementia related mortality and deaths by suicide were reduced by at least a third in the highest performing quarter of intelligence test score versus the lowest quarter.

Historical demography and longevity genetics: back to the future

In the literature, the familial component of human longevity has been investigated using survival to extreme age and age at death as phenotypes of survival. The former actually refers to longevity whereas the latter refers to individual or population based lifespan. Both definitions are often used in the context of longevity research which is confusing and incorrect. Another complication is that most studies exclude infant and child mortality by applying a lower limit age threshold when considering the lifespan of a population or group of individuals. Unfortunately, there is no consensus on the age threshold for longevity studies. As a result of both the inconsistent use of terminology and different lower and upper limit age thresholds, the comparison of longevity studies is generally problematic. We will refer to longevity as survival into extreme old ages whereas lifespan refers to age at death related measures.

Progress in longevity research is also hampered by the fact that longevity is likely dependent on an interplay between combinations of multiple genes and environmental factors which makes it difficult to separate environmental from genetic influences. In fact, environmental influences likely moderate genetic effects on longevity. Several genealogical studies have attempted to estimate the heritability of lifespan and longevity. These studies can be divided into two categories based on the type of data they used; (1) twin data and (2) pedigree data. Unlike animal studies in a lab setting, the effects of the environment on longevity in human studies cannot be controlled. In twins at least the variation in early environment is minimized as compared to other family based studies. In all cases, heritability estimates and the effect of specific gene variants on lifespan and longevity depends on the populations studied and their past and present environmental conditions.

It can be concluded from study results that the heritability of lifespan is between 0.01 and 0.27 in the population at large. The large variation in the heritability estimates indicates a prominent role for differential environmental influences on the estimates. Studies showing that siblings of centenarians and longevous sib-pairs have a high probability to also become a centenarian or longevous, respectively, and studies, which show that longevous parents have a high probability to bear longevous offspring, provide indications that the heritability of longevity may be higher than that of lifespan.

However, the heritability of longevity has only been investigated once in a twin study design, though of limited sample size. In addition, the heritability of longevity has been investigated more often in pedigree studies but the studies raise several questions about their design, sample size, and generalizability. Establishing the heritability of longevity is necessary for case definitions in genetic studies focused on gene mapping. Hence, researchers' attention should shift from lifespan to longevity and the heritability of longevity should be estimated in an appropriate design with a sufficiently large sample.

Cardiac syndrome X has the standard risk factors for cardiovascular disease, which is to say age of the individual and degree of excess fat tissue carried by the individual. It is a comparatively poorly understood variety of structural alteration and failure of blood vessels, however. The risk factors are well known, but the biochemistry is yet to be mapped in full. Here, researchers shed more light onto what is taking place under the hood.

"Older obese patients and sometimes women who suffer heart failure go to the cardiac catheterization lab and the cardiologist finds nothing that would explain their heart failure. They have normal large blood vessels in the heart still the heart failure has developed." What isn't readily seen with these routine exams is the thickened walls that can hinder dilation of the small capillaries fed by these bigger vessels, a condition called coronary microvascular dysfunction, or cardiac syndrome X.

In patients and animal models, who are both older and obese, researchers have found a key dynamic in the dysfunction is an enzyme called ADAM17, which is involved in a huge variety of functions like releasing growth factors as we develop, but also implicated in diseases from Alzheimer's to arthritis. ADAM17 levels increase in obesity while levels of its natural inhibitor, the protein caveolin-1, decrease with age, enabling the perfect storm. ADAM17 was discovered 20 years ago for its ability to cut and release previously inactive tumor necrosis factor, or TNF, from the cell membrane. TNF is a major promoter of inflammation that also directly impacts the function of the endothelial cells that line blood vessels. The scientist found that ADAM17 cleaves TNF from fat, releasing it into the bloodstream where it preferentially targets the heart. The bottom line: the walls of the hair-sized microvasculature become thicker, less elastic, less able to dilate and to properly sustain the heart.

The research team found ADAM17 highly expressed in fat and even higher in the blood vessels of aged human fat. The protein level was increased in younger mice on a high-fat diet, but the significant increase in its activity came with age and fat. In humans, they saw the ability of the tiny vessels to dilate significantly reduced in those ages 69 and older and further reduced in older individuals - males and females - who also were obese. They found ADAM17 present in the fat of young and old mice on high-fat diets compared to normals, but it was only significantly active in the older mice on a high-fat diet. When they looked at younger and older obese patients, again much like the mice, they found high levels of expression of ADAM17 in the lining of blood vessel walls. When they transplanted fat from aged obese mice to younger mice, it increased circulating levels of proinflammatory factors and impaired dilation of the coronary microvasculature. "It basically mimicked the old vascular phenotype in the young animals."

The researchers have started to look at antibodies that would directly target and ideally reduce levels of ADAM17 in the face of aged fat and at least delay development of small vessel disease. They further think a similar process may happen in the brains of older obese individuals, so have ongoing studies of how microvascular disease can lead to Alzheimer's in these individuals. The researchers note that young, obese individuals could help themselves avoid this and likely other diseases like diabetes, by losing weight while they are young.

Link: http://jagwire.augusta.edu/archives/45733

Researchers here demonstrate that reducing the levels of circulating insulin in mice extends life by 10% or so in the best scenario they tested. Insulin, insulin-like growth factor 1 (IGF-1), and growth hormone are all closely linked in their interactions, a well-studied area of metabolism that is connected to the pace of aging through its influence on most of the fundamental activities of cells. Adjusting metabolism to slow aging isn't a promising path forward, however. We can already see the likely bounds of the possible in the known effects of exercise, diet, and calorie restriction, as well as in some human lineages with similar loss of function mutations to those created in long-lived genetically engineered mouse lineages. Slowing down the accumulation of cell and tissue damage can only modestly slow aging. If we want more than that, we must look instead to therapies that repair and reverse this damage so as to produce rejuvenation.

As insulin and Igf1 share nearly identical downstream signaling pathways in mammals, and act in part via hybrid insulin/Igf1 heterodimer receptors that can bind to either ligand, the relative functions of these two ligands have not been completely delineated. Many studies have focused on Igf1 as the primary ligand which mediates the lifespan-altering effects through this signaling cascade in mammals, but the impact of directly altering insulin levels on longevity had not been evaluated.

Insulin resistance is a common feature of mammalian aging and a risk factor for numerous age-related diseases. Although this suggests that reducing insulin signaling could be detrimental for mammalian healthspan, it is important to consider that conventionally defined insulin resistance (i.e., impaired insulin-stimulated glucose disposal) is not a generalized reduction of all insulin signaling. Instead, some insulin-regulated processes are maintained at normal capacity in the "insulin resistant" state, while others are downregulated. Moreover, circulating levels of the insulin ligand are elevated with insulin resistance. The commonly accepted paradigm posits that insulin levels rise as a compensatory response to prevent hyperglycemia when there is insufficient insulin-stimulated glucose uptake. However, causality between the closely associated conditions of systemic insulin resistance and insulin hypersecretion has remained controversial, and it has been suggested that hyperinsulinemia could be an early, primary cause of insulin resistance, obesity, and eventually type 2 diabetes. Genetic loss-of-function experiments targeting insulin itself present an ideal opportunity to disentangle hyperinsulinemia from insulin resistance and to evaluate the lifelong effects of limiting endogenous insulin production and secretion.

To determine how moderately lowering the insulin ligand would affect late-life glucose homeostasis and longevity in mammals, we compared mice with either full or partial expression of the ancestral insulin gene Ins2. Since altering insulin gene dosage does not affect circulating insulin levels in all contexts, we used a mouse model in which the rodent-specific insulin gene (Ins1) was fully inactivated to prevent compensatory Ins1 expression. We designed our experiment to evaluate these animals in the context of two distinct diets (diet A: moderate-energy diet; diet B: high-energy diet). Remarkably, we found that across both diets, mice with reduced circulating insulin levels had improved insulin sensitivity with advanced age and exhibited lifespan extension without changing Igf1 levels. These results suggest a causal contribution for hyperinsulinemia in age-dependent insulin resistance and point to the modest suppression of insulin as a safe and attainable strategy for extending lifespan.

Link: http://dx.doi.org/10.1016/j.celrep.2017.06.048

Today, an update on the Vascular Tissue Challenge arrived in my in-box. It's been a year or so since the Methuselah Foundation and NASA jointly announced the Vascular Tissue Challenge, conducted as a part of the foundation's New Organ initiative. The challenge is a $500,000 research prize intended to draw greater attention to - and investment in - efforts that aim to surmount the greatest present roadblock in the field of tissue engineering: how to build tissues that contain the capillary networks required to sustain them. Natural tissues are packed with capillaries, hundreds passing through every square millimeter examined in cross-section. Reproducing this complexity in artificially grown tissues has proven to be very difficult. Yet other complex aspects of tissue growth have been solved: in the past few years, researchers have demonstrated themselves able to produce near fully functional organ tissues of many varieties. Unfortunately, since capillary networks are not yet a part of this picture, such solid tissue sections are limited in size to a few millimeters in their broadest dimension.

The goal of the New Organ initiative is the construction of patient-matched organs, as needed, from cell samples. To build any sizable tissue requires a life-like vascular network; there is no way around that. Given the impressive progress to date in every other aspect of tissue engineering required, however, it is fair to say that if the research community had a reliable solution for production of integrated blood vessel networks, then manufactured human organs would be only a few years distant. Thus initiatives like the Vascular Tissue Challenge are important; the creation of microscale blood vessel networks is the fulcrum for this field of medical research and development. Solve this challenge, and the first engineered organs are close.

Last June, the Methuselah Foundation and NASA officially launched the Vascular Tissue Challenge (VTC) at the White House Organ Summit, hosted by the Office of Science and Technology Policy. The VTC includes a $500,000 prize purse from NASA for the first teams that can successfully create 1cm or thicker vascularized tissues that remain functional and alive for more than 30 days. Along with this is the Center for the Advancement of Science in Space's (CASIS) "Innovations in Space Award," providing an additional $200,000 to support a research opportunity on board the International Space Station's National Laboratory. With the one year mark just behind us, we thought it was fitting to check in with the teams and see how they're doing. There's been a lot happening to advance these amazing bioengineering technologies over the last 12 months!

Since launching the Vascular Tissue Challenge, seven research organizations officially signed on to pursue the challenge of creating the thick, vascularized tissues required to win the $700,000 in awards along with the opportunity to pursue further research using the microgravity environment onboard the International Space Station. Each team is pursuing a different approach to creating vascularized tissues, and each has their own unique strategies and hurdles ahead. Here is a quick snapshot of what some of the teams have been doing and what they are planning for their next steps toward winning the Challenge before the sunset of the award at the end of 2019.

iTEAMS, Stanford University

Over the past year, iTEAMS has proposed and proved an integrated multi-scale, multi-modular system approach to overcome the challenges and tradeoff in functional vasculature requirements between major vascular lasting perfusion and capillary rapid sprouting and extensive coverage for diffusion. The former requires a slowly degradable biomaterial for sustained perfusion and the latter requires a fast biodegradable biomaterial for rapid sprouting and diffusion. The next steps being pursued are an optimization of perusable channel pathways, biomaterial candidates, and fabrication parameters. A critical upcoming milestone is to demonstrate functional microvasculature at a large scale for a long term in vitro. Team iTEAMS is working towards conducting their Vascular Tissue Challenge trials in 2018.

BioPrinter, Florida Institute of Technology

The team have developed a self-contained bioprinting system that is being used to generate tissue samples with high resolution and cell viability. They plan to use this printer to develop a sacrificial technique of bioprinting channels within a tissue sample. These channels will be used for the exchange of nutrients to cells needed to maintain viable tissue for an extended period of time. Currently, research is being conducted with various concentrations of bioink to obtain values that will result in high quality bioprinted tissue samples. In parallel, research on sacrificial techniques to create channels for nutrient flow is being conducted. The team anticipates that an official trial for the Vascular Tissue Challenge to be initiated in 2018.

Flow, Maize, and Blue, University of Michigan

The team has built a perfusion bioreactor that it is currently optimizing for customized tissue engineered vascular networks. The team hope to accomplish long-term perfusion of these vascular networks in the next 6 months with an official Vascular Tissue Challenge trial occurring sometime after that research is completed.

Techshot

Last summer, Techshot began formal efforts toward winning the Vascular Tissue Challenge by 3D printing biological materials and adult stem cells into vascular and cardiac structures on board a Zero Gravity Corporation aircraft. Test structures were printed during cycles of both zero G and high G forces, permitting evaluation of low viscosity, biological material printing in multiple gravity environments. As expected, the cycles of microgravity facilitated layer-by-layer printing of 3D structures with very low viscosities (these materials become puddles if printed on the ground). The team's next large step forward is a "Tissue Cassette" experiment that will be conducted this summer. Building upon last summer's work, Techshot will bioprint larger cardiac and vascular structures within a specialized container, a bioreactor they refer to as a "Tissue Cassette". This Tissue Cassette will not only provide an appropriate environment for culturing the 3D printed structure, it will impart physical and electrical cues to accelerate cell growth and tissue development. The bioreactor will also permit perfusion of the 3D bioprinted structure to further support cell growth in the larger printed volume.

The planned experiments will start by bioprinting identical sets of cardiac and vascular structures with an initial print size of 20mm x 30mm x 10mm. One set will stay on the ground. The second set will be loaded into a Techshot ADSEP system and launched to the International Space Station aboard SpaceX Cargo Dragon (CRS-12) on August 1, 2017. These experiments will provide insight into bioprinted cell behavior in microgravity and the associated differences in tissue development. This will provide a preliminary test of the technology Techshot plans to use for their Vascular Tissue Challenge trials that they expect to conduct after getting these results back.

Team Penn State, Pennsylvania State University

The team has made substantial progress with their research on micro-vascularization in engineered islets. In addition, the team has scaled up tissue constructs to a sub-cm^3 level and are working on expanding to the cm^3 level for the VTC trial. They have demonstrated viable vascularization with mouse cells and are currently conducting research to overcome technical issues with the co-culture of stem cell-derived human beta cells and microvascular endothelial cells. Finalizing the research to reach vascularization with these cells at the cm^3 level is the next critical step for this team, which they expect to take them into 2018 before conducting their final trials for the VTC.

Team WFIRM Bioprinting, Wake Forest University

During the past year, the WFIRM Bioprinting Team was focusing on the development of tissue-specific bioink systems that could mimic the microenvironments of each target tissues. The team assumes that these tissue-specific bioink systems can enhance the cell-cell and cell-matrix interactions that can accelerate tissue maturation/formation and functions. Up next in the team's research is to combine microvasculature created by endothelial cells with tissue-specific printed constructs. They plan to investigate the effects of endothelialized microvasculature on cell viability and tissue-specific functions of the tissue-specific printed constructs. It is not yet clear when the team's VTC trials will start, more will be known after their next research projects are completed.

Team Vital Organs, Rice University

At Rice University, Team Vital Organs is continuing to build out their 3D printing technology, characterizing the precision, cell viability and activity, designing assays for tissue assessment, and designing proper vascular architectures for complete tissue integration. Perfusion systems are complicated, but the team has a new large incubator that can now accommodate their proposed perfusion systems for the VTC. They are now working on validating long-term sterility and measurements from longitudinal assays. The team is looking forward to finishing these feasibility studies and putting together an official trial to win the Vascular Tissue Challenge within the next year.

Researchers here discuss a new cellular approach to building a biomarker of aging, a way to assess the biological age of an individual. In the SENS view of aging as accumulated molecular damage and its secondary consequences, such a biomarker must reflect the current load of damage present in an individual: people with more damage are older and suffer greater degeneration. The true value of a good biomarker of biological age is that it can be used to significantly speed up research and development, in that it will allow potential rejuvenation therapies to be assessed for their ability to turn back aging far more rapidly, cost-effectively, and accurately than is presently the case.

Sure, you know how old you are, but what about your cells? Are they the same age? Are they older, younger? Why does it matter? A team of researchers is reporting progress in developing a method to accurately determine the functional age of cells, a step that could eventually help clinicians evaluate and recommend ways to delay some health effects of aging and potentially improve other treatments, including skin graft matching and predicting prospects for wound healing.

The researchers devised a system that can consider a wide array of cellular and molecular factors in one comprehensive aging study. These results show that the biophysical qualities of cells, such as cell movements and structural features, make better measures of functional age than other factors, including cell secretions and cell energy. The team examined dermal cells from just underneath the surface of the skin taken from both males and females between the ages of 2 to 96 years. The researchers hoped to build a system that through computational analysis could take the measure of various factors of cellular and molecular functions. From that information, they hoped to determine the biological age of individuals more accurately using their cells, in contrast to previous studies, which makes use of gross physiology, or examining cellular mechanisms such as DNA methylation.

Researchers trying to understand aging have up to now focused on factors such as tissue and organ function and on molecular-level studies of genetics and epigenetics, meaning heritable traits that are not traced to DNA. However, the level in between, the cells, have received relatively little attention. This research was meant to correct for that omission by considering also the biophysical attributes of cells, including such factors as the cells' ability to move, maintain flexibility and structure. This focus emerges from the understanding that changes associated with aging at the physiological level such as diminished lung capacity, grip strength and mean pressure in the arteries "tend to be secondary to changes in the cells themselves, thus advocating the value of cell-based technologies to assess biological age." For example, older cells are more rigid and do not move as well as younger cells, which most likely contributes to the slower wound healing commonly seen in older people.

From the analysis, researchers were able to stratify individuals' samples into three groups: those whose cells roughly reflected their chronological age, those whose cells were functionally older, and those whose cells were functionally younger. The results also showed that the so-called biophysical factors of cells determined a more accurate measure of age relative to biomolecular factors such as cell secretions, cell energy, and the organization of DNA. The more accurate system could eventually enable clinicians to see aging in the cells before the person experiences age-related health decline. This in turn could allow doctors to recommend treatments or changes in life habits, such as exercise or diet changes.

Link: http://releases.jhu.edu/2017/07/11/method-determines-cell-age-more-accurately-could-help-elderly-patients/

If only all popular science articles were this good. The author here manages to accurately capture the state and uncertainties of heterochronic parabiosis research, which involves the transfer of blood between animals of different ages in search of factors that might be impacting tissue functions, either positively in youth or negatively in old age. From the results to date, I'd say that parabiosis is somewhat analogous in scope and likely impact to, say, research surrounding a class of drugs that modestly slow aging in mice. I'd not expect to see significantly better or worse advances in the treatment of aging resulting from this part of the field than from the development of mTOR inhibitors such as rapamycin. From my point of view it is an interesting area of science, but not the path ahead to rejuvenation.

Research into parabiosis can be technically challenging, and had more or less died out by the late 1970s. These days, though, it is back in the news - for a string of recent discoveries have suggested that previous generations of researchers were on to something. The blood of young animals, it seems, may be able to ameliorate at least some of the effects of ageing. In 2005, research joined the circulatory systems of mice aged between two and three months with members of the same strain that were 19-26 months old. That is roughly equivalent to hooking a 20-year-old human up to a septuagenarian. After five weeks, the researchers deliberately injured the older mice's muscles. Usually, old animals heal far less effectively from such injuries than young ones do. But these mice healed almost as well as a set of young control animals. The young blood had a similar effect on liver cells, too, doubling or tripling their proliferation rate in older animals.

Since then, a torrent of papers have shown matching improvements elsewhere in the body. No one has yet replicated the finding that young blood makes superannuated mice live longer. But it can help repair damaged spinal cords. It can encourage the formation of new neurons in mouse brains. It can help rejuvenate their pancreases. The walls of mouse hearts get thicker as the animals age; young blood can reverse that process as well. The effects work backwards, too. Old blood can impair neuron growth in young brains and decrepify youthful muscles. Finding out exactly what is happening is tricky. The working theory is that chemical signals in young blood are doing something to stem cells in older animals. Stem cells are special cells kept in reserve as means to repair and regrow damaged tissue. Like every other part of the body, they wear out as an animal ages. But something in the youngsters' blood seems to restore their ability to proliferate and encourages them to repair damage with the same vigour as those belonging to a younger animal would. In all probability, it is not one thing at all, but dozens or hundreds of hormones, signalling proteins and the like, working together. Researchers have been comparing the chemical composition of old and young blood, searching for those chemicals that show the biggest changes in level between the two.

Even with a list of targets, working out what is going on is hard. Blood is complicated stuff, and the tools available to analyse it are far from perfect. In 2014 a group suggested GDF-11 as a possible rejuvenating factor. The following year another team said that they were unable to replicate those results. They claimed the original test was sensitive to proteins besides GDF-11, messing up the results. The original team replied within months that, no, it was in fact the new test that was flawed, because it was itself picking up extra proteins. And there, at the moment, the matter stands. There are further possible explanations for parabiotic rejuvenation besides blood chemistry. One is that older animals may also benefit from having their blood scrubbed by young kidneys and livers, which mere blood transfusion would not offer. A 2016 paper described blood exchanges that were done in short bursts (thus eliminating the possibility of such scrubbing) and reported rejuvenating effects, but ones that were not as widespread as those obtained by full-on parabiosis. Another idea is that cells from the young animal, rather than chemicals in its blood, could be doing some of the work. The mechanisms by which parabiosis operates, then, are foggy.

Link: https://www.economist.com/news/science-and-technology/21724967-might-be-true-people-too

The evidence for cellular senescence to increase with age, and in doing so act as a root cause of aging, is extensive and compelling. It starts with decades of indirect evidence, increasing the research community understanding of how senescent cells behave and what the results of that behavior are at the small scale, and has led up to recent animal trials of senolytic treatments that selectively destroy senescent cells, demonstrated to produce extended life and reversal of specific, measurable aspects of aging. It is, however, still the case that from a very conservative scientific view, in which outright, direct proof of every aspect of a theory is desired, there are sizable gaps in the understanding of cellular senescence in aging. That will not stop the development of senolytic rejuvenation therapies, which can proceed on the practical basis of following the path that works, which is to say targeted removal of senescent cells, but it does make it possible to write papers on the sort noted here, in which those gaps are explored.

The present consensus view of senescence cells is that there are numerous distinct types of such cell, their senescent state caused either by stress, toxins, or reaching the Hayflick limit on cellular replication. All these classes of senescent cell behave in similar ways, and most destroy themselves quite quickly after becoming senescent, or are destroyed by the immune system. A few linger, however, and churn out a mix of signals that disrupt regenerative processes, spur inflammation, scramble important extracellular matrix structures, and alter the behavior of nearby cells for the worse. A small number of senescent cells, even just 1% by number in a tissue, can significantly damage organ function.

Nonetheless, a fair amount of this picture is not completely stitched together and beyond reasonable doubt, if the point of view is to be one of absolute proof, demanded end to end. There are self-contained studies showing benefits attained through clearing senescent cells, and of course the life span study from last year, but also question marks over how cellular senescence is assessed, what the common markers for senescence actually signify, and the degree to which senescence increases in various tissues over time. This is usual for any developing field of research. As a topic, like much of practical aging research, cellular senescence was poorly funded, near ignored for decades. Now that proofs have emerged of its importance, more researchers are interested and the funding is available to double back and fill in all the places that would benefit from more rigorous assessment. Again, that really doesn't make much difference to the development of the first generation of rejuvenation therapies based on destruction of senescent cells; that is forging ahead as an exercise in engineering rather than science. Filling in the gaps in understanding will probably help to improve the quality of the second generation of such therapies, however.

Stress, cell senescence and organismal ageing

Because cells are the fundamental building blocks of humans and animals, it is clear that cellular changes contribute to the ageing process. A major open question, however, is the nature of those changes and how exactly they contribute to degeneration and disease in old age. In 1961, it was discovered that human cells can only divide a finite number of times in culture. The limited proliferative ability of human cells in vitro, known as replicative senescence (RS), has since become a major focus of research in biogerontology. In addition to RS, a number of factors can accelerate and/or trigger cell senescence, including various forms of stress like oxidative stress.

For a long time it was debated whether the discovery of cellular senescence had any physiological relevance or was merely an artefact of cells grown in relatively artificial culture conditions. It was proposed that senescence may represent ageing, however, recent data has revealed that this view is too simplistic, since senescence has been shown to play multiple important physiological roles, such as: tumour suppression, tissue repair and wound healing, embryonic development, and age-related degeneration. In addition, senescent cells have been detected in the context of many different age-related diseases, including atherosclerosis, lung disease, diabetes, and many others.

Given the multitude of functions of senescent cells, which can be of a positive or negative nature depending on the context, it has been argued that there may be different types of senescence rather than a universal phenotype. For instance, senescence during embryonic development occurs transiently, since senescent cells are rapidly removed by the immune system after executing their role, and is not associated with the activation of a DNA damage response (DDR). In contrast, during ageing, senescent cells are thought to be persistent, induced by random molecular damage and associated with the activation of a DDR. Recent work has demonstrated that senescent cells are able to attract (potentially via the secretion of chemokines) different immune cells. It is possible that persistence of senescent cells in tissues during ageing and age-related diseases is a consequence of the inability of the immune system to clear senescent cells - in view of the well reported decline of the immune system with age - however this has not yet been experimentally tested.

Do senescent cells accumulate with age? One of the main challenges to the study of senescence in vivo has been the absence of a universal marker that can unequivocally identify senescent cells. The most widely-used marker is the presence of senescence-associated β-galactosidase (SA-β-gal) activity. Both in vitro and in vivo, the percentage of cells positive for SA β-gal increases with, respectively, population doublings and age. However, there are major limitations to the use of this marker, since SA-β-Gal staining can also be detected in immortalized cells and quiescent cells. Also, it has been suggested that a major limitation of using SA β-gal staining in vivo is a false-positive signal from macrophages and other pro-inflammatory cells. In addition, since it requires fresh tissues, its detection is not straightforward technically and has more than often generated conflicting results.

Given the challenge of identifying a specific marker able to identify senescent cells, most researchers currently rely on a multiple marker approach. Indeed, several markers have been identified which are closely associated with cellular senescence, including absence of proliferation markers, changes in heterochromatin, telomere-associated DNA damage, expression of cyclin-dependent kinase inhibitors p21, p16, and senescence-associated distension of satellites (SADS). In a variety of mouse tissues, it is clear that most of these markers increase with age; however, given the fact that most of these markers are not exclusive for senescent cells, the exact frequency of senescent cells in older tissues is still unknown. Furthermore, given the limited availability of tissues, little is known about the accumulation of senescent cells with age in healthy humans.

Interestingly, many senescence markers have also been found in post-mitotic tissues such as neurons, adipocytes, and osteocytes, which goes against the dogma that senescence is restricted to proliferating cells. It is possible that with ageing, senescence-inducing pathways (which play roles in tumour suppression and during development) can be inadvertently switched on during ageing of post-mitotic cells. However, given that the primary characteristic of senescence is a permanent cell-cycle arrest, the consequences of the activation of these pathways in post-mitotic cells are still not understood.

While there is little evidence to suggest that cells running out of divisions are a major factor in ageing, it is possible that stress and various insults are contributors to senescence in vivo. Even a small fraction of senescent cells in organs may impair tissue renewal and homeostasis, decrease organ function, and contribute to the ageing phenotype, as shown by the studies genetically ablating senescent cells. While our knowledge about senescence in vivo has increased exponentially in the last decade, this is mostly through work using laboratory mice, which have known limitations. As such, one major challenge in the field is to determine levels of senescent cells in human tissues and whether they contribute to ageing and/or pathologies in humans. Furthermore, given the diverse functions of senescent cells in processes such as repair, wound healing, cancer, development and ageing, we still need to better characterize senescence in vivo in these different contexts. Finally, we still know very little about in vivo rates of occurrence and turnover of senescent cells. Therefore, in spite of recent advances in our understanding of senescence, many questions remain and these will be timely and important areas of research for years to come.

DNA methylation is a form of epigenetic decoration that determines the pace at which proteins are produced from their genes. Epigenetic markers change constantly in response to circumstances, but amidst that dynamism there are steady patterns that correlate strongly with the damage of aging. These can be used to build a biomarker of biological age, a valuable technology when it comes to the development of treatments that target the processes of aging. Implementations of DNA methylation biomarkers of aging are now coming onto the market; you might recall I mentioned Osiris Green earlier this year. A more expensive implementation is now being offered by Epimorphy, a spin-off of Zymo Research. The spread of this technology should add a useful set of tests to any form of self-experimentation with potential rejuvenation therapies, such as senolytic treatments, in the years ahead.

Zymo Research Corp. announced today the release of a new service that can quantify biological aging in a precise manner using the myDNAge test. Based on Horvath's Clock, Zymo Research's proprietary technology is used to analyze DNA methylation patterns of over 500 loci. The new test will be sold to consumers via a newly formed company, Epimorphy, LLC, an associated company of Zymo Research, created to provide epigenetic-based tests to the consumer marketplace.

The detailed data report that the consumer will receive compares the customer's biological age to their chronological age, which could provide insight on how lifestyle and disease may have influenced their aging process, and could also be used to develop new anti-aging therapies. This test is not intended to diagnose, treat, cure or prevent any disease. Consumers can order the test online at a cost is $299 per test. Once the sample is submitted, it is prepared and analyzed using DNAge technology. A report including data analysis and biological age determination is made available for consumers.

The research community in academia and biopharma markets can also order the service for mice and human samples. "Epigenetics may hold important keys to unlocking a myriad of diseases and disorders, such as cancer, autism, Alzheimer's, and diabetes, among many others. This groundbreaking tool could provide profound insight on how biological aging is assessed. We are pleased to be able to provide this technology not only to the researcher but also to the consumer marketplace."

Link: http://www.prnewswire.com/news-releases/epigenetic-aging-clock-service-now-available-through-zymo-research-and-epimorphy-300485717.html

Fisetin is a candidate senolytic compound, demonstrated to induce apoptosis in senescent cells in a petri dish. Clearance of senescence cells is a path to rejuvenation therapies capable to some degree of turning back aspects of aging: the presence of these cells is harmful, a cause of aging. It is also a supplement, and can be obtained from a few different companies that - at present, at least - all repackage the product of a single bulk supplier. The primary reason why I'm not presently arranging a self-experimentation study of one involving this substance is that there is no demonstration that fisetin is senolytic in mice, rather than in cell cultures. One has to draw the line somewhere, and this seems like a sensible choice - it is entirely possible to see promising results in cells evaporate in live animals.

With that in mind, I found the research linked here to be interesting, even though the researchers make no mention of senescent cells. They demonstrate that fisetin added to the diet of SAMP8 mice holds back some of the accelerated aging suffered by this lineage. Do SAMP8 mice have a high load of senescent cells in comparison to their wild type counterparts, and is this a contributing cause of their accelerated aging? There is surprisingly little consideration of this question in the scientific literature, possibly because these mice are near all used in Alzheimer's disease research, a field that so far has little connection to investigations of cellular senescence. I had to do fair bit of digging to find even one paper in which this was a topic of discussion - and it presents evidence for premature senescence of SAMP8 cells in culture, rather than in live animals. Nonetheless, take a look and see what you think.

"Companies have put fisetin into various health products but there hasn't been enough serious testing of the compound. Based on our ongoing work, we think fisetin might be helpful as a preventative for many age-associated neurodegenerative diseases, not just Alzheimer's disease (AD), and we'd like to encourage more rigorous study of it." Previous research found that fisetin reduced memory loss related to Alzheimer's in mice genetically modified to develop the disease. But that study focused on genetic (familial) AD, which accounts for only 1 to 3 percent of cases. By far the bigger risk factor for developing what is termed sporadic AD, as well as other neurodegenerative disorders, is simply age. For the current inquiry, researchers turned to a strain of laboratory mice that age prematurely to better study sporadic AD. By 10 months of age, these mice typically show signs of physical and cognitive decline not seen in normal mice until two years of age.

The team fed the 3-month-old prematurely aging mice a daily dose of fisetin with their food for 7 months. Another group of the prematurely aging mice was fed the same food without fisetin. During the study period, mice took various activity and memory tests. The team also examined levels of specific proteins in the mice related to brain function, responses to stress and inflammation. At 10 months, mice not treated with fisetin had difficulties with all the cognitive tests as well as elevated markers of stress and inflammation. Brain cells called astrocytes and microglia, which are normally anti-inflammatory, were now driving rampant inflammation. Mice treated with fisetin, on the other hand, were not noticeably different in behavior, cognitive ability or inflammatory markers at 10 months than a group of untreated 3-month-old mice with the same condition. Additionally, the team found no evidence of acute toxicity in the fisetin-treated mice, even at high doses of the compound. "Mice are not people, of course. But there are enough similarities that we think fisetin warrants a closer look, not only for potentially treating sporadic AD but also for reducing some of the cognitive effects associated with aging, generally."

Link: https://www.salk.edu/news-release/evidence-shows-natural-plant-compound-may-reduce-mental-effects-aging/

Oisin Biotechnologies is developing a gene therapy approach to the clearance of senescent cells, and here I'll link to an interview with the CEO Gary Hudson conducted by the volunteers of the Life Extension Advocacy Foundation (LEAF). Oisin Biotechnologies is very much a company of our community: seed funded by the Methuselah Foundation and SENS Research Foundation, later angel investors drawn from the audience here, and headed by by one of the earliest supporters of the Methuselah Foundation and the SENS rejuvenation research programs. As regular readers will know, the accumulation of senescent cells is one of the root causes of aging, and targeted destruction of these cells has long been a part of the SENS goal of bringing aging under medical control. Senescent cells make up only a few percent of all cells in aged tissue, but that few percent secretes a potent mix of signals that cause great harm, degrading the proper function of other cells, structures, and organs, and producing chronic inflammation. In the past few years, progress towards the goal of senolytic therapies that can destroy senescent cells has accelerated, with demonstrations of extended life and reversal of many measures of aging in mice.

A number of companies are now working on a range of therapies, aiming to bring the first practical, working rejuvenation therapy to the clinic. The Oisin approach is quite different from the therapies under development by the rest of the field, however. Companies such as Unity Biotechnology are focused on traditional drug discovery and development, in search of compounds that kill senescent cells more aggressively than they kill normal cells. It bears a great similarity to the development of chemotherapeutics, and many of the current senolytic drug candidates capable of inducing apoptosis in senescent cells are in fact chemotherapeutics, tested in past years for their ability to kill cancerous cells. In contrast, the Oisin technology involves the delivery of a programmable DNA machine into cells, triggered to induce cell death by specific aspects of internal cell state, such as high levels of specific proteins. In the case of senescent cells, the machinery is triggered by p16, the most commonly agreed upon sign of cellular senescence.

It is the programmable nature of the Oisin technology that makes this company significantly different from its competitors. This was demonstrated earlier this year with the announcement that the technology is effective against cancer when triggered by p53 instead of p16. A few moments of thought might convince you that the sky is the limit here: in principle any specific cell population can be characterized by its internal state, and a variant of the Oisin treatment delivered to destroy those cells. Think of all the varieties of unwanted cell that exist, or situations in which the balance of different types of cell could be adjusted for benefit. Aged individuals are laden with errant immune cells of numerous types, for example, from those uselessly dedicated to cytomegalovirus to those causing autoimmunity. Certain types of macrophage could be culled temporarily because they hinder regeneration. Osteoclasts could be reduced in number for a while in order to allow osteoblasts to generate greater deposition of bone and turn back the course of osteoporosis. And so forth. There is far, far too much here for any one company: if you are in the life science field and have a good idea as to how to produce benefits by destroying specific cells, then you should reach out and license the technology.

Gary Hudson - Senescent Cell Clearing and Cancer Therapeutics

For those readers not familiar with how your technology works, could you give a brief summary of it?

The technology uses two elements. First, we build a DNA construct that contains the promoter we wish to target. This promoter controls an inducible suicide gene, called iCasp9. Next, we encapsulate that DNA in a specialized type of liposome known as a fusogenic lipid nanoparticle (LNP). The LNP protects the DNA plasmid during transit through the body's vasculature, and enables rapid fusion of the LNP with cell membranes. This LNP vector is considered "promiscuous" as it has no particular preference for senescent cells - it will target almost any cell type. Once it does, the DNA plasmid is deposited into the cytoplasm. It remains dormant unless the cell has transcription factors active that will bind to our promoter. If that happens, then the inducible iCasp9 is made. The iCasp9 doesn't activate unless a small molecule dimerizer is injected; the dimerizer causes the iCasp9 protein halves to bind together, immediately triggering apoptosis. This process ensures that the target cells are killed and that bystander cells are left unharmed. So far, we have not observed any off-target effects.

Many groups are engaged in researching small molecule drugs to remove senescent cells. What are the advantages of your system over the more traditional small molecule approach?

We've long thought that different populations of senescent cells might require different approaches to achieve sufficient clearance for effects to be apparent. So the various ventures that have begun using - in some cases - wildly differing protocols for senescent cells ablation may all have their place in the market. I personally like our approach because of its tremendous specificity without apparent off-target effects. The latter issue is one that purveyors of the small molecule approach must always be concerned with.

Cytomegalovirus (CMV) contributes to infectious burden and increases over time. It has been suggested that periodically purging these ineffective T cells may be useful. Have you considered using your technology for such a purpose?

Yes. We've made some initial efforts in this direction, and it is a favorite project of Aubrey de Grey at the SENS Research Foundation, but we don't have any experiments currently planned. It is on our "to do" list along with several other immune system-related experiments.

We have seen increased interest lately in increasing the ratios of H1 and H2 macrophages to treat conditions. Could your system be used to selectively destroy the H1 macrophages to favor a more healing environment?

So long as there is a promoter to be targeted, we could very likely achieve this goal. The beauty of our approach is that it is easy to try various types of promoter targets, and once we have resources to do so, we will expand our repertoire of targets. I'm not an immunologist, so someone with the necessary expertise would have to identify promoter targets and then we could have a go at it.

Have you started a mouse lifespan study to see if increased lifespan is observed with senescent cell clearance, and what sort of mice are being used?

We would like to conduct a lifespan study but haven't begun one as yet. First, lifespan studies are relatively expensive, for obvious reasons. Second, we hope to enlist an academic collaborator to participate in managing the study but we haven't located one yet. Finally, we are really focused on getting the treatment to the clinic, and through phase 1/2 studies in man. Doing anything that detracts from that goal means clinical delay.

Researchers here report on a life span study of mice genetically engineered to lack the Akt2 gene. The outcome is a greater resistance to the effects of aging on cardiac tissue, and a modest extension of life span. The researchers offer some thoughts on the likely mechanisms, suggesting that this is an example of the class of results that can be obtained via improved autophagy - though in this case, it is interesting that effects appear limited to cardiovascular tissues. The processes of autophagy act to remove damaged cellular components, particularly mitochondria, as well as many forms of metabolic waste. Thus I tend to read evidence for improved autophagy to slow aging as generally supportive of the SENS view of what should be done about aging, which is to say repair the molecular damage that causes aging. In principle the research community can build therapies that achieve a far greater and more effective level of repair than is possible through evolved mechanisms such as autophagy.

A number of hypotheses have been postulated for cardiac aging including oxidative stress, mitochondrial injury, autophagy dysregulation, and intracellular Ca2+ mishandling. Nonetheless, the precise machineries behind cardiac aging still remain somewhat elusive. Recent evidence from our laboratory and others has depicted a unique role for phosphoinositide 3-kinase (PI3K) and its downstream-signaling target protein kinase B (Akt) in aging-induced pathological changes in the heart. It was shown that the on-and-off switching of the PI3K/Akt pathway, particularly by insulin and insulin-like growth factor-1 (IGF-1), serves as a powerful physiological integrator rudimentary to life span and aging.

Our data have revealed an essential role for diminished autophagy, an evolutionarily conserved lysosome-dependent process for turnover of proteins and organelles, in Akt overactivation-induced accentuation of cardiac aging process. Autophagy plays a key role for biological aging process and cardiac homeostasis. Diminished autophagy has been shown to accelerate mammalian aging, in association with accumulation of damaged intracellular components including protein aggregate. Moreover, defective autophagy facilitates ventricular remodeling, contractile defects, and heart failure. Given the critical role for Akt in the regulation of cardiac survival and life span, this study was designed to examine the role of Akt2 ablation on aging-induced geometric, functional, and intracellular Ca2+ homeostatic changes in the heart, with a focus on autophagy and mitochondrial integrity.

Our findings indicated that Akt2 ablation prolongs life span and improves myocardial contractile function with a possible adaptive cardiac remodeling through the Sirt1-mediated autophagy regulation. In addition, Akt2 ablation alleviated aging-associated mitochondrial injury. Cardiac aging is characterized by unfavorable cardiac remodeling and function including cardiac hypertrophy, interstitial fibrosis, compromised contractility, and prolonged diastolic duration. To our surprise, Akt2 ablation negated aging-induced cardiac contractile dysfunction with a more pronounced remodeling. More prominent changes in heart mass/size, and cardiomyocyte cross-sectional area (but not fibrosis) were noted in aged Akt2-/- mice, favoring an important role for Akt2 in aging as opposed to young hearts. With the improved cardiac function in aging, the more pronounced cardiac hypertrophy in the face of Akt2 ablation seemed to suggest a state of adaptive cardiac hypertrophy in aged Akt2-/- hearts. Akt2 knockout did not elicit any notable cardiac effect at young age, suggesting that ablation of Akt2 may take time to impose cardiac remodeling and contractile effects.

Perhaps the most intriguing finding from our study is that Akt2 ablation prolonged life span and rescued against aging-induced cardiac dysfunction despite more pronounced cardiac hypertrophy. Several theories may be proposed for Akt2 ablation-elicited responses in aging. Earlier findings from our group depicted dampened phosphorylation of the Akt-negative regulator PTEN with aging, consistent with present observation of Akt activation in aging and the rationale of beneficial Akt2 ablation. Second, restored autophagy and mitophagy seem to play an important role for Akt2 ablation-induced cardioprotection. Both Akt activation, a key molecule governing cardiac survival, autophagy, and mitochondrial function, and aging have been shown to suppress autophagy. Our results revealed that Akt2 ablation restored autophagy and mitophagy in aging hearts. Our in vitro findings further revealed that autophagy induction with rapamycin improved mitophagy and contractile function. It is likely that restored autophagy and mitophagy may be responsible for prolonged survival in Akt2 knockout mice, in line with the prolonged life span with autophagy induction. Improved autophagy may improve diastolic function in senescent myocardium via preserved intracellular Ca2+ handling.

In summary, our findings suggest that Akt2 seems play an essential role in the regulation of longevity, cardiac geometry, and function in aging. Our data favor the notion that increased Akt signaling and downregulated Sirt1 with advanced aging may underscore reduced autophagy and mitophagy in aging, indicating the therapeutic potentials for Akt and autophagy/mitophagy in the management of cardiac aging. Although our study sheds some light on the interaction of Akt-Sirt1 signaling cascades on autophagy and cardiac homeostasis, the pathogenesis of cardiac dysfunction in aging, particularly in association with autophagy and mitochondria still deserves further investigation.

Link: https://doi.org/10.1111/acel.12616

Blood donation will at some point in the next decade or two be replaced with the mass manufacture of blood, produced to order and as needed. It will be far more efficient than the present system of donations and stockpiles, but there is still a great deal of work to be accomplished in order to reach this goal. The review here covers just a fraction of the scope of work, focused on the technical details of the production of platelets and their predecessor cells. Currently this is being carried out somewhat in advance of any ability to scale up to a far larger pace of production, but that will come with time. As the paper shows, there is already a considerable variety and sophistication in the equipment used to generate platelets outside the body.

Platelets (PLTs) fulfill essential functions in primary hemostasis and wound healing and maintain immunological properties, but also play a role in inflammation and cancer. In vivo, PLTs are formed by demarcation and cytoplasmatic shedding from one large precursor cell known as a megakaryocyte (MK). MKs reside within the bone marrow where they differentiate from hematopoietic stem cells. During their maturation they migrate to the sinusoids vessels, and extend protusions (proplatelets; proPLTs) through the vessel pores. The shear stress within the sinusoidal lumen supports the release of PLTs into the blood stream. Understanding the basic biology of thrombopoiesis and its physiological mechanisms is fundamental to efficiently mimic PLT production in vitro, an approach that is gaining importance for future transfusion and regenerative medicine. The demand for PLT transfusion is constantly rising. While the majority of PLT transfusions is provided to patients with reduced PLT counts after chemotherapy or hematopoietic progenitor cell transplantation, other clinical causes may require urgent PLT transfusion.

To achieve clinical numbers of in vitro generated MKs and PLTs, current next-generation strategies employ fluidic biomimetic reactors recapitulating the natural bone marrow environment. In 2006 researchers demonstrated PLT differentiation from human cord blood-derived CD34+ progenitor cells in a three-phase culture system. The first two differentiation phases were based on static cultures using hTERT human stroma cell as feeders. However, the final maturation of MKs and PLTs occurred in a suspension culture system. Another new feature introduced by this study was the co-culture of MKs in combination with human umbilical vein endothelial cells (HUVEC), since endothelial cells are known to fulfil stimulatory functions on proPLT formation.

In 2009, researchers published the first 3D PLT bioreactor built from a modular perfusion system. The device contained a central producer cell disc covered by a layer of pre-expanded CD34+ progenitor cells, while medium and gas flow occurred in separate spaces above and below this cell layer. This setup allowed the harvest of PLTs from the lower medium space over 30 days. Later, they further improved this bioreactor prototype. They increased PLT production by regulating the oxygen supply and inducing controlled shear stress with help of a continuous medium flow though the cell scaffold. These first approaches demonstrated the feasibility to produce PLTs not only in suspension cultures but also in continuous perfusion systems which can significantly facilitate the upscaling of PLT production.

In 2011 researchers established a 3D model one step ahead to a close technical analogue of the bone marrow microenvironment by the application of silk protein biomaterial. To simulate the natural niche, growth factor-coated silk microtubes (mimicking sinusoidal vessels) were embedded in modules filled with type I collagen gel. MKs were differentiated from CD34+ cells and seeded between the collagen gel and each microtube. They migrated towards the microtube and released proPLTs into the constitutive flow of media within the microtubes. However, only 7% of MKs exhibited proPLT production. In 2015 researchers presented a follow-up of this prototype, equipped with an additional silk sponge encompassing the microtube to better mimic the stiffness of the sinusoidal vessel surrounding. Moreover, they improved the entrapment of growth factors and extracellular matrix components, and seeded HUVEC into the lumen of the silk microtubes. These new features led to a threefold increase in numbers of released PLTs.

Step by step, bioreactor bioengineering for efficient PLT production became increasingly complex. In 2014, researchers presented the first PLT bioreactor-on-a-chip that, despite its small size, considered a broad spectrum of parameters to recapitulate the bone marrow microenvironment. To mimic the stiffness of the natural bone marrow, MKs were seeded in hydrogels such as alginate. To improve MK trapping, extracellular matrix proteins were added into the surrounding media, or used to coat the membrane separating the MK chamber from the lower flow chamber. ProPLT formation was stimulated with help of endothelial cell contacts, and PLT release was optimized using controlled hemodynamic vascular shear stress. In 2016 researchers developed a 'microfluidic model of the PLT generating organ', constituted by a single-flow chip, in which MKs derived from human cord blood (hCB) CD34+ cells were constitutively perfused and captured by thousands of vWF (von Willebrand factor)-coated micropillars to release PLTs into the media flow. This setup enabled a high throughput of millions of MKs.

In summary, it is currently possible to efficiently differentiate MKs from induced pluripotent stem cells (iPSCs), but they show a restricted capacity to produce PLTs in vitro. Physiologically, one MK produces thousands of PLTs into the circulation. In contrast, the protocols available only allow the production of up to hundreds PLTs per MK. This delays the possibility for clinical application of in vitro produced PLTs. Yields of PLT production may profit in the future from the harmonization of MK expansion and differentiation culture systems towards a synchronized PLT formation and release. The application of shear stress in the designed bioreactor aimed to provide a physical cue to induce a synchronized proPLT formation, extension, and PLT release. However, it remains highly desirable to identify biological or chemical signals that might support this process.

Link: https://doi.org/10.1159/000477261

The greatest challenge in tissue engineering turned out not be the production of functioning, complex tissue structures - how to convince cells to form these intricate arrangements. Researchers are rapidly establishing the diverse set of recipes needed to produce close analogs of real tissues, including cartilage, intestines, skin, heart muscle, kidney, liver, and more. All require quite different strategies to convince the various types of cells involved to take the right actions, but the best of the results so far are close enough to the real thing to function properly when transplanted. In perhaps the most compelling of recent examples, researchers built artificial ovaries that, once implanted, enabled mice to reproduce in the normal, natural fashion. Overall, progress in building functional tissue from a patient's own cells is in fact going very well.

What is the greatest challenge, then? It is to be found in blood vessels. Not in the production of large vessels such as arteries, as a number of research groups have succeeded in producing structures that work just as well as naturally grown arteries, but in recreating the networks of tiny capillaries that thread every cubic millimeter of naturally grown tissue. Without this capillary network, researchers are limited to the production of thin sheets and tiny organoid masses of engineered tissue - thin enough for nutrients to perfuse while the tissue is growing in a bioreactor, and thin enough for blood vessels to grow into the tissue to support it when it is transplanted. Any larger and the inner cells would starve. These thin tissues can be enough for some therapeutic uses, but if the end goal is the production of new patient-matched organs to order, then the blood vessel challenge must be solved.

Decellularization is one possible strategy, but this still requires the limited resource of donor organs; it works around the inability to generate capillary networks by using an existing set. Nonetheless, the goal for most of the tissue engineering community is to develop the means to build new capillary networks along with new tissues as they are grown. A variety of approaches are in various stages of development, such as the 3-D printing of fine-detail scaffolds that guide the creation of every last capillary, but the research community is still in search of a low-cost, efficient, reliably methodology. Today I thought I'd point out a good example of the sort of incremental research results that are representative of this line of work, the research community inching forward towards a better state of the art, one small step at a time:

Researchers are one step closer to growing capillaries

Researchers have shown how to use a combination of human endothelial cells and mesenchymal stem cells to initiate a process called tubulogenesis that is crucial to the formation of blood-transporting capillaries. The work is an important step with fragile endothelial cells (ECs) made from "induced pluripotent stem cells," or iPSCs, a type of cell that can potentially be made from the cells of any human patient. Because iPSCs can be patient-specific, researchers hope to find ways of using them to generate tissues and replacement organs that can be transplanted without risk of rejection by a patient's immune system. But the fragility of endothelial cells during laboratory growth has limited the utilization of this critical cell type, which is found in all vasculature.

While tissue engineers have found dozens of ways to coax stems cells into forming specific kinds of cells and tissues, they still cannot grow tissues with vasculature - capillaries and the larger blood vessels that can supply the tissues with life-giving blood. Without vascularization, tissues more than a few millimeters in thickness will die due to lack of nutrients, so finding a way to grow tissues with blood vessels is one of the most sought-after advances in the field. "Ultimately, we'd like to 3-D print with living cells, a process known as 3-D bioprinting, to create fully vascularized tissues for therapeutic applications. To get there, we have to better understand the mechanical and physiological aspects of new blood-vessel formation and the ways that bioprinting impacts those processes. We are using 3-D bioprinting to build tissues with large vessels that we can connect to pumps, and are integrating that strategy with these iPS-ECs to help us form the smallest capillaries to better nourish the new tissue."

In the process of tubulogenesis - the first step to making capillaries - endothelial cells undergo a series of changes. First, they form small, empty chambers called vacuoles, and then they connect with neighboring cells, linking the vacuoles together to form endothelial-lined tubes that can eventually become capillaries. The researchers investigated whether commercially available endothelial cells grown from iPSCs had tubulogenic potential. The test examined this potential in two types of semisolid gels - fibrin and gelatin methacrylate (GelMA). Finally, the researchers also investigated whether a second type of stem cell, human mesenchymal stem cells, could improve the likelihood of tubulogenesis. In fibrin, the team found robust tubule formation, as expected. They also found that endothelial cells had a more difficult time forming viable tubules in GelMA, but over several months and dozens of experiments the team developed a workflow to produce robust tubulogenesis in GelMA. This involved adding mesenchymal stem cells, another type of adult human stem cell that had previously been shown to stabilize the formation of tubules.

Tubulogenesis of co-cultured human iPS-derived endothelial cells and human mesenchymal stem cells in fibrin and gelatin methacrylate gels

Vascularization is critical for the maintenance of multicellular life as blood vessels provide oxygen and nutrients to tissues while also removing waste. Beyond the diffusion limit for oxygen transport, cells in tissue cannot survive or maintain normal function. The formation of vascular networks in vitro and in vivo have applications in treating ischemic disease, elucidating vascular mechanisms, screening drug efficacy, and engineering functional tissues for regenerative medicine. Toward the creation of vascular networks, methods of creating both structurally and functionally mature and complex vasculature must be identified to address the challenge of fabricating clinically-relevant tissue models and engineered tissues.

One of the several strategies toward vascularization is to create new vessel networks through cell-mediated morphologic processes similar to those seen during embryonic development. De novo vascular formation, or vasculogenesis, occurs through assembly of populations of endothelial cells into a rudimentary capillary plexus. Subsequent steps in vivo ensure vascular stabilization and maturity by generating extracellular matrix (ECM) and recruiting supporting mural cells. Further cell-cell and cell-matrix interactions encourage or antagonize vessel sprouting (angiogenesis), branching, remodeling, and pruning.

Many groups have cultured endothelial cells in vitro to generate spontaneously self-assembled vascular networks. While some groups have modeled vasculogenesis in natural matrices such as collagen and fibrin, others have demonstrated capillary networks in more synthetic environments such as GelMA and polyethylene glycol (PEG)-based hydrogels. In addition to challenges associated with the biomaterial environment, a critical aspect for cell-based clinical translation is the selection of cell sources. Human umbilical vein endothelial cells (HUVECs) have been commonly used for studying vascular morphogenesis, and supporting mural cells also have a history of various cell sources such as smooth muscle cells, but these cell types suffer from poor batch-to-batch uniformity as well as difficulties with scale-up and in some cases poor translation potential. More recent work has demonstrated the ability of human bone marrow derived mesenchymal stem cells (hMSCs), which are multipotent even well into adulthood, to serve in a supporting mural role for endothelial cells.

Here the potential to derive functional endothelial cells from induced pluripotent stem cells offers high batch uniformity, standardization, scale-up, and the potential for personalization. Commercially available iPS-ECs have been previously shown to form connected capillary-like networks in 2D and 3D studies with Matrigel. We sought to further validate these findings in additional matrix formulations and with live genetic reporters to provide additional tools for cell tracking and characterization. Here, we explored a cell-based strategy to form tubule networks using clinically relevant cell sources and biomaterials. We utilize iPS-ECs in monoculture or in co-culture with hMSCs in natural fibrin and semi-synthetic GelMA environments, track the progression of vasculogenesis, and quantify the network character of nascent tubules. Our results further supports the hypothesis that tubulogenesis is driven by intracellular vacuole formation and intercellular vacuole fusion. By using cell-based strategies for vascularization we allow biology to dictate the microvascular organization and exploit cellular interactions between iPSECs and hMSCs to stabilize networks when the extracellular environment cannot.

Thanks to a great deal of hard work and advocacy, there is now a much greater enthusiasm and public discussion in the research community regarding treatment of the causes of aging than was the case at the turn of the century. This is as opposed to continuing the past strategy of attempts to patch over the late stages of age-related diseases without addressing their root causes. Nonetheless, many researchers are still reluctant to openly advocate for significant extension of human life spans, and bury that goal in favor of talking about compression of morbidity, shortening the period of disability at the end of life.

What is the point of the exercise, however, if not to aim high, at pushing out the duration of both health and overall life span by decades and more in the only practical way possible, which is by repairing the damage that causes aging? We are machines, and like all machines, our working, fully functional life span is determined by the degree of ongoing repair. Only when repair fails will we decline. To my eyes, failure to acknowledge radical life extension as a primary goal only serves to strengthen support for poor approaches to the treatment of aging, strategies such as calorie restriction mimetic drug development that cannot possibly produce meaningful gains in healthy human life spans - because they not not forms of repair, only ways to modestly slow damage accumulation.

Life extensionism is a global movement with long-term traditions. The idea, that aging is similar to a disease and should be treated as such, was first suggested in the early 1900s. Since then, the study of aging biology has revealed the underlying processes of aging, such as DNA damage, toxic proteins aggregation and cross-links, cellular senescence, nutrient sensing deregulation and others, and proven the plausibility to address these processes to modify the dynamics of aging.

Even though aging itself is not described as a disease in the International Classification of Diseases (ICD), there is no doubt that aging is the major cause of many severe diseases, and the global population could benefit from bringing aging under medical control. Many existing drugs have been found to be geroprotective (protecting the body against the the aging process). However, what would happen if scientists applied geroprotective technologies to humans, remains a subject of numerous misconceptions.

This is the human life course as it was before the development of modern medicine: somewhere around their 50s people started to develop different age-related diseases, then died from them some 15-20 years later. As a result of the past century of development, however, now people reach their 50s, age-related diseases start to manifest, but modern medicine allows us to slow down their progression, so people live longer - but this is the period of illness that is extended, because this medicine fails to address the causes of aging. This is exactly why Brian Kennedy from the Buck Institute calls our healthcare system a "sickcare" system: we are keeping people alive for longer, but we are keeping them sick, generating a burden for our system of healthcare and social support: we have many people living longer in disability.

We can do better by developing interventions to address the aging processes. These interventions are meant to be applied in middle age, before the manifestation of age-related diseases, in order to extend the healthy period of life, or healthspan, while the period of illness is postponed and will remain relatively short. This could allow people in their 50s to look like they are 30, and in their 70s also look younger, be stronger, and feel as good as in their 50s. So what we mean by life extension is actually the extension of the healthy and productive period of life, free of disease and disability. In this "extended" society the majority of people could enjoy their lives for much longer and actively contribute to the development of the economy regardless of their chronological age.

Link: http://www.leafscience.org/what-is-the-goal-of-life-extension/

Researchers here report on the development of a method to enable real-time visualization of the current degree of cellular senescence present in living tissues, using an improved version of existing florescence techniques. If accurate enough, this could replace the current standard approach of biopsy and staining of the sample for analysis. Note that the paper isn't open access; you'll have to obtain a copy from the usual underground sources. A practical method of assessing cellular senescence burden that works in live animals will be a big step forward for the field, as it should reduce the cost of many of the activities involved in the production of senolytic therapies, treatments capable of destroying senescent cells and thus reversing their contribution to the aging process. Consider the ability to accurately track the presence of senescent cells in the same animal from moment to moment across a lifetime and through varied senolytic dosages and treatments, for example, information that at present is challenging and costly to obtain.

The main purpose of cellular senescence is to prevent the proliferation of damaged or stressed cells and to trigger tissue repair. However, upon persistent damage or during aging, the dynamic process of tissue repair becomes inefficient and senescent cells tend to accumulate. This accumulation in tissues is believed to impair tissue functions and accelerate aging. It has been demonstrated that genetic ablation of senescent cells ameliorates a variety of aging-associated diseases, reverts long-term degenerative processes, and extends longevity. Inspired by these findings, strategies to prevent, replace, or remove senescent cells have become of interest. For instance, there is an increasing interest in the development of senolytic molecules able to induce apoptosis preferentially in senescent cells.

A related key issue in this field is the design of probes to accurately detect senescent cells in aged or damaged tissues. However, one of the major obstacles limiting progress in this research area is the lack of real-time methods to selectively track senescence in in vivo systems. Detection of senescent cells usually relies on the detection of senescence-associated βGal (SAβGal), and several fluorescent or chromogenic probes have been reported for the visualization of this enzymatic activity. However, these first-generation probes are usually unsuitable for in vivo imaging as they rely on chromogenic changes or on the use of classical one-photon fluorescence excitation. As an alternative, recent stimulating studies developing two-photon fluorescent probes for the visualization of βGal activity have been described. However, some of the reported probes are synthesized by using tedious multistep protocols. Another common drawback is the fact that probes are tested in cultured cells or in animal models that were not directly related to senescence.

In view of the aspects mentioned above, we report herein a novel molecular probe for the two-photon fluorogenic in vivo detection of senescence. The probe (AHGa) is based on a naphthalimide fluorophore as a signaling unit containing an L-histidine methyl ester linker and an acetylated galactose attached to one of the aromatic nitrogen atoms of the L-histidine through a hydrolyzable N-glycosidic bond. Probe AHGa is transformed into AH in senescent cells resulting in an enhanced fluorescent emission intensity. Targeting of senescent cells in vitro with AHGa was validated with the SKMEL-103 cancer cell line treated with the chemotherapeutic palbociclib to induce senescence. A remarkable fluorescence emission enhancement (ca. 10-fold) in the presence of AHGa for palbociclib-treated SK-MEL-103 (senescent) cells was observed when compared with control SK-MEL-103 cells, due to the formation of AH.

The ability of tracking senescence of probe AHGa was also studied in vivo by employing mice bearing subcutaneous tumor xenografts generated with SK-MEL-103 melanoma cells and treated with palbociclib. Tumors in palbociclib-untreated mice showed negligible fluorescence emission both in the absence or in the presence of AHGa, whereas tumors in mice treated with palbociclib and intravenously injected with AHGa showed a clear fluorescent signal. A marked emission enhancement (ca. 15-fold) in tumors treated with palbociclib compared to nontreated tumors was observed. AH fluorescence was only found in senescent tumors but not in other organs. The combination of selectivity, sensitivity, and straightforward synthesis make AHGa an efficient OFF-ON two-photon probe for the in vivo signaling of senescence.

Link: https://doi.org/10.1021/jacs.7b04985

For those who haven't been keeping a close eye on the evolution of blockchain systems such as Bitcoin and Ethereum, and the ever-expanding collection of altcoins built atop or otherwise reliant upon the few core blockchains, the recent spate of large Initial Coin Offerings (ICOs) might seem as though they arrived from out of the blue. Startup companies have been raising tens of millions of dollars on the basis of the most flimsy and unrealistic of business proposals, simply by launching and then selling a new set of limited issue tokens based on the Ethereum system. The promise of these tokens being used in some future API or system of exchange is barely even visualized in many cases, let alone planned or under construction. Yet the tokens are eagerly purchased in exchange for bitcoins or ether cryptocurrency, and then go on to trade for multiples of that price. Those of us in fields like longevity science that struggle for funding might well look at this and ask how we can participate in this apparently magical money fountain.

So what is going on here? The answer to that comes in two parts. Firstly, the technical underpinnings. Blockchains considered in the abstract are a use of cryptography to solve an important problem in distributed collaboration. Within their bounds, they can be used to enable verification of identity, trust between anonymous parties, business ledgers that do not rely upon any one central party, escrow that doesn't require a trusted escrow holder, and so on. This clearly has value, and the fact that the various cryptographically assured tokens associated with blockchains trade at a price is due to the underlying value of what can be achieved with blockchain technologies. Bitcoin is a first generation, comparatively crude blockchain, while Ethereum opens up the technology to allow the operation of arbitrary logic in the way in which cryptographic tokens and the blockchain operate. In both cases there are open markets where the tokens associated with the blockchain can be traded, an operation that is carried out without the need for any market maker, using the power of the blockchain to enable trusted exchanges between arbitrary third parties, ensured by cryptographic exchanges. This is a very high level sketch indeed, and I'd encourage you to read some of the longer summaries for laypeople that can be found online.

That blockchains in the abstract have value - and potentially considerable value in the longer term - doesn't explain why ICOs exist in their present form, enriching startup owners on the basis of dubious business propositions and minimal effort, however. The current consensus view is that there is a lot of money bottled up in some combination of (a) the cryptographic tokens held by people who came into ownership early-on, and (b) the wealth of countries like China with strong currency controls. Mostly the latter option. The flood of money into ICOs is driven by these sources of wealth seeking a place to convert or move their assets, and since this tends to raise the market value of these tokens in the short term, this drags in every speculator in town. Many fairly sophisticated entities with deep pockets are now involved in cryptocurrency trading.

Thus when an ICO takes place, sells out quickly, and the tokens purchased are immediately sold for a profit on the open market, along the way money from currency-controlled regions moves to other jurisdictions via the blockchain as an intermediary, people with large unrealized gains in bitcoins and ether can diversify their holdings, and various other entities can achieve their own goals. So in the short term, it is likely that a great deal of the current market value of blockchains lies in their being a very accessible way to work around currency controls, and ICOs are just a particularly convenient manifestation of this point. Absent regulatory intervention - something that is anticipated by observers in the US, since ICOs look a lot like a way to circumvent SEC rules on startup fundraising - this will probably continue for some years, I'd imagine, if what I've said here is an accurate assessment of why the current situation exists.

So then, back to the question at hand: how could the funding-starved longevity science community drink from this money fountain, while at the same time offering a legitimate use of an ICO? The most obvious path forward seems to involve some form of Kickstarter-like model of funding development by preordering the product. This of course has a high rate of failure, but that seems to be accepted by both Kickstarter backers and by the SEC, tacitly or otherwise, as a way to bring in the necessary funding to a startup company to allow an attempt at development of the product. The further you are in advance of an actual product the more morally dubious it becomes to sell preorders; when you are researching whether or not your approach to building a produce is possible at all, one can argue that it is somewhat outrageous to be taking preorders. (Arguably many Kickstarter projects that are purely development work are also making outrageous claims of certainty in their ability to deliver, but the similarities between that situation and the uncertaintities of real scientific research are superficial at best).

Nonetheless, for research that is further along the pathway, this seems defensible. I'll paint a few scenarios of varying degrees of plausibility and risk of failure here. Let us look at senolytic rejuvenation therapies, for example. Imagine that Oisin Biotechnologies hires a programmer to create a simple Ethereum redemption token type. Oisin pledges to exchange a token for their senolytic treatment at a time at which the cost of that service is $10,000 or less, in any jurisdiction where the treatment is approved for clinical use. Perhaps there are some additional perks, such as token holders gaining priority when space is limited. Some fraction of those tokens are then put out in an ICO. The expected plan would be to sell several tens of millions of dollars of these tokens in exchange for $10,000 each in ether, in the full understanding that the entities initially buying these tokens have no great interest in what they are later to be used for. Then convert the ether into dollars, and treat that as a form of fungible loan or obligation - one that can be obtained somewhat more easily and at much better terms than are available through any existing financial institution. Later funding rounds and deals with third parties to provide the services offered to token holders may be used to dilute the effective cost of this loan and of honoring the tokens.

Alternatively, consider a group of people with a suitable biotechnology firm on contract who make much the same ICO offer, but selling tokens at $2,000, and pledging a place in an open human trial of whichever package of senolytics they settle upon. Depending on the amount raised, they pledge to run mouse studies for the promising senolytic drug candidates with only cell studies, and initial human volunteer tests for senolytic drug candidates with only animal data. They offer no guarantee as to which senolytics will be used in the end, and the expected package for people who redeem the token is a kit sent in the mail, with instructions on how to coordinate with a local physician to obtain before and after measurements. You can adjust the dollar amount and the type of support and logistics offered by the venture, ranging from the minimal product described above to travel to a location for a medical tourism-like package, to ensure better data collection.

The point here is that none of these things could do very well when it comes to raising funds in the present environment of crowdfunding absent this unusual dynamic flowing through the blockchain system. They are legitimate products, analogous to many Kickstarter efforts, but our community of longevity science supporters simply isn't large enough and longevity science is not yet entrenched enough in popular culture to bring in tens of millions in this way. But near anything put in the path of the money flows and incentives currently operating in the major blockchains right now will, if properly executed, stand a good chance of raising significant funding in this way. Will that continue, or will it be diluted to nothing by the gold miners even now heading in that direction? Who knows. But you don't find out without giving it a try. It is of course the responsibility of those who do this to conduct themselves in an ethical way that reflects well upon our community, but I think this to be a practical possibility, and one we should look into.

The protein FGF21 came to be an area of interest because its production is increased as a result of calorie restriction, an intervention that extends healthy life span in near all species tested to date. Further investigation found that genetic engineering to artificially boost FGF21 production extends life in mice, probably through effects on the well-known insulin signaling systems that appear involved in the way in which the operation of metabolism determines natural variations in life span. Like many such approaches to slowing aging in mice, it isn't expected to have as significant an effect in long-lived humans as it does in short-lived mice. Researchers are also interested in the positive impact of FGF21 on regeneration, however: it has been shown to slow thymus degeneration and enhance liver regeneration, for example. Here, researchers further investigate the impact of altered levels of FGF21 on metabolism:

Mildly stressing muscle metabolism boosts levels of a beneficial hormone that prevents obesity and diabetes in mice, according to a new study. The new findings show that triggering a certain type of metabolic stress in mouse muscle cells causes them to produce and secrete significant amounts of fibroblast growth factor-21 (FGF21), which then has widespread beneficial effects on whole-body metabolism. The mice in the experiments were completely protected from obesity and diabetes that normally develop due to aging or eating a high-fat diet. Moreover, triggering the FGF21 production after the mice had become obese and diabetic reversed these conditions and returned the mice to normal weight and blood sugar levels.

"There is a biological phenomenon known as hormesis where a little bit of stress a can be a good thing." Researchers used genetic engineering to reduce levels of a mitochondrial protein called OPA1 in the muscles of mice. Mitochondria are tiny organelles that produce a cell's energy. This OPA1 deficiency disrupted muscle metabolism and caused a small amount of muscle loss in the mice. Despite the mild muscle atrophy, which did decrease grip strength, the older mice with OPA1 deficiency had greater endurance on the treadmill than older control mice. In addition, activity levels and energy expenditure that normally decline in mice as they age were preserved in OPA1 deficient mice.

Interestingly, the altered mice also were completely protected from the weight gain and glucose intolerance that normally develop in mice as they age or when they eat a high-fat diet. Moreover, the research team showed that reducing OPA1 levels in muscle, after mice had become obese and diabetic, reversed these problems - normalizing body weight and reversing glucose intolerance even though the high fat diet continued. These metabolic improvements correlated with increased levels of circulating FGF21. The researchers were able to prove that muscle was the source of the FGF21 by creating a mouse that had the OPA1 deficiency and also was missing the FGF21 gene in muscle. These mice were no longer able to produce FGF21 in muscle in response to OPA1 deficiency, and, just like control mice, they became obese and developed diabetes. "These experiments prove that muscle is the source of circulating FGF21 in the OPA1 deficient mice, and that muscle-derived FGF21 prevents diet-induced obesity and insulin resistance in these mice."

Further investigation demonstrated that the small degree of mitochondrial stress induced in muscle by the reduction of OPA1 is sufficient to activate another cellular stress response pathway called endoplasmic reticulum (ER) stress, which then dramatically increases FGF21 levels. "The follow up work on this will be understanding how a little bit of mitochondrial stress can actually increase the ER stress response and if we can mimic that safely. There are agents that have been used to activate ER stress pathways. So, I think the opportunity here would be to find ways to turn on this pathway in a very controlled way to get enough of this subsequent FGF21 response in muscle to be of benefit."

Link: https://medcom.uiowa.edu/theloop/news/tweaking-muscle-metabolism-prevents-obesity-and-diabetes-in-mice

Targeting therapies to some combination of neoantigens, distinctive markers on the surface of cancerous cells that the immune system learns to recognize, and which vary from patient to patient, represents an advance in the specificity of targeted cancer immunotherapy. It should, in principle, better rouse the immune system to attack cancerous cells, while producing fewer side-effects. Researchers here report on an early human trial of this sort of approach; the initial results look promising, certainly from the perspective of an absence of serious side-effects, though a more robust demonstration of the ability to reduce tumor burden is still needed.

A personal cancer treatment vaccine that targets distinctive "neoantigens" on tumor cells has been shown to stimulate a potent, safe, and highly specific immune anti-tumor response in melanoma patients. Antigens are molecules that are displayed on the surface of cells and stimulate the immune system. Neoantigens are molecules on cell's surfaces that are produced by DNA mutations that are present in cancer cells but not in normal cells, making neoantigens ideal targets for immune therapy against cancer. The vaccines used in the phase I trial contained up to 20 neoantigens, derived from an individual patient's tumor. The vaccines were administered to patients to train their immune system to recognize these neoantigens, with the goal of stimulating the immune system to destroy the cancer cells that display them.

While other immunotherapies, such as checkpoint inhibitor drugs, also trigger immune responses against cancer neoantigens, they are not designed to be specific. They can also induce responses against normal tissue antigens, leading the immune system to attack normal tissues and cause toxicity in a subset of patients. The researchers found that the personal vaccine induced a focused T cell response against several tumor neoantigens, beyond what is normally seen in response to existing immunotherapies.

The vaccine was administered to six patients with melanoma whose tumors had been removed by surgery and who were considered at high risk for recurrence. The vaccinations were started at a median of 18 weeks after surgery. At a median of 25 months after vaccination, four of the six patients showed no evidence of cancer recurrence. In the other two patients, whose cancer had spread to their lungs, the disease recurred after vaccination. At that point, they began treatment with the drug pembrolizumab, which inhibits the PD-1 immune checkpoint. Both patients had complete resolution of their tumors and remain free of disease according to imaging scans.

The study results suggest, that a personalized neoantigen vaccine can potentially overcome two major hurdles in cancer therapy. One is the heterogeneity of tumors - the fact that they are made up of cells with a variety of different traits, which often allows cancers to evade drugs targeted to malignant cells having a single genetic abnormality. The vaccine, because it contains many different neoantigens from the tumor, targets multiple genetic types of tumor cells. A second hurdle in cancer is to generate an immune response sharply focused on cancer cells while avoiding normal cells and tissues. This aim was achieved by the vaccine, which appeared to have few "off-target" effects, causing only flu-like symptoms, fatigue, rashes, and irritation at the site of the vaccine injection, according to the report.

Link: http://www.dana-farber.org/Newsroom/News-Releases/personal-neoantigen-vaccine-prompts-strong-anti-tumor-response-in-patients-new-study-shows.aspx

Autophagy is the name given to a collection of recycling mechanisms involved in cellular maintenance. These processes clear out metabolic waste and break down damaged cellular components so that the parts, proteins and their constituents, can be used elsewhere. The better documented forms of autophagy involve the coordination of (a) systems that flag structures and molecules for recycling, (b) systems that engulf the flagged materials in membranes for delivery to cellular recycling centers, and (c) the recycling structures called lysosomes, packed with enzymes capable of dismantling up most of what they will encounter.

Autophagy fails with age, and this failure is thought to contribute to degenerative aging to some degree; certainly many of the methods of modestly slowing aging in laboratory species appear to at least involve - and in some cases rely upon - increased autophagy. Exactly why does autophagy falter with age, however? There are a lot of answers to that question, of varying degrees of incompleteness, speculation, and supporting evidence. The challenge here, as for everything that goes on inside a cell, is that autophagy is a highly dynamic, enormously complex chain of mechanisms. Failures could be subtle and hard to detect in any one component part, or they could be distributed throughout the system, and there are a lot of pieces to examine. It has taken decades for the modern research community to gather today's comparatively sophisticated, partial picture of what is going on under the hood, and the tools of biotechnology are only now gaining the capacity to do better than this given a reasonable amount of time and funding.

A further consideration is that autophagy is a large enough research space to develop specializations: teams will tend to have more experience in just one aspect of this set of processes. It is, like much of the life sciences, a case of the blind men and the elephant, and intensive, ongoing collaboration is required in order to gain any sort of holistic picture. Many autophagic mechanisms no doubt all become dysfunctional in their own particular ways across the course of aging, and each such chain of cause and effect reaches from the beginning of some form of fundamental molecular damage through numerous stages to reach whatever layer of the onion that any given scientist happens to be investigating. When people publish papers on the age-related decline of autophagy, it is always worth bearing this in mind: it is rare that anyone is working with more than a slice of the whole at one time.

That said, the research here is an example of the sort of approach needed to improve the present understanding of how autophagy works in detail, and thus build a better map of where it runs off the rails over the course of aging. You might compare the report here with, say, the standard SENS view of dysfunctional autophagy resulting from hardy metabolic waste accumulated in lysosomes, or the discovery that loss of autophagy can be restored at least partially through genetic engineering to add more receptors to lysosomes, increasing their ability to receive flagged materials for recycling. The lysosome is just one part of a much larger set of autophagic systems, however, and problems can certainly exist elsewhere - though it has to be said that the findings noted below are consistent with theories placing the whole of the problem in the lysosome, and thus supportive of the SENS approach to therapies.

Scientists Take a Deeper Dive Into Cellular Trash

"Autophagy," which means "self-eating" based on its Greek roots, is the normal physiological process the body's cells use to remove viruses, bacteria, and damaged material from the cell. Autophagy also helps cells "clean house" by recycling building blocks - similar to the way we recycle glass, plastic and metal. In recent years, defective autophagy has been linked to age-related diseases such as cancer, neurodegeneration and heart disease. "Increasingly, researchers are asking whether there is an age-related decline in autophagy and if it's connected to diseases that occur more frequently in older individuals. Exposing how autophagy becomes faulty with age may reveal opportunities for us to therapeutically intervene and correct the process to promote health aging."

Autophagy is a dynamic, multi-step process that starts with the formation of a double-membrane sac in the cell cytoplasm called the isolation membrane (IM). These structures engulf cellular material and debris, expanding in size to form vesicles called autophagosomes (APs). Finally, APs fuse with lysosomes to form autolysosomes (ALs) that digest and release the breakdown products for re-use, much like a recycling plant would repurpose incoming trash. "A major challenge with understanding how aging impacts autophagy is that researchers have been capturing a dynamic process with static measurements. Autophagy is most commonly monitored by counting the number of APs, which really only provides a snapshot of the process - similar to how counting the number of garbage trucks on the street doesn't tell you how much garbage is actually being recycled at the plant. And typically older organisms have an increased number of APs, but we don't know exactly why."

"We wanted to ask how age impacts autophagy - is it at the beginning of the process by increasing the rate at which APs are formed, or, by analogy, how many garbage trucks are rolling out on the street - or is it at the end of the process by blocking the conversion of APs to ALs, i.e., how much recycling is taking place at the recycling plant. Either one of these scenarios would cause an increased number of APs, but knowing which one would help pinpoint where interventions may be helpful. We found that there is indeed an age-dependent decline in autophagy over time in all tissues examined. We further provide evidence that the increase in APs results from an impairment at a step after APs are made. So basically the autophagy recycling process becomes incomplete with age by stopping somewhere after APs are formed. This research is important because it helps provide time- and site-of-action information for potential future interventions directed at sustaining autophagy to extend lifespan. Our next step will be to perform biochemical research to further pinpoint exactly how autophagy fails to complete its cycle, possibly providing targets to develop specific interventions."

Spatiotemporal regulation of autophagy during Caenorhabditis elegans aging

Macroautophagy (hereafter referred to as autophagy) is a multistep cellular recycling process in which cytosolic components are encapsulated in membrane vesicles and ultimately degraded in the lysosome. As interest in this pathway and its pathophysiological roles has increased, it has become clear that measurement of autophagic vesicle levels at steady state, without monitoring the overall pathway flux, can lead to controversial results. Autophagy is commonly monitored by enumerating APs under steady-state conditions, also referred to as the AP pool size, using a GFP-tagged Atg8 marker. During AP formation, Atg8 is cleaved, conjugated to phosphatidylethanolamine, and inserted into the vesicle membrane, thus serving as a marker for IMs and APs. However, GFP-Atg8 only reports on the size of the IM and AP pools, not the rate by which IMs and APs are formed, or converted to ALs. For example, an increase in GFP-Atg8 could result from increased formation of APs or blockade of the downstream steps.

A tandem-tagged mCherry-GFP-Atg8 reporter, which separately monitors both IMs/APs and ALs can help distinguish between these possibilities.Specifically, when used in combination with chemical inhibitors of autophagy tandem-tagged reporters can assess autophagic activity in so called autophagic flux assays. Although tandem-tagged Atg8 markers have been used extensively to monitor autophagy in mammalian cells, as well as in adult Drosophila melanogaster and in Caenorhabditis elegans embryos, this reporter has not previously been used in adult C. elegans, and no comprehensive spatial or temporal analyses of autophagic activity have been reported in any animal thus far.

Autophagy plays important roles in numerous cellular processes and has been linked to normal physiological aging as well as the development of age-related diseases. Furthermore, accumulating evidence in long-lived species demonstrates that autophagy genes are required for extended longevity. In particular, autophagy is essential for lifespan extension by inhibition of the nutrient sensor mTOR. In C. elegans, autophagy genes are also required for the long lifespan induced by other conserved longevity paradigms, such as reduced insulin/IGF-1 signaling, germline ablation, and reduced mitochondrial respiration, and all these longevity mutants have increased transcript levels of several autophagy genes.

To better understand how aging affects autophagy in C. elegans, we employed a GFP-tagged and a novel tandem-tagged (mCherry/GFP) form of LGG-1 (a C. elegans ortholog of Atg8) to investigate the spatial and temporal autophagy landscape in wild-type (WT) and long-lived daf-2 mutants and germline-less glp-1 animals. Our data indicate that WT animals displayed an age-dependent increase in AP and AL numbers in all tissues, which flux assays suggest reflects a decrease in autophagic activity over time. In contrast, daf-2 and glp-1 mutants showed unique age- and tissue-specific differences consistent with select tissues displaying elevated, and in one case possibly reduced autophagic activity compared with WT animals. Moreover, tissue-specific inhibition of autophagy in the intestine significantly reduced the long lifespan of glp-1 mutants but not of daf-2 mutants, suggesting that autophagy in the intestine of daf-2 mutants may be dispensable for lifespan extension. Our study represents the first efforts to comprehensively analyze autophagic activity in a spatiotemporal manner of a live organism and provides evidence for an age-dependent decline in autophagic activity, and for a complex spatiotemporal regulation of autophagy in long-lived daf-2 and glp-1 mutants.

Human biochemistry does include systems capable of breaking down or otherwise removing the hyperphosphorylated tau protein deposits observed to be associated with the neurodegenerative conditions known as tauopathies, a class that includes Alzheimer's disease. Obviously, these mechanisms are far from adequate in the normal operation of aged metabolism, but could they be boosted to effectively clear out deposits of broken proteins? That is essentially what is taking place in the development of immunotherapies to clear out β-amyloid and tau in Alzheimer's patients, harnessing the immune system to the task. But are there other, more fundamental approaches that may just involve enhancing the amounts or activities of specific proteins? The research here suggests that this might be the case.

Inside the cell, proteins need to be folded to be functional and active. Molecular chaperones are key enzymes that assist in folding proteins by stabilizing nascent polypeptide chains and by facilitating interactions that help stabilize a final structure. These chaperones also prevent the aggregation of newly formed proteins and can shunt misfolded proteins toward degradation pathways. In addition to interacting with newly synthesized proteins, chaperones also help to maintain cellular homeostasis by triaging toxic protein aggregates, which are responsible for causing neurodegenerative diseases.

Two proteins that can form these toxic aggregates are tau and α-synuclein, which form tangles in Alzheimer's disease and Lewy bodies in Parkinson's disease, respectively. These proteins aggregate to form small, soluble aggregates termed oligomers and long fibrils often termed amyloids, both of which are thought to be toxic. Here we show that a chaperone, cyclophilin 40 (CyP40), interacts with and dissolves tau and α-synuclein aggregates. CyP40 may accomplish this by interacting with proline residues in these proteins, which are known to play a key role in fibril stability. We show that CyP40 both lowers tau fibrils and oligomers in mice that overexpress tau protein and preserves cognition in these transgenic animals.

While being the first human PPIase to display disaggregation activity, CyP40 is not the first disaggregase to be identified. Certain chaperone complexes have been shown to facilitate the disaggregation of oligomers and fibrils. The existence of amyloid disaggregases presents a new avenue for therapeutic strategies. The procognitive effects of CyP40 overexpression in the tauopathic brain suggest that strategies to either induce or deliver disaggregases to the central nervous system could halt or even rescue cognitive deficits associated with neurotoxic amyloids.

Though CyP40 can directly interact with the chaperone heat shock protein Hsp90, the effects described here do not appear to be Hsp90 dependent. Further studies are required to determine if there are endogenous mechanisms to increase CyP40 activity either through the up-regulation of CyP40 expression, by increasing CyP40 stability, or by increasing the enzymatic activity of CyP40. Recent work suggests that upon cellular stress Hsp90 may dissociate from CyP40, leading to an increased pool of more catalytically active CyP40. This may hint at a possible mechanistic pathway by which CyP40 may be "turned on" in response to stress, including toxic amyloid build-up. In addition to CyP40, there are currently 41 known human PPIases within the cyclophilin, FKBP, and parvulin families. Therefore, future screening may reveal additional PPIases with activities similar to CyP40, including disaggregation. Additionally, CyP40 and other PPIases should be further characterized for disaggregation activity against proline-containing amyloids, especially those associated with disease.

Link: https://doi.org/10.1371/journal.pbio.2001336

Researchers here report on progress in engineering a few parts of the digestive system. The intestine and sphincter work here goes together with advances in the production of small sections of functional stomach tissue reported earlier this year. The field is doing well, considering that the challenge of generating the blood vessel networks necessary to support larger tissue masses has not yet been resolved. Researchers are finding a fair number of areas where they can proceed to potentially produce useful therapeutic outcomes even absent that capability.

Researchers have reached important milestones in their quest to engineer replacement tissue in the lab to treat digestive system conditions. They have verified the effectiveness of lab-grown anal sphincters to treat a large animal model for fecal incontinence, an important step before advancing to studies in humans, and also achieved success in implanting human-engineered intestines in rodents. The lab-engineered sphincters are designed to treat passive incontinence, the involuntary discharge of stool due to a weakened ring-like muscle known as the internal anal sphincter. The muscle can lose function due to age or can be damaged during child birth and certain types of surgery, such as cancer. Current options to repair the internal anal sphincter include grafts of skeletal muscle, injectable silicone material or implantation of mechanical devices, all of which have high complication rates and limited success.

The team has been working to engineer replacement sphincters for more than 10 years. In 2011, the team was the first to report functional, lab-grown anal sphincters bioengineered from human cells that were implanted in immune-suppressed rodents. The current study involved 20 rabbits with fecal incontinence. The sphincters were engineered using small biopsies from the animals' sphincter and intestinal tissue. From this tissue, smooth muscle and nerve cells were isolated and then multiplied in the lab. In a ring-shaped mold, the two types of cells were layered to build the sphincter. The entire process took about four to six weeks. In the animals receiving the sphincters, fecal continence was restored throughout a three month follow-up period, compared to the other groups, which did not improve. Measurements of sphincter pressure and tone showed that the sphincters were viable and functional and maintained both the muscle and nerve components. Currently, longer follow up of the implanted sphincters is close to completion with good results.

The intestine project is aimed at helping patients with intestinal failure, which is when the small intestine malfunctions or is too short to digest food and absorb nutrients essential to health. Intestinal transplant is an option, but donor tissue is in short supply and the procedure has high mortality rates. "A major challenge in building replacement intestine tissue in the lab is that it is the combination of smooth muscle and nerve cells in gut tissue that moves digested food material through the gastrointestinal tract." Through much trial and effort, the team has learned to use the two cell types to create "sheets" of muscle pre-wired with nerves. The sheets are then wrapped around tubular molds made of chitosan.

In the current study, the tubular structures were implanted in rats in two phases. In phase one, the tubes were implanted in the omentum, which is fatty tissue in the lower abdomen, for four weeks. Rich in oxygen, this tissue promoted the formation of blood vessels to the tubes. During this phase, the muscle cells began releasing materials that would eventually replace the scaffold as it degraded. For phase two, the bioengineered tubular intestines were connected to the animals' intestines, similar to an intestine transplant. During this six-week phase, the tubes developed a cellular lining as the body's epithelial cells migrated to the area. The rats gained weight and studies showed that the replacement intestine was healthy in color and contained digested food.

Link: https://www.eurekalert.org/pub_releases/2017-07/wfbm-rms062917.php

One of the ongoing offshoots from the mainstream of calorie restriction research is the investigation of the impact of sensing food on the effects of dietary intake and the operation of metabolism. While there is no necessary reason for research into sensing of nutritional cues to be connected to research into reduced calorie intake, this is how things have worked out in practice. It all stems from calorie restriction research projects some years back in which the scientists involved noted that the flies in their studies seemed to undergo short-term changes in metabolism that were independent of the content of the food provided, and even occurred a little in advance of the flies actually undertaking the new, lower calorie diet.

Via further experimentation, this led to the conclusion that scent plays an important role in the regulation of metabolism in this and other lower species. For example it is possible to block the benefits of eating less in flies by providing an environment filled with the scent of greater amounts of food. The neural structures involved appear to listen as much to what is scented of food content as to what is actually consumed. In the past few years, this line of inquiry has moved from lower animals into mice. This is reasonable; the calorie restriction response of improved health and extended healthy life span came into being very early in the evolution of life, and appears to some degree or another in near all species and lineages tested to date, mammals included. So if the basic cellular processes are much the same between all of these species, widely dispersed across the tree of life, why not also the importance of olfactory mechanisms?

So we come to today's research results, which retain the investigation of scent in metabolic response to diet, but depart from calorie restriction for the other end of the spectrum: high calorie diets and obesity. Normally this isn't all that interesting as a topic for the audience here, but as a new set of data to take back to current investigations of sensory manipulation of calorie restriction responses, it is worth noting. If nothing else, the size of the effect in mice is certainly very surprising, even given somewhat analogous results in flies and worms. It certainly raises questions as to what similar examinations might find in human regulation of metabolism.

Smelling your food makes you fat

Our sense of smell is key to the enjoyment of food, so it may be no surprise that in experiments, obese mice who lost their sense of smell also lost weight. What's weird, however, is that these slimmed-down but smell-deficient mice ate the same amount of fatty food as mice that retained their sense of smell and ballooned to twice their normal weight. In addition, mice with a boosted sense of smell - super-smellers - got even fatter on a high-fat diet than did mice with normal smell. The findings suggest that the odor of what we eat may play an important role in how the body deals with calories. If you can't smell your food, you may burn it rather than store it.

These results point to a key connection between the olfactory or smell system and regions of the brain that regulate metabolism, in particular the hypothalamus, though the neural circuits are still unknown. Mice as well as humans are more sensitive to smells when they are hungry than after they've eaten, so perhaps the lack of smell tricks the body into thinking it has already eaten. While searching for food, the body stores calories in case it's unsuccessful. Once food is secured, the body feels free to burn it.

The smell-deficient mice rapidly burned calories by up-regulating their sympathetic nervous system, which is known to increase fat burning. The mice turned their beige fat cells - the subcutaneous fat storage cells that accumulate around our thighs and midriffs - into brown fat cells, which burn fatty acids to produce heat. Some turned almost all of their beige fat into brown fat, becoming lean, mean burning machines. In these mice, white fat cells - the storage cells that cluster around our internal organs and are associated with poor health outcomes - also shrank in size. The obese mice, which had also developed glucose intolerance - a condition that leads to diabetes - not only lost weight on a high-fat diet, but regained normal glucose tolerance.

The Sense of Smell Impacts Metabolic Health and Obesity

The regulation of whole-body energy homeostasis relies on an intricate balance between food intake and energy expenditure. This balance requires the coordinated response of peripheral and central neuronal inputs including hormones, multiple peptides, and neurotransmitters. In the hypothalamus, the melanocortin system in the arcuate nucleus (ARC) controls feeding in response to circulating insulin and leptin levels. Among the many sensory stimuli that influence behavioral decisions about food choice, olfactory inputs are likely to contribute to the regulation of energy homeostasis. Remarkably, the sensory perception of a hidden food cue, without its ingestion, at least transiently switches the activation state of AgRP and POMC neurons. In mice and other rodents, the hypothalamus receives indirect inputs from olfactory sensory neurons (OSNs) through signals entering from the main olfactory bulb (MOB) and transmitted to the centers of the olfactory cortex. Therefore, olfactory signals may prime the activity of key homeostatic neurons in the hypothalamus to adapt systemic metabolism under conditions of anticipated food intake.

We investigated the role of OSNs in the control of energy balance. To this end, we examined the consequence of genetically ablating the ability of animals to smell, by disrupting OSNs, on whole-body energy homeostasis in lean and obese animals. We find that mice with reduced olfaction, i.e., hyposmia, are leaner upon diet-induced obesity (DIO) either before or after the onset of obesity. These animals exhibit increased energy expenditure and enhanced fat burning capacity as a consequence of enhanced sympathetic nerve activity in brown adipose tissue (BAT) and inguinal white adipose tissue (iWAT). Conversely, we describe that conditional ablation of the IGF1 receptor in OSNs results in enhanced olfactory perception. Complementing the results observed in the hyposmic animals, these hyperosmic mice have increased adiposity and insulin resistance. Collectively, the results reveal a critical role for olfactory sensory perception in coordinately regulating peripheral metabolism via control of autonomic innervation.

The finding that OSNs can control peripheral metabolism is intriguing, and multiple mechanisms could be engaged in this circuitry. It is mainly thought that the hypothalamus receives indirect inputs from OSNs through the MOB and transmitted to the centers of the olfactory cortex. Interestingly, direct connections between discrete subpopulations of OSNs and several nuclei from the hypothalamus have been observed, reinforcing the idea that an active circuitry initiated in OSNs might influence metabolic homeostasis. Our data strongly indicate a circuit that relays information to autonomic neurons and may require central neurons. In line with this hypothesis, fiber photometry recording of AgRP and POMC neurons activity in the hypothalamus of awake, behaving animals shows that the perception of food rapidly switches the activation state of these neurons upon hunger and can be immediately reversed by removing the food cues. Additionally, olfactory inputs may be integrated by a complex interplay of different hypothalamic and brainstem nuclei expressing appetite-modulatory neuropeptides. Regardless, the potential of modulating olfactory signals in the context of metabolic syndrome or diabetes is attractive. The data presented here show that even relatively short-term loss of smell improves metabolic health and weight loss, despite the negative consequences of being on a high-fat diet.

Mitochondrial DNA damage is thought to be important in aging, but not all such damage is similarly relevant to aging. For example, researchers have produced mice that generate excessive numbers of point mutations in mitochondrial DNA, and these mice appear to suffer little harm as a result (with the caveat that different groups have found different degrees of outcome in this sort of investigation). Deletion mutations, however, are a different story. Some deletions result in mitochondria that are both dysfunctional and privileged in some way, better able to replicate or evade quality control mechanisms than their peers, even while they fail to properly perform their assigned tasks. These broken mitochondria quickly take over the mitochondrial population of a cell, turning that cell into a malfunctioning exporter of damaging oxidative molecules.

Unfortunately comprehensive proof of this picture, as opposed to the existing strong indirect evidence, has yet to be assembled. That proof may or may not arrive before the development of some form of rejuvenation therapy based on prevention or repair or working around deletion mutations, such as the allotopic expression of mitochondrial genes. Such a therapy would in and of itself provide strong evidence for or against mitochondrial mutations as a cause of aging, based on whether or not it works in animal studies. For now, more indirect evidence is what we have, however, and here researchers here provide a new set of supporting evidence for the importance of mitochondrial DNA deletions in degenerative aging by comparing samples from people with and without Alzheimer's disease. On average, comparing people of the same chronological age, those suffering from later stages of age-related disease should have a higher load of the forms of cell and tissue damage that cause aging.

Research suggests that mitochondrial changes are a driving force, rather than a consequence, of the aging process and Alzheimer's disease pathogenesis. Although point mutations of mitochondrial DNA have been hypothesized as being a critical cause of aging, there is evidence that they may not be fully explanatory. Mitochondria are dynamic organelles with very short half-lives. Continuous replication of mitochondrial DNA (mtDNA) is required for assignment to new mitochondria, resulting in a significant error rate and accumulation of mutated in mtDNA genome over time and space. We hypothesized that, beyond point mutations, different types of mtDNA rearrangements should be extensively distributed in aging cells. As these rearrangements are often not detected by routine methods such as polymerase chain reaction, we applied the approach of directly sequencing mtDNA from isolated mitochondria derived from fresh frozen brain samples.

Our data show that different types of mitochondrial rearrangements are very common in both the aging brain and Alzheimer's disease (AD) brain. Three types of mitochondrial DNA (mtDNA) rearrangements have been seen in post mortem human brain tissue from patients with AD and age matched controls. These observed rearrangements include deletion, F-type rearrangement, and R-type rearrangement. F-type rearrangement is defined as fragments with two different sections of mtDNA joined together in the same direction. R-type rearrangement is defined as rearrangement of mtDNA originating from two different orientations of mtDNA fragments. We detected a high level of mtDNA rearrangement in brain tissue from cognitively normal subjects, as well as the patients with Alzheimer's disease (AD). The rate of rearrangements was calculated by dividing the number of positive rearrangements by the coverage depth. The rearrangement rate was significantly higher in AD brain tissue than in control brain tissue (17.9% versus 6.7%). Of specific types of rearrangement, deletions were markedly increased in AD (9.2% versus 2.3%).

Evidence indicates that mitochondrial dysfunction has an early and preponderant role in Alzheimer's disease. Our data supports this, as the AD brain samples had more than 2.7 times the recombinant rate of similarly-aged controls. Significantly, the rate for deletion in AD was 4 times that of the control samples. The position of deletion joining points was not evenly distributed across the entire genome and instead was concentrated between regions 6kb and 15kb of the mitochondrial genome, which happens to be the area containing the DNA sequences for synthesizing all three cytochrome oxidases necessary for correct electron transport chain function. This makes it is reasonable to advance the concept that increased deletions in this area may affect the ability of mtDNA to synthesize cytochrome oxidase. Our results are consistent with reports of decreased cytochrome oxidase activity in AD brain samples.

Link: https://doi.org/10.1371/journal.pone.0154582

This article covers some of the advances of recent years in understanding the effects of varied forms of calorie restriction in humans. Efforts to quantify the results and find a good 80/20 point, at which most of the effects of longer and more stringent reductions in calorie intake are still evident, have resulted in practical outcomes. A number of quite interesting discoveries have been made along the way, such as the ability of longer fasting periods to clear out and replace damaged immune cells to some degree.

The second phase of the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE 2) trial demonstrated that it's feasible for humans to limit calories for an extended period. In addition, participants who cut back on calories lost weight and kept it off for the duration of the study. There were no adverse effects on quality of life and the participants netted improvements in blood pressure, cholesterol, and insulin resistance - all risk factors of age-related diseases. Significant changes in the study's primary end points -resting metabolic rate and core body temperature - didn't materialize, however. These two factors are believed to slow aging in animal models of caloric restriction.

Scientists have known since the 1930s that restricting calories by roughly 20% to 50% without malnutrition dramatically extends the healthspan and lifespan of some strains of rodents, and in the decades that followed, caloric restriction has been shown to increase the healthy lifespan of creatures ranging from yeast to guppies to monkeys. It's still an open-ended question whether dietary intervention - or any intervention at all - can dramatically extend humans' maximum lifespan. But epidemiological evidence and cross-sectional observations of centenarians and groups that voluntarily cut their calories strongly suggest that the practice could help people extend their average lifespan and live healthier, as well. While participants in the CALERIE 2 trial did benefit from the intervention, they likely would have had better results had they achieved a full 25% reduction in calories.

"You can prescribe whatever you want, but it's another story to have the people following that religiously." Having come to terms with this reality, scientists have been seeking more practical approaches. They've increasingly become interested in fasting-based analogues to daily caloric restriction, such as intermittent or alternate-day fasting. The results of a recent phase 2 trial published earlier this year suggest that less severe energy restriction could provide bigger improvements with fewer fasting days per month. In the trial, dieters only had to restrict their calories 60% for 5 consecutive days a month over 3 months to get the benefits of the so-called "fasting-mimicking diet."

Researchers initially tested this diet in middle-aged mice, subjecting them to 4 consecutive days of the fast twice a month until their deaths. Mice on the diet lived an average of 11% longer than control mice and had fewer cancers, less inflammation, less visceral fat, slower loss of bone density, and improved cognitive performance. Autopsies revealed that fasting shrunk the rodents' kidneys, hearts, and livers, but the refeeding period appeared to kick start regeneration, increasing bone marrow-derived stem cells and progenitor cells and returning organs to normal weights. Researchers also tested the diet in a small pilot clinical trial. After 3 monthly cycles of a 5-day fasting-mimicking diet, the 19 generally healthy participants in the intervention group reported no major adverse effects and had decreased risk factors and biomarkers for aging, diabetes, cardiovascular disease, and cancer compared with the control group, which maintained its normal caloric intake. Those results were confirmed in a larger phase 2 trial reported this year, which enrolled 100 generally healthy participants.

Link: https://doi.org/10.1001/jama.2017.6648

Useful activities in our community can be powered either by zealotry or by money. Zealotry has the advantage of being cheap, but the profound disadvantages of being rare, unreliable, and never quite optimally opinionated for the task at hand. Set a zealot to a challenge and you get the output the zealot decides upon, and only for so long as he or she is suitably motivated by whatever internal alchemy is at work in that particular case. Sustainable, reliable, long-term zealots only exist in stories. Money, on the other hand, has the disadvantage of being expensive, but for for so long as income is greater than expenditure, it can be used to produce reliable, sustainable, long-term outcomes. Changing the world always starts with the zealots, but the whole point of the subsequent bootstrapping process is to transition to money rather than zealotry as a power source just about as rapidly as possible. The future is defined by the few visionaries who care greatly enough to set aside their lives to work upon it, but it is enacted by the vastly greater number of people who take a paycheck and go home at the end of the work day.

To the extent we agree that the advocacy, fundraising, and other matters accomplished via Fight Aging! are good things, we'd like to see more of this taking place. More of it, and not dependent on the fickle motivations of zealots. Ultimately that means finding ways to do what Fight Aging! does, but for profit, with money. In this I do not mean Fight Aging! itself, which will be powered by zealotry until such time as the alchemy fails, at which point it will vanish just like everything else does in time, but something like it, and preferably dozens of varied somethings. Experimentation and diversity drive progress, and we won't find out exactly what it is that Fight Aging! is doing suboptimally without the existence of many other attempts at the same types of initiative.

In the years that I have been running Fight Aging!, I've seen many longevity science interest and news sites come and go. Zealotry has a short half-life. When it comes to the money side of the house, things haven't been much better, however. The typical ad-supported sites roll over and die fairly quickly; there never was enough money in that to do it for a niche interest such as ours over the past fifteen years. Their business models fail, and they linger a little while on the fumes of zealotry until that also departs. The initiatives that try sponsorship from the "anti-aging" marketplace tend to last longer, but are so corrupted by that revenue that they quickly lose all possible usefulness and relevance. You can't take money from people pushing interventions that do not work and still speak with correctness and authority.

See the Life Extension Foundation's long-running magazine, for example; how is any layperson supposed to tell the difference between the bulk of self-serving nonsense and the occasional perspicacious and useful article? And these are people who are strong supporters of the use of medicine to end aging, and fund some quite sensible research with proceeds from their business, but is really isn't possible to discern this from their materials, where they are doing just as much damage to the future of the field of longevity science as any other random "anti-aging" supplement company. The point of the exercise is to identify and advocate lines of research and development with high expectation values when it comes to effects on healthy life span, and unfortunately all of the ready money willing to pay for eyeballs-slash-victims involves selling snake oil or convincing the world that snake oil is the way forward.

This might change. One could envisage a Fight Aging! clone comfortably sponsored by the rounding errors in Unity Biotechnology's annual budget, or by some near future responsible confederacy of clinics offering senolytic therapies. Here the challenge becomes the more subtle one of being beholden to the controllers of a particular approach or orthodoxy that happens to work. It is infinitely better than taking money from people selling resveratrol laced with outright lies about the state of the science, but still has its problems. A more desirable situation is represented by, say, ALZFORUM, in which the money comes from a large research funding source, and is thus more agnostic on what can and can't be said. Still, we're talking about degrees of editorial freedom, not its absence. Money always comes with at least some strings attached. Further, research funding sources with an interest in this sort of thing are not common, sad to say.

Another interesting model, somewhat similar to that for ALZFORUM, perhaps, is that represented by Geroscience, supported by Apollo Ventures. For a venture fund, running an online magazine is a small expense, and well justified given the uses it can be put to, even if comparatively editorially independent. A venture fund is an opinion crystallized into money, a wager on the future of an industry that will tend to do better the more that people agree with its core opinion. So why not have a magazine to talk up the market and raise awareness? I'm actually quite surprised that this approach doesn't have a wider adoption in venture capital circles. Geroscience has a likely life span of a decade or more because it is coupled to a fund, which is plenty of time to gather a sizable audience by producing a quality product, but I don't think that the owners are going about things in quite the right way to gain that broader visibility and higher traffic. This is possibly because they have no need to do that to satisfy their immediate goals. Daily or near-daily updates in addition to longer articles are necessary and powerful, and they are not doing this.

A further option for involving money in the process as a slow replacement for initial zealotry is that used by Longecity to some degree, and by the Life Extension Advocacy Foundation of late, which is sponsorship by members and patrons. I really can't point to many past examples of this in our space, and it unclear as to whether this is because ours is a small, comparatively young community measured in the grand scheme of things, or because this approach to introducing money is hard to carry out. I do think we have a challenge in the form of cheap research costs; this is of course a blessing for the pace of research and the ability to crowdfund useful work, but makes it hard to fund any of the many necessary areas of community infrastructure that are not research. When meaningful research projects and meaningful advocacy projects cost the same few tens of thousands of dollars, it is a tough choice to give to the latter. The rational actors in our community of supporters near always makes the short-term decision to donate to the SENS Research Foundation rather than to the organization helping to expand awareness of SENS and raise funds for the SENS Research Foundation. This isn't sustainable, however, because it means that necessary functions in our community wind up propped up by zealotry rather than money - and that always comes to its inevitable end sooner rather than later.

In any case, there is no particular conclusion to this line of thinking today, beyond a note that I'd like to see more Fight Aging! alternatives out there, ones running on some basis other than volunteer efforts, but which nonetheless are capable of unbiased advocacy and discussion of the best approaches to enhancing healthy human longevity.

Genetic and other interventions that extend life span in only one gender of a laboratory species seem not to involve large effects, judging from those discovered to date. In this example, a gene known to be involved in DNA repair is found to decline with age in a more pronounced way in female flies. In turn, enhanced levels of the protein produced from this gene extend only female median life span in flies, by something like 10-25% according to the data presented in this paper. This isn't all that large an effect in the grand scheme of things; short-lived species have a far greater plasticity of life span in response to environment and genetic alterations, and researchers have produced far larger gains than this in flies using methods that are known to produce very little effect on life expectancy in humans.

This is the way things tend to work: members of longer lived species have life spans that are relatively unresponsive to environmental influences and single gene alterations that produce quite large changes in the life spans of flies, worms, and mice. These interventions are are all based on producing altered states of metabolism capable of slowing down the pace of aging in some way, however. They are a slowing of the accumulation of damage, without any attempt to repair that damage. There is as yet no data on how the other approach to the problem, actually repairing that cell and tissue damage in order to produce rejuvenation, will differ between short-lived and long-lived species. This will arrive in the years ahead; there is life span data now for senescent cell clearance in mice, and something like a five year study of efficient senolytic treatments in old humans should provide enough data to estimate the effects on human life span.

According to the disposability hypothesis of aging, functional decline results from the accumulation of stochastic damage, for example, due to somatic mutations, and is counteracted by investment into somatic maintenance and repair. Accumulation of DNA damage due to decreased repair can accelerate aging, as is observed in progeroid syndromes in humans and mouse models. Similarly, increased exposure to DNA damaging agents, for instance during chemotherapy, can lead to a phenotype of acquired premature progeroid syndrome. Accelerated accumulation of DNA damage and premature aging phenotypes are typically well correlated, but whether improved DNA damage repair (DDR) can extend organismal life span remains largely unclear.

In the fruit fly (Drosophila melanogaster), a well-studied model for dissecting the mechanisms of aging, spontaneous somatic mutations accumulate with age, and defective DNA repair is associated with reduced life span. However, overexpression of DNA repair factors in the fly seems to have highly variable, sometimes contradictory effects that depend on sex, developmental stage, and the tissue of intervention. For instance, PARP-1 modifies histones, transcription factors and repair enzymes in response to DNA breaks, and its endogenous activity is well correlated with life span in several mammalian species. In Drosophila, overexpression of PARP-1 prolongs life span in both sexes, yet only when restricted to the adult nervous system. Similarly, overexpression of Gadd45, a regulator of DNA repair and cellular stress responses, in the nervous system increases fly life span but ubiquitous expression is lethal. Thus DNA repair factors can affect Drosophila life span and stress resistance either positively or negatively, depending on the sex and on whether overexpression is ubiquitous or limited to the nervous system. Interestingly, all repair factors that were expressed throughout the adult fly body were found to shorten life span.

Here, we examine the role of adult-specific overexpression of the DNA repair factor Prp19 in affecting life span, stress resistance, and DNA damage in Drosophila. Biochemically, PRP19 interacts with multiple players in the DNA repair pathways. Apart from its role in the DNA damage response, an intriguing aspect of PRP19 function is its concomitant and essential involvement in co-transcriptional splicing, where the PRP19 complex regulates the rearrangement of the spliceosome.

In support of a role for PRP19 in the aging process, it has previously been shown that decreased levels of PRP19 accelerate the induction of cellular senescence in mouse embryonic fibroblasts, reduce self renewal of mouse hematopoietic stem cells, increase UV-A-induced skin aging in mice and decrease differentiation of human adipose-derived stromal cells. Conversely, increased levels of PRP19 extend the replicative potential and total life span of cultured human endothelial cells. However, the role of PRP19 in organismal life span is unknown. Here, we show that ubiquitous overexpression of the Drosophila ortholog of PRP19, dPrp19, reduces DNA damage and extends organismal life span of adult female flies. Our results suggest that PRP19 plays an evolutionarily conserved role in the DNA damage response, aging, and stress resistance.

Link: https://doi.org/10.1038/s41514-017-0005-z

Researchers have recently demonstrated the ability to transplant seeded scaffolds in order to engineer the growth of new bile duct structures in mice. The engineered bile ducts became functional - not exactly the same as a natural bile duct, but close enough to perform the same tasks. This approach, once mature, has the potential to restore liver function in conditions involving bile duct failure.

Researchers have grown 3D cellular structures which, once transplanted into mice, developed into normal, functioning bile ducts. Bile ducts are long, tube-like structures that carry bile, which is secreted by the liver and is essential for helping us digest food. If the ducts do not work correctly, for example in the childhood disease biliary atresia, this can lead to damaging build of bile in the liver. The study suggests that it will be feasible to generate and transplant artificial human bile ducts using a combination of cell transplantation and tissue engineering technology. This approach provides hope for the future treatment of diseases of the bile duct; at present, the only option is a liver transplant.

The researchers extracted healthy cells (cholangiocytes) from bile ducts and grew these into functioning 3D duct structures known as biliary organoids. When transplanted into mice, the biliary organoids assembled into intricate tubular structures, resembling bile ducts. The researchers then investigated whether the biliary organoids could be grown on a 'biodegradable collagen scaffold', which could be shaped into a tube and used to repair damaged bile ducts in the body. After four weeks, the cells had fully covered the miniature scaffolding resulting in artificial tubes which exhibited key features of a normal, functioning bile duct. These artificial ducts were then used to replace damaged bile ducts in mice. The artificial duct transplants were successful, with the animals surviving without further complications.

"Our work has the potential to transform the treatment of bile duct disorders. At the moment, our only option is liver transplantation, so we are limited by the availability of healthy organs for transplantation. In future, we believe it will be possible to generate large quantities of bioengineered tissue that could replace diseased bile ducts and provide a powerful new therapeutic option without this reliance on organ transplants. This demonstrates the power of tissue engineering and regenerative medicine. These artificial bile ducts will not only be useful for transplanting, but could also be used to model other diseases of the bile duct and potentially develop and test new drug treatments."

Link: http://www.cam.ac.uk/research/news/artificial-bile-ducts-grown-in-lab-and-transplanted-into-mice-could-help-treat-liver-disease-in

One of the interesting items that has emerged from the discovery of the cause of progeria, a condition that strongly resembles accelerated aging, is that this single molecular cause is also present to a much smaller degree in normally old individuals. Progeria is caused by a mutation in the lamin A (LMNA) gene, important in the establishment of cell structure, and therefore also important to the correct function of just about every vital cellular process. The condition is very rare because this mutation must randomly occur in a germ cell or during very early embryonic development. It is an inherited condition in that sense, but patients don't live long enough to have children of their own. The mutated form of the lamin A protein is known as progerin, and over the past decade researchers have noted that small amounts of progerin can also be found in normal individuals.

Here, it is important to note that what are commonly referred to as accelerated aging conditions, progeria being one example, are not in fact accelerated aging. They look that way, superficially at least, but they are better thought of as runaway damage conditions. One type of cellular damage, in many cases a type of cellular damage that - so far as we know - has little to no relevance in normal aging, runs amok. The result is some combination of impaired regeneration, impaired DNA maintenance, cells that become broken and dysfunctional, tissues and organs with failing functionality. This sounds a lot like aging, true, but then so does poisoning or viral disease when it is expressed in those terms. The result is functional decline, dysfunction, and death, but the details are different, and the deeper you look into the biochemistry, the more different they become. Just as you can't learn much about aging from examining victims of slow poisoning, you also can't learn much about aging from any narrow form of molecular breakage that doesn't occur to a significant degree in normal aging.

What about progerin, however? Did I not just mention that it does appear in normally aged tissues? Well, this is true, it does. So do a great many other things, however. The trick lies in proving that there is a significant contribution to degenerative aging resulting from progerin. A number of research groups have been slowly chasing this down over the past fifteen years, with an increasing focus on cellular senescence, as the cells of progeria patients appear to have at least some aspects in common with senescent cells, even if there are marked differences between the two. Senescent cells, of course, are now well recognized to be a contributing cause of normal degenerative aging. Another area of interest is the possible impact of progerin on stem cell activity, required for tissue maintenance. This maintenance activity declines with aging, likely a response to rising levels of cellular damage that serves to reduce cancer risk, but the research community is a fair way from being able to pin down specific causes and the degree to which they contribute to this loss of function.

The open access paper noted here is representative of the state of the field, in which researchers are starting to be confident enough in their understanding of progerin in normal aging to advance possible mechanisms for its effects, and run animal studies to try to put some numbers to those claims. The authors link progerin with cellular senescence in fat tissue, in the sense they think a small number of progerin-loaded cells are accelerating the creation of lingering senescent cells, which go on to carry out their characteristic damage to health and tissue function. Unfortunately, I'd say the results published here are a little too tentative to provide good support for the authors' theory on what is taking place under the hood, for all that it sounds plausible. It is an interesting direction, however, and I would expect to see further similar work on this topic in the years ahead.

Rare progerin-expressing preadipocytes and adipocytes contribute to tissue depletion over time

One of the major physiological changes that arises with aging is the loss of subcutaneous white adipose tissue (sWAT). White adipose tissue is known to be involved in energy storage, in the form of lipids, but also in immunity, adipokine and inflammatory cytokine production. Different fat depots can be found in both humans and mice, which appear to have distinct functions. Subcutaneous fat works as an endocrine organ, secreting, in particular, the hormones leptin and resistin. Its role is to store triglycerides and free-fatty acids in order to prevent their ectopic deposition. In the case of lipoatrophy, sWAT's ability to store energy is impaired, which results in ectopic fat deposition either in visceral depots or in non-adipose sites.

The investigation of premature aging syndromes has had a considerable impact on the understanding of some of the bases of physiological aging. One of these syndromes is the Hutchinson-Gilford Progeria Syndrome (HGPS), commonly known as Progeria, a rare genetic disease characterized by clinical features resembling certain aspects of premature aging. Although several mutations have been reported to cause HGPS, this disease most often results from a de novo point mutation in the LMNA gene. Progerin accumulates at the inner nuclear membrane causing distortion of the membrane and disrupting nuclear functions. Accumulation of progerin is thought to be responsible for abnormal functional changes associated with HGPS including suppressed Nrf2 antioxidant pathway signalling and impaired adult stem cell function.

HGPS shares several features with normal aging, one of them being the loss of sWAT. Several studies have revealed the presence of low levels of progerin or rare progerin-expressing cells in normal fibroblasts (between 0.5% and 3%) and arteries (between 0.001% and 1.97%), with amounts sometimes increasing during aging. Low tissue levels of progerin can either be attributed to low expression in many cells, or to high expression in a small fraction of cells. However, it is still arguable that low levels of progerin significantly contribute to the reduced tissue function associated with aging.

In this study, we used a mouse model with sustained long-term expression of human progerin in a low frequency of cells of the adipose tissue to determine the contribution of progerin to progressive sWAT depletion. Our results provide evidence that adipose tissue is highly sensitive to progerin expression and further emphasize progerin's possible causal role in certain tissue alterations during aging. However, the frequency of progerin positive cells in the sWAT of our mouse model was higher than what was observed in healthy human sWAT, in which progerin could not be detected on protein level. Other researchers have suggested a hypothetical model whereby aging of adipose tissue results in cellular senescence and consequent tissue pathology. Our results provide evidence that a similar mechanism is to be found in subcutaneous fat, with progerin accumulation during aging triggering a cascade of events contributing to progressive tissue depletion.

We propose that with chronic exposure to low numbers of progerin expressing cells, sWAT pathology begins, initially with hyperproliferation. Hyperproliferation in turn contributes to abnormal cellular development and subsequent senescence. As paracrine activity is high in adipose tissue, senescence spreads to surrounding cells through activation of the senescence-associated secretory phenotype (SASP). Simultaneously, aging sWAT accumulates DNA double-strand breaks, which upon reaching a certain threshold lead to an increase in cell death, encouraging macrophage infiltration, as well as exacerbating the senescence phenotype. This pro-inflammatory environment of the adipose tissue ultimately activates the immune system machinery resulting in systemic inflammation.

Everyone who advocates for far longer and far healthier human lives, a goal to be achieved through progress in medicine, sooner or later runs into the "death is necessary to give life meaning" objection. It sounds deep, but turns out to be complete nonsense once you start to break it down into its component parts for examination. The meaning of your life is what you decide it to be, and that is determined while living, while being alive to think, plan, and achieve. Living is what is necessary to give a life meaning for the person who lives it, and it isn't as though other opinions really count in this matter. This strangely nonsensical argument for death is really just another facet of the naturalistic fallacy coupled with the lazy conservatism inherent in human nature. It is painting what happens to be the state of the world now as the best of all possibilities, because it is easier to do that than to set forth to change it. There is no state of the world so terrible that you would not find the majority talking themselves into accepting it as the status quo.

It is not uncommon for people to accept, rather uncritically, the stale cliché according to which life gets its meaning from death, and without the latter, it would not have meaning. If rejuvenation can stave off death and extend lives indefinitely, will these extended lives be utterly meaningless? No. Time and time again have I said this before, but I still fear that this misconception may be one of the worst enemies of rejuvenation; consequently, I spend much time thinking about its roots and how to debunk it. Whether life gets its meaning from death or not, people who think it does implicitly admit that life has no meaning per se. In a general sense, this is correct. Meaning is not an intrinsic property of anything. To paraphrase a common adage, meaning lies in the head of the beholder, and that's where you should expect to find the meaning - if any - of anything, life included. In other words, it is up to you to find meaning in your life, and you should neither expect it to have meaning by default, nor let others decide for you what the meaning of your life is.

It is obvious why a strong wish to live exists: if I fear death and try to avoid it by all possible means, I stand a better chance to live long enough to reproduce than somebody who isn't so afraid. Therefore, evolution has penalised creatures who did not have a strong survival instinct, and rewarded those who did. This is why we hold our lives so dear. Human intelligence made us extremely fit for survival; our curiosity and drive to answer questions that we ourselves ask are among the things that make us unique on this planet. Eventually, they made us wonder why we die. Evolution has made us fear death and wish to live indefinitely, but at the same time, it has not given us the means to fulfill that wish.

The first and most evident sign of our attempts to address this problem are religions. Yes, we fear death and don't want it, but we don't really die, only the body does, or so is the claim. Some of us have resorted to accepting it, which seems to boil down to convincing yourself there's nothing to fear in death and you're okay with it. The final way to circumvent the death paradox is the fabled 'meaning of life'. What better way can there be to rationalise death and escape our mortal fear of it than making it what gives life itself its meaning? Far from being something we should fear or avoid, death becomes thus essential, for without it, life would have no point.

What does it even mean, to give meaning to life? Most would probably agree that filling your life with activities, people, and things you love and enjoy is a valid candidate for the meaning of life; so is helping others, or doing something for the common good; something that we feel is appreciated by others, and are thus gratified by. Giving meaning to life might mean doing some of these things, and clearly, none of these potential meanings is given to life by death. However, these are viable options but aren't the answer, because there is no single answer. You decide what is the meaning of your life; not old legends, not old myths, not clichés, not other people; you do. Thus, the only way death could be the meaning of your life would be if you decided so, which I hope you won't do. Ultimately, there's nothing especially wise in accepting death. The natural length of our lifespans is the result of a meaningless, purposeless process that happened for no other reason than the fact it could.

Link: https://rejuvenaction.wordpress.com/2017/06/29/the-meaning-of-death/

Eric Verdin is the present CEO of the Buck Institute for Research on Aging. From my perspective most of the research programs carried out there, with the notable exception of matters involving cellular senescence, is fairly distant from the SENS rejuvenation research we'd like to see prosper. The Buck Institute as a whole reflects the broader research community focus on greater understanding of how aging progresses at the detail level, absent intervention, and on the development of ways to modestly slow the accumulation of damage, such as calorie restriction mimetic drugs.

Thus even among those researchers interested in treating aging as a medical condition, our community still needs to persuade many more of them to work on damage repair strategies capable in principle of producing rejuvenation in the old, rather than tinkering with metabolism to merely slow down the rate at which damage accrues. The hope is that as SENS approaches such as senescent cell clearance show themselves to be far more reliable, as well as cheaper and faster to bring to the clinic, this will happen. Meanwhile we have the existence of numerous research centers of a size comparable to the Buck Institute, with ten times the annual budget of the SENS Research Foundation, working on comparatively little that can possible produce meaningful outcomes in aging in the near future.

Biologist Eric Verdin considers aging a disease. His research group famously discovered several enzymes, including sirtuins, that play an important role in how our mitochondria - the powerhouses of our cells - age. His studies in mice have shown that the stress caused by calorie restriction activates sirtuins, increasing mitochondrial activity and slowing aging. In other words, in the lab, calorie restriction in mice allows them to live longer. His work has inspired many mitochondrial hacks - diets, supplements, and episodic fasting plans - but there is not yet evidence that these findings translate to humans.

Why is there so much energy and excitement surrounding aging research right now?

Something happened in the 1990s. There were three groups that did an experiment that was really unexplained. Those groups all identified unique mutations in laboratory species that could actually increase lifespan. At that time, it was a quite astute observation in the way they completely turned upside down our conception of what aging was. The whole idea of aging was sort of an entropy problem where everything falls apart like your car rusting, but what these papers showed is that you can make a single change in one whole organism like C. elegans with a 100 million base pair genome, and you can double its lifespan. That by itself was mindboggling for a lot of people and suggested there might be pathways to regulate aging, and if there are pathways that means there are proteins, and that means you can eventually develop drugs. Today we're at a point where people are considering starting clinical trials. This is why there is so much excitement and interest.

The Buck Institute focuses on research aimed at increasing healthspan. What do you mean by healthspan?

The whole mission of the Buck is not only to increase healthspan but also lifespan, but we don't want to increase lifespan at the expense of healthspan. Every decade over the last hundred years, lifespan has increased by two years. That's amazing because we've gone from an average life expectancy in the 1900s, which was around 47, to 77 today. That's an incredible achievement, but this extended lifespan is not all rosy. We also have an epidemic of what we call the chronic disease of aging.

Can those incredible increases in lifespan continue? Is there an upper limit?

There currently is an upper limit, and the upper limit is probably around 115, 120. You have a very large number - 100 billion people to choose the number of people that have ever lived - and you have only one who has made it through to 122, Jeanne Calment. The second oldest was 119. That's already a pretty good limit. If we could all live to 110 healthy and a disease in the last five years of life, I think most people would sign for this. But this does not anticipate future developments in biology. I've been in experimental biology for about 30 years. What we're doing today is just amazing in comparison to what we were doing when I started. You can't imagine what we will be able to do in biology in 30, 50, 100 years. That's why I don't like the idea that there's an absolute upper limit that man will never live above 120.

Why isn't there more interest in aging research in the larger biomedical community?

Aging research is a real paradigm shift in a way that really changes much of what we think about these chronic diseases. I think the biggest resistance is from medicine because medicine is organized in a way that is not so compatible with what we're doing. Medicine is organized based on organs. You have a heart attack, you go see a cardiologist, and he's going to take care of your heart by deferring the risk for heart attacks and controlling high blood pressure or high cholesterol. What our field is proposing is that aging is the major risk factor for all of these diseases. We should start targeting not cholesterol and blood pressure. I mean, you still have to do this, but if you start targeting the mechanism of aging, you will have a much more profound effect against all of these diseases. That really is the promise of what we're doing.

Link: http://aging.nautil.us/feature/226/how-aging-research-is-changing-our-lives