$36,000
$24,768

The Fight Aging! Algorithm

This query turned up in my in-box today:

I have long relied on your blog to stay informed about aging research. I wonder if you could write a post (or point me to one) describing your general method of information gathering and analysis. When I attempt to follow the biogerontology literature directly, I find many individual papers of interest but often lack the wider context. I know of few sources that can consistently provide a background of general developments in the field, historical progression, expert analysis, etc. This is why a blog like yours is very useful to me. Might you elaborate on your sources? How do you aggregate and sift through papers (is there specific software for this you prefer)? Are there other blogs or news feeds you use routinely? What about staying apprised of developments in biotech and industry outside of academia? Any advice on these matters would be greatly appreciated.

Now I know that some time back I wrote a post on the sites I reference when searching for news, recent research, and other items of interest. Fight Aging! has grown to the point at which I sometimes lose old posts - I know they are there somewhere, but I cannot find them, or at least not without wading through thousands of posts by hand, which isn't going to happen. The aforementioned post on news sources is one such lost item as of today: Google isn't much help when searching Fight Aging! for terms like "news," "science," and "site," as you might imagine. So here I'll take the lazy way out and scribe a fresh outline of my process.

(With the note that I'd be extremely happy to see fifty or more people doing exactly what I'm doing here, while finding new audiences, validating the topic, giving it their own spin, and so forth. One day my fingers are going to fall off, or a bus will land on me, and it will be a shame if at that time it's still the case that I'm not completely irrelevant. Success in propagating a sensible, SENS-favoring view of longevity science should be accompanied by the emergence of many more fellow travelers in the news-relay and opinion business - and there are still all too few such folk).

The Search

Every day I check a few science publicity outlets:

These two complement each other well. ScienceDaily is usually slower to put out new materials, which means I have two chances to notice something interesting, and it will be presented in two different ways. I also check Google News on a daily basis with a handful of trivial searches - things like "aging science," "regenerative medicine," and so forth.

Every few days I'll run through PubMed with a pair of very simple searches:

Similarly, one or twice a week I'll wander through likely blogs (most of which are listed in the main page sidebar here at Fight Aging!), specialist news sites like The Scientist, and a couple of the more prolific open access journals like Impact Aging or some of the BioMed Central publications.

Beyond this, the last line of finding things is having them found for me. Readers are often kind enough to point things out by email, which is very helpful. Social news sites like /r/science and mailing lists such as KurzweilAI, the GRG, and transhumantech help to ensure that I at least notice the more newsworthy items that I otherwise missed.

This is all done by hand: web browser, mail client, mark 1 eyeball. I make fast judgement calls on what I'll likely find interesting on the basis of titles, summaries, and occasionally skimming an article. This isn't rigorous by any means, but it's how the general tenor of what is presented here emerges: I know the topics I'm interested in, and I know what catches my eye. Sticking to a manual, vague, varying site-by-site approach also means that I tend to follow themes from day to day and week to week. If I've been looking over cancer research for the past couple of days, then I'm more likely to notice something relevant and linked in that field than is otherwise the case, for example.

Everything that I find or is found for me goes into the stack for later.

The Stack

The stack is my in-box: mail sent to myself, with links and sometimes notes, one source or post idea per email without much in the way of any distinguishing labels. This works well for me, as I want things to fall off the bottom of the stack. If something in my stack is three weeks old, that means I've looked at it at least twice with fresh eyes and both times decided it wasn't as interesting or relevant as some other topic. Time to delete it and move on.

One of the best outcomes from an item sitting in the stack for a couple of weeks is that sometimes someone else will write a far better blog post or article on the topic than I would ever have managed. This is definitively a win in my book, and that better post goes to the top of the stack, while the original link is dropped.

I post a few times a day, which means I'm dipping small samples from a vast river of happenstance and events, and over time trying to construct relevance in a bigger picture. There will always be more later, and nothing of importance happens once and then never again in the world of science. I'm not worried about missing out on anything that I consider important despite the eminently and deliberately haphazard approach I take. I'm almost certainly missing many things that someone else might consider important - Fight Aging! is nothing if not a consideration of a narrow slice of the life sciences and its application.

(And yes of course this could all be automated, giving me one big homogeneous stack of stuff in a single window to meander through and flag every morning, but where's the fun in that? It wouldn't even speed up the process).

News Posts

The first couple of posts of the day are simple links to recent news or research, usually accompanied by a little explanation of the relevance, or pointers to past instances where the topics were mentioned at Fight Aging! In other words, why did I notice this? Why do I think it's worth mentioning? How does it fit into my view of the bigger picture? That flows very naturally from the process of noticing interesting news in the first place.

News items come from the stack, which I look over every day. A non-scientific, entirely arbitrary ranking system runs somewhere in the depths of what passes for a brain here, leading to the two items to run with. On the pro side:

  • Do I have a strong and defensible opinion on this that makes me itch to type a few sentences?
  • Is there a good earlier discussion of the underlying science in the Fight Aging! archives?
  • Do I find it especially interesting, or a sign of meaningful progress?
  • Is it directly relevant to SENS-like goals of rejuvenation biotechnology?

And con:

  • Have I already mentioned this recently, or written a very similar post of late?
  • Did this actually turn out to be less interesting than I initially thought?
  • Is it stale news, too long in the stack?
  • Am I presently tired of this particular topic, meaning I probably won't do it justice?

Having picked what I'm going to post, I then search the Fight Aging! archives for earlier references: this is an important step, as it's how I keep my understanding of the bigger picture in place, given that there's far to much going on to remember in more than outline form. I may run to Google or Wikipedia for lay explanations of any biochemistry or other items that are new to me, and which I have to better understand in order to grasp the point. Wikipedia, I have to say, is great for undergraduate-level life science materials, and moderately good for popularized medical research.

It isn't all that common nowadays that I do find myself bogged down in trying to understand an item from the stack - on the one hand there are selection effects (i.e. my understanding) operating on the news I pick out while browsing, and on the other hand I've been doing this for a decade. Still, new is interesting. But if it is the case that I have to spend more than a handful of minutes on figuring this out, then the item in question will certainly require more explanation for passing readers than is good for a news post; I tend to throw those back to the stack and mark them for use in longer and more detailed blog posts.

Blog Post

The last post of the day is a longer item, and it is usually the case that I'll have been pondering what to write in the back of my mind since looking over the stack earlier in the day. This is a chance to take more time to talk about relevance and focus in on a couple of pieces of the jigsaw puzzle that is modern longevity science, where it is heading, and where it could be heading. I have my views, and Fight Aging! is one manifestation of that inexact process by which views develop and interact with ongoing reports from reality.

Writing is a mood thing, however, even for a brief handful of paragraphs. Unless I'm fired up or provoked on a topic, then I will generally write about a specific research result in a wider context - in essence just a longer news post with a different format. Fight Aging! is an exomemory of sorts, and putting more posts into place helps ensure that later posts will be both better informed and placed in a more helpful context.

In Summary

So in summary: Fight Aging! is a largely manual process of my telling you what I find interesting or relevant, and why I find it interesting or relevant. No magic and very little technology, just practice and opinion in equal measure.

Infusing Large Numbers of Immune Cells as a Therapy

Since it is possible to take a patient's cells and generate a very large number of immune cells, far more than the patient would ever have normally, and since it's possible to make some alterations to immune cells to make them more effective, why not do this? It's probably the case that even generally healthy older people would benefit from a regular infusion of large numbers of their own immune cells, or even donor cells, given the way in which the immune system declines with age, but under present medical regulation you'll only ever see it deployed as a treatment for late stage disease:

[Researchers] have successfully infused large numbers of donor T-cells specific for a key anti-leukemic antigen to prolong survival in high-risk and relapsed leukemia patients after stem cell transplantation. [T-cells were] taken from a donor, programmed in the lab to recognize the Wilm's Tumor Antigen 1 (WT1) and kill leukemia cells, grown in large numbers, and then infused into patients to promote anti-leukemic activity. The WT1 protein is overexpressed in leukemias and is in part responsible for why the cells have become leukemic.

All of the patients [received] adoptively transferred infusions of billions of enhanced CD8 cytotoxic T-cell clones. They were considered at high risk of death because they had already relapsed and/or had a poor prognosis due to unfavorable characteristics of their leukemia.

Four of the 11 patients in the trial received infusions of T-cells that targeted WT1 and were generated in the presence of IL-21. One had detectable relapsed disease and entered complete remission shortly after the T-cells were infused. All four survived after T-cell therapy without relapse for more than 30 months without suffering graft-vs.-host-disease and required no additional anti-leukemic treatment, according to the study.

Among the seven patients who received infused T-cells generated without the presence of IL-21, two showed direct evidence of anti-leukemic activity, including one patient with advanced progressive disease who had a temporary response.

Link: http://www.sciencedaily.com/releases/2013/02/130227151248.htm

One View of the Widespread Unthought Opposition to Engineered Human Longevity

The average fellow in the street thinks that helping people to live longer is a bad idea, and usually expresses some combination of the Tithonus Error (the misapprehension that life extension technologies would make you live in increasing frailty, rather than extending youth) and the modern mixed package of environmentalist / classist / Malthusian / conservative beliefs on wealth and privilege: that equality should come by tearing down those at the top and halting progress, that there are too many people in the world, that any sort of increased consumption is evil, that changing anything to do with aging is bad.

This is the major challenge for the future development of means to extend human life - that most people reject it, even at their own cost, even when their beliefs about the way the world works are easily shown to be false: there is no overpopulation, only waste and corruption; stopping progress and trying to impose equality inevitably leads to something like the economic ruins of the old Soviet Union; Malthus was wrong in his time and still wrong now; and so forth.

Here is an educator's point of view, from one more embedded in the culture that rejects progress than most:

Our minds are perhaps hardwired to interpret the world in terms of simplistic patterns (like "haves" and "have nots"), but that does not mean it is an accurate representation of reality. Education should challenge our preconceived ideas of the world and dogma.

When I teach the weeks of my course on aging and life extension these points become most salient. I am always struck by the fact that (a) very few students understand that chronic diseases are the leading cause of death in the world, and (b) that chronic disease is a problem for both rich and poor countries, and (c) that people in poorer regions of the world actually age, and that this can cause them to experience suffering, disease, a decline in income, etc. I could go on.

Here are actual comments (I am paraphrasing from memory) I have heard students and others express when discussing population aging, global health and a Darwinian approach to medicine: "Old people should die sooner of disease so younger people can get a job". "A cure for cancer already exists, but Big Pharma makes more money off of cancer than curing it". "Wouldn't it be boring being alive longer and thus being married to the same person for longer?" "We shouldn't modify the rate of aging as it is unnatural". "Why don't we just spend all health research money on saving children and forget about helping those who are lucky enough to have lived a long life?" "Slowing human aging will destroy the planet".

Such sentiments are common, and part of my research involves trying to understand why people have such attitudes, and how one can help people come to critically examine such attitudes. The students that I encounter who have strong convictions that the world is overpopulated, and that the future of the planet is a bleak one because of population growth, typically have little knowledge of demography.

Link: http://colinfarrelly.blogspot.com/2013/02/the-anti-science-left-on-agenda.html

Health Extension and Science Funding

I mentioned the Health Extension group late last year. It is a Bay Area grassroots initiative associated with the technology startup community, with salons and presentations sponsored by the SENS Research Foundation (SRF) among others. California is home to a fair chunk of the US aging research community and related relevant science labs, and the SRF has their research center there in the Bay Area - so it's good to see that the technology community continues the evolution of its support for longevity science.

As an aside, it is interesting to speculate as why there is - and so far as I am aware, always has been - a strong undercurrent of support for engineered human longevity amongst those who work with software for a living, as well as other forms of engineer. From the viewpoint of someone immersed in the entrepreneurial technology startup community, medicine and the development of real, actual therapies to slow or reverse aging shows the promise of a massive market yet to exist, combined with a lazy, over-regulated incumbent industry that's alternating between making a hash of things or doing nothing to advance the state of the art. So it's an engineering problem, it's the classic industry in need of disruption, it's the brief pause before a massive revolution in medicine and biotech, and so forth. If you dwell in the space where technology and starting companies overlaps, it's not hard to see dollar signs and opportunities when it comes to longevity science. It's also not hard to see that regulation is preventing or destroying so much of what could be happening on this front - but that might be worked around via medical tourism and overseas commercial development. To get the research done first and worry about the rest later is a good motto.

In any case, I see that Health Extension is showing signs of moving in the logical direction of fundraising and assembling projects that might be crowdfunded, or punted in the direction of philanthropists, or otherwise brought into the confluence of money and intent. This no doubt mixes something of the Biocurious circuit, something of the fundraising for research projects carried out by Longecity in past years, the growing interest in longevity science found in the technology community, plus the face-to-face networking of the Bay Area folk, and the tendency for that community to spawn meaningful projects at a fair rate.

We shall see where it all goes, and I'm all for more people trying to get things done in this space. There is a massive opportunity ahead: figure out how to persuade sufficient funding to implement the SENS vision of rejuvenation therapies soon enough to extend our own lives in health and vigor. Or fail to achieve that end, and suffer and die a few short decades from now. Sooner or later a sizable minority of the members of exactly the sort of wealthy and active community that generates technology companies in the Bay Area will start to realize just how much it is in their self-interest to aggressively push on progress in rejuvenation biotechnology. All that takes is money - there are detailed plans waiting for the necessary research and development funding.

Cautious Studies Tend to Disprove Dietary Longevity Claims

A research group is presently working through a grand tour of replicating longevity claims in mice, using careful and cautious study designs that eliminate calorie restriction effects as much as is possible. This sort of approach shows that many past claims of dietary additions that modestly extend life in mice were probably the result of inadvertent calorie restriction - which is why you have to look carefully at every study to make sure that researchers controlled for this issue. Calorie restriction has a comparatively large effect on life span in smaller animals, such that even mild restriction can swamp all other contributions to life span that occur in a study:

Phytonutrients reportedly extend the lifespan of C. elegans, Drosophila, and mice. We tested extracts of blueberry, pomegranate, green and black tea, cinnamon, sesame, and French maritime pine bark (Pycnogenol and taxifolin), as well as curcumin, morin, and quercetin for their effects on the lifespan of mice. While many of these phytonutrients reportedly extend the lifespan of model organisms, we found no significant effect on the lifespan of male, F1 hybrid mice, even though the dosages used reportedly produce defined therapeutic endpoints in mice.

The compounds were fed beginning at 12 months of age. The control and treatment groups were isocaloric with respect to one another. A 40% calorically restricted and other groups not reported here did experience lifespan extension. Body weights were unchanged relative to controls for all but two supplemented groups, indicating most supplements did not change energy absorption or utilization.

Published reports of murine lifespan extension using curcumin or tea components may have resulted from induced caloric restriction. Together, our results do not support the idea that phytonutrient-antioxidants and anti-inflammatories are potential longevity therapeutics, even though consumption of whole fruits and vegetables is associated with enhanced health- and lifespan.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23432089

A Podcast Interview With Aubrey de Grey

An audio interview with Aubrey de Grey of the SENS Research Foundation:

Like it or not, aging is a byproduct of the daily activity of life. But Aubrey de Grey believes that the molecular and cellular damage that defines aging and creates disability and disease can be targeted for medical interventions that restore health and radically extend life. We spoke to de Grey, chief scientific officer and founder of the SENS Research Foundation, about the need to think differently about aging, how a new era of regenerative medicine might slow or reverse its effects, and why it is necessary to focus on medical interventions rather than prevention to have a significant impact.

In this interview, Dr. de Grey discusses SRF's approach to treating the diseases of aging, and how it differs from most of the research being done today in gerontology. He also talks about his own background, and how he came to the field.

Link: http://www.burrillreport.com/article-forever_young.html

In Targeted Cell Destruction Research, Nanoparticles and Viruses are Categories that Will Blur at the Edges

Targeted cell killing technologies are one of the most important developments to emerge from the cancer research community. Beyond the immediate target of cancer cells there are in fact a whole range of specific types of cell that we'd like to periodically eliminate from the body, safely, and with minimal damage to surrounding tissue. Senescent cells, for example, contribute directly to the aging process as they accumulate with the passing of years. Also, the immune system fails in part because it has a limit on the number of cells it can support, and too many of those cells become uselessly specialized to detect and combat mild herpesviruses like CMV that cannot be cleared from the body by its own natural processes. Getting rid of those cells would free up space that is very much needed.

All of these cell types have their characteristic differences, and given a reliable way to take advantage of those differences then some form of targeted destruction can be unleashed to improve health and reverse this aspect of aging. Two of the more popular approaches to targeted cell destruction in the cancer research community involve nanoparticles such as dendrimers and viruses. The former is a bottom-up approach to building a tool: the construction of comparatively simple, minimalistic assemblies that are designed to link together and deliver a collection of specific designer molecules - perhaps a sensor to match to a type of cell, something to cause the cell to ingest the particle and its payload, and something that will sabotage the cell. Viruses on the other hand are much more complex entities, and their use embodies more of a found tool approach: some are useful because they have a preference for cancer cells over normal cells. Others can be tailored to act that way, but you work with what you can find in the wild or breed in the lab.

As researchers build better nanoparticle-protein assemblies and become more adept at manipulating viruses to exhibit specific desired behaviors, the line between the two will eventually blur. Viruses are about as close as you can get to chemistry while still being something that is generally accepted as being biology. There's a way to go yet - no-one is producing self-replicating nanoparticles for medical use that I'm aware of - but it will happen.

Here's an example of ongoing work at the virus end of the community, showing how researchers are becoming more readily able to alter the mechanisms of viral activity to achieve the desired result, in this case improving its ability to target cancer cells and only cancer cells:

Virus shows promise as prostate cancer treatment

Newcastle disease virus kills chickens, but does not harm humans. It is an oncolytic virus that hones in on tumors, and has shown promising results in a number of human clinical trials for various forms of cancer. However, successful treatments have required multiple injections of large quantities of virus, because in such trials the virus probably failed to reach solid tumors in sufficient quantities, and spread poorly within the tumors.

The researchers addressed this problem by modifying the virus's fusion protein. Fusion protein fuses the virus envelope to the cell membrane, enabling the virus to enter the host cell. These proteins are activated by being cleaved by any of a number of different cellular proteases. They modified the fusion protein in their construct such that it can be cleaved only by prostate specific antigen (which is a protease). That minimizes off-target losses, because these "retargeted" viruses interact only with prostate cancer cells, thus reducing the amount of virus needed for treatment.

Retargeted Newcastle disease virus has major potential advantages over other cancer therapies. [Its specificity for prostate cancer cells means it would not attack normal cells, thereby avoiding the various unpleasant side effects of conventional chemotherapies. In previous clinical trials, even with extremely large doses of naturally occurring strains, "only mild flu-like symptoms were seen in cancer patients."

Parthogenesis in Regenerative Medicine

This popular science piece looks at parthogenesis as an alternative to both embryonic stem cells and induced pluripotency reprogramming as a source of stem cells:

Parthenogenesis is a form of asexual reproduction that occurs naturally in plants, insects, fish, amphibians and reptiles. During this process, unfertilized eggs begin to develop as if they've been fertilized. In 2007, researchers induced human egg cells with chemicals mimicking fertilization so they would undergo the process. The result were parthenogenetic cells that share the same properties as embryos, except that they can't grow further. The cells are akin to pluripotent stem cells derived from embryos, which means they have the ability to develop into different types of cells - including heart cells.

[Researchers] used this knowledge to turn body cells of mice into parthenogenetic stem cells, which were then grown into mature, functional cardiomyocytes. Researchers used these cells to engineer myocardium - heart muscle - with the same structure and function of normal myocardium. The muscle was then grafted onto the hearts of the mice that had contributed the original eggs for parthenogenesis, where it worked the same way as existing muscle.

Link: http://blogs.smithsonianmag.com/science/2013/02/growing-new-hearts-without-using-embryonic-stem-cells/

Very Healthy Elder Athletes Don't Actually Tell Us All That Much About Aging

A number of studies have shown that it is possible to be both old and very healthy in comparison to your peers, and surveying older athletes is a good way to find some of those old, very healthy people. The big question is one of causation: are they healthy because they are athletes, or did they become healthy athletes because they are more physically robust, thanks to genetic or other differences? This is a part of the uncertainty over whether more exercise is always better and the degree to which genetics versus lifestyle versus chance contributes to the course of aging.

People who exercise on a regular basis up to the age of 80 have the same aerobic capacity as someone half their age, says a new study. "These athletes are not who we think of when we consider 80-year-olds because they are in fantastic shape. They are simply incredible, happy people who enjoy life and are living it to the fullest. They are still actively engaged in competitive events."

Researchers examined nine endurance athletes from northern Sweden and compared them to a group of healthy men from Indiana in the same age group who only performed the activities of daily living with no history of structured exercise. The endurance athletes were cross-country skiers, including a former Olympic champion and several national/regional champions with a history of aerobic exercise and participation in endurance events throughout their lives. The athletes exercised four to six times a week, averaging 3,700 more steps per day than the non-exercisers.

Members of the two study groups rode exercise bikes as researchers measured oxygen uptake. When the participants reached total exhaustion, they had reached maximum oxygen uptake (also known as VO2 max). Skeletal muscle biopsies were then taken to measure the capacity of their mitochondria, the aerobic base of their muscle and other cells. The study also found the endurance athletes established new upper limits for aerobic power in men 80-91 years old, including a maximum oxygen uptake that was nearly twice that of untrained men their age.

"To our knowledge, the VO2 max of the lifelong endurance athletes was the highest recorded in humans in this age group, and comparable to nonendurance-trained men 40 years younger. We also analyzed the aerobic capacity of their muscles by examining biopsies taken from thigh muscles, and found it was about double that of typical men. In fact, the oldest gentleman was 91 years old, but his aerobic capacity resembles that of a man 50 years younger. It was absolutely astounding."

Link: http://cms.bsu.edu/news/articles/2013/2/80-could-be-the-new-40

Stem Cell Aging is Most Likely Very Complicated

It is my estimate that reversing stem cell aging is not likely to arrive first in the list of possible near term advances in rejuvenation biotechnology. It is a hard problem. In fact it will only arrive at all because the stem cell research community is very large, well-funded, and energetic, and because those researchers have to solve the problem of diminished stem cell activity with age in order to effectively deliver therapies. Most of the foreseeable uses of stem cell-based regenerative medicine involve treating degenerative age-related conditions, but only if an age-damaged metabolism can be stopped from persistently sabotaging the desired end result of treatment.

The accumulating knowledge of recent years suggests that stem cell aging is very complicated. It may occur in quite different ways in the scores of different stem cell populations, not all of which are presently well understood. It may depend on the ecology of stem cell niches, which are themselves more complicated entities than the stem cells they shelter. The different niches supporting different stem cells can diverge greatly in form and function as well.

For example, if you look back at work on FGF signaling in the stem cell niche from last year, you might note that it involves satellite cells in muscle - one of the better-studied stem cell populations - but there is no reason to expect the findings to be repeated in any other stem cell population. There is no necessary reason for the mechanisms that lead to the similar end result of declining stem cell function to be the same in different tissue types; they only had to evolve to do roughly the same thing, not work the same way.

As another example of the complexities of stem cell aging, you might look at this open access paper:

http://impactaging.com/papers/v5/n1/full/100530.html

The causes underlying aging remain poorly understood. One prominent theory is that a decrease in stem cell function over time plays a significant role in tissue aging, which ultimately manifests at the organismal level. This could be through cell-intrinsic alterations in the stem cell pool, cell-extrinsic changes affecting stem cell function, or a combination of both. However, the noticeable exception to this idea was the fact that the skin, which contains some of the most amenable and best-studied stem cell populations and which progressively loses its ability to maintain tissue homeostasis with age, had no previously documented age-associated changes in stem cell function.

Recent work has now uncovered a subset of epidermal stem cells in the hair follicle bulge that undergoes significant changes during normal aging. Using [a well characterized mouse model] to study and isolate stem cells during aging, this study identified increases in stem cell number but decreases in functional capacity of this population over time, and advances the hypothesis that broader age-associated stem cell alterations contribute significantly to skin aging.

In light of this finding, it is important to keep in mind the diverse heterogeneity of stem cell populations present in the mammalian epidermis. This heterogeneity not only applies to functionality, but also manifests in a compartmentalized fashion, with discrete sets of stem cells occupying distinct anatomical niches, including the interfollicular epidermis (IFE), the hair follicle (HF) bulge, and the isthmus region at the interface of the IFE and HF. It is this heterogeneity, in both location and function that likely masked previous attempts to identify aging stem cell changes in skin

Even skin is very complex, with many populations of distinct stem cells. The hair follicle stem cells noted above are unusual given that there are apparently more of them with age. That is a contrast with studies of other stem cell types: much of the debate over satellite cells in muscle was whether the number of cells was diminishing or just their capacity to act, for example. So what does this all mean? It means that it is a good thing that the stem cell research establishment is large and growing, as it needs to be large and growing in order to have a good chance of success over the next few decades in the issue of stem cell aging.

SENS Research Foundation Site Redesign

The SENS Research Foundation works on the foundational biotechnologies that will be needed to create therapies capable of reversing aging: ways to make mitochondrial DNA damage irrelevant, removing harmful aggregates that build up with age within and between cells, and so forth. The Foundation staff kicked off the first phase of a major site redesign earlier this year, and rolled out the second stage this past weekend. So head over and take a look:

If this is your first time visiting our site, welcome. If you've been here before, you're no doubt noticing plenty that is new: an updated site design, a variety of new content, a new logo, and a new organizational name: "SENS Research Foundation".

It all centers around a new tagline: reimagine aging.

For a public charity, a tagline can be an enormously powerful thing. Our vision and mission statements remain the primary guides to our planning, but the tag is everywhere, on every business card and letter and web page. More than any other document or phrase, it naturally becomes the daily reminder of who we are and what we are about.

Of course we are still "advancing rejuvenation biotechnologies" just as vigorously as when we carried that tagline over the last couple years. We still aim to introduce a new premise for the pharma and biotech industries. And now, our successes in our research, our collaborations, our conferences, and our educational programs have made us increasingly aware of the need to refocus our messaging to people being exposed to us for the first time.

Link: http://sens.org

Considering DNA Methylation and Aging

An article on DNA methylation, which researchers have demonstrated to have the basis for a biomarker of aging; some of the patterns that tend to occur in the way in which these epigenetic decorations to DNA occur correlate well with biological age. This author is optimistic that manipulating DNA methylation can slow aging, which is something of a programmed aging point of view - that epigenetic changes are a root cause of aging and give rise to the damage of aging we can observe, rather than vice versa. It doesn't seem to me that the evidence rises to support that view and course of action over trying to repair the underlying damage of aging. If damage is the root cause, then when it is reverted the DNA methylation changes should also be restored to youthful levels.

How does the body know how old it is? Our metabolisms change as we get older, even though our DNA doesn't change. Different genes are activated at different times of life, and the timing of gene expression is what controls growth, development, sexual maturity, and perhaps aging as well. The body keeps accurate track of how old it is, though there has been no scientific agreement about where the clocks are, or how they work. Recently, some biologists have suggested that one such biological clock might reside in the epigenetic state of the DNA. If this is true, epigenetics will become an attractive, though challenging, target for anti-aging research.

If we knew where the body kept its "clock", then perhaps we could target the clock itself with biochemical interventions. We would not just be able to slow the progress of aging, but reset the clock to an earlier age.

DNA is decorated with methyl groups, small molecular add-ons that act like "Do Not Disturb" signs for the underlying gene. A gene that is decorated with methyl groups is passed over, and not expressed. Patterns of methylation are programmed into the genome at birth, and they are known to change over a lifetime. The new idea is that these changes can constitute a reference, like a clock face that informs the cell about the body's stage of life, so that it can appropriately adjust its gene expression, and thence its entire metabolism.

If we're really lucky, it will turn out that humans, like flies, respond well to a dumb, across-the-board increase in methylation. [The] methyl transferase system in humans is more complicated, but it will still be far easier to engineer a general increase in methylation than to copy youthful methylation patterns in detail. This question could be posed in research project that we know how to do now.

Link: http://hplusmagazine.com/2013/02/22/dna-methylation-an-epigenetic-aging-clock/

The Old Have Been Persuaded to See Themselves as Worthless

One of the more depressing consequences of degenerative aging is the pervasive ageism of our societies. It is taken as read that the old are worth less than the young, are less deserving, their wants and desires less meaningful, their rights to the pursuit of life and happiness weak to nonexistent. This is something that even the old themselves are largely sold on, one of those shared cultural myths that isn't so much taught as absorbed and spread invisibly, clinging on to every story and conversation as a cloud of assumptions and implicit judgments of value.

The value of a life diminishes with age, or so goes the belief - and as we are creatures of hierarchy and position, it's a short step from there to trampling on the old in any number of ways. If the young get to it before the old trample themselves, in any case. Ageism is as much a matter of people telling themselves that they are of little value as anything else.

Below you'll find the rather gloomy viewpoint of a near-70-year-old, informed by the Tithonus Error, the incorrect view that extended life achieved through biotechnology will result in more and increasingly decrepit old age rather than more vigor and youth as is in fact the case. As Aubrey de Grey asked in a recent editorial, why do people completely ignore what the research community says on this topic? Or for that matter, why do they ignore history? The incidental lengthening of human life achieved over the past two centuries through general improvement in medical technologies has been an extension of youth rather than an extension of old age.

The public doesn't stick its head in the sand in the same way for heart disease or Parkinson's research. One might well ask why this happens for aging. Here is a telling sort of a quote when it comes to self-value:

Please welcome the 150-year-old woman

Maybe it's time to ask medical science to shut it down already. Maybe there's something about our bodies that has a sell-by date. Maybe we're not supposed to stare vacantly into space while eating up money and time. There is so much else for science to be doing. There are the cancers that get people in their 30s and 40s and 50s. There are orphan diseases, with not enough sufferers to warrant full-scale research efforts. There are those wounded in war and the challenges they present. Surely all of these matters deserve more attention than how to make sure a 110-year-old person lives to be 125.

I speak myself as someone on the cusp of 70. I am not fond of disease and decay, and I think medical science should be all over finding cures for whatever I've got. But I have visited nursing homes, and seen the floors of lost people, technically alive but not aware of their surroundings, bewildered by everything.

Is this really a vision of the future that you want to have, or you want your parents to have? The geriatric lifestyle seems an awful lot like just taking up space. That's not really anybody's ambition for their end-of-life situation, but it happens anyway. People run out of friends and loved ones; they disappear from memory and from society. And yet they survive.

The goal of longevity science is to roll out ways to slow, halt, and reverse aging: making people healthy and physiologically younger for longer, not older and increasingly frail for longer. Researchers are all agreed on that goal, and say as much in their publications and to the press. Yet as you can see, there remains something of a disconnect - the message has yet to come through to the public at large.

Drugs to Slow Aging are a Matter of When, Not If

It is pleasing to see this sort of article emerging from a university publicity group - a part of the necessary trend within the scientific community towards making it acceptable and desirable to talk about extending human life through biotechnology. The silence of the research community on this topic across past decades was very harmful to the prospects for progress and funding in the field of aging research and longevity science.

That said, it is problematic that the vast majority of resources and researchers presently focus on modestly slowing aging rather than trying to repair and reverse the causes of aging. Based on what we know today, it is probably harder to safely adjust metabolism to slow down aging than it is to repair the root causes of aging to restore a metabolism back to its youthful state. Further, slowing aging is of no use to old people, whereas repair based approaches are useful - and given that people in middle age today will be old by the earliest possible time that therapies might emerge, it won't be all that great if all those therapies can do is slow down the progression of aging.

So more work on SENS and similar repair-based strategies, and less fiddling around with calorie restriction mimetics, longevity genes, and the like, is what we need to see if there is to be an effective near-term lengthening of human life. That result has to be based on rejuvenation, not slowing of aging.

Evidence is accumulating that not only is it possible to slow down aging, but that by doing so the onset and progression of multiple age-related diseases can be delayed. "Slowing aging should increase both lifespan and healthspan - the period of life spent in relatively good health, free from chronic disease or disability. A shared feature of most medically relevant diseases is that your risk of dying from them increases dramatically as you get older. Unlike traditional approaches, which tend to focus on a specific disease, targeting the aging process itself has a much greater potential to improve human health."

Many experts in the biology of aging believe that pharmacological interventions to slow aging are a matter of 'when' rather than 'if'. A leading target for such interventions is the nutrient response pathway defined by mTOR, a protein that controls cell growth. "Inhibition of this pathway extends lifespan in model organisms and confers protection against a growing list of age-related pathologies. Characterized inhibitors of this pathway are already clinically approved, and others are under development. Although adverse side effects currently preclude use in otherwise healthy individuals, drugs that target the mTOR pathway could one day become widely used to slow aging and reduce age-related pathologies in humans."

Link: http://www.washington.edu/news/2013/02/21/drugs-to-slow-aging-are-a-matter-of-when-not-if/

An Example of the Future of Stem Cell Therapies

One major branch of future progress in stem cell therapy will discard transplantation of cells in favor of manipulating the signals that tell local cells what to do - which is generally what the transplanted cells are actually doing anyway. This will become more effective as researchers gain a better understanding of the intricacies of cell signalling relevant to growth and repair, but here is an early example of what can be done with this sort of approach:

In the first human study of its kind, researchers activated heart failure patients' stem cells with gene therapy to improve their symptoms, heart function and quality of life. [Researchers] delivered a gene that encodes a factor called SDF-1 to activate stem cells like a "homing" signal.

SDF-1 is a naturally occurring protein, secreted by cells, that guides the movement of other cells. Previous research [has] shown SDF-1 activates and recruits the body's stem cells, allowing them to heal damaged tissue. However, the effect may be short-lived. For example, SDF-1 that's naturally expressed after a heart attack lasts only a week. In the study, researchers attempted to re-establish and extend the time that SDF-1 could stimulate patients' stem cells. Study participants' average age was 66 years.

Researchers injected one of three doses of the SDF-1 gene [into] the hearts of 17 patients with symptomatic heart failure and monitored them for up to a year. Four months after treatment, they found: 1) Patients improved their average distance by 40 meters during a six-minute walking test. 2) Patients reported improved quality of life. 3) The heart's pumping ability improved. 4) No apparent side effects occurred with treatment.

"We found 50 percent of patients receiving the two highest doses still had positive effects one year after treatment with their heart failure classification improving by at least one level. They still had evidence of damage, but they functioned better and were feeling better." Researchers are now comparing results from heart failure patients receiving SDF-1 with patients who aren't. If the trial goes well, the therapy could be widely available to heart failure patients within four to five years.

Link: http://www.eurekalert.org/pub_releases/2013-02/aha-sc021813.php

Noting the Inaugural Breakthrough Prize Awards

The Breakthrough Prize in Life Sciences is a new and narrowly focused Nobel-like initiative launched by a noteworthy Russian entrepreneur in collaboration with some of the high net worth individuals that the California start up community has produced over the past decade. The tagline is much as follows:

Breakthrough Prize in Life Sciences is founded by Art Levinson, Sergey Brin, Anne Wojcicki, Mark Zuckerberg and Priscilla Chan, and Yuri Milner to recognize excellence in research aimed at curing intractable diseases and extending human life. The prize is administered by the Breakthrough Prize in Life Sciences Foundation, a not-for-profit corporation dedicated to advancing breakthrough research, celebrating scientists and generating excitement about the pursuit of science as a career.

Note that "extending human life" in the middle there. It looks like we'll have to wait to see whether the ongoing prize initiative will place any real emphasis on that goal, however. The eleven inaugural awards of $3 million each went to researchers who don't have a great deal to do with longevity research.

Eleven scientists, most of them American, were scheduled to be named on Wednesday as the first winners of the world's richest academic prize for medicine and biology - $3 million each, more than twice the amount of the Nobel Prize. The award, the Breakthrough Prize in Life Sciences, was established by four Internet titans led by Yuri Milner, a Russian entrepreneur and philanthropist who caused a stir last summer when he began giving physicists $3 million awards.

Cancer and its mechanisms form the dominant theme in this first set of awards. In some cases the scientists' work touches on aging, such as the telomere research of Titia de Lange, but then so do a great many other line items - it's quite possible to run a very successful career as a telomere researcher without contributing towards efforts to extend human life by intervening in the aging process.

That said: this is an entirely sensible and rational effort. In the long view the only thing that really matters is progress in technology - not money, not politics, not the chatter of the masses, but technology. What was built and invented, and how fast it arrived. What use is money if you can't use it to change the world for the better? The best way to do that today is through spurring progress in biotechnology. The greatest gains for all humanity, wealthy and poor alike, over the decades to come will be attained through advances derived from the life sciences: better medicine, longer lives, and ultimately the defeat of degenerative aging.

This Nobel for the 21st century is a step in the right direction and to be applauded. It is encouraging to see that the right ideas about medicine, biotechnology, and the near-term promise of radical, transformative applications are percolating through the community of high net worth individuals - that some are seeing clearly enough how and why they can make a difference. Still, the Breakthrough Prize is a drop in the bucket of what could be accomplished should any similarly-sized group of billionaires decide to devote a few hundred million dollars towards developing rejuvenation biotechnologies of the sort specified in detail in the SENS plan.

Injectable Scaffold Gel to Spur Heart Regeneration

Researchers are here working on an injectable gel scaffold material that appears to improve regeneration of heart damage:

[Researchers have] developed a protein-rich gel that appears to help repair cardiac muscle in a pig model of myocardial infarction. The researchers delivered the hydrogel via a catheter directly into the damaged regions of the porcine heart, and showed that the product promoted cellular regeneration and improved cardiac function after a heart attack. Compared to placebo-treated animals, the pigs that received a hydrogel injection displayed a 30% increase in heart volume, a 20% improvement in heart wall movement and a 10% reduction in the amount of scar tissue scar three months out from their heart attacks.

[The researchers] developed their hydrogel by stripping muscle cells from pig hearts, leaving behind a network of proteins that naturally self-assembles into a porous and fibrous scaffold upon injection into heart tissue. They previously tested its safety and efficacy in rats, where they found increased cardiac function and no toxicity or cross-species reactivity.

Link: http://blogs.nature.com/spoonful/2013/02/injectable-gel-repairs-damage-after-heart-attack-in-pigs.html

Bioengineering an Ear

An application of 3-D printing and regenerative medicine:

[Researchers] described how 3-D printing and injectable gels made of living cells can fashion ears that are practically identical to a human ear. Over a three-month period, these flexible ears grew cartilage to replace the collagen that was used to mold them. A bioengineered ear replacement like this [would] help individuals who have lost part or all of their external ear in an accident or from cancer. [Replacement ears] are usually constructed with materials that have a Styrofoam-like consistency, or sometimes, surgeons build ears from a patient's harvested rib. This option is challenging and painful for children, and the ears rarely look completely natural or perform well.

To make the ears, [researchers] started with a digitized 3-D image of a human subject's ear, and converted the image into a digitized "solid" ear using a 3-D printer to assemble a mold. [This] high-density gel is similar to the consistency of Jell-o when the mold is removed. The collagen served as a scaffold upon which cartilage could grow. The process is also fast: "it takes half a day to design the mold, a day or so to print it, 30 minutes to inject the gel, and we can remove the ear 15 minutes later. We trim the ear and then let it culture for several days in nourishing cell culture media before it is implanted."

Link: http://www.sciencedaily.com/releases/2013/02/130220184728.htm

Rejuvenation Research for February 2013

The latest issue of Rejuvenation Research is available online for those with a subscription. Here is the opening to the editorial by scientist-advocate Aubrey de Grey:

Competing Causes of Chronic Ill Health: What Do We Do and What Should We Do?

One of the foremost sources of frustration and incredulity among biogerontologists, in regard to the view of their work held by others, is the public's widespread inability (or unwillingness) to appreciate how huge would be the benefit to health and to the economy arising from even modest progress in comprehensively postponing the ill health of old age, and thus how parlously inappropriate is the prevailing level of funding for biogerontology in general and for translational biogerontology in particular. For at least the past decade, there has been a positive crescendo of expressions of this point in the general-audience scientific and policy literature authored not only by renegades such as myself but by those whose mainstream credentials are second to none.

A host of explanations for people's resistance to this message are proffered perennially. Arguably the most convincing is that people are just so certain, in their own minds, that no amount of money thrown at translational biogerontology would ever actually deliver even a modest postponement of age-related ill health that they reason that such money would be wasted, even despite the argument for it. In a nutshell, they feel that any number (the benefits of success), however large, when multiplied by zero (the chance of success), is still zero. The explanation leads, of course, the supplementary question of why people are so much less willing to accept expert opinion on this topic, to wit, that the chance of success is certainly not zero.

One of the papers that caught my eye in this issue of the journal is authored by a research group mentioned a couple of years back here at Fight Aging!, when they showed a form of adult stem cell to be effective in regenerating damage to the pancreas. They are calling these stem cells "pathfinder cells" - there is something of a proliferation of such names as various groups stick labels on their work, and it is probably the case that at this point there is a great deal of overlap between types of stem cells, mechanisms for extracting them from tissue, and the names given by different researchers. This is especially true when commercial ventures are involved, for all the expected economic reasons.

Here the pathfinder group publishes on the use of their branded cell type for kidney regeneration:

Pathfinder Cells Provide A Novel Therapeutic Intervention For Acute Kidney Injury

Pathfinder cells (PCs) are a novel class of adult-derived cells that facilitate functional repair of host tissue. We used rat PCs to demonstrate that they enable the functional mitigation of ischemia reperfusion (I/R) injury in a mouse model of renal damage.

Female C57BL/6 mice were subjected to 30 min of renal ischemia and treated with intravenous (i.v.) injection of saline (control) or male rat pancreas-derived PCs in blinded experimentation. Kidney function was assessed 14 days after treatment. [Analysis] demonstrated that the overwhelming majority of repaired kidney tissue was mouse in origin. Rat PCs were only detected at a frequency of 0.02%. These data confirm that PCs have the ability to mitigate functional damage to kidney tissue [following injury].

Kidneys of PC-treated animals showed evidence of improved function and reduced expression of damage markers. The PCs appear to act in a paracrine fashion, stimulating the host tissue to recover functionally, rather than by differentiating into renal cells. This study demonstrates that pancreatic-derived PCs from the adult rat can enable functional repair of renal damage in mice. It validates the use of PCs to regenerate damaged tissues and also offers a novel therapeutic intervention for repair of solid organ damage in situ.

This behavior has been seen in a range of stem cell transplant studies: regeneration is not occurring because the transplanted stem cells are building new tissue, but rather because they alter the local environment and deliver orders to existing local cell populations. At some point in the future, this whole class of treatment will cease to involve cells, and therapies will consist of only the necessary signals - but there's a way to go yet in order to achieve that goal.

Only Some Mitochondrial DNA Damage Contributes to Aging

This research might be taken to illustrate the point that only some specific mutations in mitochondrial DNA (mtDNA) contribute to aging - those occurring in one of thirteen specific genes, per the SENS outline. So mice with accelerated mutation rates in all mitochondrial DNA exhibit accelerated aging, while mice with specific mitochondrial mutations that do not include those that contribute to aging do not exhibit accelerated aging.

It has been hypothesized that pathogenic mtDNA mutations that induce significant mitochondrial respiration defects cause mitochondrial diseases, and could also be involved in aging and age-associated disorders including tumor development. This hypothesis is partly supported by studies in mtDNA mutator mice: they possess a nuclear-encoded mtDNA polymerase with a defective proofreading function that leads to enhanced accumulation of random mutations in mtDNA with age, and the subsequent phenotypic expression of age-associated respiration defects and premature aging phenotypes, but not tumor development.

On the contrary, our previous studies showed that transmitochondrial mito-miceΔ carrying mtDNA with a large-scale deletion mutation (ΔmtDNA) expressed age-associated respiration defects, but not express the premature aging phenotypes. Similar results were obtained in other transmitochondrial mito-miceCOIM, which have an mtDNA point mutation in the COI gene. Recently, we generated new transmitochondrial mito-miceND6M, which have an mtDNA point mutation in the ND6 gene that is derived from Lewis lung carcinomas, and confers respiration defects and overproduction of reactive oxygen species (ROS). Mito-miceND6M did not express premature aging phenotypes, but were prone to B-cell lymphoma development. Thus, it appears to be discrepant that premature aging phenotypes are exclusively observed in mtDNA mutator mice, but not in transmitochondrial mito-mice even though they all express mitochondrial respiration defects caused by mutated mtDNA.

Link: http://dx.doi.org/10.1371/journal.pone.0055789

Discussing Inflammation and Age-Related Disease

Notes from a recent conference at the Impact Aging journal:

The workshop opened with [an] overview of the literature supporting the emergence a mild pro-inflammatory state that is closely linked to the major degenerative diseases of the elderly. The focus of the workshop was to better understand the origins and consequences of this low level chronic inflammation in order to design appropriate interventional studies aimed at improving healthspan.

For many, inflammation is simply understood as a trajectory of biomarkers, for example the appearance of IL-6 or C-reactive protein (CRP), associated with a disease. However, inflammation is a very complex response to an injury, infection, or other stimulus, in which many different cells types and secreted factors orchestrate protective immunity, tissue repair, and resolution of tissue damage. Whereas acute inflammation limits tissue damage and resolves, chronic prolongation of the inflammatory state leads to progressive tissue damage.

A central question, then, is how do we describe and begin to understand the mild pro-inflammatory state of aging. Among the causal pathways linked to the major diseases associated with aging, including physical frailty, are changes in body composition, energy imbalance, homeostatic dysregulation, and neurodegeneration. Chronic inflammation is strongly connected with each of these aging phenotypes. The inflammatory mediators IL-6, IL-18, and CRP increase with age in both women and men and are highly correlated with obesity and degenerative disease. Muscle strength, as measured by walking speed, also correlates with circulating IL-6 levels. Individuals with the lowest circulating levels had the highest walking speed. [These] data suggest that inflammation blocks critical metabolic signals that support muscle maintenance. In addition, [systemic] inflammation may predispose the microglia to a pro-inflammatory state that is associated with neurodegeneration.

Although it is not clear what causes age-associated chronic inflammation, possible mechanisms include a disregulated NF-kB pathway, impaired mitochondrial function leading to excessive reactive oxygen species (ROS) the accumulation of senescent cells, and a decline in autophagy with age. Whether reducing inflammation will lead to beneficial effects on human health and function is the defining biological and medical challenge of the next decade.

Link: http://impactaging.com/papers/v5/n1/full/100531.html

Considering Optimization of Exercise Again

Can exercise be optimized in any meaningful way for the average, basically healthy individual? Can you dig through the research literature and, based on what you find, be fairly certain that you should exercise for an hour daily rather than half an hour, or run rather than use a rowing machine, or make some other similar adjustment to your schedule of moderate regular exercise? At this point, I think that the answer remains a qualified "no."

Research strongly supports moderate exercise over no exercise. You are absolutely doing yourself harm by being sedentary. After that the data becomes a lot more malleable and less certain. The research community can't say for sure whether athletes are benefiting over the long term from all the additional exercise they do, for example. Professional athletes appear to live modestly longer than the general populace, but there's no convincing demonstration that this is because of what they do versus being the results of a selection effect based on the fact that you have to be unusually robust to succeed as a professional athlete.

For the rest of us, in our considerations of jogging versus exercise bikes, much of the data gathered doesn't reliably support any choice over another once you've made the basic, essential decision to undertake regular aerobic exercise. The waters are muddy, however. In the past few years, large studies have emerged to confirm that time spent sitting appears to raise mortality rates and lower life expectancy regardless of exercise taking place in between those seated periods. See this, for example, although the publicity materials don't make it terribly clear that thought did go into the causality of the effect:

Office Workers Beware: Sitting Time Associated With Increased Risk of Chronic Diseases

Compared with those who reported sitting four hours or less per day, those who sat for more than four hours per day were significantly more likely to report having a chronic disease such as cancer, diabetes, heart disease and high blood pressure. The reporting of chronic diseases rose as participants indicated they sat more. Those sitting for at least six hours were significantly more likely to report having diabetes.

Researchers said that although most of the current evidence is suggestive of a causal connection, they cannot be certain in this study whether volumes of sitting time led to the development of chronic diseases or whether the chronic diseases influenced sitting time.

Then there is the recent paper below, which might be put into much the same broad context of muddying the waters when it comes to exercise and lifestyle choices.

Minimal Intensity Physical Activity (Standing and Walking) of Longer Duration Improves Insulin Action and Plasma Lipids More than Shorter Periods of Moderate to Vigorous Exercise (Cycling) in Sedentary Subjects When Energy Expenditure Is Comparable

Epidemiological studies suggest that excessive sitting time is associated with increased health risk, independent of the performance of exercise. We hypothesized that a daily bout of exercise cannot compensate the negative effects of inactivity during the rest of the day on insulin sensitivity and plasma lipids.

Conclusions: One hour of daily physical exercise cannot compensate the negative effects of inactivity on insulin level and plasma lipids if the rest of the day is spent sitting. Reducing inactivity by increasing the time spent walking/standing is more effective than one hour of physical exercise, when energy expenditure is kept constant.

It is tempting to leap to the thought that this sort of mechanism is needed to explain how standing versus sitting can have an effect on long-term health, but there is still much work to be done in order to convincingly knit all these statistical studies together with basic mechanisms in that way. So in the meanwhile, it continues to look like the 80/20 path is regular moderate aerobic exercise - and of course some form of calorie restriction. There's no real debate over whether or not these options are beneficial.

An Example of Scaffolds to Encourage Bone Regrowth

The use of nanoscale-featured scaffold materials is common in regenerative medicine research. Here is an example that can be used to improve and guide the regrowth of bone:

Artificial bone, created using stem cells and a new lightweight plastic, could soon be used to heal shattered limbs. Researchers have developed the material with a honeycomb scaffold structure that allows blood to flow through it, enabling stem cells from the patient's bone marrow to attach to the material and grow new bone. Over time, the plastic slowly degrades as the implant is replaced by newly grown bone.

Scientists developed the material by blending three types of plastics. They used a pioneering technique to blend and test hundreds of combinations of plastics, to identify a blend that was robust, lightweight, and able to support bone stem cells. Successful results have been shown in the lab and in animal testing with the focus now moving towards human clinical evaluation.

"We were able to make and look at a hundreds of candidate materials and rapidly whittle these down to one which is strong enough to replace bone and is also a suitable surface upon which to grow new bone. We are confident that this material could soon be helping to improve the quality of life for patients with severe bone injuries, and will help maintain the health of an ageing population."

Link: http://www.southampton.ac.uk/mediacentre/news/2013/feb/13_26.shtml

Aging is Emphatically Not an Inescapable Destiny

An interview with Aubrey de Grey of the SENS Research Foundation in Tendencias21, a Spanish publication. The occasion is the publication of a Spanish language edition of Ending Aging:

[Tendencias21]: Do you think that aging and death are not an inescapable destiny of human being?

[Aubrey de Grey]: What is this thing "aging and death" in the question? It is very instructive that there is so much fatalism about aging that people consider aging to be synonymous with death. Death - from any cause, including causes that are related to how long ago you were born and also causes that are not - is not what I am working to avert. I am working to avert aging, i.e. the ill-health that is currently an inescapable consequence of being alive for a long time. And yes, I think that aging is emphatically NOT an inescapable thing - I am sure that it will eventually be defeated with medicine.

[Tendencias21]: What are the steps or progress made so far by the science that could prolong human life and improve its quality, despite the passage of time?

[Aubrey de Grey]: All the therapies that we need for the control of aging are within reach. In some cases, such as stem cell therapies to replace cells that die and are not automatically replaced by cell division, we are very close - clinical trials are already in progress. In other cases we are still working with mice, or even just cells in a dish, but even there we have a clear way forward to the development of medicine for people.

[Tendencias21]: Do you believe that, in the not too distant future, we could avoid the ballast of the degenerative diseases associated with aging?

[Aubrey de Grey]: Yes I do. I think we have at least a 50% chance of developing truly comprehensive rejuvenation medicine within 25 years, just so long as the early-stage, proof-of-concept research that is going on right now is adequately funded.

Link: http://www.tendencias21.net/Aubrey-de-Grey-Aging-is-emphatically-not-an-inescapable-destiny_a15346.html

Incremental Advances in Machine-Nerve Interfaces

Computational hardware, electronics, and biotechnology are three of the most rapidly advancing fields of human endeavor at the present time. The years ahead are going to be most interesting, even though progress always seems far too slow and incremental while living it a day at a time. One field that sits within the broad overlap of machinery, computing, and biology is that of nerve-machine interfaces, which spans the gamut from the creation of machines to take on the job of a biological nerve structure, through simulation of nervous system behavior, through to attaching machinery to nerves in order to form a new gestalt system.

Examples of this work being demonstrated today are very crude in comparison to what will be possible in the future - but the path forward, while slow and incremental, definitely leads towards functional prosthetics that are fully tied into a biological nervous system. This sort of technology is important to the 2045 Initiative view of the future, but is less relevant to the SENS vision for human longevity, which is (rightly I think) focused on the biology we have and how to repair it.

Prosthetic technologies of all sorts are a competitor for regenerative medicine, both having the goal to alleviate serious injuries involving loss of body parts or their function. I'm not sure I see a viable outline for the next five decades in which increasingly sophisticated prosthetics can be used to extend life meaningfully - there are parts of the body that you can't easily replace with machinery, even once arbitrary neural interfaces are a robust and easily constructed concern, and so we must learn how to rejuvenate the brain and its supporting structures at a bare minimum regardless of what else happens. The biotechnologies needed for this goal do not seem likely to emerge until after the research community can already rebuild most of the rest of the body, as the brain is a far more complex structure of diverse cells, mechanisms, and cell types than any other organ.

In any case, here are two examples of the present state of play in nerve-machine interfaces of varying degrees of sophistication, both aimed at restoring function in cases of crippling injury.

The quest for a better bionic hand

Silvestro Micera, of the École Polytechnique Fédérale de Lausanne (EPFL) in Switzerland, is paving the way for new, smart prosthetics that connect directly to the nervous system. The benefits are more versatile prosthetics with intuitive motor control and realistic sensory feedback - in essence, they could one day return dexterity and the sensation of touch to an amputee.

Micera and colleagues tested their system by implanting intraneural electrodes into the nerves of an amputee. The electrodes stimulated the sensory peripheral system, delivering different types of touch feelings. Then the researchers analyzed the motor neural signals recorded from the nerves and showed that information related to grasping could indeed be extracted. That information was then used to control a hand prosthesis placed near the subject but not physically attached to the arm of the amputee.

Walking again after spinal injury

In the lab, rats with severe spinal cord injury are learning to walk - and run - again. Last June in the journal Science, Grégoire Courtine, of the École Polytechnique Fédérale de Lausanne (EPFL), reported that rats in his lab are not only voluntarily initiating a walking gait, but they were sprinting, climbing up stairs, and avoiding obstacles after a couple of weeks of neurorehabilitation with a combination of a robotic harness and electricalchemical stimulation.

[Recently, he outlined] the range of neuroprosthetic technologies developed in his lab, which aim to restore voluntary control of locomotion after severe spinal cord injury. He explains how he and his colleagues are interfacing the central nervous system with stretchable spinal electrode arrays controlled with smart stimulation algorithms - combined with novel robotic rehabilitation - and shows videos of completely paralyzed rats voluntarily moving after only weeks of treatment. Courtine expects to begin clinical trials in human patients within the next two years.

Adiponectin in Centenarians

Adiponectin shows up here and there in considerations of the relationship between metabolism and natural variations in longevity. Researchers here demonstrate an association for adiponectin in human centenarians:

The physiological mechanisms that promote longevity remain unclear. It has been suggested that insulin sensitivity is preserved in centenarians, whereas typical aging is accompanied by increasing insulin resistance. The oldest-old individuals display raised total adiponectin levels, despite the potential correlation between enhanced adiponectin and all-cause and cardiovascular mortality.

A group of 58 Polish centenarians (50 women and 8 men, mean age 101±1.34 years) and 68 elderly persons (55 women and 13 men, mean age 70±5.69 years) as controls [were used] to evaluate the level of adiponectin and its isoforms in sera of centenarians and to assess associations between adiponectin and metabolic parameters.

The concentrations of all adiponectin isoforms were significantly higher in the oldest-old participants. In the centenarian group, total adiponectin positively correlated with age and HDL-cholesterol, and HMW-adiponectin was negatively associated with insulin and triglycerides. The long-lived participants had a lower incidence of hypertension, type 2 diabetes, overweight and obesity, with lower concentrations of serum glucose and insulin, and reduced [insulin resistance].

Our findings support the thesis that centenarians possess a different adiponectin isoform pattern and have a favorable metabolic phenotype in comparison with elderly individuals. However, additional work is necessary to understand the relevance of these findings to longevity.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23396152

DNA Damage and Reproductive Aging

Researchers here dig into the mechanisms by which female capacity for reproduction diminishes with age. This produces an interesting data point to add to the debate over the degree to which nuclear DNA damage might be a contributing cause of aging:

A woman's eggs decline in quality and quantity as she ages, at least in part because an important DNA repair pathway becomes impaired. The pathway, which includes proteins encoded by the well-known BRCA genes, is supposed to repair double-strand breaks in DNA. But as women get older, the study found, repair mechanisms lose efficiency and reproductive cells accumulate damaged genes and often commit suicide.

While women are born with 1 million oocytes, only about 500 turn into full-fledged eggs over their lifetime. By the time women reach their early 50s, the remaining oocytes have almost completely degraded. Why the oocytes degrade so rapidly in comparison to other body tissues was a mystery.

[Researchers] first tested mouse and human oocytes for double-strand breaks and found that the damage increased significantly with age. They also looked at expression of several repair proteins in the cells. Expression of BRCA1 and a handful of other repair genes decreased with age. The results implied that dysfunction in DNA repair may lead to genomic damage seen in aging oocytes.

The researchers studied both mice and women with mutations in the BRCA1 [gene]. People with mutations in BRCA1 had lower oocyte reserves in their ovaries than those without the mutations, and mice with BRCA1 mutations had smaller litters of pups than wild type mice.

Link: http://www.the-scientist.com/?articles.view/articleNo/34375/title/Why-Women-s-Eggs-Don-t-Last/

Protein Restriction Slows Progression of Mouse Model of Alzheimer's Disease

Calorie restriction slows the progression of near all measurable aspects of degenerative aging, and improves near all measures of health. It extends life by up to 40% in mice, and one of the interesting challenges for the study of metabolism is to explain the mechanics of how it can improve health so greatly in humans while failing to extend life to the same degree as it does in shorter-lived mammals. There is a good evolutionary explanation for this phenomenon; the expected length of a naturally occurring famine is the same whether you are a mouse or a man, and thus life span changes in response to famine must be more dramatic in a shorter lived species in order to have a decent chance of surviving it to reproduce. But that doesn't tell us how it happens under the hood.

Some of the triggers for the metabolic changes of calorie restriction involve sensing protein levels. Maintaining the same calorie intake while reducing dietary protein levels captures some fraction of the full effects of calorie restriction, with methionine seemingly the most important triggering protein.

Here a noted calorie restriction researcher shows protein restriction to slow the progression of a mouse model of Alzheimer's disease - which is pretty much the expected result, given what we know so far of how the effects of protein restriction map to those of calorie restriction:

Low-protein diet slows Alzheimer's in mice

Mice with many of the pathologies of Alzheimer's Disease showed fewer signs of the disease when given a protein-restricted diet supplemented with specific amino acids every other week for four months. Mice at advanced stages of the disease were put on the new diet. They showed improved cognitive abilities over their non-dieting peers when their memory was tested using mazes. In addition, fewer of their neurons contained abnormal levels of a damaged protein, called "tau," which accumulates in the brains of Alzheimer's patients.

Upcoming studies [will] attempt to determine whether humans respond similarly - while simultaneously examining the effects of dietary restrictions on cancer, diabetes and cardiac disease. "We had previously shown that humans deficient in Growth Hormone receptor and IGF-I displayed reduced incidence of cancer and diabetes. Although the new study is in mice, it raises the possibility that low protein intake and low IGF-I may also protect from age-dependent neurodegeneration."

The team found that a protein-restricted diet reduced levels of IGF-1 circulating through the body by 30 to 70 percent, and caused an eight-fold increase in a protein that blocks IGF-1's effects by binding to it. IGF-1 helps the body grow during youth but is also associated with several diseases later in life in both mice and humans. Exploring dietary solutions to those diseases as opposed to generating pharmaceuticals to manipulate IGF-1 directly allows [researchers] to make strides that could help sufferers today or in the next few years.

"We always try to do things for people who have the problem now. Developing a drug can take 15 years of trials and a billion dollars. Although only clinical trials can determine whether the protein-restricted diet is effective and safe in humans with cognitive impairment, a doctor could read this study today and, if his or her patient did not have any other viable options, could consider introducing the protein restriction cycles in the treatment - understanding that effective interventions in mice may not translate into effective human therapies."

You might take note of those last remarks as indicative of one of the ways in which regulation steers researchers towards deliberately aiming to produce marginal benefits rather than revolutionary advances - slowing the pace of progress and shutting down promising avenues of medical science before they even get started.

Nitric Oxide and Longevity in Nematodes

Nitric oxide shows up in many places in the the biochemistry of longevity, the processes by which differences in the operation of metabolism influence the pace of aging. In this example, however, it isn't particularly clear that it has any great relevance to human biology:

Although humans and many other organisms have the enzyme needed to produce nitric oxide, C. elegans does not. Instead, [the] worm can "hijack" the compound from the soil-dwelling Bacillus subtilis bacterium that is not only a favored food but also a common colonist within its gut. This resourcefulness [partially] explains why worms fed B. subtilis live roughly 50 percent longer than counterparts fed Escherichia coli, which does not produce the compound.

In the new study, the average C. elegans lifespan increased by nearly 15 percent, to about two weeks, when researchers fed the worms nitric oxide-producing B. subtilis bacteria, compared to worms fed mutant B. subtilis with a deleted nitric oxide production gene. The research group also used fluorescent sensors to show that C. elegans does not make its own nitric oxide gas. When the worms were fed normal B. subtilis bacteria, however, the fluorescent signal appeared in their guts.

Fluorescent labeling and other tests also demonstrated that B. subtilis-derived nitric oxide penetrated the worms' tissues, where it activated a set of 65 genes. Some had been previously implicated in stress resistance, immune response, and increased lifespan, though others have unknown functions. Importantly, the researchers showed that two well-known regulatory proteins were essential for activating all of the genes.

"What we found is that nitric oxide gas produced in bacteria inside the worms diffuses into the worm tissue and activates a very specific set of genes acting through two master regulators, hsf-1 and daf-16, resulting in a high resistance to stress and a longer life. It's striking that a small molecule produced by one organism can dramatically affect the physiology and even lifespan of another organism through direct cell signaling."

Link: http://www.eurekalert.org/pub_releases/2013-02/jhm-jhr021213.php

On Greater Longevity in Colder Environments

Why do cold-blooded species live longer in colder environments? Researchers have a prospective mechanism that is shared by mammals:

Scientists have known for nearly a century that cold-blooded animals, such as worms, flies and fish all live longer in cold environments, but have not known exactly why. Researchers [have] identified a genetic program that promotes longevity of roundworms in cold environments - and this genetic program also exists in warm-blooded animals, including humans. "This raises the intriguing possibility that exposure to cold air - or pharmacological stimulation of the cold-sensitive genetic program - may promote longevity in mammals."

Scientists had long assumed that animals live longer in cold environments because of a passive thermodynamic process, reasoning that low temperatures reduce the rate of chemical reactions and thereby slow the rate of aging. "But now, at least in roundworms, the extended lifespan observed at low temperature cannot be simply explained by a reduced rate of chemical reactions. It's, in fact, an active process that is regulated by genes."

[Researchers] found that cold air activates a receptor known as the TRPA1 channel, found in nerve and fat cells in nematodes, and TRPA1 then passes calcium into cells. The resulting chain of signaling ultimately reaches DAF-16/FOXO, a gene associated with longevity. Mutant worms that lacked TRPA1 had shorter life spans at lower temperatures.

Because the mechanisms [also] exist in a range of other organisms, including humans, the research suggests that a similar effect might be possible. The study also links calcium signaling to longevity for the first time and makes a novel connection between fat tissue and temperature response. Researchers have known that lowering the core body temperature of warm-blooded animals, such as mice, by 0.9 degrees Fahrenheit can extend lifespan by 20 percent, but it hasn't been practical for humans to attempt to lower the core body temperature.

It's worth noting that past research has shown that not all methods of lowering core body temperature in mammals will extend life. It matters how it's done, which suggests that it isn't so much temperature as the particular mechanisms that are running that is driving the effect. For example, calorie restriction is associated with a lower core body temperature.

Link: http://www.eurekalert.org/pub_releases/2013-02/uom-sca021413.php

Are You an Ambitious Life Science Student? Intern at the SENS Research Foundation this Summer

Here is a great opportunity for undergraduate and recently graduated life scientists: a chance to intern this coming summer at the SENS Research Foundation, an ambitious and well-connected organization that funds work on repairing the cellular and molecular damage that causes aging. If this is an area of applied medical biotechnology that interests you - and it should, as today you stand at the ground floor of a field that will expand in decades ahead to dwarf present behemoth research communities like the cancer establishment - then I encourage you to apply. If this isn't your cup of tea, then point it out to any biologist friends you might have.

2013 Summer Internships at the SENS Research Foundation

SENS Research Foundation's summer internships are for undergraduates (students working towards a Bachelor's degree) and students who have just completed their undergraduate work. Interns in this program can expect to do a considerable amount of scientific research using various techniques in the biosciences, which can include PCR, western blotting, DNA purification, gel electrophoresis, and many others. Each intern will be working on a different project, so no two will be doing the exact same thing. Though interns will build their lab skills considerably during their internship period, the strongest applicants will already have laboratory experience.

In 2013, SENS Research Foundation will be placing summer interns at four different locations: SRF's own Research Center in Mountain View, California; the Buck Institute for Research on Aging in Novato, California; the Wake Forest Institute for Regenerative Medicine in Winston-Salem, North Carolina; and SUNY Upstate Medical University in Syracuse, New York. You will be able to apply to all four of these locations at the same time using our application. Note that the SRF Research Center and the Buck Institute are in the same metropolitan area: the San Francisco Bay Area.

The application deadline for our summer internship program is March 31, 2013 at 11:00 PM PST. However, there will be an early deadline for applicants who would like to be considered for the SUNY Upstate program: February 24th, 2013 at 11:00 PM PST. Each program will run on its own schedule, with its own stipend and arrangements.

Connections make the world go round, and certainly do wonders for your future career in a field. This is a chance to make important connections in the longevity science community, working in laboratories run by leaders in the field, and at the same time start to do your part to advance the state of rejuvenation biotechnology. You might take a look at the SENS Research Foundation's annual reports for an in-depth look at the ongoing work that takes place in their research center and partner laboratories in the US and Europe.

Searching for Commonalities in Cancer

The broad variety and rapid change in mechanisms within cancerous cells is one of the reasons that cancer is hard to tackle - every cancer is different and evolving. Circumventing this to find truly effective cancer therapies will require the discovery of some mechanistic commonality that can be targeted, some biological process that all cancers depend on and which distinguishes their cells from non-cancerous cells. The proposed SENS approach, for example, is to go right to the root and remove all ability to lengthen telomeres in the body, as all cancers depend on that. The mainstream research community aims to find markers for cancer stem cells, or low-level mechanisms shared between cancers to some degree and which can be sabotaged to slow down or reverse progression of the disease. Not all shared mechanisms are sufficient to build a true cure, unfortunately.

Here is an example of one such lesser mechanism in the early stages of research and development:

Epithelial to mesenchymal transition is important to embryonic development, turning stationary epithelial cells into mobile mesenchymal cells to move them within the embryo. For example, a cell might be converted and then gather with other cells forming, for example, the kidney. Once there, it transitions back to an epithelial cell again and stays put. Research has shown that carcinomas, tumors that form in the epithelium (lining) of organs are able to reactivate EMT. About 85 percent of all solid tumors are carcinomas.

"We found that FOXC2 lies at the crossroads of the cellular properties of cancer stem cells and cells that have undergone epithelial to mesenchymal transition (EMT), a process of cellular change associated with generating cancer stem cells. There are multiple molecular pathways that activate EMT. We found many of these pathways also activate FOXC2 expression to launch this transition, making FOXC2 a potentially efficient check point to block EMT from occurring."

[Researchers believe] that targeting FOXC2 pathway [will] be an effective therapeutic strategy for inhibiting EMT and consequently reducing EMT/cancer stem cell-associated metastasis, relapse and therapy resistance.

Link: http://www.sciencedaily.com/releases/2013/02/130213131940.htm

Dietary Fatty Acids and Autophagy

The cellular housekeeping processes of autophagy show up everywhere in considerations of metabolism and aging: better repair of cellular damage and removal of unwanted metabolic byproducts has a noticeable beneficial effect on the longevity of an organism. Many of the genetic manipulations that extend life in laboratory species have been shown to enhance autophagy, just as does the practice of calorie restriction.

Here researchers find that the marginal benefits resulting from the inclusion of omega fatty acids in the diet may also result from increased autophagy:

Researchers have discovered that simple mutations in genetic pathways conserved throughout evolution can double or triple the lifespan of C. elegans and that similar mutations in the corresponding mammalian pathways also regulate lifespan. Many of these mutations also make animals resistant to starvation, suggesting that common molecular mechanisms may underlie both response to nutrient deprivation and the regulation of lifespan.

To find these mechanisms [scientists] searched genomic databases covering many types of animals for shared genes that respond to fasting by changing their expression. She found that expression of the C. elegans gene lipl-4 increases up to seven times in worms not given access to nutrients. A transgenic strain that constantly expresses elevated levels of lipl-4, even when given full access to food, was found to have increased levels of arachidonic acid (AA), an omega-6, and eicosapentanoic acid (EPA), an omega-3 fatty acid and to resist the effects of starvation.

Following the implication that omega fatty acids stimulate a process leading to starvation resistance, the researchers found that feeding AA and another omega-6 fatty acid, but not EPA, activated autophagy in non-transgenic C. elegans with full access to nutrients. Since activation of autophagy has been shown to increase lifespan in several genetic models, the authors tested the effect of omega-6 fatty acids on C. elegans lifespan and found that roundworms consuming a full normal diet supplemented with omega-6 fatty acids lived 20 to 25 percent longer than usual.

Since dietary supplementation with both omega-3 and omega-6 fatty acids has been shown to prevent or improve several human health conditions, the researchers tested the response of cultured human cells to omega fatty acid supplementation. As in C. elegans, the human cells responded to supplementation with the omega-6 acids, but not to EPA, by activation of autophagy, measured by levels of marker proteins. That result suggests that omega-6 acids induce autophagy across the full range of multicellular animal species. The researchers then showed that the lifespan-increasing properties of omega-6 fatty acids in C. elegans depend on the presence of genes required for autophagy.

Link: http://www.eurekalert.org/pub_releases/2013-02/mgh-crp021313.php

Much of Modern Aging Research in a Short and Pithy Nutshell

This caught my eye and I thought I'd share. The abstract is a good encapsulation of the majority of modern research into aging and longevity: understanding and explaining, with no great impetus to apply the knowledge gained to date.

The ins and outs of aging and longevity

As a nod to the oft-quoted evolutionary theorist George Williams, "It is remarkable that after a seemingly miraculous feat of morphogenesis, a complex metazoan should be unable to perform the much simpler task of merely maintaining what is already formed". How and why we age are mysteries of the ages.

The "how" of this mystery is the purview of experimental biologists who try to understand the basic processes that lead to system maintenance failure - from the level of molecules to that of entire organisms - that we term "aging".

The "why" of this mystery is the purview of evolutionary theorists whose ideas shape the questions that biogerontologists pose, on the basis of the premise put forth by another preeminent geneticist and evolutionary biologist, Theodosius Dobzhansky, that "[n]othing in biology makes sense except in the light of evolution". These experimental and evolutionary perspectives converge in the modern science of aging, and its curious cousin "longevity", in an attempt to unify extensive findings from diverse areas of biology.

It's important to remember that it is still the case that very little of aging research is in any way aimed at producing potential interventions to slow or reverse aging. Further, aging research itself is a backwater in comparison to fields like cancer research, or other larger research efforts that focus on named diseases of aging. Those research efforts are almost entirely aimed at plugging holes rather than prevention, researchers picking small parts of late stage pathology and then seeking to commercialize therapies based on small gains from old-style drug discovery programs. The regulatory straightjacket enclosing the medical research community permits little else. None of that will be a source of great improvements in human longevity; it is the cause of the gentle incidental increase in human life expectancy at older ages (at a pace of perhaps a month every year at the moment), but it can't do much more than that.

Little of medical research focused on aging is ambitious. Little is relevant to tackling the roots of aging. Little is focused on moving beyond the slow historical plodding and focus on treating end-stage disease. All of this must change, and the present state of affairs is why it is so important to support efforts like those of the SENS Research Foundation, which are aimed in the right direction, directly relevant to extending healthy life spans, and likely the draw in more of the research community as they progress.

Comments on Teaching an Ethical View of Life Extension

Some comments from a social studies professor with an interest in engineered human longevity:

This year I devote two whole classes to aging and the ethics of life extension. Last week was our first class on the topic and I asked my students, who are all graduate level students in the humanities and social sciences, how many of them had taken a course where aging was either the focus, or even just a topic covered in, the course. Not a single hand went up! This simply reinforced my conviction that it is absolutely essential to teach the course I am teaching, and to dedicate two weeks to aging and the ethics of life extension. I hope it helps to fill what is an unfortunate gap in the education our students receive.

In my opinion, the aging of the world's populations is the most interesting and important development of the 21st century. And yet the education our students (many of whom will go on to be teachers, professors, politicians, work in public policy, law, medicine, etc.) receive is one that is completely blind to this reality. This neglect is itself an oddity worthy of serious reflection. Why do so many scholars in the humanities and social sciences appear to have "aging blinders" on? I think the answer to this question is complex, and many distinct cultural and institutional factors account for this neglect. I will write a longer post about this in a few weeks. I believe that one of the main reasons for this neglect is that scholars ignore the ultimate causation of morbidity, mortality and behaviour.

While the proximate causation of mortality (such as poverty and war) is on the radar of many in the humanities and social sciences, they do not adopt as diverse an explanatory toolbox as they ought to. Once you add an evolutionary perspective into the mix, the questions, topics and debates to be discussed and pondered are wondrous and pressing. And doing this has profoundly altered the topics I work on, and the manner in which I approach them, in both ethics and political theory.

Link: http://colinfarrelly.blogspot.com/2013/02/teaching-ethics-of-life-extension.html

Arguing DNA Damage as a Cause of Aging

A stochastic accumulation of nuclear DNA damage progresses throughout life. This is definitely a cause of increased cancer risk, one of the reasons why cancer is predominantly a disease of the old, but is it also a contributing cause of degenerative aging in general? This is an arguable proposition, with some researchers suggesting that DNA damage doesn't meaningfully impact aging over the length of a human life span, while others consider it the most important cause of aging.

Here is a review paper on the subject. It is always pleasant to see researchers openly discuss increasing life span through biotechnology, even if I don't necessarily agree with the likely effectiveness of the research path they choose. It is still the case that many scientists will not talk openly about the goal of extending human life.

Genome instability has long been implicated as the main causal factor in aging. Somatic cells are continuously exposed to various sources of DNA damage, from reactive oxygen species to UV radiation to environmental mutagens.

To cope with the tens of thousands of chemical lesions introduced into the genome of a typical cell each day, a complex network of genome maintenance systems acts to remove damage and restore the correct base pair sequence. Occasionally, however, repair is erroneous, and such errors, as well as the occasional failure to correctly replicate the genome during cell division, are the basis for mutations and epimutations. There is now ample evidence that mutations accumulate in various organs and tissues of higher animals, including humans, mice, and flies. What is not known, however, is whether the frequency of these random changes is sufficient to cause the phenotypic effects generally associated with aging. The exception is cancer, an age-related disease caused by the accumulation of mutations and epimutations.

Here, we first review current concepts regarding the relationship between DNA damage, repair, and mutation, as well as the data regarding genome alterations as a function of age. We then describe a model for how randomly induced DNA sequence and epigenomic variants in the somatic genomes of animals can result in functional decline and disease in old age. Finally, we discuss the genetics of genome instability in relation to longevity to address the importance of alterations in the somatic genome as a causal factor in aging and to underscore the opportunities provided by genetic approaches to develop interventions that attenuate genome instability, reduce disease risk, and increase life span.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23398157

Deconstructing Deathism, an Essay

The essay linked below was originally published in 2004, but I have no recollection of reading it back then - so I'm going to assume that many of you folk also missed it the first time around. Another item lost to the mists of memory is exactly where and when I first heard the term "deathism," in the sense of an outlook that promotes death as a good thing rather than something to be avoided. You won't find much mention of it prior to 2007 here at Fight Aging!, for example. Deathism is usually put forward in the context of aging as an essentially conservative view: deathists are people who stand against change and for the continuation of the status quo, often without any great consideration, no matter how terrible it might be, and no matter that rampant change is underway in all aspects of human life and society nowadays.

Many similarities can be found when comparing the person who believes that everyone should live the same lives as their parents, aging to death at the same count of years, with the person who doesn't want a new train line built, or decries the latest addition to the downtown skyline, or waxes nostalgic for the foods of yesteryear. But there is an important difference here: people who advocate for the continuation of death and aging are also advocating destruction, pain, and suffering on a grand scale in a way that other conservatives are not. Destruction, pain, and suffering is invariably not their motivation, but it is what they call for nonetheless, and that fact should not be swept politely under the table.

Tens of millions of lives are lost every year, and hundreds of millions more are locked in terrible degenerative suffering and frailty - the human cost of death by aging year upon year is four times that of an eternally ongoing World War II, a horrific toll that our society does its best to ignore. Thus it is socially acceptable to say that aging should continue, and the average person in the street will claim to want to age and die on the same schedule as his or her parents - because that is the socially correct answer, the conforming answer, the one that seems to be taught at a young age by some form of educational osmosis. Sheep and cliffs spring to mind.

Here are the opening paragraphs of the essay mentioned above, in which the author adopts a more optimistic view of the pervasiveness of the desire for a life without end, albeit sidelined into generally unhelpful religious directions. I encourage you look though the whole thing:

Deconstructing Deathism - Answering Objections to Immortality

In Aesop's ancient fable, the fox seeks the juicy grapes to quench his thirst on a hot, sunny day. Finding them out of reach, however, he concludes "they must be sour." The thirst for longer life and better health, which would hopefully extend to a happy existence of indefinite duration, is basic to human nature. Just about everyone has been tempted by these appealing "grapes," notwithstanding that a substantial extension of maximum human life-span, healthy or not, is quite out of reach at present, and always has been. Mortality is a basic feature of earthly life. Yet humans, who seem to be the first life forms on the planet to understand this, are not happy with it. Yes, it's "natural," but our instincts tell us it's still not "okay."

The roots of our irrepressible immortalism stretch well into prehistoric times, as is suggested, for example, by the burial of artifacts such as hunting implements with the dead. In more recent though still ancient times, the feeling flowered into major religions that promised the sought-for immortality and a happy future existence. Many of these belief systems are still with us and their adherents total perhaps about half the humans alive today.

We see then how the wish for existence beyond the biological limits has survived the intractable difficulties that its practical realization has offered. In recent years, moreover, hopes for death-transcendence have taken on new life through scientific advances that offer possibilities of addressing the problem directly. The mechanisms of aging are being unraveled and eventual, full control of the aging process and known diseases is anticipated by some forward-looking people, along with other life enhancements not previously known. People can meanwhile arrange for cryopreservation in the event of death, in hopes that resuscitation technology will eventually be developed, along with the means to reverse or cure any affliction they may have suffered, including aging itself.

Not everyone, of course, can be counted among the immortality-seekers or supporters, even when the new scientific perspective is taken into account. Among those who freely reject the "grapes" of life extension are a predictable fraction who would find them sour as well. These critics defend a counterproposal of deathism, namely, that not only is one's eventual demise inevitable and final (the grapes are out of reach) but that this should be seen in a positive light (but sour anyway, so not to worry).

Relative Risk For Causes of Cognitive Decline

Cognitive decline, like most of the consequences of aging, stems from a range of root causes. Here researchers look at which of these causes contribute the most to the harmful end result:

Vascular brain injury from conditions such as high blood pressure and stroke are greater risk factors for cognitive impairment among non-demented older people than is the deposition of the amyloid plaques in the brain that long have been implicated in conditions such as Alzheimer's disease, a study [has] found. The research was conducted in 61 male and female study participants who ranged in age from 65 to 90 years old, with an average age of 78. Thirty of the participants were clinically "normal," 24 were cognitively impaired and seven were diagnosed with dementia, based on cognitive testing.

The researchers also sought to determine whether there was a correlation between vascular brain injury and the deposition of beta amyloid (Αβ) plaques, thought to be an early and important marker of Alzheimer's disease. [They] also sought to decipher what effect each has on memory and executive functioning.

"We looked at two questions. The first question was whether those two pathologies correlate to each other, and the simple answer is 'no.' Earlier research, conducted in animals, has suggested that having a stroke causes more beta amyloid deposition in the brain. If that were the case, people who had more vascular brain injury should have higher levels of beta amyloid. We found no evidence to support that."

"The second was whether higher levels of cerebrovascular disease or amyloid plaques have a greater impact on cognitive function in older, non-demented adults. Half of the study participants had abnormal levels of beta amyloid and half vascular brain injury, or infarcts. It was really very clear that the amyloid had very little effect, but the vascular brain injury had distinctly negative effects. The more vascular brain injury the participants had, the worse their memory and the worse their executive function - their ability to organize and problem solve."

Link: http://www.eurekalert.org/pub_releases/2013-02/uoc--vbi021113.php

An Upcoming Oxford Debate With Aubrey de Grey and Richard Faragher

Via the SENS Research Foundation:

Dr. Aubrey de Grey, SENS Research Foundation's Chief Science Officer, will be debating Dr. Richard Faragher, Chair of the British Society for Research on Ageing and Professor of Biological Gerontology at the University of Brighton, at Oxford's Sheldonian Theatre on February 19. Dr. de Grey will argue that the diseases of aging can be treated comprehensively by SENS therapies, and that these therapies could be developed in the coming decades, given sufficient research and funding. Dr. Faragher will dispute these points.

Most importantly, both researchers agree that aging research is critically underfunded, and is the key to a healthier future. SENS Research Foundation is proud to be a sponsor of this event, and looks forward to an insightful debate about the most direct and effective research strategies for addressing age-related disability and disease. We would like to thank the Oxford University Society of Biomedical Sciences for hosting the event.

Link: http://sens.org/outreach/outreach-blog/dr-de-grey-debate-oxford

Commentary Machinations

I can assure you, the visiting reader, that under the hood this website is a marvel of just-good-enough. So too for the comment system, which for many years has been set to moderate everything and only publish a submitted comment on manual approval by yours truly - a process which can take some hours. That has made it somewhat challenging to have an actual conversation in the comments here at Fight Aging!, and I greatly appreciate those of you who persevere nonetheless.

All comments have been moderated because (a) any and all online discussions of aging and medicine attract spam like flies to honey, (b) the last time I put any thought into this, good spam filtering was too computationally expensive to run locally with the tools to hand, and (c) change is slow in this neck of the woods. It took me five years to get from thinking of a site redesign to actually doing it, for example. A lot of smaller and obvious-in-hindsight improvements (such as better formatting for the news posts) have also tended to happen far later than they might.

So to spam: the automated spam robots are easy enough to block while a site remains small enough to avoid personal attention from those who write the spam scripts. Since few if any of these robots actually run the Javascript on a site (too slow when you are trying to hit as many vulnerable sites as possible), you can just make your comment submission form depend on some unique, easily changed, hard to read Javascript that must run in a browser. The gargantuan manual spam industry is harder to fend off, however: this is formed of some combination of people in poor countries who are paid a tiny amount to spam relentlessly, plus people in rich countries who haven't yet figured out that you don't build your own modest online brand by spamming links to your site everywhere with a text field, plus some oddities like captcha-solving networks and the like.

The spam robots, when I bothered to record their activities, accounted for a thousand attempted comment submissions each day at times. This is the consequence of Fight Aging! being fairly high in Google's search listings for some terms beloved by the "anti-aging" marketplace. Almost everything to do with medicine can command high prices in online advertising, however, and hence drive a great deal of spam activity. Dentistry accounts for a fairly high fraction of the medical spam I see, for example, which is interesting.

Unlike the automated spam, manual spam activity trends with how likely it is to work. Spammers talk to one another, and so a policy of 100% moderation works very well to get rid of them - since none of the manual spammers can see their comments getting through, they tend to give up. After years of this situation, I see as few as a dozen of these manual spam submissions a week.

So to come to the point of this post: I finally signed up for the Akismet spam detection service and stopped moderating comments. The upshot of this is that (a) your comments will (most likely) be posted immediately on submission, making conversations somewhat more viable, a radical idea I realize, and (b) I will see a growth in manual spam over the weeks and months ahead as the manual spammers figure out that there is only a commodity third party spam filter to worm their way past. It remains to be seen as to what degree Akismet will leave me cleaning up after the fact, either deleting spam that should have been blocked or restoring legitimate comments unfairly flagged, but so far (small sample bias) it's caught everything it should and passed the rest.

More on mTOR and Gender Longevity Differences

This paper comes from a group that considers aging to be a programmed process involving later-life overactivity of processes vital to early-life development rather than the result of stochastic accumulation of unrepaired cellular and molecular damage. I think that this view isn't well supported by the balance of evidence, but it does illustrate the complexity of aging that such divergent interpretations of the same data exist. The researchers' views don't diminish the data they produce from animal studies, but do mean that you have to read their interpretations of the data with that bias in mind:

One of the most long-standing mysteries of gerontology is that the females of most species live longer than the males. Not only most mammals but also women of different nations and at most historical periods live longer. Ironically, it may seem that males do not age faster but simply are weaker at any age. In fact, the mortality rate is higher in young males and teenagers too. Importantly, however, old males die from age-related diseases, whereas young males mostly die from risky behavior and physical competition with each other. While risky competition increases chances of mating and offspring, this simultaneously results in high accidental mortality (from fights) and males die young. There is no reason for them to be naturally selected for slower aging. Therefore, animals with a high accidental death rate tend to age faster. It is exceptionally important for such males early in life to be bigger and stronger (even on the cost of accelerated aging).

In brief, early in life, TOR drives growth, robustness and reproduction, while causing aging and age-related diseases later in life. This example of antagonistic pleotropy is in line with the evolutionary theory. We speculate that aging as a continuation of growth driven by the same mTOR pathway, leading to aging and diseases of aging culminating in organismal damage and death.

In sum, mTOR may drive both growth and aging, associated with hyper-functions coupled with signal-resistance and malfunction, loss of homeostasis, leading to development of deadly diseases of aging such as cardiovascular and metabolic diseases, neurodegeneration, cancer and organ atrophy or failure. We hypothesize that males have a higher levels of mTOR activity, providing advantage (and bigger size) for young males even though accelerated aging and early death might follow.

Link: http://impactaging.com/papers/v4/n12/full/100528.html

Blocking Development of Rheumatoid Arthritis in Mice

Progress towards a different approach to therapies for autoimmune conditions such as rheumatoid arthritis, though still not one that addresses root causes directly:

Scientists have demonstrated a new strategy for treating autoimmune disease that successfully blocked the development of rheumatoid arthritis in a mouse model. They say it holds promise for improved treatment of arthritis and other autoimmune disorders in people.

Infusing a highly specific type of cell that regulates immune responses into arthritis-prone mice shut down the cascade of inflammation that damages tissues and joints. The method worked best when the infusions of CD8+ Treg cells were given at the same time that the animals were injected with a protein that triggered the arthritis-causing autoimmune reaction. "We found we could almost completely inhibit the disease in this setting."

Even when administered weeks after the disease was initiated, CD8+ Treg infusions combined with low doses of methotrexate - a commonly used drug for rheumatoid arthritis - were able to significantly slow the arthritis process. The new strategy also blocked disease progression when the scientists injected peptide antigens to expand the rodents' own pool of CD8+ Tregs, rather than infusing them from outside. Overall, the results "suggest that [these] strategies represent a promising therapeutic approach to autoimmune disorders."

Link: http://www.eurekalert.org/pub_releases/2013-02/dci-nsp020713.php

Final Complexity is Less Relevant than that of Root Causes

I think we can all agree that, separately, each of aging, cancer, and Alzheimer's disease is a complicated phenomenon. Is cancer more or less complicated than aging, however? Are the likely several different disease processes leading to a similar end presently lumped under the heading of Alzheimer's disease more or less complex than either cancer or aging? I think that arguments could be made for any ordering of the three, though not all of them are good arguments, and anything that fits in this short blog post is going to involve a fair amount of hand-waving. We could compare the funding and researcher man-years devoted to understanding each, for example, or papers published, or some other similar research metric. I suspect that cancer wins by those measures, if we airily assume that greater amounts of funding are led by the fact that there is much more to catalog at the level of genes, proteins, and cellular mechanisms. I don't think that this is a safe assumption.

If we look at the SENS vision of aging, or indeed any damage-based model of how and why we age, we might say that aging is more simple than Alzheimer's, or more simple than any age-related condition. Aging stems from simple root causes, which expand out into massively complex and varied failure modes as damage interacts with damage and systems flail and fail in any number of ways. To draw an analogy, the rust that eats iron structures is a very simple, homogenous thing - a trivial set of a few chemical reactions, easily described, easily prevented. Yet a structure can fail in countless ways due to rust, as the progression and damage caused is stochastic. Which girder or support will be eaten to breaking point first? Similar structures might fail in similar ways more often, perhaps because they allow moisture to linger in the same places.

But you get the point: from simple causes great complexity can arise. The more complex the structure, the greater the number of failure modes that simple forms of damage can cause. We humans are tremendous complex, vast, interlinked arrays of molecular machinery, and in most modern theories of aging the few rusts we are theorized to suffer (some with much more evidence than others) are pretty simple at root. Thus any age-related condition must be more complex than its cause, aging, by virtue of being an end result rather than the cause of that end result. That is one way of looking at it. Another is to view the end state of aging as a whole and measure that complexity - which is obviously also much more complex than the simple processes that gave rise to it.

Does the complexity of the end state of aging matter, however? Or for that matter, the end state of cancer or Alzheimer's disease? This is not an idle question, as it points to the consequences that result from different core philosophies or approaches in medicine and medical research. Do we fix a problem by working to understand its end states and then try to clean up after or block every branching failure mode, or do we aim to remove the root causes and then let our biology try to restore itself?

That is not a question with a correct answer for all times and places: sometimes it isn't enough just to remove a root cause, sometimes the root cause is unknown. It is clear, however, that when it comes to age-related conditions a great deal of modern medicine runs along the lines of being an ever more sophisticated means of sticking a finger into the rapidly eroding hole in the dam, rather than repairing the hole in a way that will last. Consider the widespread efforts to safely remove amyloid beta in Alzheimer's disease, for example: it seems likely that this is not a case of treating root causes, which remain poorly understood at this time, but rather cleaning up the most evident of the biological signatures.

The regulatory structure for medicine and medical research in the US and Europe biases researchers towards the goal of producing what are ultimately less effective treatments for end causes. The system is so set up that the path of least resistance is to research some part of the complex pathology of a late-stage disease, where there is more room to carve out something that can be patented, and then build what are essentially palliative medicines for people who are very sick, having long suffered their particular named condition. Prevention and root causes don't yet get anywhere near as much attention. When it comes to aging itself, it isn't even legal in the US to try to produce and commercialize a clinical therapy that might do some good.

But prevention and root causes are exactly where the attention should be when it comes to aging and age-related diseases. Root causes are simple, end stages are complex: that is reflected in the cost and time required to produce therapies. The way to harness the complexity of our self-repairing biology rather than fight against it is to look to removing causes rather than cleaning up after the spreading tree of secondary and tertiary consequences. This has long been understood by the public and researchers alike when it comes vaccination, poisons, and all sorts of other areas of medicine. Somehow it has gone a little astray in the matter of aging and age-related disease. That must change.

An Interview With Judith Campisi

Scientific American interviews Judith Campisi, a member of the SENS Research Foundation's scientific advisory board and a noted figure in the aging research community. You'll note that her views are fairly conservative, much closer to the mainstream of longevity science than to SENS, however:

[SciAm]: Why is it so hard to figure out what causes aging?

[Judith Campisi]: In many ways we already know what causes aging. We just don't know what causes aging in the kind of molecular detail that would allow us to intervene in large meaningful ways. It's not even clear that once we solve those mysteries we will be able to intervene in aging or dramatically extend longevity.

I started my career studying cancer. Look at all the things we have learned since the 1970s about how cancers form in the body. And yet, still the best cures we have for most cancers are sledgehammers. Biology is complex - and this is a reality that the public has to come to grips with and our legislators have to come to grips with.

I predict aging will follow the same trajectory as cancer research. Why is aging so difficult to figure out? It's because it's a really tough problem. I think it's tougher than cancer. The time has come to really wallow in the complexities.

[SciAm]: What would you say is one of the biggest mysteries of aging research?

[Judith Campisi]: Why do organisms with remarkable genetic similarity have sometimes remarkable differences in life span? We know that for the most part, many of the processes that go on in the human body also go on in yeast and mice. Yet, yeast live a few days, a mouse lives about three years, and people live for decades. We really do not know what evolution has done to take basically the same genes and produce different life spans.

[SciAm]: Is that where the naked mole rat comes in?

[Judith Campisi]: Yes. The mystery shows up even in species that are mouselike. The naked mole rat is more related to the mouse than to us - it looks like a mouse. And yet it lives for 30 years, or 10 times longer than a regular mouse. On top of all that, it has signs of oxidative damage that exceeds that of the mouse.

Now there are three ideas that scientists have come up with to try to explain why naked mole rats live so long: Maybe oxidative damage doesn't cause aging. Maybe naked mole rats are evolutionary oddities. And then my personal favorite, maybe it's not oxidative damage that is the problem but how the cell responds to the damage. But that's all speculative.

Link: http://www.scientificamerican.com/article.cfm?id=aging-ask-the-experts-can-aging-be-controlled

Parkinson's Disease as Localized Garbage Catastrophe

Alpha-synuclein is associated with Parkinson's disease (PD), and is believed to play a central role in the mechanisms that cause the destruction of dopamine-generating neurons, and thus the pathology of the condition. Here, researchers dig deeper into the processes involved:

Overexpression of a protein called alpha-synuclein appears to disrupt vital recycling processes in neurons, starting with the terminal extensions of neurons and working its way back to the cells' center, with the potential consequence of progressive degeneration and eventual cell death. "This is an important new insight. I don't think anybody realized just how big a role alpha-synuclein played in managing the retrieval of worn-out proteins from synapses and the role of alterations in this process in development of PD."

Using a variety of leading-edge imaging technologies, including a new fluorescent tagging technique developed for electron microscopy, [the] scientists created three-dimensional maps of alpha-synuclein distribution both in cultured neurons and in the neurons of mice engineered to over-express the human protein. They found that excess levels of alpha-synuclein accumulated in the presynaptic terminal - part of the junction where axons and dendrites of brain cells meet to exchange chemical signals.

"The over-expression of alpha-synuclein caused hypertrophy in these terminals. The terminals were enlarged, filled with structures we normally don't see." [As] alpha-synuclein accumulates in the terminals, it appears to hinder normal degradation and recycling processes in neurons. This would progressively impair the release of neurotransmitters. In time, the neurons might simply stop functioning and die.

Link: http://www.sciencedaily.com/releases/2013/02/130207141402.htm

Reforging the Brain, One Small Piece at a Time

The repair of aging in the human brain will have to proceed one small step at a time. Either the rejuvenation biotechnologies of the SENS program will prove sufficient to remove every aggregate and process that stops an old brain maintaining itself like a young brain does, or there must be an even more patchwork quilt of therapies, each one fixing some form of damage. The former is a much more efficient path towards meaningful healthy life extension than the latter, but the vast majority of laboratory research and related funding goes towards progress on the harder, slower road.

So reforging the brain: if we're not thinking about picking out the fundamental forms of cellular and molecular damage that cause aging and then letting the body repair itself, then the list of repairs is a long one. There is myelin to be restored where it wears away; the matter of diminished stem cell activity and so ever fewer new neurons created to replace losses; the failure of structures like the choroid plexus that remove unwanted metabolic byproducts from cerebral fluids; the malfunctioning of the brain's complex complement of immune cells; and so on for many, many more items.

Here are a couple of research releases, each looking at one small aspect of the brain's fine structure, and giving some insight into means of repair.

Cells Forged from Human Skin Show Promise in Treating Multiple Sclerosis, Myelin Disorders

The source of the myelin cells in the brain and spinal cord is cell type called the oligodendrocyte. Oligodendrocytes are, in turn, the offspring of another cell called the oligodendrocyte progenitor cell, or OPC. Myelin disorders have long been considered a potential target for cell-based therapies. Scientists have theorized that if healthy OPCs could be successfully transplanted into the diseased or injured brain, then these cells might be able to produce new oligodendrocytes capable of restoring lost myelin, thereby reversing the damage caused by these diseases.

It took [researchers] four years to establish the exact chemical signaling required to [transform human induced pluripotent stem cells, or hiPSCs, into] OPCs in sufficient quantities for transplantation and each preparation required almost six months to go from skin cell to a transplantable population of myelin-producing cells.

They found that the OPCs spread throughout the brain and began to produce myelin. They observed that hiPSC-derived cells did this even more quickly, efficiently, and effectively than cells created using tissue-derived OPCs. The animals were also free of any tumors, a dangerous potential side effect of some stem cell therapies, and survived significantly longer than untreated mice. "The new population of OPCs and oligodendrocytes was dense, abundant, and complete. In fact, the re-myelination process appeared more rapid and efficient than with other cell sources."

Dickkopf makes fountain of youth in the brain run dry

Cognitive decline in old age is linked to decreasing production of new neurons. [Scientists] have discovered in mice that significantly more neurons are generated in the brains of older animals if a signaling molecule called Dickkopf-1 is turned off. In tests for spatial orientation and memory, mice in advanced adult age whose Dickkopf gene had been silenced reached an equal mental performance as young animals.

Neural stem cells in the hippocampus are responsible for continuous supply of new neurons. Specific molecules in the immediate environment of these stem cells determine their fate: They may remain dormant, renew themselves, or differentiate into one of two types of specialized brain cells, astrocytes or neurons. One of these factors is the Wnt signaling molecule, which promotes the formation of young neurons. However, its molecular counterpart, called Dickkopf-1, can prevent this.

Stem cells in the hippocampus of Dickkopf knockout mice renew themselves more often and generate significantly more young neurons. The difference was particularly obvious in two-year old mice: In the knockout mice of this age, the researchers counted 80 percent more young neurons than in control animals of the same age. Moreover, the newly formed cells in the adult Dickkopf-1 mutant mice matured into potent neurons with multiple branches. In contrast, neurons in control animals of the same age were found to be more rudimentary already.

An Actuarial Overview on Human Longevity and Mortality

When you look at the vast sums of money involved, one might argue that the actuarial community has a greater incentive to understand aging than the aging research establishment does - billions of dollars rest on the degree to which predictions of future human longevity match up to reality. Unfortunately for the actuaries (and the rest of us) that future is very uncertain. We stand at a cusp in biomedical research, an era of rapid progress in fundamental biotechnology, and one in which great leaps forward in application may or may not happen at any time.

Producing true rejuvenation in laboratory mammals is a matter of a billion dollars and ten years or so at this point in time, and the vagaries of human organization that lead up to sufficient interest and funding to start on that goal are essentially random: perhaps we manage to talk the world around to it five years from now, perhaps fifteen, perhaps longer. Who knows - it's a people and persuasion issue, and those are hard to pin to a timeline.

Here is an interesting PDF that tours some of the present thinking on human longevity by the actuarial community:

Longevity is an important issue: the implication of increasing longevity has far-reaching effects for our social programs; and for our financial security as we grow into old age. It is also a trend which actuaries are well suited to analyze: we have unique training and experience that allows us to distill large volumes of data into key elements that can inform predictions of future events. As we partner with other experts, we are helping to shape the discussion on the implications of increasing longevity.

First, around the globe people are living longer. While there is evidence that the rate of improvement is different between men and women, and between people of different races, geographies and social statuses, the evidence remains that we are all living longer.

Secondly, our understanding of what factors have a material effect on our expected lifetime is growing, but it is not complete. In particular, our understanding of older age mortality is limited, in part because the data at older ages is sparse and of varying quality. There are open questions related both to the rate of improvement and the ultimate age at which it is appropriate to assume a mortality table should end.

Thirdly, in many regions, there is no broad consensus on the appropriate base mortality rates and improvement factors that should be used to value life-contingent liabilities, or on the models that should be used to forecast those rates into the future. This creates challenges for practitioners who must develop their own projections; inefficiencies as the use of different data, assumptions and models leads to different mortality forecasts; and inconsistencies across disciplines - for example, between the pension and insurance communities - as each develops its own independent view of future mortality. Having said this, the actuarial community has dealt with issues of this magnitude in the past: We need to begin to hone in on techniques that will allow us to become comfortable with the wide variances that can be produced by our projection models. As evidenced by the material presented in the body of this report, there are techniques - stress testing, scenario testing, risk heat maps, screening systems - that we can use to give us insight into what base mortality rates and improvement factors could be.

Link: http://www.soa.org/files/research/projects/research-2013-soa-living-100.pdf

A Popular Science Article on the Study of the Axolotl

From the Australian press, an example of one of a number of research groups that are studing the axolotl with an eye to mapping the mechanisms that drive their exceptional regenerative prowess:

They are masters at regenerating their own limbs, tails, jaws, retina and heart. They can recover from spinal chord and brain injury and can easily tolerate organ transplants. And to top things off, they don't get cancer. Meet the axolotl, otherwise known as the Mexican walking fish. ''This animal guards so many interesting biological secrets. Things that would leave humans in a wheelchair or dead they can just repair in no time at all.''

In Mexican walking fish, limbs can be removed and re-grown without so much as a scar and, amazingly, the heart can regenerate after having a third of it removed. Similarly, it can have sections of its spinal chord ''cut and pasted'' without killing it. Try doing that to a lab rat - let alone any other mammal. Some of the key genes that regulate spinal chord regeneration in axolotls have been established and compared with that of the mouse and rat.

Chief among the questions surrounding the axolotl is whether a cure for cancer might lie beneath the translucent skin of the albino axolotl. Essentially, controlling cancer is about controlling cell growth. ''Cancer is like a wound that never heals and how the immune cells deal with this perpetuates cancer and allows rogue cells to proliferate and grow crazy. How axolotls can suppress cancer and activate regeneration is one of the things [we] would like to get to.''

Link: http://www.theage.com.au/national/the-secret-to-running-repairs-20130207-2e18h.html

The Quest for Reversible Cryopreservation

Much of the talk of low-temperature preservation of tissue here at Fight Aging! directly relates to the cryonics industry: the work of preserving the brains of those who age to death prior to the advent of rejuvenation biotechnology, so that they have some possible chance at a longer life in the future. There is a large mainstream cryobiology industry and research community that shares essentially the same goals when it comes to organs and tissues, although cryobiologists have historically been quite hostile towards cryonics groups. It's the same old story of the conformist mainstream pushing away anyone who is doing something out of the ordinary - yet all bold new technologies and approaches start exactly that way, with a small group moving the boundaries of the possible and the plausible.

In any case, back to the commonalities: both cryobiologists and cryonicists want to produce the means for reversible cryopreservation rather than the presently irreversible methods of vitrification used on the human patients stored at Alcor, the Cryonics Institute, KrioRus, and so forth. Presently irreversible is not forever irreversible, of course, but the cryoprotectant compounds used now are pretty toxic, which adds an additional level of difficulty to the task of restoring patients to life. A reasonable argument is that given that this task requires technologies such as swarms of medical nanorobots, and sufficient control over small-scale biology to be able to repair arrangements of macromolecules within cells, then sequestering toxic molecules along the way shouldn't be a big deal by comparison.

So the cryobiologists want to be able to store organs and other large tissue masses in the same way that we can presently store embryos - in the deep freeze, so that donated organs or organs grown to order can be stored until needed. The cryonics community includes some groups with expertise in this area, such as 21st Century Medicine, and the development of reversible cryopreservation would be one of the potential spin-off technologies that could draw greater funding and interest into cryonics.

Here is an article on the present state of work on cryopreservation not directly related to the cryonics industry:

For most animals on the planet, prolonged exposure to temperatures below freezing means death. But for the wood frog (Rana sylvatica), and for an unlikely collection of other organisms ranging from insects to plants to fish, surviving the cold is a routine part of life. The Alaskan Upis beetle survives at -60°C in the wild and down to -100°C in a laboratory. Species of Arctic fish swim fluidly through -2°C water, and snow fleas hop atop snow banks at -7°C. These animals all have tricks either to survive freezing, called freeze tolerance, or to lower their internal freezing temperature so they don't freeze at all, called freeze avoidance.

However, cooling a tissue that is not adapted to tolerate or avoid freezing - as cryobiologists seek to do with human organs - is a whole different ball game. One can expect irreversible and widespread damage from the formation of ice crystals at temperatures below 0°C: cells shrivel and collapse, extracellular matrices rip apart, blood vessels disintegrate.

But researchers aren't giving up. Organ cryopreservation, if possible, would transform medicine the way refrigeration transformed the food industry. Currently, human organs harvested for transplant are not frozen - they are kept in cold storage, which prevents deterioration for a few hours at the most. Human hearts, for example, can be preserved for only 4 to 5 hours. But if scientists could learn the tricks of the trade from nature, and add days, weeks, or even years to the lifetime of an organ, hospitals could bank frozen organs for transplant as needed.

Over the last 70 years, the technique for freezing human sperm and embryos, a mainstay of fertility clinics, has not differed much from how frogs freeze in Ohio- add a glut of glycerol and lower the temperature slowly. But today, clinics and hospitals are turning to a technique that no known organism experiences in nature - transforming tissues to glass.

Vitrification is the rapid cooling of a substance to a glass state, achieved by pumping enough cryoprotectants into cells or tissues, and cooling them fast enough, so that they transform into an ice-free glass. Through vitrification, scientists have successfully completed two of the most complex examples of cryopreservation to date: a 40,000-cell fly embryo and a rabbit kidney.

Though it won't be easy, many believe that organ cryopreservation should be possible. Indeed, thanks to chemical cryoprotectants and sophisticated freezers, scientists and companies already have techniques to freeze sperm, eggs, embryos, and pools of cells such as blood or stem cells. And in the last decade, successful preservation of some solid tissues has offered hope that the long-neglected field is not dead in the water.

In 2005, heart surgeons in Israel used an antifreeze protein from fish to preserve rat hearts at −1.3°C for 21 hours, then successfully transplanted them into recipient rats, where the hearts pumped away for 24 hours prior to dissection for analysis. In 2003, [21st Century Medicine], a California company similarly preserved a rabbit kidney at below-freezing temperatures and then thawed and transplanted it into a recipient rabbit, which remained healthy with that kidney alone for more than a month. And since 2000, researchers at the US Department of Agriculture have been cryopreserving the embryos of tropical flies for years at a time, then thawing them with ease and watching them hatch and live normal lives.

Telomere Length as Biomarker of Somatic Redundancy

A paper of relevance to the reliability theory view of aging:

Biomarkers of aging are essential to predict mortality and aging related diseases. Paradoxically, age itself imposes a limitation on the use of known biomarkers of aging, because their associations with mortality generally diminish with age. How this pattern arises is however not understood. With meta-analysis we show that human leucocyte telomere length (TL) predicts mortality, and that this mortality association diminishes with age, as found for other biomarkers of aging. Subsequently, we demonstrate with simulation models that this observation cannot be reconciled with the popular hypothesis that TL is proportional to biological age.

Using the reliability theory of aging we instead propose that TL is a biomarker of somatic redundancy, the body's capacity to absorb damage, which fits the observed pattern well. We discuss to what extent diminishing redundancy with age may also explain the observed diminishing mortality modulation with age of other biomarkers of aging. Considering diminishing somatic redundancy as the causal agent of aging may critically advance our understanding of the aging process, and improve predictions of life expectancy and vulnerability to aging-related diseases.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23346961

Being Overweight is Harmful at All Ages, In No Way Protective

Researchers here argue that flawed data led to some scientists to conclude that being overweight is less harmful to long-term health than it in fact is:

Obesity kills, giving rise to a host of fatal diseases. This much is well known. But when it comes to seniors, a slew of prominent research has reported an "obesity paradox" that says, at age 65 and older, having an elevated BMI won't shorten your lifespan, and may even extend it. A new study takes another look at the numbers, finding the earlier research flawed. The paradox was a mirage: As obese Americans grow older, in fact, their risk of death climbs.

The researchers argue that past studies of longevity and obesity were biased due to limitations of the National Health Interview Survey, or NHIS, which provides information on obesity. The survey excludes individuals who are institutionalized, such as in a hospital or nursing home - a group largely made up of seniors. Consequently, the data is overrepresented by older respondents who are healthy, including the relatively healthy obese. What's more, many obese individuals fail to make it to age 65 - and thus do not live long enough to participate in studies of older populations.

"Obesity wreaks so much havoc on one's long-term survival capacity that obese adults either don't live long enough to be included in the survey or they are institutionalized and therefore also excluded. In that sense, the survey data doesn't capture the population we're most interested in."

Link: http://www.eurekalert.org/pub_releases/2013-02/cums-oao020513.php

Towards a Goal that Can Never Be Attained

It is a polite fiction in some parts of the aging research community that the goal of the scientists' work is to improve health in the old without improving longevity. Like all the best polite fictions, it survives because many people have come to actually believe this line. It arose during the period when researchers couldn't talk openly about extending human life without risking their funding and their careers: proposing improvements to health in the old was the way to raise funds when you couldn't talk about extending healthy and overall life span. Sad to say, but the research and funding community was, up until comparatively recently, in the business of discouraging research and researchers who might head in that direction - or at the very least in the business of saying nothing about the matter in public. There is surprisingly little shame evident from those who engaged in those practices back in the day, now that things are somewhat different.

If we look at aging from the high level abstraction of reliability theory, it becomes clear that it should be impossible to improve health without also extending life. Aging is an accumulation of damage, and improving health involves fixing or preventing that damage. The statistics of the way in which any machinery - our bodies included - ages and fails, and the statistics of how long that failure will take to happen, depend on the level of unrepaired damage in the system's component parts. Arguing the opposite side of that position, that is is possible to fix damage without extending life expectancy, is a steep hill to climb: you have to come up with a convincing explanation as to why a human doesn't behave like any other physical system that undergoes limited self-repair - which starts to sound suspiciously like vitalism.

Nonetheless, we still see things like this, buried in the introduction to abstracts from one of last year's conferences:

The purpose of the 2012 conference was to provide a forum for the presentation and discussion of various assays of measuring physiological performance and function and determining what assays of function could be used to asses healthspan of a mouse. Longevity is a precise endpoint (binary, the individual is either alive or it is dead), but the true goal of aging research is to increase the health of the elderly, not their longevity. That is, the goal is to enhance and extend healthspan, defined as the portion of our lives spent free of serious illnesses and disabilities.

I think it's a problem that a fair proportion of researchers in this field continue to either (a) put forward the proposition that you can improve long-term health without extending life as a matter of fact, or (b) conveniently omit any discussion of extended longevity as a possible goal or result of their work. This is to say nothing of the ethics of actually trying to avoid extending life span in a field where it is a possibility.

There are some who point to the well-known "rectangularization of the survival curve" as evidence for it being possible to extend healthy life without extending overall life span. This gradual change in historical mortality rates at every age has been achieved without deliberate attempt to extend maximum life span - but nonetheless resulted in reduced burdens of biological damage at every age, largely due to control of infectious disease. One might argue that today, even considering vaccination, the majority of effort and funding in modern medicine goes towards trying to patch over failed health after the fact rather than on forms of prevention. That is something that must change, and not just by placing great weight on ways to periodically repair the cellular and molecular damage that causes aging.

In recent years, some researchers have examined survival data and point out that of the two possible contributions to changes in the survival curves - rectangularization on the one hand and increases longevity on the other - it is increased longevity that is the more important factor. See these items from the archives, for example:

In low-mortality countries, life expectancy is increasing steadily. This increase can be disentangled into two separate components: the delayed incidence of death (i.e. the rectangularization of the survival curve) and the shift of maximal age at death to the right (i.e. the extension of longevity). ... The gain of years due to longevity extension exceeded the gain due to rectangularization. This predominance over rectangularization was still observed during the most recent decades.

So one can't convincingly point to rectangularization as a sign that it is possible to increase health in the old without lengthening their lives, even if this were an ethical goal to be discussing.

Chromatin and Transposons in Senescent Cells

Senescent cells have removed themselves from normal operation and really should be destroyed, either by their own programmed cell death processes or by the immune system. Senescent cells accumulate with age, however, and while in place cause harm to surrounding tissues. Removing these unwanted and damaging senescent cells with targeted cell killing technologies is one of the necessary goals in longevity science; it has already been shown to provide benefits in gene-engineered mice, and several lines of research are presently leading towards the tools needed to build therapies to attain the same results for everyone else.

Here is another example of the way in which senescent cells are not in good shape:

Parasitic strands of genetic material called transposable elements - transposons - lurk in our chromosomes, poised to wreak genomic havoc. Cells have evolved ways to defend themselves, but in a new study, [researchers] describe how cells lose this ability as they age, possibly resulting in a decline in their function and health.

"The cell really is trying to keep these things quiet and keep these things repressed in its genome. We seem to be barely winning this high-stakes warfare, given that these molecular parasites make up over 40 percent of our genomes." Cells try to clamp down on transposons by winding and packing transposon-rich regions of the genome around little balls of protein called nucleosomes. This confining arrangement is called heterochromatin, and the DNA that is trapped in such a tight heterochromatin prison cannot be transcribed and expressed. What the research revealed, however, is that carefully maintaining a heterochromatin prison system is a younger cell's game. "It's very clear that chromatin changes profoundly with aging."

Young and spry cells distinctly maintain open "euchromatin" formations in regions where essential genes are located and closed "heterochromatin" formations around areas with active transposable elements and few desirable genes. The distinction appeared to become worn in aging, or senescent, cells. In the observations, the chromatin that once was open tended to become more closed and the chromatin that was once closed, tended to become more open. Then the scientists compared the DNA that was coming from open or closed chromatin formations in the young and senescent cells. In their study not only did they find that the chromatin lockdown was breaking down, but also that the newly freed transposons were taking full advantage.

What's not clear from the study is the relevance of the damage that the cells suffer from the transposable element jailbreak and resulting genetic crime spree. "Is the transposition really bad for the organism or is it something that happens so late that by that point the organism has already accumulated so much age-associated damage? Then maybe this extra insult of transposition is not going to make a lot of difference."

Link: https://news.brown.edu/pressreleases/2013/01/senescence

Gene Copy Number Variations Associated With Longevity

One imagines that genetic copy number variations between individuals will prove to be much like other small differences in DNA, in that there are many tiny contributions to longevity, and it is hard to find consistent results in different study populations.

Copy number variations (CNVs) are rare losses and gains in DNA sequences that have been importantly implicated in the pathogenesis of various neurodevelopmental and psychiatric diseases. As opposed to SNP genotypes which have revealed common variants conferring modest relative risk to the individual with the variant, CNVs are often rare variants not observed or extremely rare in a normal control population and conferring high relative risk. SNP arrays have vastly improved the detection of CNVs across the human genome, [but] it remains to be determined if there are certain gene classes or networks of genes that are pathogenic or disease-causing in general, and if there are other gene networks that may be protective in the same manner. One way of testing this is to compare CNV states and frequencies between pediatric and geriatric subjects and determine if certain CNVs are lost in the older age group (i.e. suggesting pathogenic impact with shortened lifespan), and if other CNVs are enriched and considered protective.

To test the hypothesis that rare variants could influence lifespan, we compared the rates of CNVs in healthy children (0-18 years of age) with individuals 67 years or older. CNVs at a significantly higher frequency in the pediatric cohort were considered risk variants impacting lifespan, while those enriched in the geriatric cohort were considered longevity protective variants. We performed a whole-genome CNV analysis on 7,313 children and 2,701 adults of European ancestry. [Positive] findings were evaluated in an independent cohort of 2,079 pediatric and 4,692 geriatric subjects. We detected 8 deletions and 10 duplications that were enriched in the pediatric group, while only one duplication was enriched in the geriatric cohort. Population stratification correction resulted in 5 deletions and 3 duplications remaining significant in the replication cohort.

Evaluation of these genes for pathway enrichment demonstrated ~50% are involved in alternative splicing. We conclude that genetic variations disrupting RNA splicing could have long-term biological effects impacting lifespan.

Link: http://dx.doi.org/10.1371/journal.pone.0053846

Planning to Live to 110

I'll spare you a link to one of the talking heads of the "anti-aging" marketplace discussing her plans to live to 110, and how other folk might, hypothetically, follow along at home. You can find it easily enough via Google if so inclined. It puts me in mind of the following entirely made-up short exchange:

Me: I hear you are planning to live to 110?

Talking Head: Yes.

Me: So you must be donating handsomely to help fund the SENS research program, which aims to repair the causes of aging, right?

Talking Head: No.

Me: You're not planning this very well at all, then, are you?

People show up every now and again in public forums with talk of planning to live for a long time in good health using nothing more than supplements, diet, and exercise: make all the right lifestyle choices, eat a good diet, don't get fat, be calorie restricted, and so forth. There's even a billionaire who was talking a good game on the topic a couple of years back. Good health practices all raise the odds of living a healthier life, but with present day medical technology those odds don't see you making it to 90, let alone 100 or 110. Living as healthily as possible gives you slim odds - perhaps somewhere a little north of 25% - of celebrating your 90th birthday under present medical capabilities. The odds get worse if you let yourself go.

The simple, unfortunate truth of the matter is this: if eating exceedingly well really could let people live to 100 and beyond with any reliability, then this would be well known, and the world population would include thousands upon thousands upon thousands of centenarians.

So plan away, planners. It won't help all that much in achieving any goal related to the number of candles on your cake, though it may well make your life much more pleasant along the way. Good health is a very underrated thing, usually by those who still have it. The only way the planner demographic will reliably hit their high-end life span targets is by benefiting from advances in medical technology, i.e. from the results of actions and initiatives that have absolutely nothing to do with their personal health practices. For the presently older demographic, those advances would have to be of the sort envisaged in the Strategies for Engineered Negligible Senescence (SENS): ways to actually create rejuvenation in the old by addressing the cellular and molecular damage that causes aging.

The bottom line here: if you're planning to live to 110, then you aren't planning very well if those plans don't largely revolve around helping to fund rejuvenation research of the sort pioneered by the SENS Research Foundation. Advances in medicine don't just happen: they require money, advocacy, and hard work. Which of those are you helping out with?

The Proximal Cause of Aging From the Point of View of the Programmed Aging Camp

I noted a review paper a few months back that considered the proximal cause of aging in terms of the evolution of cellular damage versus damage repair mechanisms. That aging is caused by an accumulation of certain forms of molecular and cellular damage is the dominant paradigm at present, though there is always debate over which forms of damage are primary, which secondary, and which important over a human life span. Of those researchers who aim to intervene in aging, most look to merely slow down the pace of damage by manipulating metabolism, while a minority follow the Strategies for Engineered Negligible Senescence (SENS) plan and aim to repair and reverse the damage without changing our metabolism.

Meanwhile, off in left field there are those who theorize that aging is an evolved program, and therefore could be halted or reversed by suitable changes to metabolism or the genes governing it. To their eyes damage doesn't cause aging, it is a result of the program. This is something of a dangerous viewpoint, should it gather steam, even worse than the "slow aging by metabolic manipulation" camp for steering researchers away from the most effective course for treating aging - which is the SENS approach of repairing damage. But it is a sign of just how complex aging is as a phenomenon that we can still see such widely divergent interpretations of the existing data.

Here is an open access consideration of the proximal cause of aging from one of the more prolific researchers in the programmed aging camp, by way of illustrating the points made above. You should probably read the whole thing, as the argument made is somewhat hard to excerpt and condense:

As discussed in detail previously, aging is of course not a program, but it is a quasi-program, a useless and unintentional continuation (or run on) of developmental programs. Similarly, cellular senescence is a continuation of cellular growth. In brief, over-stimulation leads to increased functions - [harmful hyperfunctions].

But what about the molecular damage? It was assumed that molecular damage contributes to aging because it accumulates with time. Well, over time you may accumulate money in your bank account. However, neither accumulation of molecular damage nor accumulation of money is a cause of your aging. Yes, molecular damage must accumulate. But although molecular damage accumulates, it does not necessarily limit lifespan, particularly if other causes limit life span. By analogy, if everyone died from accidents, starvation and infection early in life, then aging and age-related diseases (such as obesity and atherosclerosis) would not even be known. By the same token, "aging" due to molecular damage will not manifest itself, if aging due to hyperfunction invariably limits life span.

For complex organisms like mammals the relationships between hyperfunctions (aging), diseases and damage (decline) are:

1. Hyperfunctions (increased cellular functions) including hypertrophy are primary. This is the essence of aging, which silently causes malfunctions and age-related diseases.

2. Decline of functions, malfunctions and atrophy are secondary. For example, hyper-stimulation of beta-cells by nutrients and mitogens can cause its apoptosis. Here is important to emphasize however that apoptosis can be also a form of hyperfunction, unneeded continuation primary function such as apoptosis during development of the immune system.

3. Damage is caused by aging, not the reverse.

4. Damage is not molecular. It is macro-damage (tissue, system and organ damage), like stroke, infarction, metastases, broken hip fracture and renal failure. Damage may take a form of sudden "catastrophe", even though hyperfunctional aging slowly generates diseases for decades. If a patient survives infarction (due to medical intervention), she can live for many years, reflecting the fact that catastrophe was not due to the burden of molecular damage.

Link: http://impactaging.com/papers/v4/n12/full/100525.html

The First Person to Live to 150 Has Already Been Born

Wagering on the proposition that the person who will first reach 150 years of age is already alive is no wager at all, really. It's a very safe bet that at some point in the next century the medical technologies needed for significant human rejuvenation will be developed. The risky bet is on whether it will happen soon enough for those of us in mid-life now - that will take much more advocacy, public enthusiasm, and rapid growth in research funding than has so far emerged.

Here is an interview with Aubrey de Grey of the SENS Research Foundation at Forbes:

[Forbes]: Please comment on the myth of aging how how we need not accept it as "just part of getting old".

[de Grey]: It's always been a mystery to me why this isn't totally obvious to everyone. Do we let cars fall apart when they get old? - yes in general, but not if we really want them not to - that's why we have 50 year old VW Beetles driving around, and even vintage cars. It's bizarre that people don't see that the exact same thing is true of the machine we call the human body, just that that machine is a lot more complicated so the development of sufficiently comprehensive preventative maintenance is a lot more challenging.

[Forbes]: Could you briefly explain the nature of free radicals and the role in aging?

[de Grey]: Free radicals come in a lot of flavours, and a number of them are created by the body. Some of them are good for us, but others are harmful, because they react with and damage molecules that we need for survival, such as our DNA. The body has a massive array of defences against these problems, which can be grouped into four categories - tricks to minimise the rate at which these toxic free radicals come into existence in the first place, enzymes and compounds that react harmlessly with them before they can react harmfully with something else, chemical tricks that make the harmful reactions happen less easily, and systems that repair the resulting damage after it's occurred - but those tricks are not completely comprehensive, so some damage still occurs and accumulates throughout life. We'd like to stop that happening, and we could theoretically do it by enhancing to perfection any one (or more) of those four types of defence. My view is that the last one, repairing damage post hoc, is the most practical. Eliminating free radical production would involve completely redesigning aspects of our metabolism, especially the way we use oxygen to extract energy from food. It would also have the problem that even the bad free radicals are also good in some ways, so we actually need them around somewhat; this is also the problem with perfecting the elimination of free radicals via harmless reactions. Ramifying our cells so that the reactions just don't occur is also tantamount to completely redesigning the body, So we're left with perfecting repair.

[Forbes]: The digital health and quantified self movement are increasingly gaining steam. Do you see this an a critical step forward in the quest for longevity?

[de Grey]: Not really, no. It's valuable, but only temporarily. That's because all personalised medicine is only valuable temporarily, while the treatments for such-and-such a condition are only modestly effective and can thereby be made more effective by being tuned to the specifics of the patient. We don't have personalised polio vaccines, because we don't need them - the same vaccine just works perfectly, on everyone.

[Forbes]: Does the wait for "extensive data" and "controlled trials" adversely impact innovation in aging research?

[de Grey]: Yes, but it adversely impacts innovation across all medical research. There's a huge need for greater creativity in the regulatory process, and that's coming: "adaptive licensing" is a big theme in that area right now.

Link: http://www.forbes.com/sites/johnnosta/2013/02/03/the-first-person-to-live-to-150-has-already-been-born-revisited/

Working on the Use of Decellularization to Make Pig Hearts Suitable for Human Transplantation

Decellularization involves taking a donor organ and stripping its cells, leaving just the shaped extracellular matrix behind. When new cells of the right types are seeded into the matrix, they will inhabit it, grow, and follow its cues to rebuild the tissue as it was. This might prove to be a shortcut to the future of organs grown to order - you can't use it to produce an organ such as the heart from scratch, but you can take animal organs and make it possible to transplant them into humans with minimal risk of rejection.

This, at least, is the goal. So far decellularization has worked for some human donor tissues, such as veins, replacing the donor's cells with those of the recipient to remove immune rejection issues. This suggests that it will work just fine for animal organs too. Researchers are working on opening the doors to widespread xenotransplantation of pig organs, for example, by turning porcine tissues into those of the organ recipient.

Saving lives with help from pigs and cells

One recent morning, a pig heart hung suspended in a clear homemade tank in the lab built for Taylor and her team. Filled with detergent, the heart had expanded to the size of a large man's fist, excess liquid dripping slowly out its sides.

Once the heart is thoroughly cleaned, hard-working human stem cells - immature cells found in our organs and tissues that help repair damage on a daily basis - will bring it to life. "We can take stems cells from bone marrow, blood or fat and place them onto a heart, liver or lung scaffold," Taylor explains. "My motto for a long time has been 'Give nature the tools and get out of the way.' "

Taylor and her team will add stem cells to the heart one of two ways: by inserting a tube in the aorta and letting the cells drip inside, or by injecting the cells with a syringe through the wall of the heart. A heartbeat is perceptible after just a few days. Within a few weeks, the heart is strong enough to pump blood.

Taylor predicts that in the next two years, she and her team will approach the U.S. Food and Drug Administration and ask to do a first-in-human study with the bio-artificial hearts. "Will it be a whole heart? Probably not," Taylor says. "But it could be a cardiac patch or a valve. We might start with a piece to show the safety and efficacy of the technology."

A Podcast Interview With Aubrey de Grey

From a few weeks back, an audio interview with Aubrey de Grey of the SENS Research Foundation:

Anti-aging scientist and biogerontologist Aubrey de Grey told [the host] about his work with the SENS Foundation, an organization he founded with the purpose of defeating aging. According to him, aging is treated as a disease that should be defeated by targeting the 7 cellular activities that cause us to age. Dr. de Grey discussed the science that researchers at SENS are studying to back up the claim that we could live to 1000 years some day soon. "The problem is the funding," de Grey said. "We've been trying to fight what we've described as the pro-aging trance." The pro-aging trance, according to Dr. de Grey, is the social conception we have that death is inevitable. "No one wants to keep cancer, no one wants to keep heart disease, so what would we want to keep aging?" de Grey asks. Part of Aubrey de Grey's work is marketing his ideas and helping to diminish the acceptance society has of death. Citing his long beard which [the interviewer] said looked "like Rasputin's," de Grey said, "This is something my team and I have discussed. It's something that helps me stick in people's minds."

[The interviewers] briefly talked about the social, economic, and cultural consequences of a longer life extension. When [the interviewers] pressed de Grey on these issues, Aubrey reiterated that his work is not a "longevity issue, but a health care issue, so stop thinking of it that way please." Aubrey pressed that the key for his scientific success lies in his publicity: getting more exposure and raising money through his foundation.

Link: http://glucksolutions.podomatic.com/entry/index/2013-01-18T12_39_16-08_00

Wrapping Nanoparticles in Cell Membranes

Here is another small step on the way towards the creation of artificial cells as medical devices. If you can wrap nanoparticles in cell membranes, then its not hard to see that disguising any arbitrary nanomachinery that way is on the agenda - such as those that can dispense or create proteins, or perform other tasks inside our tissues.

By cloaking nanoparticles in the membranes of white blood cells, [scientists] may have found a way to prevent the body from recognizing and destroying them before they deliver their drug payloads. "Our goal was to make a particle that is camouflaged within our bodies and escapes the surveillance of the immune system to reach its target undiscovered. We accomplished this with the lipids and proteins present on the membrane of the very same cells of the immune system. We transferred the cell membranes to the surfaces of the particles and the result is that the body now recognizes these particles as its own and does not readily remove them."

Nanoparticles can deliver different types of drugs to specific cell types, for example, chemotherapy to cancer cells. But for all the benefits they offer and to get to where they need to go and deliver the needed drug, nanoparticles must somehow evade the body's immune system that recognizes them as intruders. The ability of the body's defenses to destroy nanoparticles is a major barrier to the use of nanotechnology in medicine. Systemically administered nanoparticles are captured and removed from the body within few minutes. With the membrane coating, they can survive for hours unharmed.

"Being able to use synthetic membranes or artificially-created membrane is definitely something we are planning for the future. But for now, using our white blood cells is the most effective approach because they provide a finished product. The proteins that give us the greatest advantages are already within the membrane and we can use it as-is."

Link: http://www.sciencedaily.com/releases/2013/01/130131144114.htm