Fight Aging!

There will be a SENS Foundation meeting in Los Angeles this coming Wednesday, October 5th. The following is from the Foundation's coordinator Maria Entraigues; if you're in the area an interested then RSVP to the email address provided below.

It's been a long time, since the last occasion that we got together! We at the SENS Foundation have been very busy working harder than ever to take our accomplishments to the next level, and it's been very fruitful. We would like to share this with you in this very special gathering in a most delightful setting.

This will be an exceptional occasion, we will be very lucky to have our CSO, Dr. Aubrey de Grey, presenting some important remarks, as well as our CEO Mike Kope giving an extraordinary presentation. On top of this, we will have special guest Ms. Sonia Arrison, author of the book "100 Plus - How the coming age of longevity will change everything, from Careers and Relationships to Family and Faith." She will engage in a conversation with Aubrey about her new book. Each attendee will get a free copy, and she will be happy to sign it!

Apart from feeding your brain to total satisfaction with interesting and remarkable information, we will also feed you with delicious finger food, beer, and beverages and to make the night "100 Plus" percent perfect, we will have live music by Ancient Lasers closing the event!

Date: Wednesday, October 5, 2011
Time: 6:00 PM

Location: The beautiful house of the Finfers
173 North Anita Avenue
Los Angeles, CA 90049
(Brentwood, near Sunset and Bundy)

6:00 PM -- Reception
7:00 PM -- "100 Plus" Panel, with Author Sonia Arrison and Dr. Aubrey de Grey
7:30 PM -- Q&A
8:00 PM -- Presentation by Mike Kope "The Rise of Rejuvenation Biotechnology"
9:00 PM -- Live music by Ancient Lasers (mingling and networking)

Please RSVP by e-mail. I can't wait to see you all!

Maria Entraigues
maria.entraigues@sens.org
SENS Foundation Global Meeting Coordinator, Volunteer Coordinator
http://www.sens.org
http://sens.org/take-action/volunteer

The SENS Foundation has a growing presence at both ends of California. As you might know, the Foundation's research center is in the Bay Area, and a number of the research institutions in California have both a strong interest in aging research and ties to the Foundation. Some of the folk formerly participating in research at the Foundation are even a part of the biotech side of California start up culture nowadays. Which is not to mention the presence of philanthropist Peter Thiel and his interest and connections in longevity science, and a range of other interested supporters. Connections and relationships are what make the world go round, and one purpose of the ongoing series of Los Angeles meetings is to help enlarge that web of support so to better enable the future growth of the SENS Foundation - and alongside it the new field of rejuvenation biotechnology.

Life science students intern at the SENS Foundation research center in the Bay Area as a part of the Foundation's broader academic initiative, working on the foundations of future rejuvenation therapies. Biotechnology has advanced to the point at which bright graduates can help to meaningfully advance the state of the art, and here is a report from one such: "Sarah Fazal joined our research center team as an intern for the summer. Over the past few months, she worked with our MitoSENS team, primarily verifying the integration of DNA transfected into cells and detecting RNA expression levels. Her efforts contributed greatly to the progress our MitoSENS team has made over recent months, and she presented those results in a poster at our recent SENS5 conference in Cambridge. ... The current project for mitoSENS is allotopic expression, which involves copying the mitochondrial DNA into the nucleus. My project required checking for integration of the DNA transfected into cells, and detecting RNA expression levels. By the end of the summer, I had done this successfully for 4 out of the 13 genes involved in oxidative phosphorylation that are still encoded by mitochondrial DNA. I spent my summer mostly doing PCRs (polymerase chain reaction), DNA and RNA isolations, cell culturing, and gel electrophoresis. I learned to perfect these techniques, to think critically when my results weren't as expected, and to design experiments. My experience at SENS helped shape me into a more confident and better experienced scientist. I would definitely recommend volunteering for this foundation; the experience was educational, the research is open-minded, determined, and bold, and the staff is friendly, welcoming, and helpful."

Link: http://sens.org/node/2408

Rapamycin is known to extend life in mice, so researchers are looking into the mechanisms and possible uses as a therapy for age-related diseases. "Previous studies have shown that inducing autophagy ameliorates early cognitive deficits associated with the build-up of soluble amyloid-β (Aβ). However, the effects of inducing autophagy on plaques and tangles are yet to be determined. While soluble Aβ and tau represent toxic species in Alzheimer's disease (AD) pathogenesis, there is well documented evidence that plaques and tangles also are detrimental to normal brain function. Thus, it is critical to assess the effects of inducing autophagy in an animal model with established plaques and tangles. Here we show that rapamycin, when given prophylactically to 2-month-old 3xTg-AD mice throughout their life, induces autophagy and significantly reduces plaques, tangles and cognitive deficits. In contrast, inducing autophagy in 15-month-old 3xTg-AD mice, which have established plaques and tangles, has no effects on AD-like pathology and cognitive deficits. In conclusion, we show that autophagy induction via rapamycin may represent a valid therapeutic strategy in AD when administered early in the disease progression." This research is actually fairly indicative of the field as a whole: mechanisms that are potentially modestly useful as ways to slow aging across life are forced into consideration as late-stage therapies only. This happens because regulators will not permit commercialization of ways to treat aging in otherwise healthy people - they only permit treatments for named diseases. So progress is necessarily sub-optimal where it is permitted at all.

Link: http://dx.doi.org/10.1371/journal.pone.0025416

I just added to the Fight Aging! Resources page a small number of links to journals and other scientific archives that I graze from time to time. I left out the broad life science journals that sometimes touch on aging in favor of searchable archives and publications dedicated to aging and longevity science. I also tend to favor open-access journals as the resulting material gives me more to read and more to write about. I'd be a pauper if I acquiesced to paywall demands for everything I find interesting enough to want to read, but fortunately paywalls are not the future of scientific publishing. The smaller the hurdle to propagation of scientific knowledge, the more the scientific community will benefit, as the propagation of that knowledge is a very important part of generating support for funding and development of clinical applications.

If you have suggestions for a few other journals or resources that follow the general theme of those already there, let me know.

This minor site update was spurred by my noticing that research blog Ouroboros briefly roused from its slumber to speak about Pathobioliogy of Aging & Age-related Diseases, a new open access journal on aging that launched earlier this year. Its remit looks promising for those of us interested in aging as accumulated molecular damage, and the development of means to repair that damage.

The pursuit of investigations into the science of aging is really designed to understand why cellular processes begin to fail with advancing age, and what molecular events contribute to this failure. In this regard, the distinction between aging and the diseases associated with aging becomes less clear, and they are most likely driven by the same or similar events related to biological decline.

With the launch of Pathobiology of Aging & Age-related Diseases, we hope to enlighten the scientific community by recognizing outstanding pathobiology-based scientific contributions, allowing scientists to communicate data that might be of less interest in other journals more focused on generic aging or specific scientific disciplines. Aging is indeed an 'old' problem and is being studied in a variety of ways that use mammalian model systems to identify mechanistic pathways that can be targeted to maintain healthy living. In this regard, we are providing a 'new' venue for disseminating information that specifically focuses on the pathobiological aspects of aging and the chronic diseases directly associated with aging.

Hopefully this will provide a source of interesting material in the years ahead. A good way for laypeople to learn more about the field of aging and longevity science is to browse the open access journals on a regular basis. If you skip over what is hard and read what isn't, then sooner or later you'll find that less and less of the content is beyond you, and that you understand far more than you used to. I see that process as one of the compelling arguments for destroying the old paywall model of scientific publication: how can laypeople casually increase their knowledge when everything is locked away beyond the impulse decision to spend a little time reading?

Here is a different way of looking at the material consequences of living a life that allows you to become obese: "The United States has the highest prevalence of obesity and one of the lowest life expectancies among high-income countries. We investigated the relationship between these 2 phenomena. ... We estimated the fraction of deaths attributable to obesity by country, age, and sex and reestimated life tables after removing these deaths. To allow for a possible secular decline in obesity risks, we employed alternative risks from a more recent period. ... In our baseline analysis, obesity reduced US life expectancy at age 50 years in 2006 by 1.54 years for women and by 1.85 years for men. Removing the effects of obesity reduced the US shortfall by 42% for women and 67% for men, relative to countries with higher life expectancies. Using more recently recorded risk data, we estimated that differences in obesity still accounted for a fifth to a third of the shortfall. ... The high prevalence of obesity in the United States contributes substantially to its poor international ranking in longevity."

Link: http://www.ncbi.nlm.nih.gov/pubmed/21940912

A piece by Aubrey de Grey at the Huffington Post: "as things stand, no amount of insight into age-related pathology can be sufficient to develop outright cures. Some diseases are the end results of aging, just as starvation is the end result of fasting. The nature of aging is such that many age-related infirmities are certain to afflict anyone who lives long enough. And this will remain the case, until a technology is developed which ameliorates the general decrepitude of old age which underlies these diseases. One can, therefore, identify the future direction of medicine by considering the nature of old age itself. What exactly is being taken from us, year after year, from cradle to grave? As time goes by, your hair goes grey, your face gets coarser, you put on weight, you become weaker, more susceptible to disease, and so on. But what do these things have to do with each other? Fortunately, the answer is not so complex as one might anticipate. Most people think of the science of aging as being very incomplete. It is true that aging as a process is not completely understood (biogerontology, the study of aging, involves many competing theories). But the state of disrepair that aging leaves people in can be observed directly, and in great detail. A comparison between two perfect snapshots of old and young tissue would provide us with a very multi-faceted damage report. The aged tissue is riddled with "junk" molecules (by-products of normal metabolic functions) in and between cells, which do not dissipate, not even as the body heals and replenishes itself day in and day out. It would also show an accumulation of unwanted cells, and a depletion of necessary cells. All this damage reduces our tissue function, then our organ function, and eventually it kills us. How this damage accumulates, and how it leads to our demise, are matters of some dispute. But the bare facts of how our tissues alter over time already provide us with enough of a compass with which to chart the future course of medicine."

Link: http://www.huffingtonpost.com/aubrey-de-grey-phd/age-related-diseases_b_985019.html

Updates to the Fight Aging! site tend to come in waves, as and when my time frees up sufficiently between the ebb and flow of other projects. The next wave isn't here yet, but will be, so I thought I'd solicit opinions. By all means add yours in the comments to this post.

One thing I hear a lot of is the request for like/share buttons for Facebook, Twitter, and so on - that won't be happening. I've performed this experiment already (you might recall that the previous design included sharing buttons) and the difference between having them and not having them in terms of engagement, new visitors, and overall traffic was minimal. On the other hand, they definitely slowed down page load time and made the site that little bit more ugly into the bargain. More importantly, they tracked visitors, adding to the growing databases that will be used for whatever purposes that the social sites will come up with the future; I'm not of the mindset to help them with the construction of their panopticon foundations at the expense of visitors to my little corner of the web. So on the whole I'm happy to force on you the modest make-work of cutting and pasting the URL you wish to share with your friends - and for a little more make-work you could even arrange matters for your browser to insert a share button regardless of what I do. Ultimately the web page transmitted to you by a server is no more than a suggestion as to what you should actually view: with the proper tools you can rearrange web pages on the fly before they are presented to you.

Another reason to skip the share buttons is that many of them deliver what I would regard as worthless traffic. StumbleUpon is particularly bad in this respect: my logs are full of people turning up from that site, arriving at a long and interesting post, and leaving after a few seconds. Hundreds upon hundreds of them, every day. StumbleUpon is, in some of its incarnations, a channel-surfing engine with infinite channels; people click the button and only stop if something catches their eye in a faction of a second. Next to nothing here will do that, and these are not people likely to be engaged by the Fight Aging! message. I lose nothing by failing to cultivate that traffic.

(The Google Analytics script that still runs on the site will no doubt eventually succumb to the frame of mind outlined in the paragraphs above, but for now it at least somewhat anonymizes your IP address and is fairly easily blocked).

Other suggestions fall into the bucket of fleshing out the functionality: making the site more portal-like at their grandest, such as by adding forums, most popular or most commented lists in the sidebar, more and more varied content, and so on. The less grand suggestions are tweaks to functionality to provide features seen on other tech news and essay sites, or minor additions to content, such as to stop displaying the full text of each post on the home page, enabling visitors to post links to relevant content more easily, adding a list of journals to the resources section, make the comment section more apparent. Thing of that ilk.

Some of these I agree with, some of them I don't. I should explain that Fight Aging! is something of a hybrid of two functions in its present structure. Firstly, it has some pretensions to being a stream of fresh content: a news and opinions site that is relevant to aging research and longevity science. In this it is little different from most blogs and newsletters: we all understand roughly how these things work. They care about the traffic of the now, and comparatively little for their archives, so they tend to become involved in a race for the bottom in gathering attention and being first - quality and correctness come a distant second, and they measure success by page views because that's what drives their revenues. I've never been particularly interested in playing that game. It's useful and, I think, necessary to have a modest flow of new content in order to continue to be relevant as an item of interest in your community, but that's all that's needed: enough to remain relevant so that people will listen when you have something to say.

So much of what you see on revenue-generating news and blog sites is inappropriate or not terribly useful for Fight Aging! The share buttons are a good example: if an item is there for the purposes of accelerating the race to the bottom of the pool of shallow attention, then I don't need it. I'd argue that shallow attention doesn't get you anywhere in the business of advocacy to grow a small community with big, complex ideas, such as the present longevity science community. What you need is engaged, quality attention. It is my belief that shallow attention only becomes useful, or at least convertible into results such as funding or labor, when you have a massive community and you're trying to gain a popular consensus of some sort among the public at large.

The second function of Fight Aging! is to act as a beacon and resource for people who are on the verge: interested enough to look into life extension, aging, and rejuvenation biotechnology, but neither connected nor particularly aware of the community. When they stumble over Fight Aging! in searches, I see that as a chance to inform and educate. So I place a great deal more value on the Fight Aging! archives than I would if this were only a standard issue blog or news site, and the fact that pages in those archives are littered with links to more general and introductory content is important.

So when I think about what should be done in the next wave of alterations to Fight Aging!, I am thinking in terms of advocacy and growth, which may map in some way to the web traffic I see here, but which is definitely not the same as a straight measure of traffic or engagement or any other metric easily chased. In terms of expansion versus focus, I'm presently more in favor of focus: it would be good to narrow down to look at the things that work and see about how to make them more useful, more functional, more widely used, more influential. For example, it's been a while since I've seriously looked at how I might improve the Fight Aging! newsletter or broaden its reach, despite the fact that it has thousands of subscribers. The same goes for the RSS feeds, which have a presently unknown reach and utilization.

On the expansion side, it's not that I'm not in favor of big glittering longevity science web portals, but that I don't think the community is large enough to support such a thing at this point in time. It's my impression that the present longevity science community - people who are interested enough to be a part of the discussion, or who are in the research community, or who are donating funds, and so forth - is at the size sufficient for an active web forum or two and a couple of mailing lists and newsletters. I think that because that number of forums, mailing lists, and newsletters is pretty much what has emerged organically. If there was the interest and the headcount for more than that, then it would already exist; there are any number of people out there whose business is to sniff out new communities and launch websites to serve them news before anyone else does, and they are largely absent - or worse than absent, off servicing the "anti-aging" marketplace instead, as there's real money over there. This is unfortunate, and we'd all like matters to be further along, but it is what it is, or at least until we help it bootstrap into something more.

In any case, to return to the original point, there will be time for some updates and change ahead - make your preferences known now or forever hold your peace.

Exercise is generally beneficial to long term health in many ways - though it's somewhat cruel that it's so beneficial for the suffers of conditions that make it hard to exercise: "physical activity improves arthritis symptoms even among obese mice that continue to chow down on a high-fat diet. The insight suggests that excess weight alone isn't what causes the aches and pains of osteoarthritis, despite the long-held notion that carrying extra pounds strains the joints and leads to the inflammatory condition. ... Many cases of arthritis are associated with obesity and inactivity, so [the] researchers set out to determine whether a high fat diet induces knee osteoarthritis, and then whether exercise provides a protective effect. Using two sets of male mice - half fed a high-fat diet and the other fed regular chow - the researchers noted significant differences among the two groups. The mice on the high-fat food gained weight rapidly, processed glucose poorly and had much higher blood levels of molecules that trigger the chronic inflammation associated with osteoarthritis. But when these animals got regular running wheel workouts, many of the harmful effects diminished - even though the mice ate the same high-fat food and shed no weight. Glucose tolerance improved, while the inflammatory response was disrupted among key signaling molecules called cytokines, easing the development of arthritis. If the extra weight on the joints had been the cause of the arthritis, the researchers noted, exercise would have exacerbated the problem. Instead, it helped. ... I don't want to say exercise is turning off that inflammatory signal, it just impairs it." The fat tissue accumulated by the obese is a trigger for inflammation via chemical signaling; weight on joints may not be aggravating arthritis, but the increase to levels of chronic inflammation will do just that. Better to be both exercising and shedding the excess fat than just one or the other.

Link: http://www.eurekalert.org/pub_releases/2011-09/dumc-eea092111.php

From Popular Science: "Giving cardiac patients a heart of gold nanowires could ensure engineered tissue works like it should, pulsing in unison to make the heart beat. First growing nanowires and then growing heart cells, [engineers] say their new muscle-machine blended heart patch improves on existing cardiac patches, which have trouble reaching a consistent level of conductivity. ... Electrical signals shared among calcium ions dictate when cardiomyocytes contract, making the heart beat. But tissue scaffolds are often made with materials like polylactic acid or alginate, which act as insulators, so the signals are blocked. This makes it difficult to get all the cells in a piece of tissue to coordinate their signals and beat in time, which in turn makes it difficult to build a very big or very effective heart patch. The [rsearch team] gets around this problem by integrating gold, an excellent conductor. They mixed alginate, a gummy substance often used in tissue scaffolds, and grew gold nanowires throughout it. Then they seeded the alginate with cardiomyoctes from rat embryos, and monitored calcium levels to gauge their electrical conductivity. Compared to a typical scaffold system, the gold nanowire cells' conductivity improved by three orders of magnitude."

Link: http://www.popsci.com/technology/article/2011-09/heart-patch-gold-nanowire-helps-rebuild-cardiac-tissue

The aging of the human adaptive immune system takes and interesting and distinct form when compared with the aging of other organs and processes. There is accumulating cellular damage, yes, but there is also a very important and ongoing process of misconfiguration: an otherwise largely sound system ceasing to function correctly not because it is damaged per se, but because it becomes poorly organized. That is, potentially, a much easier problem to solve than many of the other challenges presented to us by aging.

The way in which this misconfiguration happens is described back in the Fight Aging! archives. The short version is that the adaptive immune system remembers all threats, but has a limit to the number of cells it can produce; eventually too much of its quota is taken up by memory cells and too little by cells that are actually equipped to destroy things. A small range of persistent but otherwise mostly harmless viruses, such as cytomegalovirus (CMV), greatly speed up this process by hanging around for decades and constantly provoking the immune system into uselessly devoting ever more memory cells to their existence.

There are a range of possible ways to deal with this issue, with varying levels of complexity, cost, and permanence: adding more cells cultured from the patient's own stem cells, destroying the unwanted memory cells using targeted therapies of the sort under development in the cancer research community, and so forth. One of the presentations given at the SENS5 conference discusses the latest research in this area:

Aging is associated with an increased susceptibility of older individuals to new and emerging infections; poor responses to vaccination compound this vulnerability. ... In both mouse and man, repeated interactions between reactivating viruses such as CMV and antiviral T cells leads to memory T-cell inflation (MI) with increasing accumulation of these cells over the lifespan. It was hypothesized that MI may exact a price for the immune system: competition between inflating, CMV-specific memory T-cells and naive T-cells supposed to defend against all other infections may impair the maintenance of a diverse naive T-cell pool, consequently leaving the individual at a disadvantage when exposed to a new pathogen. We have directly tested this hypothesis using a mouse model of lifelong persistent infection.

There is also video of the presentation, which I think you'll find interesting - the research community is clearly within striking distance of a range of novel and effective repair methodologies for immune system aging:

You might recall that RAGE, the receptor for advanced glycation end-products (AGEs), is thought to have a role in Alzheimer's disease - it's a mechanism that can explain some of the diabetes-like risk factors noted for the development of this condition, making it look a lot like a lifestyle disease. Here, researchers look at RAGE vaccines as a possible Alzheimer's therapy: "In Alzheimer's, the amyloid protein can accumulate in the brain instead of being eliminated by the body's natural defenses, nestling between the neurons and forming impassable plaques. Amyloid and the way it gets there could be targets for a new vaccine. ... RAGE, or receptor for advanced glycation endproducts, proteins bind to amyloid and transport it into the brain ... Research has shown that RAGE may also contribute to the inflammation and damage that amyloid causes to the brain's nerve cells. [Scientists are] researching a vaccine that targets RAGE and amyloid by using the body's own immune system to protect against their over-production and eventual build-up. ... Unfortunately, all of the vaccines for Alzheimer's that have been through clinical trials have failed. Part of the reason why could be that they're just not comprehensive enough. Most only target amyloid. Our hope is that by taking a more encompassing approach, we will be more effective. So far, that's exactly what we're seeing in our experiments. ... Early results have shown improved cognition and memory in animal models of Alzheimer's ... We need to move on to larger animal studies. We have a lot we still don't know about the vaccine itself. For example, we know that amyloid and RAGE bind together, but we don't know why the binding creates such a stable complex. We have these end points, but we still don't know some of the basic science that needs to be known so that we can push ahead."

Link: http://medicalxpress.com/news/2011-09-award-winning-alzheimer-vaccine.html

A review paper on the roles of oxidative stress in aging, both negative and positive: "Oxidative stress is considered to be a major detrimental factor limiting longevity, as originally postulated in the free radical theory of aging. The oxidative stress leads to accrual of damaged/misfolded proteins, increased mutagenesis rate and inflammation. Ironically, due to its ability to accumulate over time (as it was seen in many neurodegenerative disorders), oxidative damage also emerged as a consequence of longevity per se. The human life-span exceeds that of most mammalian species at least 4 times (median life span records across 900 mammalian species is ~16 years). Importantly, anti-oxidative stress adaptations are not subjects of evolutionary pressure at post-reproductive age, which further contributes to the buildup of oxidative damage in aging individuals. Yet, paradoxically, in short-lived Caenorhabditis elegans, oxidative stress might have beneficial effect on longevity by connecting to the nutrition signaling pathways [such as those activated through calorie restriction]. It was suggested that aging is driven by over-activation of signal-transduction pathways such as the nutrient-sensing pathway, while oxidative stress may be both one of its activators and effectors."

Link: http://impactaging.com/papers/v3/n9/full/100385.html

The Tithonus Error is one of the learned patterns by which people reject life extension out of hand: from roots in childhood and education and stories, a majority of people come to believe that extending life means making people older for longer. Most people have an entirely justified horror of the later stages of degenerative aging, and so the idea of more of that just isn't on the table. The rejection of more life under those terms is instinctive and visceral.

This rejection is based on a false premise, however, and all that rational fear of aging is piled atop a single irrational misunderstanding. The goal of all medicine, and especially longevity science, is to enable people to be younger for longer, not older for longer. Aging is nothing but damage, and longevity therapies will be no more than ways to slow, or for preference repair, the accumulation of that damage. A machine with less damage is a machine that works better for longer, not a machine that lingers on its dying gasp for longer.

That rational fear of aging is big and powerful, however, and it's been somewhat hard to fight one's way past it to point out that "older for longer" just isn't going to happen. See these rather depressing studies for example:

Wishes to Die in Older People

Understanding Why Older People Develop a Wish to Die

The wish to die had either been triggered suddenly after traumatic life events or had developed gradually after a life full of adversity, as a consequence of aging or illness, or after recurring depression. The respondents were in a situation they considered unacceptable, yet they felt they had no control to change their situation and thus progressively "gave up" trying. Recurring themes included being widowed, feeling lonely, being a victim, being dependent, and wanting to be useful. Developing thoughts about death as a positive thing or a release from problems seemed to them like a way to reclaim control.

Aging takes everything from us in the end, piece by piece, and eventually even our desires and our will to live crumble in the face of physical and mental decay. Younger people understand that this lies in their future, and most believe that it is a certainty, unavoidable. They've seen what happens to older relatives, they read, and they learn - they base their expectations of the future on what they were taught by experience and observation. It doesn't matter that the pace of chance in technology will render much of that obsolete and useless in decades to come; it's still the case that people, in a deep-seated way, expect to live a life similar to that their parents and grandparents lived.

The prospects for medical technology offer much, much more than that - but the medical control of aging and defeat of all disease is an opportunity to be seized rather than a certainty already in the bag for those people in middle age today. Rejuvenation biotechnologies may or may not happen in time for us. I'd say most likely not if a supermajority of people keep their heads stuck in the sand of the Tithonus Error, refuse to think seriously about aging and medicine, and refuse to do anything constructive to help speed research and development. Things only tend to happen with speed and certainty when there are large communities of supporters: millions of people demanding progress and pitching in to help in their own small ways, enabling scientific communities of tens of thousands and billions of dollars of investment in the cutting edge of research.

We see that in fields like regenerative medicine. We don't see it yet for longevity science. That must change if we are to expect similar degrees of progress towards therapies in the years ahead.

From In Search of Enlightenment: "On this WHO website the fact that chronic disease killed 9 million people under the age of 60 last year is highlighted. This is of course a human tragedy that should be mitigated. That is twice the number of deaths estimated to be caused by all injuries in the world. However, if you do the math on this data, that means that 27 million people worldwide died from chronic disease that is caused (primarily, though the story is complex) by aging. This is 75% of the world's chronic disease burden. Aging is the leading cause of disease and death in the world today. ... Not only that, it is the largest health threat today. In just a decade of the chronic diseases of aging the world's population will suffer more more disease and death than in any decade of the worst wars and conflicts in human history. Everyone agrees that conflict and war is bad for us, and that our governments should strive to ensure there is lasting peace between nations. And yet few people today realize how important it is that our governments also support the science and innovation that could modulate the rate of biological aging, thus keeping our bodies and minds healthy for as long as possible. If we hope to make a serious dent on the tsunami of chronic disease that will afflict the 2 billion people worldwide who will be over age 60 by the middle of this century we need to prioritize the study of the biology of aging. Only by retarding the process of cellular and molecular decline can we hope to delay, and possibly compress, chronic disease in the foreseeable future." The post is generally on the right side of the line insofar as the demographics are concerned; you may or may not agree with the political view and reach for government as the agency of first resort.

Link: http://colinfarrelly.blogspot.com/2011/09/globe-article-on-cost-of-chronic.html

Via ScienceDaily: researchers "have turned back the clock on mature muscle tissue, coaxing it back to an earlier stem cell stage to form new muscle. Moreover, they showed in mice that the newly reprogrammed muscle stem cells could be used to help repair damaged tissue. The achievement [opens] the door to the development of new treatments to combat the degeneration of muscle associated with muscular dystrophy or aging. ... Muscle formation has been seen as a one-way trip, going from stem cells to myoblasts to muscle fiber, but we were able to get a multi-nucleated muscle fiber to reverse course and separate into individual myoblasts. For many years now, people have wanted to do this, and we accomplished that by exposing the tissue to small molecule inhibitor chemicals rather than altering the cell's genome. ... These tiny chemicals go inside the cell and change the way the cell behaves without changing its genome. The inhibitors were only used for 48 hours, enough time for the fused myofibers to split into individual cells, and then they were washed away. The cells can proceed to live and die as normal, so there is no risk of them dividing uncontrollably to become tumors. ... rather than going back to a pluripotent stage, we focused on the progenitor cell stage, in which cells are already committed to forming skeletal muscle and can both divide and grow in culture. Progenitor cells also differentiate into muscle fibers in vitro and in vivo when injected into injured leg muscle. ... To test the viability of the newly regenerated myobasts, the researchers first cultured them in the lab to show that they could grow, multiply and fuse normally into new myofibers. The researchers then injected the de-differentiated myoblasts into live mice with damaged muscles. ... After two to three weeks, we checked the muscle and saw new muscle fibers that glowed green, proving that the progenitor cells we derived from mature muscle tissue contributed to muscle repair in vivo in mice."

Link: http://www.sciencedaily.com/releases/2011/09/110922121403.htm

I see that Maria Konovalenko has posted notes on a few of the presentations on longevity science given at SENS5:

Dr. Laura Niklasson from Yale University is working on lung engineering. Human lung is an extremely complicated organ. There's 23 generations of branching of airways, they are up to 200 microns in diameter. 70 square meters for gas exchange. More than 100 million air sacks all together. Engineered lung must have right mechanical properties, autologous cells, adequate surface area for gas exchange and adequate barrier to prevent flooding of airways with blood constituents after implantation. ... Scientists implanted engineered half lung in a rat. It was 95% as efficient as a native lung in terms of gas exchange. But in several hours they got thrombosis. Also they saw a little bit of blood cells in airways, so the barrier was not perfect. After being improved this technique can be used to engineering human lungs.

...

John Jackson gave a beautiful overview of thymic involution and told us about the ongoing experiments in the Wake Forest Institute for Regenerative Medicine on thymus engineering.

...

I personally found the talk by Dr. Charles Greer the most fascinating one. Aparently, there is a subsytem in our brain that is constantly regenerating. The rate and quality of this regeneration process doesn't decline with age. It's the olfactory system. Sensory neurons in olfactory system die every 6-8 weeks. Neurogenesis is constant. New neurons come from the subventricular zone. It's like a river of migrating neurons to olfactory bulb.

Meanwhile, the SENS Foundation volunteers are steadily uploading conference video to a YouTube channel - the John Jackson presentation on tissue engineering for the thymus is amongst those already available:

You might also find the following presentation to be of interest. It's a part of the broader LysoSENS program, which involves finding ways to safely remove the age-related build up of various damaging metabolic byproducts and other chemicals that our cellular recycling mechanisms normally struggle with. One of these compounds is 7-ketocholesterol:

7-ketocholesterol (7KC) is a cytotoxic oxysterol that plays a role in many age-related degenerative diseases. 7KC formation and accumulation occur in the lysosomes in a number of cell types, hindering enzymatic transformation, and increasing the chance for lysosomal membrane permeabilization.

We assayed the potential to mitigate 7KC cytotoxicity and enhance cell viability by transiently transfecting human fibroblasts to overexpress several 7KC-active enzymes. One of our engineered constructs, a lysosomally-targeted cholesterol oxidase that lacked isomerization activity, significantly increased cell viability

Orchestrated by the SENS Foundation, progress is slowly being made in developing the roots of what probably at first be drugs, designed molecules - possibly attached to targeting mechanisms like tailored nanoparticles - that either break down 7-ketcholesterol and other varied harmful compounds we'd be better off without or instruct the cell itself to better perform that task. The only thing stopping that progress from being faster is a lack of large-scale funding.

Via ScienceDaily: researchers "have identified more than 70 genes that play a role in regenerating nerves after injury, providing biomedical researchers with a valuable set of genetic leads for use in developing therapies to repair spinal cord injuries and other common kinds of nerve damage such as stroke. ... the scientists detail their discoveries after an exhaustive two-year investigation of 654 genes suspected to be involved in regulating the growth of axons - the thread-like extensions of nerve cells that transmit electrical impulses to other nerve cells. ... We don't know much about how axons re-grow after they're damaged. When you have an injury to your spinal cord or you have a stroke you cause a lot of damage to your axons. And in your brain or spinal cord, regeneration is very inefficient. That's why spinal cord injuries are basically untreatable. ... While scientists in recent decades have gained a good understanding of how nerve cells, or neurons, develop their connections in the developing embryo, much less is known about how adult animals and humans repair - or fail to repair - those connections when axons are damaged. ... Of particular interest [are] the six genes that appear to repress the growth of axons. ... The discovery of these inhibitors is probably the most exciting finding [because] identifying and eliminating the inhibiting factors to the re-growth of axons could be just as essential as the biochemical pathways that promote axon re-growth in repairing spinal cord injuries and other kinds of nerve damage."

Link: http://www.sciencedaily.com/releases/2011/09/110921144604.htm

From In the Pipeline: "I'd say that the whole sirtuin story has split into two huge arguments: (1) arguments about the sirtuin genes and enzymes themselves, and (2) arguments about the compounds used to investigate them, starting with resveratrol and going through the various sirtuin activators reported by Sirtris, both before and after their (costly) acquisition by GlaxoSmithKline. That division gets a bit blurry, since it's often those compounds that have been used to try to unravel the roles of the sirtuin enzymes, but there are ways to separate the controversies. I've followed the twists and turns of argument #2, and it has had plenty of those. It's not safe to summarize, but if I had to, I'd say that the closest thing to a current consensus is that (1) resveratrol is a completely unsuitable molecule as an example of a clean sirtuin activator, (2) the earlier literature on sirtuin activation assays is now superseded, because of some fundamental problems with the assay techniques, and (3) agreement has not been reached on what compounds are suitable sirtuin activators, and what their effects are in vivo. It's a mess, in other words. But what about argument #1, the more fundamental one about what sirtuins are in the first place? That's what these latest results address, and boy, do they ever not clear things up. There has been persistent talk in the field that the original model-organism life extension effects were difficult to reproduce, and now two groups (those of David Gems and Linda Partridge) at University College, London (whose labs I most likely walked past last week) have re-examined these. They find, on close inspection, that they cannot reproduce them. ... It's important to keep in mind that these aren't the first results of this kind. Others had reported problems with sirtuin effects on lifespan (or sirtuin ties to caloric restriction effects) in yeast, and as mentioned, this had been the stuff of talk in the field for some time. But now it's all out on the table, a direct challenge."

Link: http://pipeline.corante.com/archives/2011/09/22/the_latest_sirtuin_controversy.php

You might have noticed recent investigations into exactly how embryos generated by an old collection of cells - people like you and I - turn out to be made of young cells. After all, every other clump of cells we generate is also old.

Quite unexpectedly we found that the level of protein damage was relatively high in the embryo's unspecified cells, but then it decreased dramatically. A few days after the onset of cell differentiation, the protein damage level had gone down by 80-90 percent. We think this is a result of the damaged material being broken down.

If we're lucky there's a potent life-extending therapy in there somewhere, but of course the odds are good that the process by which the early embryo repairs most of its damage is tightly bound to the embryonic nature of its cellular machinery and will be somewhere between very challenging and next to impossible to safely apply to organized, differentiated structures of adult cells. The difference between "very challenging" and "next to impossible" is probably about twenty years of technological development in this era - but we shall see. This seems worth watching.

The researchers involved in this latest research into embryonic development think that the proteasome is the root of this profound embryonic damage repair process. This is a recycling mechanism in the cell that is separate and distinct from the lysosome that regular readers are probably sick of hearing about by now, focused on breaking down every errant protein that looks like it doesn't belong, is unwanted, or is somehow malfunctioning.

The rate of accumulation of damaged proteins and larger cellular components is important in determining the pace of aging, and this is illustrated by the degree to which the recycling processes of autophagy keeps turning up in investigations of various longevity-enhancing mutations and environmental circumstances. If a machine accumulates gunk and broken parts, then it tends to break down more rapidly and in more ways - and we are in effect very complex machines. Aging is damage. This model is somewhat complicated by the fact that we can repair ourselves, by those repair mechanisms - like the proteasome and lysosome - are also machines, and prone to damage. Once the spiral down starts it tends to accelerate, and eventually you wind up with the aptly named garbage catastrophe view of aging.

But here is an example of quite different research into aging and the activities of the proteasome - in yeast rather than people. Yet it still shows that, as for other forms of recycling mechanism, healthy life span lengthens as these cellular maintenance tool kits work harder.

Elevated Proteasome Capacity Extends Replicative Lifespan in Saccharomyces cerevisiae

The ubiquitin/proteasome system (UPS) is an integral part of the machinery that maintains cellular protein homeostasis and represents the major pathway for specific protein degradation in the cytoplasm and nuclei of eukaryotic cells. Its proteolytic capacity declines with age. In parallel, substrate load for the UPS increases in aging cells due to accumulated protein damage. This imbalance is thought to be an origin for the frequently observed accumulation of protein aggregates in aged cells and is thought to contribute to age-related cellular dysfunction.

In this study, we investigated the impact of proteasome capacity on replicative lifespan in Saccharomyces cerevisiae using a genetic system that allows manipulation of UPS abundance at the transcriptional level. The results obtained reveal a positive correlation between proteasome capacity and longevity, with reduced lifespan in cells with low proteasome abundance or activity and strong lifespan extension upon up-regulation of the UPS in a mechanism that is at least partially independent of known yeast longevity modulating pathways.

All told, the longevity science community hasn't devoted as much attention to the proteasome as to other housekeeping mechanisms, but that will probably change in the years ahead. All it takes is one widely noticed mouse study with an impact on aging to generate a great deal more attention.

No-one should be surprised by the plausibility of rejuvenation biotechnology, as old people create young children, and only a tiny hint of the damage that makes people old seeps through that process. So we know that there exist ways for cells and larger structures to extremely effectively manage their level of damage - and some of the explorers in stem cell science have already recreated these processes outside their normal context. Here is a further exploration of what happens when old animals create young animals: "Although the body is constantly replacing cells and cell constituents, damage and imperfections accumulate over time. Cleanup efforts are saved for when it really matters. ... I have a daughter. She is made of my cells yet has much less cellular damage than my cells. Why didn't she inherit my cells including the damaged proteins? That's the process I'm interested in. ... A few days after conception, the cells in the embryo all look the same - they are unspecified stem cells that can develop into any bodily cell type. As the process of cell specification (differentiation) begins, they go from being able to keep dividing infinitely to being able to do so only a limited number of times. This is when they start cleansing themselves. ... Quite unexpectedly we found that the level of protein damage was relatively high in the embryo's unspecified cells, but then it decreased dramatically. A few days after the onset of cell differentiation, the protein damage level had gone down by 80-90 percent. We think this is a result of the damaged material being broken down. ... In the past, researchers have believed that the body keeps cells involved in reproduction isolated and protected from damage. Now it has been shown that these types of cells go through a rejuvenation process that rids them of the inherited damage." Can this process be isolated and applied safely to ordinary cells elsewhere in the body? Time will tell, but it's a worthy goal to aim for given its demonstrated effectiveness.

Link: http://www.physorg.com/news/2011-09-body.html

One possible form of future immune therapy involves growing vast numbers of tailored immune cells, far more than would ever naturally be present in the body, and then infusing them to sweep away the target problem - cancer being an early target for this sort of approach. Here is some groundwork for these future therapies: "Adult stem cells from mice converted to antigen-specific T cells - the immune cells that fight cancer tumor cells - show promise in cancer immunotherapy and may lead to a simpler, more efficient way to use the body's immune system to fight cancer ... Tumors grow because patients lack the kind of antigen-specific T cells needed to kill the cancer. An approach called adoptive T cell immunotherapy generates the T cells outside the body, which are then used inside the body to target cancer cells. ... It is complex and expensive to expand T cell lines in the lab, so researchers have been searching for ways to simplify the process. [They] found a way to use induced pluripotent stem (iPS) cells, which are adult cells that are genetically changed to be stem cells. ... Any cell can become a stem cell. It's a very good approach to generating the antigen-specific T cells and creates an unlimited source of cells for adoptive immunotherapy. ... By inserting DNA, researchers change the mouse iPS cells into immune cells and inject them into mice with tumors. After 50 days, 100 percent of the mice in the study were still alive, compared to 55 percent of control mice, which received tumor-reactive immune cells isolated from donors."

Link: http://www.sciencedaily.com/releases/2011/09/110920111812.htm

Sirtuins are most likely a dead end, or more charitably a stepping stone for researchers seeking after the mechanisms that link natural variations in metabolism to natural variations in life span, especially those induced by the practice of calorie restriction. It was one of the earliest identified pieces of the puzzle, but possibly not a useful piece in the final analysis. This has become increasingly likely as an outcome over the years as meaningful results failed to emerge from drug development based on the manipulation of sirtuins. But this happens all the time: it's larger than usual news in the scientific community only, I think, because very large sums of money have moved into this line of research over the past years, and it's one of the earliest threads that might have led to drugs that modestly slowed aging.

Though I should note, as usual, that it is a massive strategic error for the research community to focus on undertaking expensive research programs that can - at best reasonable expectation - only produce a very modest slowing of aging after the usual couple of decades of work from early results to broadly available clinical application. That strategic error is, unfortunately, well entrenched and well underway. The real and important battle of the next decade is to convince the research community, on the merits of the proposal, to ditch work on metabolic manipulation in favor of SENS-like biological repair approaches that offer the possibility of actual, working, meaningful rejuvenation of the old at the end of an expensive, large-scale twenty year research program.

But back to sirtuins, which are today's news. Here are a couple of items for you from around the web:

Longevity Gene Debate Opens Trans-Atlantic Rift

the idea that sirtuins promote longevity appeals to scientists because of experiments that were started in yeast and repeated in two other standard laboratory organisms, the roundworm and the fruit fly. It is these foundation experiments that have now come under attack by David Gems and Linda Partridge, researchers on aging at University College London. In an article published Wednesday in the journal Nature, they and colleagues have re-examined experiments in which roundworms and flies, genetically manipulated to produce more sirtuin than normal, were reported to live longer. Both experiments were flawed, they say, because the worms and flies used as a control were not genetically identical to the test organisms. The London researchers report that they have repeated the experiments with proper controls and found that extra sirtuin does not, after all, make the worms or flies live longer.

Is The 'Longevity' Gene Sirtuin One Big Research Error?

And in the last decade, sirtuin has probably been one of the industry's biggest bets, ever since high levels of this protein were linked to longer, healthier lives in a variety of animals and it was suggested that they could be behind the increased longevity seen with calorie restriction (drastic restriction of calories, without malnutrition is known to increase longevity and retard age-related diseases). So how did we get here, 10 years on, concluding that it is all a mistake?

So it all goes. The bottom line for us is, however, that even if sirtuins were the key to replicating calorie restriction, they wouldn't be the basis of the future medicines of rejuvenation. Rejuvenation biotechnology can only be based on means of repairing the damage of aging, not changing metabolism a little to gently slow down aging. Other than the SENS Foundation, I don't see any research-focused organization seriously pushing this viewpoint at the present time. That's a big problem: it means that most of the money going into aging and longevity science will have little to no effect on the future of your life span: it will be going towards a continuation of the present trend that adds a small fraction of a year to the life expectancy of adults with each passing year. The newborns get a bigger fraction of a year for their measure of life expectancy at birth, but none of us reading this now are lucky enough to be that fresh to the picture. Bigger gains than this modest trend, a trend that will see us dead with only a couple of additional years to show for it if it continues as-is, will require a radical shift in the research community's strategic vision, and a focus on repair-based biotechnologies. Not surtuins, in other words, and nothing that looks much like sirtuin research either.

A general interest article on supercentenarians from the Sacramento Bee: "Avice Nelson Clarke paused in her recollections of her long-ago childhood in England to make a remarkable understatement. 'I've seen lots of life already,' she said. At 111, with memories spanning the horse-and-buggy age, the Space Age and the digital age, she is on the outside edge of the nation's trend toward increasing longevity. The oldest old - supercentenarians, as aging experts refer to them - remain rare: Clarke is one of four Sacramento-region residents who reported their ages as 110 or older in the 2010 U.S. census. ... The census recorded a total of 46 Californians in the supercentenarian category. Another 27 people in the Sacramento region reported their ages as 105 to 109, census figures show. While the number of centenarians has boomed in recent decades 96,000 across the country in 2010, according to the Social Security Administration, up from 37,000 only 20 years ago the nation's population of people 110 and older has remained fairly stable. ... The world's verified oldest person ever, Jeanne Calment, died in France in 1997, age 122 years and 164 days. ... Despite the world's aging population, no one's come close to that since then. That speaks to the limits of the human life span. ... Through blood tests and gene sequencing of the oldest old, scientists want to discover the secret of their extraordinary longevity ... How have they managed to live so long? We think their longevity is inherited. They have virtually nothing else in common. Some are smokers, and some never smoked. Some are drinkers, and some never drank. They don't have the same diets. But they have long-lived parents and siblings. It must be in the DNA. ... The key age is the early 80s for men and 90 for women. If you can get to that age without dementia or major heart disease or stroke, it's the idea of getting over the hump into healthy aging. ... Even so, 40 percent of the oldest old [survive] illnesses that prove fatal to others. ... Maybe they have some kind of functional reserve. The people who live the longest seem better able to deal with illness. They have a propensity to remain independent much longer than the rest of us."

Link: http://www.sacbee.com/2011/09/20/3923381/supercentenarians-the-oldest-old.html

A possible road to rejuvenating some portions of the declining mechanisms of tissue regeneration in the old: "The regenerative power of tissues and organs declines as we age. The modern day stem cell hypothesis of aging suggests that living organisms are as old as are its tissue specific or adult stem cells. Therefore, an understanding of the molecules and processes that enable human adult stem cells to initiate self-renewal and to divide, proliferate and then differentiate in order to rejuvenate damaged tissue might be the key to regenerative medicine and an eventual cure for many age-related diseases. ... We demonstrated that we were able to reverse the process of aging for human adult stem cells by intervening with the activity of non-protein coding RNAs originated from genomic regions once dismissed as non-functional 'genomic junk' ... adult stem cells undergo age-related damage. And when this happens, the body can't replace damaged tissue as well as it once could, leading to a host of diseases and conditions. ... The team began by hypothesizing that DNA damage in the genome of adult stem cells would look very different from age-related damage occurring in regular body cells. ... They compared freshly isolated human adult stem cells from young individuals, which can self-renew, to cells from the same individuals that were subjected to prolonged passaging in culture. This accelerated model of adult stem cell aging exhausts the regenerative capacity of the adult stem cells. Researchers looked at the changes in genomic sites that accumulate DNA damage in both groups. ... We found the majority of DNA damage and associated chromatin changes that occurred with adult stem cell aging were due to parts of the genome known as retrotransposons ... By suppressing the accumulation of toxic transcripts from retrotransposons, we were able to reverse the process of human adult stem cell aging in culture." The next step would be to look at this process in old animals, and see what happens when it is reversed.

Link: http://www.sciencedaily.com/releases/2011/09/110920163215.htm

I'd mentioned the book "100 Plus" a couple of weeks ago, authored by Sonia Arrison:

To my eyes, the book is essentially a fast overview of the last ten years of science, debate, important subjects, and noteworthy people in the aging research and longevity advocacy communities. ... 100 Plus is, I think, a good book to give to the average fellow in the street who would be flattened and slain by the attempt to read Aubrey de Grey and Michael Rae's Ending Aging. That book is where the meat is - but 100 Plus is a Cliff's Notes for the current state and direction of longevity science and the advocacy community supporting it. That is a useful thing: a person reading 100 Plus will wind up in roughly the same place as a casual reader of the high points of Fight Aging!

I notice that Arrison is doing the book promotion rounds with vigor. The resulting materials include a number of audio and video interviews, such as these from Changesurfer Radio:

100 Plus: The Coming Age of Longevity pt1

100 Plus: The Coming Age of Longevity pt2

Dr. J. chats with Sonia Arrison, a futurist and policy analyst who has studied the impact of new technologies for the Pacific Research Institute (PRI). They discuss her new book 100+: How the Coming Age of Longevity Will Change Everything, from Careers and Relationships to Family and Faith.

There is also official video of her presentation at the recent SENS5 conference, which you will find is posted to the conference YouTube channel, with thanks to the SENS Foundation volunteers for the time they take to make that happen:

Yet another benefit of regular exercise: "Researchers have long known that regular exercise increases the number of organelles called mitochondria in muscle cells. Since mitochondria are responsible for generating energy, this numerical boost is thought to underlie many of the positive physical effects of exercise, such as increased strength or endurance. Exercise also has a number of positive mental effects, such as relieving depression and improving memory. However, the mechanism behind these mental effects has been unclear. In a new study in mice, [researchers] have discovered that regular exercise also increases mitochondrial numbers in brain cells, a potential cause for exercise's beneficial mental effects. ... The researchers assigned mice to either an exercise group, which ran on an inclined treadmill six days a week for an hour, or to a sedentary group, which was exposed to the same sounds and handling as the exercise group but remained in their cages during the exercise period. ... Confirming previous studies, the results showed that mice in the exercise group had increased mitochondria in their muscle tissue compared to mice in the sedentary group. However, the researchers also found that the exercising mice also showed several positive markers of mitochondria increase in the brain ... The study authors note that this increase in brain mitochondria may play a role in boosting exercise endurance by making the brain more resistant to fatigue, which can affect physical performance. They also suggest that this boost in brain mitochondria could have clinical implications for mental disorders, making exercise a potential treatment for psychiatric disorders, genetic disorders, and neurodegenerative diseases."

Link: http://www.the-aps.org/press/releases/11/31.htm

Via EurekAlert!: "The ability to produce neuroprotectors, proteins that protect the human brain against neurodegenerative disorders such as Parkinson's and ALS, is the holy grail of brain research. A technology developed at Tel Aviv University does just that, and it's now out of the lab and in hospitals to begin clinical trials with patients suffering from amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease. ... the technology is now a patent-pending process that takes stem cells from a patient's own bone marrow and causes them to differentiate into astrocyte-like cells, which are responsible for the well-being of the brain's neurons. The cells release neurotrophic factors, or neuroprotectants, which have been shown to play a key role in reducing the progress of ALS, a debilitating disease characterized by the progressive degeneration of motor neurons, resulting in paralysis of a patient's limbs and organ function. ... In the mouse model, we were able to show that the bone marrow derived stem cells prevent degeneration in the brain following injection of selective neurotoxins. ... Researchers also demonstrated that transplantation of these cells increased the survival rate in the mouse model of ALS and significantly delayed the progress of motor dysfunction. ... The technology was licensed to BrainStorm Cell Therapeutics that has developed it into a clinical grade product called NurOwn, which is now being used in a clinical trial at Jerusalem's Hadassah Medical Center. BrainStorm Cell Therapeutics has recently struck an agreement to expand clinical trials to Massachusetts General Hospital in collaboration with the University of Massachusetts Medical School."

Link: http://www.eurekalert.org/pub_releases/2011-09/afot-ubm091911.php

The liver occupies an interesting intersection between regenerative medicine, the biology of aging, progress towards organ regrowth biotechnologies, and learning how lower animals can naturally regenerate organs. Human livers are more capable of self-repair and regrowth than any of the other internal organs in a human, and also seem to age more gracefully than other aspects of our biology. Researchers who focus on understanding how metabolism leads to aging learn a great deal by examining differences such as these: why one species lives longer or regenerates more readily, or why one organ system degenerates more slowly. So why does the average liver hold its own over the years more effectively than the average kidney or lung? It is possible that the answers to that and other, similar questions may inform the next generation of biotechnologies, capable of slowing or repairing the damage of aging, or capable of granting greater regenerative powers to humans than are presently the case. Equally, they may not - but the research community won't know until they put in the time needed to find out.

On this topic, I recently noticed an open access paper that acts as an introduction to this view of the liver, an organ situated at a crossing point between various fields of study that are relevant to engineered longevity:

Liver Regeneration and Aging: A Current Perspective

Many organ systems exhibit significant age-related deficits, but, based on studies in old rodents and elderly humans, the liver appears to be relatively protected from such changes. A remarkable feature of the liver is its capacity to regenerate its mass following partial hepatectomy.

Reports suggests that aging compromises the liver's regenerative capacity, both in the rate and to the extent the organ's original volume is restored. There has been modest definitive information as to which cellular and molecular mechanisms regulating hepatic regeneration are affected by aging. Changes in hepatic sensitivity to growth factors, for example, epidermal growth factor (EGF), appear to influence regeneration in old animals.

...

Aging appears to compromise liver regeneration by influencing several pathways, the result of which is a reduction in the rate of regeneration, but not in the capacity to restore the organ to its original volume.

It occurs to me that, given the present state of knowledge and underlying biochemistry, work on liver regeneration - or forms of liver rejuvenation, such as that demonstrated by Cuervo's team three years ago - might be expected to produce significant results ahead of work on other organs, all other things being equal. We shall see.

Another study that points to the value of regular exercise: "Low aerobic exercise capacity is a powerful predictor of premature morbidity and mortality for healthy adults as well as those with cardiovascular disease. For aged populations, poor performance on treadmill or extended walking tests indicates closer proximity to future health declines. Together, these findings suggest a fundamental connection between aerobic capacity and longevity. ... Through artificial selective breeding, we developed an animal model system to prospectively test the association between aerobic exercise capacity and survivability (aerobic hypothesis). ... Laboratory rats of widely diverse genetic backgrounds [were] selectively bred for low or high intrinsic (inborn) treadmill running capacity. Cohorts of male and female rats from generations 14, 15, and 17 of selection were followed for survivability and assessed for age-related declines in cardiovascular fitness including maximal oxygen uptake (VO(2max)), myocardial function, endurance performance, and change in body mass. Median lifespan for low exercise capacity rats was 28% to 45% shorter than high capacity rats. VO(2max), measured across adulthood was a reliable predictor of lifespan. During progression from adult to old age, left ventricular myocardial and cardiomyocyte morphology, contractility, and intracellular Ca(2+) handling in both systole and diastole, as well as mean blood pressure, were more compromised in rats bred for low aerobic capacity. Physical activity levels, energy expenditure (Vo(2)), and lean body mass were all better sustained with age in rats bred for high aerobic capacity."

Link: http://www.ncbi.nlm.nih.gov/pubmed/21921265

Researchers establish a link between calorie restriction, aging, and telomere length in yeast, but one which poses more questions than it answers: "Dietary restriction promotes longevity in many species, ranging from yeast to primates, and delays aging-related pathologies including cancer in rodent models. There is considerable interest in understanding how nutrient limitation mediates these beneficial effects. Much of what we have learned about the genetics of aging comes from studying isogenic model organisms, where the effects of single gene changes can be examined independently of other genetic alterations. In order to explore a broader spectrum of genetic variation and to gain insight into aging-related phenotypes as polygenic traits, we analyzed the chronological lifespan of 122 S. cerevisiae strains derived from a cross between laboratory and vineyard yeast strains. The major genetic locus controlling chronological lifespan was found to be identical to a previously mapped locus that controls telomere length. Identification of the responsible polymorphism in BUL2, a gene involved in controlling amino acid permeases, allowed us to establish a previously unrecognized link among cellular amino acid intake, chronological aging, and telomere maintenance. While human epidemiological studies have linked shortened telomeres with increased mortality, it is unclear how these processes are connected. Our results suggest that, in yeast, reduced amino acid uptake and consequent reduced nutrient signaling extend chronological lifespan but reduce telomere length."

Link: http://dx.doi.org/10.1371/journal.pgen.1002250

Time flies - it really doesn't seem like it's been two and a half years since the SENS Foundation was launched to steer the SENS research program independently of the Methuselah Foundation umbrella. Come to think of it, it really doesn't seem like eight years since the Methuselah Foundation was just a tiny thing, a couple of advocates and the first few $5,000 checks in the bank. If you look back in the Fight Aging! archives, some of the first blog posts relate to the early days of the Methuselah Foundation.

People come and go across any organization's life span - and here is news of the departure of one of the SENS Foundation co-founders for a new venture:

On 19 September, 2011, Sarah Marr will be stepping down as our Executive Vice President at SENS Foundation. She has been a committed co-founder, and she will of course continue to be a trusted advisor and closely involved with the organization. But we couldn't have her term of full-time service with us pass without noting the significant contribution she has made to the professionalism of the organization and to the quality of our overall message. She helped make us, in a very real way.

From Sarah Marr's blog:

I think it's important to understand that the Foundation is a lifetime commitment for me. I'm a co-founder, after all, and I can't imagine a world in which I'm not extolling the virtues of the organization, its mission, and the wider concept of rejuvenation biotechnology; whatever else I'm doing, or whatever environment surrounds me.

Why am I stepping down? Because I have a personal project which I wish to pursue. And given the criticality of rejuvation biotechnology, you should get a feeling for just how important I consider this next project, but also how hard it has been to reach this decision. Why can I step down now? Because the team which we've built at the Foundation over the past two-and-a-half years is so very, very talented and capable.

Non profits set up for the long term must be able to thrive independently of the turnover of their staff and leaders - to have a continuation of capabilities and culture that are too robust to much miss the loss of any one individual's time and skills. Indeed, this is one of the implicit goals for the early stages of any venture, and a very good way of measuring success in advance of more obvious results in research, fundraising, licensing, and so forth.

A short open access paper: "Hormesis (a neologism coined from the ancient Greek term hormáein, which literally means 'to set in motion, impel, urge on') describes a favorable biological response to harmless doses of toxins and other stressors. Hormesis-stimulating compounds initiate an adaptive stress response that renders cells/organisms resistant against high (and normally harmful) doses of the same agent. On the theoretical level, hormesis may constitute (one of) the mechanisms that allows stressed cells to avoid senescence and death, and hence might have some impact on the (patho)physiology of aging. Thus, measures that reportedly prolong the healthy lifespan of multiple species, such as caloric restriction and the administration of resveratrol, may do so by inducing a hormetic response ... [Hormesis] is best represented by ischemic preconditioning, the situation in which short ischemic episodes protect the brain and the heart against prolonged shortage of oxygen and nutrients. Many molecules that cause cell death also elicit autophagy, a cytoprotective mechanism relying on the digestion of potentially harmful intracellular structures, notably mitochondria. When high doses of these agents are employed, cells undergo mitochondrial outer membrane permeabilization and die. In contrast, low doses of such cytotoxic agents can activate hormesis in several paradigms, and this may explain the lifespan-prolonging potential of autophagy inducers including resveratrol and caloric restriction."

Link: http://impactaging.com/papers/v3/n9/full/100380.html

I am not unsympathetic to this viewpoint: recent research shows that "women should raise their glasses to a healthier old age, but we've heard it all before - and just the opposite. ... This is the conclusion of a study of 14,000 female nurses that started in 1976. The brainchild of the Harvard School of Public Health, Boston is the latest result from numerous studies of this nature that have produced all manner of contradictory results. ... In 1976, the [Framington study] is supposed to have shown a connection between menopause and the increased risk of heart disease, which is a bit like saying it found a connection between age and life expectancy - exactly what is one supposed to do with a datum like that? ... At the end of the day, one must ask what is the point of such studies, and specifically what is the point of a study that attempts to link the consumption of wine by women with longevity, especially when Marie Lloyd was telling us a little of what you fancy does you good way back in 1915? Rather than mounting expensive years' or decades' long studies as make-work schemes for medical scientists and their chums in Whitehall, Washington and elsewhere, the governments of the world might be better advised setting them to work to discover the actual causes of disease, and maybe to develop vaccines and other methods of combatting them, or better still, maybe they should follow in the footsteps of gerontologist Aubrey de Grey and his SENS organisation?"

Link: http://www.digitaljournal.com/article/311235

There are several rare conditions that present the appearance of accelerated aging, the changes they cause extending far enough down into the fundamentals of human biochemistry that there yet remains much to learn about their operation and some debate over whether they are in fact forms of greatly accelerated aging. The best known of these conditions are Hutchinson-Gilford Progeria (HGPS, or just progeria) and Werner syndrome; significant progress has been made in identifying their root causes over the past decade, but that is still a way removed from knowing whether there is any great relevance there insofar as concerns research into ordinary aging.

A recent open access paper takes a look at the question, though the bottom line at this time is that more time and greater understanding is needed:

Hutchinson-Gilford Progeria (HGPS) and Werner syndromes are diseases that clinically resemble some aspects of accelerated aging. HGPS is caused by mutations in the LMNA gene resulting in post-translational processing defects that trigger Progeria in children. Werner syndrome, arising from mutations in the WRN helicase gene, causes premature aging in young adults. What are the molecular mechanism(s) underlying these disorders and what aspects of the diseases resemble physiological human aging?

...

In both diseases recent evidence indicates that mutations in the genes responsible for these premature aging diseases result in increased DNA damage, particularly at telomeres. Although shortening and/or damage to telomeres is associated with proliferative arrest of cells in vitro, it remains unclear how accurately these diseases recapitulate the processes of tissue aging in humans. Here we discuss recent advances, using in vitro cell culture and mouse models of progeroid syndromes to highlight important questions that remain: A) what is the molecular mechanism of how such seemingly unrelated proteins cause similar degenerative diseases? B) are these mechanisms representative of normal aging?

Like a fair amount of nonetheless interesting research, work aimed at understanding accelerated aging conditions - and mining that knowledge for material that may prove useful in the development of ways to intervene in ordinary aging - is something of a sideshow. The trouble with science in general is that you have to spend time on the sideshows in order to confirm that they are in fact sideshows; every presently major field of endeavor in the life sciences started off small, unpromising, and prospective. I don't think the odds are good that something spectacular will result from investigations of progeria: you can't completely rule it out at this stage, but there are other places to concentrate resources that have a much higher expectation of value.

Some enthusiasm from the research community: "induced pluripotent stem (IPS) cells [are] where I'm putting almost all of my chips these days, because it combines many of my interests - genomics, sequencing, epigenetics, synthetic biology, stem cells. I don't think people have fully appreciated how quickly adult stem cells and sequencing and synthetic biology have progressed. They have progressed by orders of magnitude since we got IPS. Before that, they basically weren't working. ... There is much to be worked out. But here's the leap. If you want to accelerate this, you have to pick an intermediate target that doesn't sound so scary. So you'll start out with bone marrow patients. And you're going to basically make a synthetic version of that patient's bone marrow using IPS, which is going to work much better than the diseased bone marrow. And once this works that's going to catch on like wildfire. And then you'll do skin, and then you'll do every other stem cell you can get. ... Will people who are, say, aging but not yet sick ever be able to use this technology? I don't consider this medicine, it's preventive. I expect somebody who is truly brave, who has nothing wrong with them other than maybe the usual aging, saying: 'I want a bone marrow transplant', or intestinal, or whatever. And it will gain momentum from there. ... Initially it will be wealthy people who will try this. Ironically, wealthy people are often willing to be the guinea pigs that are really in a sense the front line of new technologies. They're the foot soldiers. They're willing to put themselves at risk, and to spend money on it."

Link: http://www.technologyreview.com/blog/experimentalman/27164/

The New York Times is running a piece on a recent small trial of immune therapy for leukemia: "A year ago, when chemotherapy stopped working against his leukemia, William Ludwig signed up to be the first patient treated in a bold experiment at the University of Pennsylvania. Mr. Ludwig, then 65, a retired corrections officer from Bridgeton, N.J., felt his life draining away and thought he had nothing to lose. Doctors removed a billion of his T-cells - a type of white blood cell that fights viruses and tumors - and gave them new genes that would program the cells to attack his cancer. Then the altered cells were dripped back into Mr. Ludwig's veins. At first, nothing happened. But after 10 days, hell broke loose in his hospital room. He began shaking with chills. His temperature shot up. His blood pressure shot down. He became so ill that doctors moved him into intensive care and warned that he might die. His family gathered at the hospital, fearing the worst. A few weeks later, the fevers were gone. And so was the leukemia. There was no trace of it anywhere - no leukemic cells in his blood or bone marrow, no more bulging lymph nodes on his CT scan. His doctors calculated that the treatment had killed off two pounds of cancer cells. A year later, Mr. Ludwig is still in complete remission. Before, there were days when he could barely get out of bed; now, he plays golf and does yard work."

Link: http://www.nytimes.com/2011/09/13/health/13gene.html?pagewanted=all

We age in part because a small number of important genes in our mitochondria are broken over time by the polluting effects of their day to day operation: broken genes mean the protein machines produced from their blueprints are also broken, or cannot be produced at all. Mitochondria are bacteria adapted to act as the power plants for our cells, swarms of them circulating inside every cell - and perversely the broken ones tend to win out in the ongoing, dynamic process of replication, damage control, and recycling of cellular machinery that takes place inside all of our cells. Cells can become overtaken by broken mitochondria, each herd of malfunctioning power plants spawned from one original chance breakage, and enough of these unfortunate cells produce a chain of unpleasant consequences throughout the body. Aging is damage, after all. This is a long story, and a better introduction than this can be found back in the archives, however.

SENS stands for the Strategies for Engineered Negligible Senescence, a detailed proposal for what must be done at the cellular and molecular level to reverse the damage of aging and thereby rejuvenate the old. SENS-related research is to vary degrees conducted in labs around the world, and where the research community isn't already large and hard at work - such as in the field of regenerative medicine - the SENS Foundation organizes and encourages research programs. One of the earliest SENS programs to move from concept to actual research, starting back when the initiative was conducted by the Methuselah Foundation, is MitoSENS: a way to use biotechnology to prevent mitochondrial damage from contributing to degenerative aging.

Mitochondrial genes are distinct from those in the nucleus of a cell, and as such are vulnerable. The available repair mechanisms are not as good as those in the nucleus, and the genes in each mitochondrion are right next door to power plant machinery that sustains the cell but also kicks out damaging reactive molecules. The MitoSENS strategy is twofold: (a) gene therapy to copy the few important mitochondrial genes into the cell nucleus, known as allotopic expression, and (b) one of a range of clever biotechnological strategies to get the protein machinery produced from those gene blueprints from the nucleus back out to the mitochondria where it is needed. You might look at the work of Corral-Debrinsky's group to see this in action in a real research program: when you have nuclear copies of mitochondrial genes, it doesn't matter if the more vulnerable mitochondrial versions suffer mishaps, everything continues as before.

A further good introduction to this topic and the work of the SENS Foundation is spurring this research can be found in video recorded at the recent SENS5 conference. Conference videos are being posted to the SENS Foundation YouTube channel as they are processed, and here is an educational presentation on the state of allotopic expression of mitochondrial genes:

Sir2 in yeast is one of the earliest discovered sirtuins, an important set of genes in the study of calorie restriction. Unfortunately that research has yet to generate a useful calorie restriction mimetic drug, and is looking less promising than it did initially. But here is an interesting result: "Activation of Sir2-orthologs is proposed to increase lifespan downstream of dietary restriction (DR). Here we describe an examination of the effect of 32 different lifespan-extending mutations and four methods of dietary restriction on replicative lifespan (RLS) in the short-lived sir2Δ yeast strain. In every case, deletion of SIR2 prevented RLS extension; however, RLS extension was restored when both SIR2 and FOB1 were deleted in several cases, demonstrating that SIR2 is not directly required for RLS extension. These findings indicate that suppression of the sir2Δ lifespan defect is a rare phenotype among longevity interventions and suggest that sir2Δ cells senesce rapidly by a mechanism distinct from that of wild-type cells. They also demonstrate that failure to observe life span extension in a short-lived background, such as cells or animals lacking sirtuins, should be interpreted with caution." Things are, as ever, more complex than we'd like in other words. One of the reasons that sirtuins haven't led directly to calorie restriction mimetics is that they are only one small part in a larger mechanism, and possibly not even a critical part - just the one that was easiest to notice.

Link: http://www.ncbi.nlm.nih.gov/pubmed/21902802

Via ScienceDaily: researchers "are applying new techniques and materials to come up with artificial blood vessels [that] will be able to supply necessary nutrients to artificial tissue and maybe even complex organs in the future. ... It seemed practically impossible to build structures such as capillary vessels that are so small and complex, especially the branches and spaces in between. But production engineering came to the rescue because rapid prototyping makes it possible to build workpieces specifically according to any complex 3-D model. Now, scientists [are] working on transferring this technology to the generation of tiny biomaterial structures by combining two different techniques: the 3-D printing technology established in rapid prototyping and multiphoton polymerization developed in polymer science ... A 3-D inkjet printer can generate 3-dimensional solids from a wide variety of materials very quickly. It applies the material in layers of defined shape and these layers are chemically bonded by UV radiation. This already creates microstructures, but 3-D printing technology is still too imprecise for the fine structures of capillary vessels. This is why these researchers combine this technology with two-photon polymerization. Brief but intensive laser impulses impact the material and stimulate the molecules in a very small focus point so that crosslinking of the molecules occurs. The material becomes an elastic solid, due to the properties of the precursor molecules that have been adjusted by the chemists in the project team. In this way highly precise, elastic structures are built according to a 3-dimensional building plan."

Link: http://www.sciencedaily.com/releases/2011/09/110913122056.htm

It is possible that important future biotechnologies to enhance human longevity might be built on top of a better understanding of the mechanisms that cause similarly sized species to have quite radically different life spans. It seems just as plausible as the idea of generating a family of age-slowing biotechnologies from a better understanding of human metabolism, though who is to say at this early stage in the game just how effective any final result might be. Still, research groups are successfully raising funds, sequencing genomes, and delving much deeper into the comparative biology of aging than has been the case in the past. For example:

The Long Life of Birds: The Rat-Pigeon Comparison Revisited

As a group, birds are long-living with their maximum lifespan potential (MLSP) being on average twice that of similar-sized mammals, and it can be much greater for some individual comparisons. The most common mammal-bird comparison in the scientific literature is the rat-pigeon comparison. The rat has a MLSP of 5 y, compared to 35 y for the similar-sized pigeon (both from the AnAge database: genomics.senescence.info). This seven-fold MLSP difference has the potential to give considerable insight into the processes that determine longevity. Importantly, this is many times the longevity difference generally achieved either by genetic manipulation or environmental manipulation (such as dietary restriction).

...

We have revisited the rat-pigeon comparison in the most comprehensive manner to date. We have measured superoxide production (by heart, skeletal muscle and liver mitochondria), five different antioxidants in plasma, three tissues and mitochondria, membrane fatty acid composition (in seven tissues and three mitochondria), and biomarkers of oxidative damage. The only substantial and consistent difference that we have observed between rats and pigeons is their membrane fatty acid composition, with rats having membranes that are more susceptible to damage.

That's a pretty good piece of supporting evidence for the membrane pacemaker hypothesis of aging: longer lived species are longer lived because their cellular membranes are more resistant to damage. This ties in nicely to the role of mitochondria and mitochondrial damage in aging: swarming mitochondria in cells churn out damaging free radicals as a consequence of their day to day operations, and as a consequence damage themselves in ways that spiral out to cause all sorts of harm in the long term. If a species is more resistant to that damage in the places where it matters the most, then it lives longer.

As I have said before, I tend to view this as support for the importance of mitochondrial repair research. If resistant mitochondria give pigeons even a fair chunk of that multiplier of seven over rat life spans, then how much further could the research community take things if armed with a way to completely fix the self-inflicted mitochondrial damage rather than just resist it?

An interesting view of one benefit of autophagy, a collection of housekeeping processes that are boosted by the practice of calorie restriction: researchers have "shown that autophagy, a pathway preserved during evolution, functions to engulf and digest cholesterol accumulated in artery walls. This process facilitates the removal of cholesterol and may provide an entirely new target to reverse atherosclerosis, the main cause of heart attack and stroke. Cholesterol accumulates in the walls of arteries leading to atherosclerosis, also known as narrowing of arteries and which causes blockages and reduces blood flow to the heart. This often culminates in heart attacks and strokes. The autophagy pathway, which means self-digestion, developed early in single-cell organisms to allow the clearance of accumulated dysfunctional molecules. ... The finding that autophagy also functions to digest and liberate cholesterol from cells and the fact that we know this pathway is regulated offers hope for the development of new drugs that could activate export of cholesterol from the walls of arteries."

Link: http://www.ottawaheart.ca/content_documents/marcel-cholesterol-reversal-EN-FINAL.pdf

One approach to the next generation of cancer therapies is to use existing chemotherapy drugs coupled with cell-targeting mechanisms that deliver those drugs only to cancer cells: "A common chemotherapy drug has been successfully delivered to cancer cells inside tiny microparticles using a method inspired by our knowledge of how the human immune system works. The drug, delivered in this way, reduced ovarian cancer tumours in an animal model by 65 times more than using the standard method. This approach is now being developed for clinical use. ... It's like we've made a re-enactment of the battle of Troy but on the tiniest scale. In Troy, the Greeks fooled the Trojans into accepting a hollow horse full of soldiers - we've managed to trick cancer cells into accepting drug-filled microparticles. ... by coating tiny microparticles of around a hundredth the diameter of a human hair with a special protein called CD95, [researchers] could in fact trigger cancer cells into ingesting these particles. Not only that, but the particles could deliver a dose of a common chemotherapy drug called paclitaxel. The key to their success is that CD95 attaches to another protein called CD95L, which is found much more commonly on the surface of cancer cells than it is on normal healthy cells. Once attached, the cancer cells ingest CD95 and the microparticle with it. Inside the cell, the microparticle can unload its chemotherapy cargo, which kills the cell to reduce the size of the tumour."

Link: http://www.eurekalert.org/pub_releases/2011-09/babs-hp091211.php

The SENS Foundation volunteers are doing a great job on the video for this year's SENS5 conference, a gathering of researchers working on the foundations of rejuvenation biotechnology that was held at the start of this month. Take a look at the traditional conference photo, which is pretty much a who's who of the cutting edge of aging and longevity research, as well as important figures from the cryonics industry, funding groups, and advocacy community. The Foundation has opened a YouTube channel for conference video, and the first ones through the pipeline are posted.

I recommend starting with the SENS Foundation CEO's presentation, which is a good overview of the SENS agenda and progress for the layperson:

The remaining videos presently online are for a presentation on autophagy, the collection of processes by which cells recycle damaged components. There is every indication that autophagy may be usefully manipulated to blunt some of the degenerations of aging:

You can find more of an introduction to autophagy and its importance back in the Fight Aging! archives:

• Autophagy
• All Roads Lead to Autophagy?

The better known life extension mechanisms in lesser animals are all driven by changes in autophagy - or so say the autophagy specialists. It's true that the various hyperspecialized communities of modern biology are overly cloistered and ignorant of one another's research, but the autophagy researchers are assembling compelling evidence for this position.

At Discover Magazine: "The Postmortal is not about a post-mortal society, it is about a post-aging society. Lots and lots and lots of people die in Magary's vision. In fact, he seems to argue that in the absence of death, people will not only seek death but will create circumstances that create death and thereby, create meaning. It is only when Farrell's life is most in peril that he finds purpose in existence. But Farrell is never immortal, no one is. So my question is: is the process of aging as meaningful as the condition of being mortal? This question vexed me, because I know a great many people who have aged with grace. They wear wizened white beards or crinkled smiles that highlight eyes behind inch-thick spectacles. Some people are just awesome at being old. They have custom canes and smoke ivory pipes and say saucy things that only they can get away with. To reference Harry Potter again, Voldemort, Mr.Flees-From-Death himself, is contrasted with Albus Dumbledore and Minerva McGonagall, both of whom are walking idealizations of what the aging process should look like. But that's just it, isn't it? They are idealizations. Reality presents a grimmer picture. Alzheimer's, Parkinson's, and a laundry list of other late-onset diseases savage the body just enough that modern medicine can step in to keep the heart beating and the organs limping along while the mind deteriorates to the point of nothingness. Aging in the modern era is about slow unstoppable loss - of hearing, of memory, of mobility, of continence, of dignity. What part of that process creates meaning in our lives? ... In Magary's mind, the stop of physical aging is the stop of maturation. In this sense, I suspect Magary's indictment is not of those like Aubrey de Grey who seek the end of aging, but of those who resist maturation. Magary's values are essentially conservative. ... Human beings do not settle down because they age anymore than people have quarter-life or midlife or three-quarter life crises because they age. People are content or discontent based on the life they are currently living."

Link: http://blogs.discovermagazine.com/sciencenotfiction/2011/09/09/what-would-humanity-be-like-without-aging/

Aging is damage, and therefore we should not be surprised to see that people with more obvious signs of damage are more likely to die sooner: "According to a new, long-term [study], cognitive impairment, especially at the moderate to severe stages has an impact on life expectancy similar to chronic conditions such as diabetes or chronic heart failure. Nearly 4,000 people between the ages of 60 to 102 years, initially seen from 1991 to 1993 by primary care physicians at Wishard Health Services, a large public hospital with community health centers in Indianapolis, participated in the study. The patients were followed for 13 years. ... Previous studies have associated cognitive impairment with an increased risk for death, but most of this work focused on patients with Alzheimer disease and subjects in research centers. The patients in our study better reflect the general public, displaying no indications of disease or mild, moderate or severe cognitive impairment. We found that even mild cognitive impairment, as determined by a simple screening tool in a primary care physician's office, has a strong impact on how long individuals survive on the same order as other chronic diseases." Cognitive impairment springs from physical causes linked to general health and the pace at which aging progresses in an individual, such as the state of blood vessels in the brain, for example. More damage at the level of cells and molecules leads to more evident dysfunction that we can see with our own eyes.

Link: http://www.sciencedaily.com/releases/2011/09/110905172300.htm

SENS5, the fifth biannual conference on the Strategies for Engineered Negligible Senescence, took place last week. Researchers working on ways - or the foundation of ways - to intervene in the aging process gathered together to talk about progress on the road to rejuvenation through biotechnology.

The purpose of the SENS conference series, like all the SENS initiatives (such as the journal Rejuvenation Research), is to expedite the development of truly effective therapies to postpone and treat human aging by tackling it as an engineering problem: not seeking elusive and probably illusory magic bullets, but instead enumerating the accumulating molecular and cellular changes that eventually kill us and identifying ways to repair - to reverse - those changes, rather than merely to slow down their further accumulation.

It seems, however, that the participants were so caught up in the conference schedule that they largely failed to post reports or commentaries online. There's a little Twitter activity, and a couple of videos for one of the presentations, but that's about it. Perhaps this is a sign of maturity for the internet: later years in which eager self-publishers feel they can let their hair down and stop trying quite so hard. Material will be posted online in the weeks ahead by SENS Foundation volunteers, and that will hopefully include a video archive to match those for past SENS conferences. Meanwhile, you might take in the YouTube videos posted to date:

The videos are for this presentation, which is a discussion of one approach to finding a cheap and effective way of keeping telomeres from eroding without making them too long in the process - a complex and challenging problem that has kept a number of research groups and startup companies occupied over the past decade.

Polyamines have been of interest since spermadine was shown to extend life in mice. Another topic of growing interest is the influence of gut bacteria on metabolism and longevity, and here is research to link these two items: "In mammals, levels of polyamines (PAs) decrease during the ageing process; PAs are known to decrease systemic inflammation by inhibiting inflammatory cytokine synthesis in macrophages. ... The probiotic strain Bifidobacterium animalis subsp. lactis LKM512 is known to increase intestinal luminal PA concentrations. ... We supplemented the diet of 10-month-old Crj:CD-1 female mice with LKM512 for 11 months, while the controls received no supplementation. Survival rates were compared [and] LKM512-treated mice survived significantly longer than controls; moreover, skin ulcers and tumors were more common in the control mice." A caution here is that this result may well involve inadvertent calorie restriction: any dietary supplementation may affect appetite and thus level of caloric intake, and all studies have to be considered in light of the fact that even mild calorie restriction has beneficial effects on mouse health and life span.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3156754/

Via ScienceDaily: researchers "have unveiled a new method for making synthetic collagen. The new material, which forms from a liquid in as little as an hour, has many of the properties of natural collagen and may prove useful as a scaffold for regenerating new tissues and organs from stem cells. ... Our final product more closely resembles native collagen than anything that's previously been made, and we make that material using a self-assembly process that is remarkably similar to processes found in nature. ... Collagen, the most abundant protein in the body, is a key component of many tissues, including skin, tendons, ligaments, cartilage and blood vessels. Biomedical researchers in the burgeoning field of regenerative medicine, or tissue engineering, often use a combination of stem cells and collagen-like materials in their attempts to create laboratory-grown tissues that can be transplanted into patients without risk of immunological rejection. Animal-derived collagen, which has some inherent immunological risks, is the form of collagen most commonly used in reconstructive and cosmetic surgery today. ... Despite the abundance of collagen in the body, deciphering or recreating it has not been easy for scientists. One reason for this is the complexity collagen exhibits at different scales. ... Scientists must next determine whether cells can live and grow in the new material and whether it performs the same way in the body that native collagen does. ... clinical trials, if they prove warranted, are at least five years away."

Link: http://www.sciencedaily.com/releases/2011/09/110908124507.htm

If you spend much time reading around the topic of aging, human longevity, and medical progress, you'll soon run into the term "compression of morbidity." It is a hypothesis suggesting that advances in medical science are causing, or will cause, a compression of the terminal period of frailty, illness, and disability at the end of life, squeezing it into an ever-shorter fraction of the overall human life span. In colloquial use compression of morbidity is spoken of as a practical goal by medical researchers who do not wish to talk openly about extending human life for political or funding reasons. To my eyes the concept of compression of morbidity is rather too tied up with the self-defeating way in which gerontologists behaved with respect to human longevity for so many years: it makes it hard to discuss without pulling in the recent history of politics, funding organizations, and strategic debates within the aging research community. Some background from the archives can be found in the following posts:

• Debating Compression of Morbidity
• The Compression of Morbidity School of Thought
• On Compression of Morbidity

Compression of morbidity as a concept also touches on debates and initiatives to persuade more of the research community to adopt repair-based research strategies such as SENS. These repair-based strategies for treating - and ultimately reversing - aging emerge fairly directly from the viewpoint that aging is little more than the effects of damage accumulation at the level of our cellular and molecular protein machinery. If you look at the body as a complex system that gathers damage, such as through the lens of reliability theory, compression of morbidity begins to seem a mirage of sorts. Any intervention that can slow or repair some of the biological damage that causes aging will extend life but not do much for the period of decline at the end - it just puts it off. This is the same for any machine. If you learn how to repair biological damage sufficiently comprehensively then you could put off that final decline indefinitely, which is the SENS goal. But if you stopped undergoing those periodic repairs, then you'd age just the same way and at the same pace as someone who never had the treatment.

But to return to the point of this post, which is to introduce the concept of compression of morbidity, I should mention that I stumbled across a good introductory open access paper today, written for a general audience by the originators of the compression of morbidity hypothesis. You might find it interesting:

Compression of Morbidity 1980-2011: A Focused Review of Paradigms and Progress

The Compression of Morbidity hypothesis - positing that the age of onset of chronic illness may be postponed more than the age at death and squeezing most of the morbidity in life into a shorter period with less lifetime disability - was introduced by our group in 1980. This paper is focused upon the evolution of the concept, the controversies and responses, the supportive multidisciplinary science, and the evolving lines of evidence that establish proof of concept.

Dive in and see what you think. The authors believe the data of the past decades illustrates that compression of morbidity is in fact occurring, and that improvement in the rate is possible given that no structured effort was expended towards this goal over that time. You might look at an older post here for a alternate explanation of the data with more of a damage-based view. No-one is arguing against the trend towards increasing life expectancy in the old and falling mortality rates for age-related diseases, but there is plenty of argument when it comes to the root causes of that trend - and therefore how to improve on it.

It is now fairly well known that any animal study of longevity has to be controlled for calorie restriction, as the effects of even a modest change in dietary intake can outweigh the intended effects of the study, rendering the results useless. This is far from the only confounding factor out there, however. Here is some work on a different issue that might be problematic for longevity studies in worms: "The nematode worm Caenorhabditis elegans has been used to identify hundreds of genes that influence longevity and thereby demonstrate the strong influence of genetics on lifespan determination. In order to simplify lifespan studies in worms, many researchers have employed 5-fluoro-2'-deoxyuridine (FUdR) to inhibit the development of progeny. While FUdR has little impact on the lifespan of wild-type worms, we demonstrate that FUdR causes a dramatic, dose-dependent, twofold increase in the lifespan of the mitochondrial mutant gas-1. Thus, the concentration of FUdR employed in a lifespan study can determine whether a particular strain is long-lived or short-lived compared to wild-type." This sort of thing is one of the many reasons why it is better to weigh evidence across many studies and to be skeptical of any one study in isolation.

Link: http://www.ncbi.nlm.nih.gov/pubmed/21893079

Via EurekAlert!: "Any exercise that gets the heart pumping may reduce the risk of dementia and slow the condition's progression once it starts ... Researchers examined the role of aerobic exercise in preserving cognitive abilities and concluded that it should not be overlooked as an important therapy against dementia. The researchers broadly defined exercise as enough aerobic physical activity to raise the heart rate and increase the body's need for oxygen. Examples include walking, gym workouts and activities at home such as shoveling snow or raking leaves. ... We culled through all the scientific literature we could find on the subject of exercise and cognition, including animal studies and observational studies, reviewing over 1,600 papers, with 130 bearing directly on this issue. We attempted to put together a balanced view of the subject. We concluded that you can make a very compelling argument for exercise as a disease-modifying strategy to prevent dementia and mild cognitive impairment, and for favorably modifying these processes once they have developed. ... The researchers note that brain imaging studies have consistently revealed objective evidence of favorable effects of exercise on human brain integrity. Also, they note, animal research has shown that exercise generates trophic factors that improve brain functioning, plus exercise facilitates brain connections (neuroplasticity). ... Whether addressing our patients in primary care or neurology clinics, we should continue to encourage exercise for not only general health, but also cognitive health."

Link: http://www.eurekalert.org/pub_releases/2011-09/mc-aem090711.php

Seen from a considered distance, the culture of aging research - formed of researchers, regulators, and the interested public - operates in strange ways. No-one is permitted to treat aging: by decree of the regulators and complicity of the researchers that is taboo. But slow progress in treating aging is made nonetheless. That technological progress goes hand in hand with an intricate cultural dance that consists of splitting off pieces of the concept of aging and giving each piece a different and distinct name ("Alzheimer's disease," "osteoarthritis," "sarcopenia," and so forth). Once such a sliver of aging is named and fully accepted, it is no longer taboo to work towards treating it.

To a certain degree, culture shapes the progress of medical science. Strategies for repairing aging outright by focusing on common low-level molecular changes - like Engineered Negligible Senescence - don't mesh well with the structure of the mainstream culture of aging research, and so face an uphill battle to win greater adoption. Repair strategies do away with the whole business of parceling up a collection of end-stage symptoms of aging and declaring them a disease, and focus instead on a different vision for aging and the treatment of aging from the bottom up. Long-standing cultures are resistant to change, however, and especially resistant to radical change. That is far from the only hurdle in the way of progress, and the existence of centralized control over medicine and heavy regulation has a lot more to answer for than odd cultural ideas about how things should work, but those odd ideas are still a factor.

You can see some of this business of carving slivers from the concept of aging in a recently published retrospective article on research into the biology of neurodegenerative diseases:

Only 40 years ago it was widely believed that if you lived long enough, you would eventually experience serious cognitive decline, particularly with respect to memory. The implication was that achieving an advanced age was effectively equivalent to becoming senile - a word that implies mental defects or illness. ... Many discoveries made in the years since have given us better tools to study memory storage, resulting in a major shift away from the view of "aging as a disease" and towards the view of "aging as a risk factor" for neurological diseases. So why do some people age gracefully, exhibiting relatively minor - and at worst annoying - cognitive changes, while others manifest significant and disabling memory decline? Answers to these questions are fundamental for understanding both how to prevent disease and how to promote quality of life.

...

Looking back on the rather grim expectations concerning memory and the elderly that were held only a few decades ago, the vision today is very different and much more positive. ... The future holds great promise for the once remote dream of understanding the core biological processes required for optimal cognitive health during aging - and progress in this regard should also provide the needed backdrop for understanding and preventing the complex neurological diseases that can be superimposed on the aging brain.

The culture of the aging and broader life science research community is appropriately intricate: it's a large industry, working on exceedingly complex problems. But don't uncritically accept it for what it is; it never hurts to take a second look from a suitable distance and ask whether what you see is all that is possible, and whether it is good, useful, worse, or better than other plausible options.

A modest new application of stem cells in therapy: researchers "have used a new, leading-edge stem cell therapy to promote the growth of bone tissue following the removal of cervical discs - the cushions between the bones in the neck - to relieve chronic, debilitating pain. [The procedure] used bone marrow-derived adult stem cells to promote the growth of the bone tissue essential for spinal fusion following surgery, as part of a nationwide, multicenter clinical trial of the therapy. ... We hope that this investigational procedure eventually will help those who undergo spinal fusion in the back as well as in the neck, and the knowledge gained about stem cells also will be applied in the near future to treat without surgery those suffering from back pain. ... In the surgery, called an anterior cervical discectomy, a cervical disc or multiple discs are removed via an incision in the front of the neck. The investigational stem cell therapy then is applied to promote fusion of the vertebrae across the space created by the disc removal. ... [Using existing methods], adequate spinal fusion fails to occur in 8 to 35 percent or more of patients, and persistent pain occurs in up to 60 percent of patients with fusion failure, which often necessitates additional surgery. ... A lack of effective new bone growth after spine fusion surgery can be a significant problem, especially in surgeries involving multiple spinal segments. This new technology may help patients grow new bone, and it avoids harvesting a bone graft from the patient's own hip or using bone from a deceased donor."

Link: http://www.sciencedaily.com/releases/2011/09/110906152501.htm

Autophagy is important in longevity, and research groups are investigating this process with an the intent of developing ways to safely manipulate it: "two cellular processes - lipid metabolism and autophagy - work together to influence worms' lifespan. Autophagy, a major mechanism cells use to digest and recycle their own contents, has become the subject of intense scientific scrutiny over the past few years, particularly since the process (or its malfunction) has been implicated in many human diseases, including cancer and Alzheimer's disease. This study provides a more detailed understanding of the roles autophagy and lipid metabolism play in aging. ... The particular worm model we used in this study is known to live longer than normal worms, but we didn't completely understand why. Our results suggest that increased autophagy has an anti-aging effect, possibly by promoting the activity of a fat-digesting enzyme. In other words, it seems that recycling fat is a good thing - at least for worms. ... When worms have more fat in supply than they have demand for, it has to be stored. In these long-lived worms however, there's activation of a seemingly futile cycle of breaking down fat and re-synthesizing it. Only we found that breaking down fat is actually beneficial and perhaps not so futile after all. ... On average, they survived 25 percent longer than their normal counterparts."

Link: http://www.eurekalert.org/pub_releases/2011-09/smri-rfm083111.php

A comment from a reader on a recent zebrafish-related news post:

IMO it's a waste of money and scientists. We should only focus on mammals, because humans are no fish. It won't help us much, if at all.

That last assertion is not true, in fact. A great deal of exploratory life science research is first accomplished in species like fruit flies, nematode worms, yeast, zebrafish, and the like. Outside the realm of mammals there exists a small menagerie of species that have proven useful in the laboratory. Yet any of that work to ultimately make it to human clinics will first be repeated or confirmed in mammalian species such as mice, dogs, and primates - which might raise the question as to why researchers bother to work with flies, worms, yeast, and fish in the first place.

The answer to that question relates to the bottom line: money, time, resources. Research is by its very nature an exploratory and uncertain business, full of dead ends and unexpected pitfalls. A researcher wants to cover as much ground as he or she can for a given amount of time and money: the more that is explored, the greater the chance of finding a significant path forward. On the one hand, work with mammals will generally produce more useful information, but on the other hand working with mammals, even mice, is very expensive and time-consuming in comparison to working with flies and worms, which in turn is expensive and time-consuming in comparison to working with yeast. If infinite money and time were at hand, all research work would involve mammals, but resources are not infinite and the results of any given study are extremely uncertain.

Bear in mind that evolution produced flies, yeast, fish, and mammals from the same deep roots - and as it turned out, a lot of the mechanisms that link the operation of metabolism with variance of longevity within a species were (a) established very early on, and (b) then didn't change a great deal. It is counter-intuitive to think that researchers can learn useful things about the operation of human biology from yeast (or worms, or flies, or fish), but for some mechanisms and systems they can do just that. The further away from human biology that your model is, the more inference there must be, and the greater the risk that there is in fact some important difference between species that renders your work useless or less valuable - but that doesn't prevent work in lower species from being cost-effective.

So the story is that there is a trade-off in the life sciences between the usefulness of data and the cost of obtaining that data. When you are uncertain of the ultimate value of the work presently being undertaken - i.e. if it seems to have a high risk of failure, or a successful outcome is probably not that valuable in any case - then you won't want to spent much time and money on it until such time as it shapes up. If all indications show a good chance of success and a valuable result, then working with mammals starts to look like a better prospect, however. So we might say that work in flies, worms, yeast, and fish is undertaken in order to justify the cost of exploring the same biology in mammals.

Guanfacine is a drug used to manipulate signaling mechanisms shown to improve working memory in monkeys. Here is some further work on this topic: "Alpha-2 adrenergic receptors are potential targets for ameliorating cognitive deficits associated with aging as well as certain pathologies such as attention deficit disorder, schizophrenia and Parkinson's disease. Although the alpha-2 agonist guanfacine has been reported to improve working memory in aged primates, it has been difficult to assess the extent to which these improvements may be related to drug effects on attention and/or memory processes involved in task performance. The present study investigated effects of guanfacine on specific attention and memory tasks in aged monkeys. Four Rhesus monkeys (18-21 years old) performed a sustained attention (continuous performance) task and spatial working memory task (self-ordered spatial search) that has minimal demands on attention. Effects of a [low and high] dose of gunafacine were examined. Low-dose guanfacine improved performance on the attention task but failed to improve performance on the spatial working memory task. The high dose of guanfacine had no effects on either task. Guanfacine may have a preferential effect on some aspects of attention in normal aged monkeys and in doing so may also improve performance on other tasks, including some working memory tasks that have relatively high attention demands."

Link: http://www.ncbi.nlm.nih.gov/pubmed/21883531

An investigation of the role of growth hormone in the regenerative capacity of zebrafish: "Unlike mammals, teleost fishes are capable of regenerating sensory inner ear hair cells that have been lost following acoustic or ototoxic trauma. Previous work indicated that immediately following sound exposure, zebrafish saccules exhibit significant hair cell loss that recovers to pre-treatment levels within 14 days. Following acoustic trauma in the zebrafish inner ear, we used microarray analysis to identify genes involved in inner ear repair following acoustic exposure. Additionally, we investigated the effect of growth hormone (GH) on cell proliferation in control zebrafish utricles and saccules, since GH was significantly up-regulated following acoustic trauma. ... Pathway Analysis software was used to reveal networks of regulated genes and showed how GH affected these networks. Subsequent experiments showed that intraperitoneal injection of salmon growth hormone significantly increased cell proliferation in the zebrafish inner ear. ... GH injection increased cell proliferation in the inner ear of non-sound-exposed zebrafish, suggesting that GH could play an important role in sensory hair cell regeneration in the teleost ear."

Link: http://dx.doi.org/10.1186/1471-2202-12-88

Making predictions is hard, as the joke goes, and especially when they involve the future. That said, predicting very broad trends and general capabilities in technology seems to be somewhat tractable if you go about it in the right way, such as by researching carefully and restricting your predictions to the future capabilities of fields that present have a solid research community: large, well funded, and well supported. Even so, making specific predictions as to how future capabilities will be used is a fool's game.

I would say that the principal cause of uncertainty for the timeline leading to rejuvenation biotechnology - ways to repair and reverse the cellular and molecular damage that causes aging - is the fact that we lack a large, well-funded, well-supported research community at this time. Only comparatively small initiatives exist now, such as the SENS Foundation, and the actions, choices, and happenstance of individuals have large effects on the future timeline leading to the desired solid research community. That future community will be large enough that individual choices don't tend to have much of an effect on its progress one way or another, but here and now the element of chance is significant.

So it is much easier to look at, say, the regenerative medicine research community and make solid, well-thought predictions as to when we'll see limbs and organs regrown. Similar, one can plant flags on the field for rejuvenation biotechnology if we restrict ourselves to talking about how long things might take after large numbers of dollars, supporters, and willing scientists arrive on the scence. That's thought to be ten to twenty years and one to two billion dollars to rejuvenate old mice if you're looking at the SENS plan. But how long until the necessary dollars, supporters, and willing scientists arrive? How long is a piece of string? The bootstrapping process of persuasion and fundraising goes as rapidly as it can be made to go.

Another field of longevity science is the business of understanding and manipulating metabolism to modestly slow aging - so as to perhaps one or more of the beneficial mechanisms of calorie restriction through a drug, for example. This area of research has grown to a solid research community over the past decade: we can make reasonable predictions as to how long it might take them to show meaningful results. Unfortunately, those results won't be very helpful in the grand scheme of things; likely a few years of additional life at most for those of us who will be old by the time those products make it out of the gate, and that will have been bought at a cost of decades and billions of dollars that might have gone towards more useful work. I'm not belittling the usefulness of basic knowledge of metabolism, just the tendency to treat that as the only way forward for extending healthy life, when clearly a far better option exists.

Still, in terms of the way in which the broader public look at longevity and science, we're a long way ahead in comparison to the state of affairs back in 1990 or 2000. One of the reasons that metabolic manipulation has been able to grow into a solid field is that a great many people are starting to take it as a given that life span is increasing, albeit modestly, and that medical progress means longer lives are in the offing. That's a better starting point for new advocacy than has been the case even in the recent past. One source of this new understanding is, interestingly, the massively capitalized pensions and insurance industry: they have a loud voice, and the financial markets are an important source of news and knowledge in our culture. There are whole segments of the population who sit up and take notice when rumblings about longevity emerge from those sources rather than from scientific publications. For example:

The failure to consider future drivers of mortality in historical predictions has "contributed to employer pension funds under reserving for longevity risk and other bodies, including governments, not budgeting effectively for funding an aging population", said Daniel Ryan, head of life and health research and development at Swiss Re. The report calls on medical experts, actuaries and demographers to work together toward a greater understanding of potential future developments in human longevity.

The level of uncertainty in developments that will extend human life is making the big money in pensions, annuities, and the like uncomfortable, and has been for years now. That is, more or less, a vote of confidence in the scientific community, or at least a vote of confidence in what is possible and how likely it is thought to come to pass. Yet we're still at present stuck without a solid research and development community for rejuvenation biotechnology, something that would make the future a great deal more predictable. Helping to create that community is the first job on the list until such time as it is accomplished.

The development of engineered viruses to selectively attack cancer has been underway for a number of years, and here is an example of an early trial for one strand of this research: "Scientists modified the vaccinia virus, which is more famous for being used to develop a smallpox vaccine. The virus, named JX-594, is dependent upon a chemical pathway, common in some cancers, in order to replicate. It was injected at different doses into the blood of 23 patients with cancers which had spread to multiple organs in the body. In the eight patients receiving the highest dose, seven had the virus replicating in their tumours, but not in healthy tissue. ... We are very excited because this is the first time in medical history that a viral therapy has been shown to consistently and selectively replicate in cancer tissue after intravenous infusion in humans. Intravenous delivery is crucial for cancer treatment because it allows us to target tumours throughout the body as opposed to just those that we can directly inject. ... Infection prevented further tumour growth in six patients for a time. However, the virus did not cure cancer. Patients were given only one dose of the virus as the trial was designed to test the safety of the virus. It is thought that the virus could be used to deliver treatments directly to cancerous cells in high concentrations. ... Viruses that multiply in just tumour cells - avoiding healthy cells - are showing real promise as a new biological approach to target hard-to-treat cancers."

Link: http://www.bbc.co.uk/news/health-14730608

Via EurekAlert!, news of research to complement recent work on tissue engineered intestines in mice: "Human colon stem cells have been identified and grown in a lab-plate for the first time. ... Throughout life, stem cells of the colon regenerate the inner layer of our large intestine in a weekly basis. For decades scientists had evidences of the existence of these cells yet their identity remained elusive. Scientists [discovered] the precise localization of the stem cells in the human colon and worked out a method that allows their isolation and in vitro expansion, that is their propagation in lab-plates. Growing cells outside the body generally requires providing the cells in a lab-plate with the right mix of nutrients, growth factors and hormones. But in the same way that each of the more than 200 types of cells in our body differs from the others so too do optimal growing conditions in the lab. ... For years, scientists all over the world have been trying to grow intestinal tissue in lab-plates; testing different conditions; using different nutritive media. But because the vast majority of cells in this tissue are in a differentiated state in which they do not proliferate, they survived only for a few days. ... The scientific community now has a defined 'recipe' for isolating CoSCs and deriving stable CoSCs lines, which have the capacity to grow undifferentiated for months. ... Now that guidelines for growing and maintaining colon stem cells in the lab are in place, we have an ideal platform that could help the scientific community to determine the molecular bases of gastrointestinal cell proliferation and differentiation. It is also suspected that alterations in the biology of CoSCs are at origin of several diseases affecting the gastrointestinal tract, such as colorectal cancer or Crohn's disease."

Link: http://www.eurekalert.org/pub_releases/2011-09/ifri-sah090211.php

Industries are rather like certain forms of insect - they go through characteristic stages in their life cycle in which the look, internals, and behavior are very different. Moving from one stage to the next is a matter of growth: gaining customers, revenue, mindshare, and the funds for significant research and development. Industries start out as advocacy projects - a few people who think they're right, and have the necessary luck, skill, and staying power to convince a market into their way of thinking. In those early stages, the dynamic between leaders and followers is very different than it is in mature industries. There is a lot of passion and zealotry, people doing things for love rather than money, active advocates with strong opinions and no fear of shouting them out loud. Lots of drama, excitement, and rapid change. But as an industry grows into its later stages, and the number of customers swell, that passion and zealotry fades into the background, to be replaced by the quiet hum of businesses that are all about professionalism, standards, reassuring public faces, steady wages, and long term profits. Look at the personal computer industry, for example - it's no coincidence that all the good stories and larger than life characters are from the 1970s, back when everyone knew one another and the whole thing was a collection of people in various garages.

The computing industry succeeded, evidently, but the cryonics industry - born around the same time - never made it much beyond the early stages of growth. The reasons for this have been discussed to death over the years, so I won't go into them here, but the industry is presently in that early stage middle ground where staid, long-term business practices and the passion of the zealots are equally present and influential. This has been the case for the past twenty years, and there the industry will stay until there is significant growth in the number of customers: when an industry remains small, there is no chance for the original founders - colorful characters who are passionate enough to set out and do what most people never get around to trying - to fade away in favor of solid bottom-line-and-marketing businessmen. It it stays small for long enough, you end up with a significant fraction of embittered zealots and their drama, which is never fun.

When an initiative does succeed attracting broad support and a large community, the energy and quirks of the early activists are tempered by a sea of more sedate, everyday folk. Sometimes the pioneers are quietly airbrushed out of the official histories - once an initiative becomes large enough for its leaders to want it to look like a shiny, official, professional machine, then the original barnstormers and larger than life personalities start to be seen as a liability. Justifiably or not, they are shuffled to one side of the growing crowd. In this way, the ultimate accolade of success is to be made irrelevant in the movement you helped found: accepting that likelihood up front is the way to peace of mind for activists and advocates.

But when things don't go according to plan, and what was intended to be great fails to achieve its original promise, or moves too slowly, then the problems start. Some of the early activists, untempered by large numbers of new volunteers and supporters, become poisonous. Their hyperactivism manifests itself in perfectionism, attacks on members of the community, and other displays of frustration or bitterness: to their eyes, failure was avoidable, and the problem must be the other people involved.

While you might not think of it as such, given the $100,000+ sticker price on a cryosuspension ordered at short notice, cryonics is actually a service priced for the mass market: people who can plan enough to regularly put aside a little for the long term. Most customers pay for cryonics through life insurance, which when started in middle age is no more than a very modest monthly payment - less than your car payments, perhaps less than your car insurance payments.

There is nothing wrong with that per se, but the industry isn't overcoming the barriers to growth. The most reliable way of pushing through a barrier to growth is investment: large sums of money poured into marketing, research, development and so forth. Those of you who have been involved in young companies will know about barriers to growth: there are times when your venture speeds ahead and customers pour in seemingly of their own accord, and there are times when you hit a brick wall and the only way through is via money - spent on changing the business, spent on marketing, spent on researching how to get past the barrier ... whatever works in the end. But fundamentally, that's what investment in a business is all about: figuring a way past the next brick wall so as to become larger and thus more profitable in absolute terms.

There are two sources of capital for investment: investors and your customers. We'll leave investors out of this discussion, as there are few willing to invest in cryonics. It looks terrible as a money-making proposition, given its history, and the known cryonics-friendly philanthropists are not particularly deep pocketed in the grand scheme of things. Obtaining funding from early customers is a time-honored tradition in many businesses, however: the early customers tend to be wealthy and pay high prices for their early access to a product. The money they provide pays off the debts of prior research and development and funds ongoing growth - this is a part of the process in many industries by which products start out as a costly luxury item and later become a mass-market commodity that is both far cheaper and far better.

Cryonics seems to have skipped the costly luxury item stage in its existence, which is both interesting and possibly a liability for the industry in the long term. One might envisage some form of Cryonics Platinum organization that offers $500,000 or $1 million packages for folk like Simon Cowell, Ted Williams, politicians, and other multimillionaires who can both afford it and have use for the additional services, security, process management, and cachet that a higher price point can supply.

I have no idea whether such a thing is viable, but I don't see any obvious purely economic reason as to why it wouldn't be. It's really little different in structure than, say, the business of long-term leasing of luxury yachts or private jets and their crews. Something to think about.

An open access review paper in PDF format that discusses some of the fine details of current research into the mechanisms by which calorie restriction slows aging. This work is aimed at establishing a level of understanding sufficient to produce calorie restriction mimetic drugs that also slow aging: "The molecular mechanisms of aging are the subject of much research and have facilitated potential interventions to delay aging and aging-related degenerative diseases in humans. The aging process is frequently affected by environmental factors and caloric restriction is by far the most effective and established environmental manipulation for extending the lifespan of various animal models. However, the precise mechanisms by which caloric restriction affects lifespan are still not clear. Epigenetic mechanisms have recently been recognized as major contributors to nutrition-related longevity and aging control. Two primary epigenetic codes, DNA methylation and histone modifications, are believed to dynamically influence the chromatin structure resulting in expression changes of relevant genes. In this review, we assess the current advances in epigenetic regulations in response to caloric restriction and how this impacts cellular senescence, aging and potential extension of a healthy lifespan for humans. Enhanced understanding of the important role of epigenetics in control of aging through caloric restriction may lead to clinical advances in the prevention and therapy of human aging-associated diseases."

Link: http://www.biomedcentral.com/1741-7015/9/98

An interesting discovery, and one more benefit of exercise: "researchers have found one more reason to exercise: working out triggers influential stem cells to become bone instead of fat, improving overall health by boosting the body's capacity to make blood. The body's mesenchymal stem cells are most likely to become fat or bone, depending on which path they follow. ... The exercising mice ran less than an hour, three times a week, enough time to have a significant impact on their blood production ... In sedentary mice, the same stem cells were more likely to become fat, impairing blood production in the marrow cavities of bones. ... The composition of cells in the bone marrow cavity has an important influence on the productivity of blood stem cells. In ideal conditions, blood stem cells create healthy blood that boosts the immune system, permits the efficient uptake of oxygen, and improves the ability to clot wounds. Bone cells improve the climate for blood stem cells to make blood. But when fat cells start to fill the bone marrow cavity - a common symptom of sedentary behavior - blood stem cells become less productive, and conditions such as anemia can result. ... Some of the impact of exercise is comparable to what we see with pharmaceutical intervention. Exercise has the ability to impact stem cell biology. It has the ability to influence how they differentiate."

Link: http://www.eurekalert.org/pub_releases/2011-09/mu-ebh090111.php

Less us ponder the subject of having children in the face of the existence of aging coupled with the possibility of progressively defeating aging - perhaps to the point where some of us alive today will escape age-related death by the skin of our teeth. Or perhaps not if we don't get our act together here and now. Evidently we need to have children in order to have the chance of incrementally defeating aging by building ever better versions of a biological repair kit to reverse ever more of the damage that causes degeneration and death. This task is one of decades, long enough that it may be today's researchers who start the job, but it'll be younger hands that finish it - their children and grandchildren. Yet creating people is somewhat like drafting them into a war and a human condition that they didn't ask for:

There's a task we need you for, son, you and the rest of your generation. We may or may not manage to complete it, but we certainly won't without your help - and if we don't get this done, we're dead all too soon, a slow death, heavy on the pain and suffering. We'll be dragged away first so you get to see the end in all its horror, with plenty of sleepless nights to think it over before it happens to you as well. Oh yes, and most people don't see the need for any of this work and think the pain and suffering and death is just dandy. So that's the deal, a raw one all round - welcome to the asylum, son. No need to thank me.

I'm sympathetic to the hedonistic imperative view of pain and priorities in technological development, and I also think there's a fair but short-sighted argument to be made for nihilism along the lines of voluntary species extinction. It runs something along the lines of a utilitarian consideration of suffering, slavery, existence, natural rights, and similar concerns.

I call that short-sighted because, if we're going to be utilitarian, we should consider that the point and beneficiary of all this technological development - not to mention the bone mountain of suffering and corpses we stand upon and continue to build - is very much not us. Our own longevity and diminished future suffering is a tiny side-effect on the way to providing massively greater benefits to our future descendants, be they biological or machine intelligences. They will be so greatly endowed by the cumulative efforts in advancing technology that ensuring their existence (and ensuring that it comes about as soon as possible) will far and away outweigh our needs in any utilitarian consideration. We are short-lived, small in number, small in mind, and planet-bound evolved intelligences, while our descendants of future centuries will not be any of those things. There will be trillions of them, a near infinite variety of forms of mind, ageless, absent suffering, and hopefully wiser than us for it. They will exist because we, our forebears, and our children suffered the limitations and risks of our present existence in order to build the road that little bit further - and because we chose to inflict the same on others by bringing them into being.

So having children still looks to me largely like throwing new people into a horrible situation in order that some of them will try make it better - and with some hope that they might benefit as individuals, but also the great risk that they will not, and suffer greatly as a consequence. Beyond that, there is an abstract grail that will be enjoyed by people yet to come - our descendants made in biology or machinery - who we will likely never know, and whose era will be brilliant and golden beyond our imagining, but only if we strive to lay the foundation stones here and now.

A mainstream press article on exercise and aging: "As we age, our bodies change in ways that challenge athletic ability. But exercise also can slow down - and in some cases even prevent - some of the physiological ravages of time. ... A lot of things that we thought were just inherent to the aging process and were going to happen no matter what don't really have to happen if you maintain an appropriate lifestyle. ... How much can exercise slow down the ravages of aging? Potentially a lot. It will partially, but not completely, prevent arterial stiffening with age and completely prevent the dysfunction of the arterial lining that develops with age ... Exercise, it turns out, is probably as powerful as any other kind of prevention strategy or treatment that has been assessed so far. ... . For 21 years, researchers at Stanford University have studied the effects of consistent exercise on 284 runners 50 and older. In a 2002 article [they] reported that - 13 years into the study - a control group of 156 similar people who exercised much less on the whole than the runners had a 3.3 times higher death rate than runners as well as higher rates of disabilities. In a 2008 [study] they reported that after 19 years, 15% of runners had died, compared with 34% of the control group. After 21 years, runners had significantly lower disability levels than non-runners; their death rates from cardiovascular events, cancer and neurologic disorders were much lower than in non-runners - 65 of the runners had died of cardiovascular, neurologic and cancer events compared with 98 deaths in the control group."

Link: http://www.latimes.com/health/la-he-aging-physiology-20110901,0,5975284.story

News of another step towards the availability of autologous stem cell therapies in US clinics: "Using a patient's own bone marrow stem cells to treat acute stroke is feasible and safe ... The trial was the first ever to harvest an acute stroke patient's own stem cells from the iliac crest of the leg, separate them and inject them back into the patient intravenously. ... In order to bring stem cells forward as a potential new treatment for stroke patients, we have to establish safety first and this study provides the first evidence in addressing that goal. Now we are conducting two other stroke cell therapy studies examining safety and efficacy, one of which can be administered up to 19 days after someone has suffered a stroke. ... Of the 10 patients enrolled in the study, there were no study-related severe adverse events. ... Although the study was not intended to address efficacy, the investigators compared the study group with historical control patients ... In that comparison, the study team found a number of patients who did better compared with controls. However, [that] type of analysis has limitations." The US medical development community is years behind Korean and even Brazilian researchers in this work, who were testing bone marrow stem cells for stroke in humans back in 2004 and 2005. That sort of delay, and the financial costs accompanying it, are some of the consequences of the regulatory policies of the FDA.

Link: http://www.uthouston.edu/media/story.htm?id=3404539