Aubrey de Grey on the Engineering Philosophy of SENS

The core point of SENS, the Strategies for Engineered Negligible Senescence, is explained in this short interview: "Could you elaborate on the idea mentioned on SENS: that it isn't necessary to know, from an 'engineering' perspective, everything about the degenerative processes that occur at the cellular level in order to treat aging in the way you envision? ... The basic point we're making there is to contrast the regenerative approach with the more traditional idea of trying to make metabolism create molecular and cellular damage more slowly. In order to do the latter, we would need to understand our biology massively better than we do at present, so as to avoid creating unforeseen side-effects. By contrast, with the regenerative approach we don't need to know much about how damage comes about: it's enough just to characterize the damage itself, so as to figure out ways to repair it. We're effectively sidestepping our ignorance of metabolism. ... Rejuvenation biotechnologies are simply regenerative therapies that pre-empt the diseases and disabilities of old age. They consist of molecular, cellular or whole-organ interventions that restore the structure of the target to something like how it was in early adulthood. This includes a variety of stem cell therapies, and also tissue engineering to create artificial organs. At SENS Foundation we don't work much on those types of therapy, because they're being very capably pursued elsewhere; rather, we focus on the more neglected but equally vital components of this 'divide-and-conquer' approach to combating aging. For example, we have a large project aimed at eliminating 'molecular garbage' from cells - indigestible material whose accumulation leads to diseases like atherosclerosis and macular degeneration - by introducing non-human enzymes to augment the body's natural ability to break down unwanted by-products of metabolism."

Link: http://www.themanitoban.com/2012/02/live-longer-and-prosper/9213/

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

Working With the MitoSENS Team at the SENS Foundation

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

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

The Next SENS Foundation Los Angeles Chapter Meeting is Wednesday October 5th

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.

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

The Changing Understanding of Aging

I stumbled upon a series of open access review papers today, entitled "The Changing Understanding of Aging," written by a veterinarian for an audience of practitioners largely unfamiliar with the history and present state of aging research. As a consequence it's very readable for the layperson, and it really doesn't matter that the papers are as much focused on the animal kingdom as on human research: at the high level much of what is the case for the mammals we keep as pets is also the case for humans - the same theories apply. Only the details of our biochemistries are different, which does lead to greatly differing life spans and rates of aging, but all proceeding according to much the same fundamental mechanisms.

Part 1: Evaluating ageing theories and studies (Full PDF)

This is the first of three discussions on emerging views of ageing, its derivation, and ageing-related diseases. To offer a context for the series, this first report briefly reviews several major early and recent theoretical debates. Arguments for and against several well-known ageing theories are presented for their veterinary relevance, including mutation, pleiotropy, reproduction-longevity trade-offs, oxygen metabolism and ageing as a genomically programmed product of natural selection. ... Central ideas of these discussions include why post-reproductive life span is relatively common among animals, the nature of age-related diseases relative to stochastic or programmed origins and the disease-related implications.

Part 2: Body composition, metabolism and cell death (Full PDF)

This second of three discussions about ageing biology and diseases continues at the level of the organism, examining the relationship among body composition, late life and diseases. ... Sarcopenia is declining mass and strength of skeletal muscle during aging. Healthy humans experience a 20%-40% reduced physical strength during decades 7 and 8. In one study, prevalence of sarcopenia among 883 elderly persons ranged from 13%-24% over the ages 65 to 70 and >50% after the age of 80. ... It is disconcerting that investigators have identified early skeletal muscle mass decline in some humans, with substantial change by decade five. Potential life span implications for individuals in this category need to be monitored by primary care and specialist physicians, and not just by geriatricians. Additional implications are that new studies need to be conducted to establish whether or how subtle mid-life changes in muscle mass and strength can be observed across animal species and what concerns accrue for their health and longevity.

Part 3: Diseases of ageing (Full PDF)

A contentious debate revolves around whether ageing is purely a combined effect of stochastic events on residual programming relating to reproductive robustness, or whether ageing itself is programmed by natural selection. Emerging data indicate that the influence of genetic programming on specific late-life diseases, and even individual tissue pathologies, will probably need to be reconsidered in the light of newer theoretical possibilities.

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

Late Notice of a Possibly Interesting Journal

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?

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

Continued Work on Autophagy and Rapamycin

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-? (A?). However, the effects of inducing autophagy on plaques and tangles are yet to be determined. While soluble A? 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.

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

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

The Unreliability of Many Studies of Rodent Longevity

As noted in this paper, many researchers still fail to control for calorie intake in their studies - and thus their experimental results are largely worthless, given the impact of even mild calorie restriction on the life spans of laboratory animals: "Much of the literature describing the search for agents that increase the life span of rodents was found to suffer from confounds. One-hundred-six studies, absent 20 contradictory melatonin studies, of compounds or combinations of compounds were reviewed. Only six studies reported both life span extension and food consumption data, thereby excluding the potential effects of caloric restriction. Six other studies reported life span extension without a change in body weight. However, weight can be an unreliable surrogate measure of caloric consumption. Twenty studies reported that food consumption or weight was unchanged, but it was unclear whether these data were anecdotal or systematic. Twenty-nine reported extended life span likely due to induced caloric restriction. Thirty-six studies reported no effect on life span, and three a decrease. The remaining studies suffer from more serious confounds. Though still widely cited, studies showing life span extension using short-lived or 'enfeebled' rodents have not been shown to predict longevity effects in long-lived animals. We suggest improvements in experimental design that will enhance the reliability of the rodent life span literature. First, animals should receive measured quantities of food and its consumption monitored, preferably daily, and reported. Weights should be measured regularly and reported. Second, a genetically heterogeneous, long-lived rodent should be utilized. Third, chemically defined diets should be used. Fourth, a positive control (e.g., a calorically restricted group) is highly desirable. ... These procedures should improve the reliability of the scientific literature and accelerate the identification of longevity and health span-enhancing agents."

Link: http://www.ncbi.nlm.nih.gov/pubmed/21424790

An Approach to Step One of the Vegas Group: Bootstrapping the Codex

The Vegas Group: a so far fictional community of the next ten years that will merge the longevity advocacy and open biotech communities in order to (a) reverse engineer the most promising life-span-enhancing techniques demonstrated in the laboratory, (b) translate that work into human rejuvenation biotechnologies, and (b) make these therapies available for use via medical tourism to Asia-Pacific region clinics.

So I have been pondering how best to make the vision of the Vegas Group a reality: what steps do we take so that we wake up six or seven years from now to an open source biotech community whose members are working on enabling the best longevity therapies produced by the formal research community - and who have the overseas connections to enable responsible use of resulting therapies in a clinical setting.

The path to this future involves networking and community building in a whole new and different direction from that taken by much of the longevity advocacy community - and the construction of a codex of information, a how-to manual of recipes for replicating specific products of the formal research community in longevity science. Networking makes the world go round, and that is the most important part of any attempt to create the Vegas Group, or indeed any human endeavor: making relationships and persuading people to join in. But this is not where I can be the most effective.

So any step one for me will involve considering the codex: what it is, and how it will be constructed, maintained, and made useful to the seeds of what will be the Vegas Group - however that organization ultimately comes about, and whatever form it ultimately takes. It is very clear to me that open biotechnology will grow into a massive semi-professional sphere of activity, exactly like the open source software community today. I want to take advantage of the wave that is coming, and produce a work that will both aid that wave and in turn be aided by it.

When thinking about the way in which contributions of content are made voluntarily to any given community or site - such as Wikipedia, or blogs such as this one, or the documentation repository at your workplace - it is self-evident that very, very few people step up to produce good content. Wikipedia works because a great many people each contribute just a little, a continual process of polishing, one grain of sand at a time, applied to the bulk outlines contributed by the motivated few. But for smaller groups, you don't get polishing, you just get next to nothing in the way of contributions.

So I'm fairly certain that for the Vegas Group codex, while a wiki model may be helpful as an adjunct to a motivated community further down the line, it isn't a way to get things written at the outset - it's not a way to provide the corpus of work that a community can later polish. There are few biotechnologists in the world in comparison to, say, football fans. Look at the number of science bloggers as compared with other topics, for example. Despite this, there are still initiatives out there, however, working on pulling together repositories of techniques and knowledge: OpenWetWare for example. So the concept of producing an open collection of techniques and recipies is not a foreign one to the biotechnology community - it's just not very advanced at this stage, at least not in comparison to the bodies of knowledge associated with larger communities.

Thus I think that a larger seed, a bigger online repository of freely available and reliable recipes for longevity-related biotechnology, would act as an attractor for people willing to tinker and help out. The same class of supporters and advocates who produced initiatives like OpenWetWare will contribute to help polish its contents. Overall, the concept of a codex seems to me to be where a comparatively small amount of money could be leveraged to good effect. Consider this:

  • Creating an initial repository website and content management system isn't a significant cost given the present state of open source content management software - it's almost something I could undertake myself.
  • People with significant knowledge of biotechnology are remarkable cheap to engage at the post-graduate level. Consider that a few thousand dollars of post-graduate time can net you a long and well-informed analysis, or detailed explanation of a specific methodology.
  • It wouldn't be a good piece of writing of course - no offense is intended when I say that few post-graduate scientists can write well. Writing well is hard, and just as much a specialty as is becoming a scientist; few people have the time and inclination to specialize in more than a few things, and why should one of them be writing?
  • Fortunately, people who can write well are always in supply, desperate for work, and inexpensive. It is a buyer's market.

So I can envisage a guiding council of advisors putting together a plan for the hierarchy of topics they would like to see in the Vegas Group codex, from basic methods in biotechnology through to best attempt reverse engineering of things we know to be possible and that have been published: such as Cuervo's work on restoring youthful levels of autophagy, or protofection to replace mitochondrial DNA. The end result of that process might look something like a distillation of Fight Aging! mixed with the very elegant materials produced by the Science for Life Extension Foundation.

Codex project volunteers would then run an ongoing process of hiring post-graduates and interested researchers to write, and passing the results to starving authors who improve the output to a quality suitable for the open biotechnology community. There would of course be some back and forth between the post-graduates and the starving authors in order to reduce the inevitable translation errors, but I see this as a viable way to produce a body of knowledge that is sufficiently good to begin with - not perfect, not even necessarily very good, but sufficient.

Since only a comparatively limited reach of biotechnology is under consideration, the cost of bootstrapping such a project might be less than a few hundred thousand dollars. The things I would need to understand before getting seriously underway on a Vegas Group codex are largely related to validating that price tag. A few hundred thousand dollars would mean that it is worth starting with ten thousand dollars, some volunteers, spare time, and raising funds as we go based on the quality of work exhibited. That would be true bootstrapping, but I'd have to give thought in advance to:

  • The actual cost of generating the materials - something that I suspect won't be clear until the project is at least twenty articles in. I have a fair grasp on the range of costs for writing for hire, in fields that range from very specialist (pricey) and completely generalist (a few cents a word), but I've no idea where this market falls in that spread of values, nor how much management and general cat-herding of writers would be required.
  • The predicted size of a sufficiently large body of information, as set out by guiding experts. Is it a hundred articles, a hundred videos, a thousand images, or half that, or ten times that?
  • How to make this project attractive to the existing open biotechnology community even in its earliest stages. There is no such thing as "build it and they will come" - if anything building in isolation guarantees that you'll have few visitors.

Which comes right back around to networking and relationships: as I said, they make the world go round. On that topic, I am sadly lacking in a knowledge of the current state of the open biotechnology community - something that will have to change as I give more thought to the Vegas Group idea. No sense in reinventing the wheel if there is a wheel out there already ... or even a half-built wheel, a project where lessons were learned.

A Look at 55 Theses

I think it is a pity that most researchers don't in fact write a book or two outlining their view of science, the world, and progress at some point in their career. Scientific papers are a narrow and entirely insufficient window into a larger worldview, and many scientists have very broad and ambitious visions for the future of their field and the resulting technology. Michael Rose is one such scientist, and has written a few books along the way, of which I recommend the Long Tomorrow for an introduction to his view of aging and necessary strategic directions in the development of longevity science.

My attention was recently drawn to a site called 55 Theses that goes a step further and assembles Rose's ideas in an online series of posts, videos, and small essays - and then asks "knowing this, what can we do to make a difference in our own health and longevity?"

These theses are intended to supply a re-visioning of the scientific foundations of health and medicine. Rather than making small adjustments to a body of medical knowledge which has been developing by accretion since the time of Hippocrates, this re-visioning starts with a firm rejection of the present reductionist foundations of medicine. The human body is not an inert vessel that can be fairly viewed in terms of a definable set of chemical reactions. Rather, it is a product of an evolutionary process that has been ongoing for billions of years, an evolutionary process that has been directed by natural selection. As such, it will be argued that evolutionary biology provides the only secure foundation for understanding our health and for improving the practice of medicine.

There is a lot of material there. If you'd like to wrap your head around an alternate scientific view of longevity, as a contrast to the repair biotechnology focus of this SENS-supporting author, I recommend taking an hour or two to walk through 55 Theses. In essence, it is a step by step overview that builds supporting evidence for specific changes in human lifestyle and diet that are predicted to lead to improved health and slower aging. In the end this largely boils down to "stop eating things that you are not well adapted to eat, from an evolutionary perspective."

Older adults from all human populations are not adequately adapted to agricultural patterns of nutrition and activity, resulting in an amplification of aging under such conditions.

Rose has bred breeding ever-longer lived flies for a great many years, and 55 Theses might be thought of as a framework for extending the same concepts to human practice - analogous to the way in which calorie restriction moved from the lab to a fair-sized community of scientifically-minded human practitioners. I see no reason why a Rosean lifestyle community couldn't arise in the same fashion: it would have a greater weight of scientific evidence behind it than most health-focused gatherings, though I think it has a little way to go in order to catch up with plain old calorie restriction and exercise in that regard. But if this is where the developer of 55 Theses is heading, more power to him I say.

So 55 Theses looks like a good attempt at a philosophy of scientific health practices, similar to the ethos of the calorie restriction community: act upon the implications of supported scientific knowledge of human biochemistry, so as to have the best chance possible of making the best use of our bodies over the long-term. There is uncertainty in all things, science included, and we're all aging - but that doesn't mean it's smart to run heedlessly forward, damaging yourself more than is necessary.

In the long run, good health practices may make the difference between living long enough to benefit from future rejuvenation biotechnology or dying just a few years short of the dawn of that golden era - and to my eyes that's where the value lies. If we were not within mere decades of developing the means to defeat aging, the common state of one's health would not be so profound an issue, I suspect.

The Flip Side of Studies on Stress

Stress appears to affect long-term health and biochemistry in some fundamental ways, some of which are connected to the aging process - such as telomere length, chronic inflammation, and immune system function. So what happens when a person is the opposite of stressed? There is reason to believe that being happy over the long term has just as much of a beneficial effect as stress does a negative effect: "A review of more than 160 studies of human and animal subjects has found 'clear and compelling evidence' that - all else being equal - happy people tend to live longer and experience better health than their unhappy peers. ... Its lead author [analyzed] long-term studies of human subjects, experimental human and animal trials, and studies that evaluate the health status of people stressed by natural events. ... We reviewed eight different types of studies, and the general conclusion from each type of study is that your subjective well-being - that is, feeling positive about your life, not stressed out, not depressed - contributes to both longevity and better health among healthy populations. ... A study that followed nearly 5,000 university students for more than 40 years, for example, found that those who were most pessimistic as students tended to die younger than their peers. An even longer-term study that followed 180 Catholic nuns from early adulthood to old age found that those who wrote positive autobiographies in their early 20s tended to outlive those who wrote more negative accounts of their young lives. There were a few exceptions, but most of the long-term studies the researchers reviewed found that anxiety, depression, a lack of enjoyment of daily activities and pessimism all are associated with higher rates of disease and a shorter lifespan."

Link: http://www.sciencedaily.com/releases/2011/03/110301122156.htm

The Importance of Inflammation in Aging

As noted numerous times in the past here at Fight Aging!, chronic inflammation is a bad thing. Aging is the accumulation of damage, and the evidence strongly suggests inflammation to be a mechanism by which many different medical conditions cause damage and reduce life expectancy - such as autoimmune diseases, for example. Even the presence of excess visceral fat tissue appears to raise the risk of age-related disease and lower life span through boosting levels of inflammation. Furthermore, as you get older, and even in the best of circumstances and health, the immune system itself starts to fall into a malfunctioning state in which it causes ever greater levels of inflammation - thus producing ever more damage while at the same time failing to do its job.

Markers of inflammation correlate well with mortality rates, which is well worth keeping in mind given just how easy it is to slip into a lifestyle that greatly raises levels of inflammation.

So avoid inflammation as best you can. The easiest and some of the best tools are calorie restriction and exercise, both of which do far more for a generally healthy individual than any presently available medical technology. But not everyone has the luxury of being able to be a generally healthy individual: those suffering auto-immune disorders like rheumatoid arthritis are going suffer increasing inflammation and a lowered life expectancy until a cure arrives. So the future of health has to be as much about technological progress as it is about better using the tools that are to hand today.

Here are a couple of open access papers as a reminder of the bad things that inflammation does to you - and, for most of the younger members of the audience, via the agency of that surplus visceral fat tissue you happen to be carrying around.

Inflammation in Aging: Cause, Effect, or Both?

Aging is a progressive degenerative process tightly integrated with inflammation. Cause and effect are not clear. A number of theories have been developed that attempt to define the role of chronic inflammation in aging ... However, no single theory explains all aspects of aging; instead, it is likely that multiple processes contribute and that all are intertwined with inflammatory responses.

...

While there does not appear to be a "cure" for the complex process of aging, it should be possible to facilitate successful aging, namely, aging without significant loss of cognitive or physical function and relatively free of disease. There are lifestyle factors and potential interventions that can slow specific processes primarily through reduction or prevention of chronic inflammation and therefore forestall aging itself.

Systemic immune challenges trigger and drive Alzheimer-like neuropathology in mice

Alzheimer's disease (AD) is the most prevalent form of age-related dementia, and its effect on society increases exponentially as the population ages. Accumulating evidence suggests that neuroinflammation, mediated by the brain's innate immune system, contributes to AD neuropathology and exacerbates the course of the disease.

...

We found that a systemic immune challenge during late gestation predisposes [mice] to develop AD-like neuropathology during the course of aging. They display chronic elevation of inflammatory cytokines [and] significant impairments in working memory in old age. If this prenatal infection is followed by a second immune challenge in adulthood, the phenotype is strongly exacerbated, and mimics AD-like neuropathologic changes. ... Based on the similarity between the changes in immune-challenged mice and the development of AD in humans, we suggest that systemic infections represent a major risk factor for the development of AD.

Infections mean inflammation, of course - one of the many reasons that people exposed to a large burden of infectious disease tend not to live as long as their peers. They become more burdened by damage, from the disease process and from the inflammation that attends it, with each infection. One of the reasons that we live longer than our ancestors is that we are better at controlling and evading infectious disease: not just the diseases that kill people in youth, but the diseases that are survived.

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

Micromasonry in Tissue Engineering

A new technique for tissue engineering: "Tissue engineering has long held promise for building new organs to replace damaged livers, blood vessels and other body parts. However, one major obstacle is getting cells grown in a lab dish to form 3-D shapes instead of flat layers. ... To obtain single cells for tissue engineering, researchers have to first break tissue apart, using enzymes that digest the extracellular material that normally holds cells together. However, once the cells are free, it's difficult to assemble them into structures that mimic natural tissue microarchitecture. Some scientists have successfully built simple tissues such as skin, cartilage or bladder on biodegradable foam scaffolds. ... That works, but it often lacks a controlled microarchitecture. You don't get tissues with the same complexity as normal tissues. ... Researchers [have] come up with a new way to overcome that challenge, by encapsulating living cells in cubes and arranging them into 3-D structures, just as a child would construct buildings out of blocks. The new technique, dubbed 'micromasonry,' employs a gel-like material that acts like concrete, binding the cell 'bricks' together as it hardens. ... You can reproduce this in any lab. It's very simple. ... The short-term next step is really looking at different cell types and the viability of tissue growth."

View the Article Under Discussion: http://web.mit.edu/newsoffice/2010/tissue-legos-0513.html

Read More Longevity Meme Commentary: http://www.longevitymeme.org/news/

Does Medicine for Aging Exist?

Published at Impact Aging you'll find descriptions of the presentations given at the Second International Conference on the Genetics of Aging and Longevity, held in Moscow recently. It's a good representative sample if you'd like to know what the mainstream of aging and longevity science looks like. What I wanted to draw your attention to was this presentation and question:

Vladimir Anisimov (N.N. Petrov Research Institute of Oncology, Russia) in his presentation "Do we really have a medicine against aging?" showed results of experiments on effects of antidiabetic biguanides and rapamycin on biomarkers of aging, life span, spontaneous and chemically-induced carcinogenesis in outbred, inbred and transgenic HER-2/neu mice and in rats.

The mTOR inhibitor rapamycin prevents age-related weight gain, decreases rate of aging, increases life span and decreases carcinogenesis in transgenic HER-2/neu cancer-prone mice. Rapamycin dramatically delayed tumors onset, decreased a number of tumors per animal and tumor size. Lifelong administration of rapamycin extends lifespan in female 129/Sv mice characterized by normal mean lifespan of 2 years. Importantly, rapamycin was administrated intermittently (every other 2 weeks) starting from the age of 2 months. Rapamycin inhibited age-related weight gain, decreased aging rate, increased lifespan (especially in the last survivors) and delayed spontaneous cancer. 22.9% of rapamycin-treated mice survived the age of death of the last mouse in control group.

...

Treatment of female outbred SHR mice with metformin started at the age of 3 months increased mean life span by 14% and maximum life span by 1 month. Same treatment started at the age of 9 months insignificantly increased mean life span by 6%, whereas treatment started at the age of 15 months failed to increase life span. When started at the age of 3 and 9 months, metformin delayed time of the first tumor detection by 22% and 25%, correspondingly.

...

These results suggest that both metformin and rapamycin may be useful in prevention of cancer and extension of lifespan when used in rational and appropriate ages, doses and schedules.

Asking and attempting to answer questions like "does medicine for aging exist" is going to make you unpopular in some quarters no matter how you answer. The large and energetic "anti-aging" marketplace, eternally plagued by the dishonesty of its bad apples, has been crying "yes, yes, get your treatments for aging here" for about as long as mankind has existed. The invention of fraud no doubt followed the discovery of the concepts of value and trade by only a few heartbeats. When no-one could in fact do much of anything about aging, one might say "so what?" Fraud and lies about extending life were no different then than fraud and lies about anything else that didn't exist and couldn't be made to exist - such as the ownership rights to certain bridges, for example.

In these later days of science and reason, however, in which we stand upon the verge of building real and meaningful ways to treat aging, that commercial "anti-aging" market is a millstone around the necks of the scientific community. It is in fact a large part of the reason why up until very recently the aging research field was extremely hostile towards anyone talking seriously about treating aging.

So you are going to see care taken when people in the scientific community speak on such topics. For my part, I think it's completely fair to put forward that, by modern standards of drug development, you could point to rapamycin and metformin and say "these are candidate treatments for aging." By this I mean that they are likely to produce minimal benefits, have potentially ugly side-effects, and are not yet really tested for that specific usage in humans - which describes both a fair chunk of the drug discovery pipeline and many drugs out there in widespread use. We are willing to call those therapies for the conditions they are used to treat.

But let's be clear: as prospective therapies for aging, these drugs are terrible. Truly bad. They are far worse than exercise or calorie restriction - they produce lesser benefits and you get unpleasant side-effects into the bargain. So given all of that I don't think it is unreasonable to say that yes, treatments for aging exist at the present time, and they are awful.

(It is worth pointing out that a gain in life span of 20% in mice is not all that in the grand scheme of things. Exercise can do better, and calorie restriction does twice as well. Further, it is not seriously expected that any gain of 20% in life span in mice through metabolic alteration will translate to a similarly meaningful gain in human life span - which has to do with many of the differences that cause us to be long-lived already for our size. For example, calorie restriction is not thought to be capable of producing more than a few years of gain in maximal human life span, even while it produces large gains in health and resistance to age-related disease).

The real path to the future, to my eyes, is to skip over all of this longevity-enhancing drug discovery nonsense, interesting though it may be, and focus on repair of specific forms of cellular and molecular damage - such as the detailed methodologies proposed in the SENS vision. If SENS or similar programs for research and development fail to become a dominant approach to longevity science, and the foreseeable future thus remains a heaping helping of more longevity-enhancing drug discovery nonsense, then therapies for aging will continue to be generally awful.

I consider it to be unfortunate that the bulk of the pro-longevity aging research camp is focused on an inefficient path forward that will in the end lead to lesser benefits. It is their belief that this is the only practical way ahead: a laborious slog towards complete understanding of aging and metabolism, followed by an even more complex navigation through re-engineering that metabolism to age more slowly. The sheer scale and difficulty of that task is why many scientists feel that meaningful engineered longevity - more healthy years through science - is a long way away indeed.

...

It is likely to be easier and less costly to produce rejuvenation therapies than to produce a reliable and significant slowing of aging. A rejuvenation therapy doesn't require a whole new metabolism to be engineered, tested, and understood - it requires that we revert clearly identified changes to return to a metabolic model that we know works, as it's used by a few billion young people already. Those rejuvenation therapies will be far more effective than slowing aging in terms of additional years gained, since you can keep coming back to use them again and again. They will also help the aged, who are not helped at all by a therapy that merely slows aging.

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

Comments on Chemopreservation Versus Cryopreservation

There is some ongoing interest in plastination (or chemopreservation) as a possible alternative to cryonics (or cryopreservation) - though not yet enough for an initiative to arise that offers that service. Here is commentary on this topic: "Even if chemopreservation can be demonstrated to preserve the intricate wiring of the brain, it can be safely assumed that there will not be a massive change in demand for brain preservation technologies ... As a consequence, providers of chemopreservation will most likely operate in the same environment as providers of cryonics. That means that, as a general rule, there will be a delay between pronouncement of legal death and the start of procedures. ... There is an understandable tendency to compare brain preservation protocols under ideal conditions and favor the method that produces the best preservation. But support for either technology cannot be solely based on results produces under controlled lab conditions. Personal survival technologies should be evaluated under conditions that are most likely to be encountered by organizations that will offer them. ... One interesting aspect of the cryonics vs chemopreservation debate, though, is that it appears that some people simply feel more comfortable with one of the approaches. People who have shown the slightest interest in human cryopreservation can get really excited about the idea of chemical brain preservation. This indicates that if both approaches would be pursued actively, the growth of chemopreservation would not necessarily be at the expense of cryonics but there would be a growth in the total number of people making bio-preservation arrangements aimed at personal survival. [But] chemopreservation is not at the stage where it can be responsibly offered. The growth of this field requires a committed group of individuals who will research, develop, and implement this program. Chemopreservation does not need to be perfected before being offered (neither was cryonics) but so far most advocacy has been mostly at the conceptual level."

Link: http://www.evidencebasedcryonics.org/2012/06/20/chemopreservation-in-the-real-world/

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

Another Study Suggests that Sedentary Behavior Adds Up

You might recall a recent Australian study that put forward a correlation between time spent sitting and mortality rate, independent of other factors - i.e. the claim there being that if you sit a lot but exercise moderately then you have a lower life expectancy than if you spent less time in a chair. My thought at the time was that this sort of result ties back into levels of activity:

This is not the first study to propose this correlation, of course. There are a range of others from past years. One has to wonder what the mechanism is here, however - my suspicion is that it actually does all come back down to the level of physical activity in the end. In these massive studies the level of exercise and activity is reported by the participants. A person who stands and works is going to be somewhat more active than a person who sits and works, even though that time may not be categorized as physical activity, or reported differently.

Here is a different study that proposes much the same sort of thing. These researchers - like the authors of another recent study on Alzheimer's disease and activity - used data gathered from worn accelerometer devices rather than the self-reporting of study participants, which in theory should lead to far more confidence in the results.

Association of Sedentary Time with Mortality Independent of Moderate to Vigorous Physical Activity:

Low physical activity levels are a well-known risk factor of mortality. Previous studies have shown that people who do not meet the physical activity recommendations or those who report less moderate to vigorous activity (MVPA) are at increased risk of death. Sedentary behavior has emerged as a potential risk factor independent of MVPA and is defined as engaging in behaviors during the waking day that are done while sitting or reclining and that result in little energy expenditure above rest, such as using the computer, watching television, driving a car, or sitting at a desk.

Recent studies with objectively measured sedentary time data have shown that prolonged time in sedentary behaviors is a cardiometabolic risk factor independent of moderate to vigorous physical activity. Additionally, self-reported sedentary time in several domains including sitting, riding in a car, and TV watching is positively associated with mortality.

...

7-day accelerometry data of 1906 participants aged 50 and over from the U.S. nationally representative National Health and Nutrition Examination Survey (NHANES) 2003-2004 were analyzed. All-cause mortality was assessed from the date of examination through December 31, 2006.

...

This study shows that time spent in sedentary behavior is positively associated with mortality in this representative sample of adults aged 50 and older. Participants in the highest quartile of percentage of time spent sedentary, which corresponds to more than 73.5% of time in men and more than 70.5% in women, had more than 5 times greater risk of death compared to those in the lowest quartile. Importantly, these associations were independent of MVPA.

At some point in the future we won't really have to worry too much about things like this, as medical science will progress to the point at which maintenance of long-term health regardless of lifestyle becomes as much a non-issue as protection from the infectious diseases that plagued our ancestors. But we have a way to go towards that goal, and in the meanwhile it doesn't seem wise to sit back and assume that biotechnology will rescue you from casual negligence. Maybe you'll get lucky, but for those of us in the middle stages of life it looks uncertain indeed. The coming decades are on the cusp between the era of aging as a fact of life and aging as a treatable and reversible medical condition - a lot of deaths will fall on the wrong side of that line, so why not try to shift the odds on whether yours is one of them? Every year gained is big deal in this sort of situation.

The flip side of that coin is, of course, helping to make rejuvenation biotechnology come about more rapidly. If you like being alive and in good shape, it makes sense to work on both (a) common sense health basics like exercise and calorie restriction, and (b) assisting scientific progress. You live in an age in which you can easily accomplish both of these things, thanks to a wealth of health knowledge at your fingertips, and the spread of volunteer, philanthropically funded organizations like SENS Foundation and Methuselah Foundation.

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

A Tale of Telomerase

Michael Rae has written a long post at the SENS Foundation on the topic of the recently published Spanish study that produced life extension in mice through a telomerase gene therapy. He has been following this line of research closely for some years, and has been critical of the results reported in the past. The post is well worth reading for a better view of both the chronology and the limitations of the work that led to this latest result.

Tale of Telomerase: Lessons and Limits in a Late-Life Launch

The connection between telomeres, telomerase, and cellular and organismal "aging" was a matter of significant scientific interest but little public awareness until the early 1990s, when Dr. Michael West founded Geron Corporation. In the process of launching that venture, and in the following years, West succeeded in embedding a controversial thesis deeply into the public imagination: that the (re)activation of telomerase in somatic cells could retard or even reverse the degenerative aging process. There were always problems with this thesis, and with public (mis)understandings of it, but its sheer simplicity and public prominence has in direct and indirect ways advanced scientific research that has answered many of the questions that thesis forced upon the scientific community, and opened up important new avenues for research in telomre biology and in biomedical gerontology.

The most direct and important fruits of that expansion of research into telomerase have been studies on the pharmacological and transgenic activation of telomerase in the tissues of aging mice. Several such reports have appeared over the years, each hailed prematurely as evidence of the life- and health-extending power of the enzyme. The most important of these studies have been a series of experiments by María Blasco, PhD, SENS Foundation Research Advisory Board member and Director of the Molecular Oncology Programme at Spain's National Cancer Research Centre (CNIO). A tantalizing new report in this series has just appeared -- but to understand it in context, we will first review those that led up to it.

You should read the whole thing; it is very educational, and a good illustration of the way in which there are no sudden breakthroughs in science - just sudden attention paid to steadily ongoing progress. Each new advance rests upon decades of past work and the efforts of a range of other research groups. It also illustrates the need to look past the headlines to pick at the details of heralded research. For example:

several caveats must be noted about the results themselves, and their implications for medical therapies against the degenerative aging process in humans. As in the previous studies, the apparent increases in survival in this new report were, in fact, ambiguous. The study was substantially underpowered to detect a true increase in maximal lifespan; and even taking the results at face value, the reported survival data - even for treated animals - were, once again, well within the range typical for well-husbanded, untreated control mice reported in other studies.

...

Additionally, there was relatively little effort invested in ruling out a possible effect of Calorie restriction (CR) in this study.

...

Presuming, however, that the life- and healthspan benefits reported in this study should be taken at face value, the ultimate question is their human translatability - and there are reasons to be skeptical that a similar therapy could be safely used to retard the degenerative aging process in humans. Some would note first that safe and effective gene therapy is not yet available for our species - but that, like many other matters in biomedical gerontology, is only a matter of time and investment. Of greater concern is the safety of telomerase therapy, granted the very different body plans of humans as compared to mice.

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

Skin Cells from the Old Made into Beating Heart Muscle Cells

Ongoing work in regenerative medicine: "scientists have succeeded in taking skin cells from heart failure patients and reprogramming them to transform into healthy, new heart muscle cells that are capable of integrating with existing heart tissue. The research [opens] up the prospect of treating heart failure patients with their own, human-induced pluripotent stem cells (hiPSCs) to repair their damaged hearts. As the reprogrammed cells would be derived from the patients themselves, this could avoid the problem of the patients' immune systems rejecting the cells as 'foreign'. ... Recent advances in stem cell biology and tissue engineering have enabled researchers to consider ways of restoring and repairing damaged heart muscle with new cells, but a major problem has been the lack of good sources of human heart muscle cells and the problem of rejection by the immune system. Recent studies have shown that it is possible to derive hiPSCs from young and healthy people and that these are capable of transforming into heart cells. However, it has not been shown that hiPSCs could be obtained from elderly and diseased patients. In addition, until now researchers have not been able to show that heart cells created from hiPSCs could integrate with existing heart tissue. [Researchers] took skin cells from two male heart failure patients (aged 51 and 61) and reprogrammed them by delivering three genes or 'transcription factors' ... Crucially, this reprogramming cocktail did not include a transcription factor called c-Myc, which has been used for creating stem cells but which is a known cancer-causing gene. ... The resulting hiPSCs were able to differentiate to become heart muscle cells (cardiomyocytes) just as effectively as hiPSCs that had been developed from healthy, young volunteers who acted as controls for this study. Then the researchers were able to make the cardiomyocytes develop into heart muscle tissue, which they cultured together with pre-existing cardiac tissue. Within 24-48 hours the tissues were beating together. ... The tissue was behaving like a tiny microscopic cardiac tissue comprised of approximately 1000 cells in each beating area. ... Finally, the new tissue was transplanted into healthy rat hearts and the researchers found that the grafted tissue started to establish connections with the cells in the host tissue."

Link: http://www.eurekalert.org/pub_releases/2012-05/esoc-stp052112.php

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

In Search of Specific Epigenetic Predictors of Longevity

Just as the research community is sifting the world for correlations between variations in the human genome and variations in human longevity, so too are scientists beginning to pay greater attention to the role of the epigenome. The DNA in every one of our cells is better thought of as a whirling, dynamic machine rather than a static blueprint. It is in motion, a blur, a thousand thousand feedback loops involving the production of proteins that selectively alter the process of producing proteins. The amount of any one specific protein in a given cell produced from its DNA blueprint rises and falls dynamically, in response to environmental conditions, time of day, status of the cell's internal machinery, and a million other variations tuned by evolution. The epigenome is this dynamic partner to the static genome, a catalog of how genes become tagged and the changes that result from those tags. Epigenetics is the study of how DNA interacts with the machinery of protein construction to selectively modify the output in response to circumstances - and what that then means for cells, organs, and the operation of the body as a whole.

Just as there are genetic variations that subtly contribute to human longevity, we should expect there to be equally subtle epigenetic variations - though more complex, and harder to uncover. Research here contributes to the grand debate over the degree to which aging is programmed: is the epigenetic contribution to aging a matter of growing disarray in the processes of tagging and correcting levels of protein production, arising due to damage, or are there signs of programmed changes in levels of protein production that cause damage and dysfunction?

A paper from earlier this year claims epigenetic biomarkers of longevity in nematode worms, a much simpler animal to study than we mammals:

Why do some individuals live longer than others? ... Inter-individual variation in human longevity has not been found to be under substantial genetic control, with heritability generally between 15% and 30% ... The situation is thrown into relief in studies of C. elegans, in which genetically identical siblings reared in identical environments usually experience different lifespans. In this work, we show that physiological differences between identical animals begin to appear relatively early in life and that markers of ill health in young adulthood presage shorter lifespans.

Using fluorescent markers to examine the level of activation of several genes, we found three regulatory microRNA genes [in] which early-adulthood expression patterns individually predict up to 47% of lifespan differences. Though expression of each increases throughout this time, mir-71 and mir-246 correlate with lifespan, while mir-239 anti-correlates. Two of these three microRNA "biomarkers of aging" act upstream in insulin/IGF-1-like signaling (IIS) and other known longevity pathways, thus we infer that these microRNAs not only report on but also likely determine longevity. Thus, fluctuations in early-life IIS, due to variation in these microRNAs and from other causes, may determine individual lifespan.

The educated guess at this point is that the way in which natural, unmodified life span emerges depends a little on the DNA blueprint, a lot on the environment, but just as much on chains of chaotic happenstance in the enormously complex operations of metabolism. We might consider that last line item a form of stochastic accumulation of molecular damage to cells: even with all other things being equal, individuals will age at somewhat different rates because initially small, localized differences in biological damage snowball over time into widely diverging system-wide outcomes.

Interestingly, it looks like there are good signposts on that road; we shall no doubt see how good or useful epigenetic biomarkers turn out to be in humans. Certainly a large community of researchers are hotly engaged in trying to uncover truly reliable biomarkers that measure aging or predict longevity, so if there is something to be found in the epigenome they will eventually find it.

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

Linking Autoimmunity and Atherosclerosis via Inflammatory Processes

Via ScienceDaily: "Individuals who suffer from autoimmune diseases also display a tendency to develop atherosclerosis - the condition popularly known as hardening of the arteries. Clinical researchers [have] now discovered a mechanism which helps to explain the connection between the two types of disorder. The link is provided by a specific class of immune cells called plasmacytoid dendritic cells (pDCs). ... Using laboratory mice as an experimental model, the researchers were able to show that pDCs contribute to early steps in the formation of athersclerotic lesions in the blood vessels. Stimulation of pDCs causes them to secrete large amounts of interferons, proteins that strongly stimulate inflammatory processes. The protein that induces the release of interferons is produced by immune cells that accumulate specifically at sites of inflammation, and mice that are unable to produce this protein also have fewer plaques. Stimulation of pDCs in turn leads to an increase in the numbers of macrophages present in plaques. Macrophages normally act as a clean-up crew, removing cell debris and fatty deposits by ingesting and degrading them. However, they can also 'overindulge,' taking up more fat than they can digest. When this happens, they turn into so-called foam cells that promote rather than combat atherosclerosis. In addition, activated, mature pDCs can initiate an immune response against certain molecules found in atherosclerotic lesions, which further exacerbates the whole process. ... The newly discovered involvement of pDCs in the development of atherosclerosis [reveals] why the stimulation of pDC that is characteristic of autoimmune diseases contributes to the progression of atherosclerosis. The findings also suggest new approaches to the treatment of chronic inflammation that could be useful for a whole range of diseases."

Link: http://www.sciencedaily.com/releases/2012/04/120404102943.htm

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm