Fight Aging! Newsletter, March 4th 2013

March 4th 2013

The Fight Aging! Newsletter is a weekly email containing news, opinions, and happenings for people interested in aging science and engineered longevity: making use of diet, lifestyle choices, technology, and proven medical advances to live healthy, longer lives. This newsletter is published under the Creative Commons Attribution 3.0 license. In short, this means that you are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!



- Nanoparticles and Viruses Will Blur at the Edges
- Health Extension and Science Funding
- Neurons Can Outlast Their Host, But is That Relevant?
- Discussion
- Latest Headlines from Fight Aging!
    - Calorie Restriction Protective of Specific Brain Mechanisms
    - Another Study on Inheritance of Human Longevity
    - Infusing Large Numbers of Immune Cells as a Therapy
    - One View of the Widespread Unthought Opposition to Engineered Human Longevity
    - Cautious Studies Tend to Disprove Dietary Longevity Claims
    - A Podcast Interview With Aubrey de Grey
    - Parthogenesis in Regenerative Medicine
    - Very Healthy Elder Athletes Don't Actually Tell Us All That Much About Aging
    - SENS Research Foundation Site Redesign
    - Considering DNA Methylation and Aging


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

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

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


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

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

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

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


A paper on the life span of neurons in relation to their host organism was published earlier in the year and has been doing the rounds in recent days:

"Neurons in mammals do not undergo replicative aging, and, in absence of pathologic conditions, their lifespan is limited only by the maximum lifespan of the organism. Whether neuronal lifespan is determined by the strain-specific lifetime or can be extended beyond this limit is unknown. Here, we transplanted embryonic mouse cerebellar precursors into the developing brain of the longer-living Wistar rats. The donor cells integrated into the rat cerebellum developing into mature neurons while retaining mouse-specific morphometric traits.

"In their new environment, the grafted mouse neurons did not die at or before the maximum lifespan of their strain of origin but survived as long as 36 mo, doubling the average lifespan of the donor mice. Thus, the lifespan of neurons is not limited by the maximum lifespan of the donor organism, but continues when transplanted in a longer-living host."

This is indeed the barnstorming age of biotechnology. As you might already know, we humans possess many nervous system cells that we were born with and which will last our entire lifetime. This is in contrast to much of the rest of our body where cells are replaced over various timescales, from years for some tissues to days for others. It is even that case that some individual macromolecules within brain cells last unchanged throughout life - not just the cell remaining on station for a lifetime, but some of its fundamental building blocks as well.

The fact that many neurons are never replaced is the source of a range of frailties and age-related conditions that result from increasing damage or buildup of unwanted metabolic byproducts in these long-lived cells. Nonetheless, it seems very reasonable to expect that our neurons are capable of outlasting the present limits of human life span, given the fact that it isn't neurodegeneration that kills supercentenarians - their brain cells are, by and large, still marching along even in the final years. No, death by aging is a systems failure, not a timed simultaneous failure of all the components that make up that system.

Is work on rodent neurons quoted above particularly relevant, or does it change anything? I is interesting, but I think that the answer is "no." We already know that developing the means to repair existing neurons in the brain is necessary. Boosting the rate at which new neurons are created will almost certainly be helpful, but a good portion of the brain stores the data that is the mind - those neurons and their encoded data have to be preserved and maintained, not replaced wholesale. So here it seems to me that knowing that neurons have a longer shelf-life doesn't change anything in the game plan.

Further, there's no guarantee that the longer neuron shelf-life in rodents has any great relevance to human cells. The analogous human study might be to pull long-lived neurons from a supercentenarian and culture them in a 3-D engineered environment that replicates their home tissue as closely as possible. Then you wait - for a fair number of decades. By the time that experiment comes to any interesting result, the whole issue will be moot. Either we will be dead, or SENS-like rejuvenation biotechnologies will be developed, and in either case researchers will already know so much more about cellular biology that they will be long past the point of answering all the questions that the study might help to resolve.


The highlights and headlines from the past week follow below. Remember - if you like this newsletter, the chances are that your friends will find it useful too. Forward it on, or post a copy to your favorite online communities. Encourage the people you know to pitch in and make a difference to the future of health and longevity!



Friday, March 1, 2013
Calorie restriction produces a general slowing of the progression of degenerative aging and creates sweeping changes at all levels of metabolism. Thus it should not be a surprise to find protective effects no matter how deep you dive into the biochemistry of calorie restricted laboratory animals. Here's one of the many more detailed examples, looking at the abundances of receptors known to be important in brain function: "The effects of aging and long-term caloric restriction, on the regulation of neuropeptide Y (NPY) Y(1), Y(2) and Y(5) receptors subtypes, was studied in 20-month-old male rats fed ad libitum (AL) or submitted to a 40% caloric restriction for 12 months. In the brain of 3-month-old AL rats, the distribution and densities of Y(1), Y(2) and Y(5) receptors were in agreement with previous reports. In the brain of 20-month-old AL rats, a decrease of NPY receptor subtype densities in regions having important physiological functions such as the cingulate cortex, hippocampus and dentate gyrus, thalamus and hypothalamus was observed. In contrast, caloric restriction had multiple effects. It induced specific decreases of Y(1)-receptor densities in the dentate gyrus, thalamic and hypothalamic nuclei and lateral hypothalamic area and Y(2)-receptor densities in the suprachiasmatic nucleus of hypothalamus. Moreover, it prevented the age-induced increase in Y(1)-receptor densities in the ventromedial hypothalamic nucleus and decrease in the mediodorsal thalamic nucleus, and increased Y(2)-receptor densities in the CA2 subfield of the hippocampus. These results indicate that caloric restriction not only counteracts some of the deleterious effects of aging on NPY receptor subtype densities but exerts specific effects of its own. The overall impact of the regulation of NPY receptor subtypes in the brain of old calorie-restricted rats may protect the neural circuits involved in pain, emotions, feeding and memory functions."

Friday, March 1, 2013
Studies suggest that longer life expectancy runs in families to some degree - though it is always the case that what you get in the genetic lottery can be squandered by poor lifestyle choices. Gene variants appear to be more important in determining remaining life expectancy at older ages than at younger ages, which is another way of saying much the same thing. Either way, the end result will be the same until we can build rejuvenation biotechnology. "According to the findings of some recent studies, the centenarians' offspring appear to represent a promising model for research on longevity and healthy aging. This study compares the health status and the functional status of three groups of subjects: 1. individuals with two long-lived parents (one of whom centenarian), 2. individuals with only one long-lived (centenarian) parent, and 3. individuals with no long-lived parents. The goal is to verify whether the centenarians' offspring display any advantage over the offspring of both non-long-lived parents and to evaluate whether the longevity of the non-centenarian parent provides a further advantage. A total of 374 subjects (mean age approximately 70 years) was examined. A threshold for longevity was established for non-centenarian parents through demographic data available for Italy (males surviving to at least 81 years of age and females to 87 years). The participants were assessed for their health and functional status by means of a standardized questionnaire and tests of physical performance. Data were analyzed using multivariate regression models adjusted for socio-demographic characteristics and risk factors for age-related pathologies. The results of the study show that centenarians' offspring have a better functional status, a reduced risk for several age-related pathologies and reduced drug consumption than the offspring of non-long-lived parents. In addition, the health status of centenarians' offspring does not appear to be influenced by the longevity of the second parent. It therefore seems possible to conclude that at ages around 70 years the genetic contribution to health status deriving from having one centenarian parent is not substantially improved if the other parent is also long-lived."

Thursday, February 28, 2013
Since it is possible to take a patient's cells and generate a very large number of immune cells, far more than the patient would ever have normally, and since it's possible to make some alterations to immune cells to make them more effective, why not do this? It's probably the case that even generally healthy older people would benefit from a regular infusion of large numbers of their own immune cells, or even donor cells, given the way in which the immune system declines with age, but under present medical regulation you'll only ever see it deployed as a treatment for late stage disease: "[Researchers] have successfully infused large numbers of donor T-cells specific for a key anti-leukemic antigen to prolong survival in high-risk and relapsed leukemia patients after stem cell transplantation. [T-cells were] taken from a donor, programmed in the lab to recognize the Wilm's Tumor Antigen 1 (WT1) and kill leukemia cells, grown in large numbers, and then infused into patients to promote anti-leukemic activity. The WT1 protein is overexpressed in leukemias and is in part responsible for why the cells have become leukemic. All of the patients [received] adoptively transferred infusions of billions of enhanced CD8 cytotoxic T-cell clones. They were considered at high risk of death because they had already relapsed and/or had a poor prognosis due to unfavorable characteristics of their leukemia. Four of the 11 patients in the trial received infusions of T-cells that targeted WT1 and were generated in the presence of IL-21. One had detectable relapsed disease and entered complete remission shortly after the T-cells were infused. All four survived after T-cell therapy without relapse for more than 30 months without suffering graft-vs.-host-disease and required no additional anti-leukemic treatment, according to the study. Among the seven patients who received infused T-cells generated without the presence of IL-21, two showed direct evidence of anti-leukemic activity, including one patient with advanced progressive disease who had a temporary response."

Thursday, February 28, 2013
The average fellow in the street thinks that helping people to live longer is a bad idea, and usually expresses some combination of the Tithonus Error (the misapprehension that life extension technologies would make you live in increasing frailty, rather than extending youth) and the modern mixed package of environmentalist / classist / Malthusian / conservative beliefs on wealth and privilege: that equality should come by tearing down those at the top and halting progress, that there are too many people in the world, that any sort of increased consumption is evil, that changing anything to do with aging is bad. This is the major challenge for the future development of means to extend human life - that most people reject it, even at their own cost, even when their beliefs about the way the world works are easily shown to be false: there is no overpopulation, only waste and corruption; stopping progress and trying to impose equality inevitably leads to something like the economic ruins of the old Soviet Union; Malthus was wrong in his time and still wrong now; and so forth. Here is an educator's point of view, from one more embedded in the culture that rejects progress than most: " Our minds are perhaps hardwired to interpret the world in terms of simplistic patterns (like "haves" and "have nots"), but that does not mean it is an accurate representation of reality. Education should challenge our preconceived ideas of the world and dogma. When I teach the weeks of my course on aging and life extension these points become most salient. I am always struck by the fact that (a) very few students understand that chronic diseases are the leading cause of death in the world, and (b) that chronic disease is a problem for both rich and poor countries, and (c) that people in poorer regions of the world actually age, and that this can cause them to experience suffering, disease, a decline in income, etc. I could go on. Here are actual comments (I am paraphrasing from memory) I have heard students and others express when discussing population aging, global health and a Darwinian approach to medicine: "Old people should die sooner of disease so younger people can get a job". "A cure for cancer already exists, but Big Pharma makes more money off of cancer than curing it". "Wouldn't it be boring being alive longer and thus being married to the same person for longer?" "We shouldn't modify the rate of aging as it is unnatural". "Why don't we just spend all health research money on saving children and forget about helping those who are lucky enough to have lived a long life?" "Slowing human aging will destroy the planet". Such sentiments are common, and part of my research involves trying to understand why people have such attitudes, and how one can help people come to critically examine such attitudes. The students that I encounter who have strong convictions that the world is overpopulated, and that the future of the planet is a bleak one because of population growth, typically have little knowledge of demography."

Wednesday, February 27, 2013
A research group is presently working through a grand tour of replicating longevity claims in mice, using careful and cautious study designs that eliminate calorie restriction effects as much as is possible. This sort of approach shows that many past claims of dietary additions that modestly extend life in mice were probably the result of inadvertent calorie restriction - which is why you have to look carefully at every study to make sure that researchers controlled for this issue. Calorie restriction has a comparatively large effect on life span in smaller animals, such that even mild restriction can swamp all other contributions to life span that occur in a study: "Phytonutrients reportedly extend the lifespan of C. elegans, Drosophila, and mice. We tested extracts of blueberry, pomegranate, green and black tea, cinnamon, sesame, and French maritime pine bark (Pycnogenol and taxifolin), as well as curcumin, morin, and quercetin for their effects on the lifespan of mice. While many of these phytonutrients reportedly extend the lifespan of model organisms, we found no significant effect on the lifespan of male, F1 hybrid mice, even though the dosages used reportedly produce defined therapeutic endpoints in mice. The compounds were fed beginning at 12 months of age. The control and treatment groups were isocaloric with respect to one another. A 40% calorically restricted and other groups not reported here did experience lifespan extension. Body weights were unchanged relative to controls for all but two supplemented groups, indicating most supplements did not change energy absorption or utilization. Published reports of murine lifespan extension using curcumin or tea components may have resulted from induced caloric restriction. Together, our results do not support the idea that phytonutrient-antioxidants and anti-inflammatories are potential longevity therapeutics, even though consumption of whole fruits and vegetables is associated with enhanced health- and lifespan."

Wednesday, February 27, 2013
An audio interview with Aubrey de Grey of the SENS Research Foundation: "Like it or not, aging is a byproduct of the daily activity of life. But Aubrey de Grey believes that the molecular and cellular damage that defines aging and creates disability and disease can be targeted for medical interventions that restore health and radically extend life. We spoke to de Grey, chief scientific officer and founder of the SENS Research Foundation, about the need to think differently about aging, how a new era of regenerative medicine might slow or reverse its effects, and why it is necessary to focus on medical interventions rather than prevention to have a significant impact. In this interview, Dr. de Grey discusses SRF's approach to treating the diseases of aging, and how it differs from most of the research being done today in gerontology. He also talks about his own background, and how he came to the field."

Tuesday, February 26, 2013
This popular science piece looks at parthogenesis as an alternative to both embryonic stem cells and induced pluripotency reprogramming as a source of stem cells: "Parthenogenesis is a form of asexual reproduction that occurs naturally in plants, insects, fish, amphibians and reptiles. During this process, unfertilized eggs begin to develop as if they've been fertilized. In 2007, researchers induced human egg cells with chemicals mimicking fertilization so they would undergo the process. The result were parthenogenetic cells that share the same properties as embryos, except that they can't grow further. The cells are akin to pluripotent stem cells derived from embryos, which means they have the ability to develop into different types of cells - including heart cells. [Researchers] used this knowledge to turn body cells of mice into parthenogenetic stem cells, which were then grown into mature, functional cardiomyocytes. Researchers used these cells to engineer myocardium - heart muscle - with the same structure and function of normal myocardium. The muscle was then grafted onto the hearts of the mice that had contributed the original eggs for parthenogenesis, where it worked the same way as existing muscle."

Tuesday, February 26, 2013
A number of studies have shown that it is possible to be both old and very healthy in comparison to your peers, and surveying older athletes is a good way to find some of those old, very healthy people. The big question is one of causation: are they healthy because they are athletes, or did they become healthy athletes because they are more physically robust, thanks to genetic or other differences? This is a part of the uncertainty over whether more exercise is always better and the degree to which genetics versus lifestyle versus chance contributes to the course of aging. "People who exercise on a regular basis up to the age of 80 have the same aerobic capacity as someone half their age, says a new study. "These athletes are not who we think of when we consider 80-year-olds because they are in fantastic shape. They are simply incredible, happy people who enjoy life and are living it to the fullest. They are still actively engaged in competitive events." Researchers examined nine endurance athletes from northern Sweden and compared them to a group of healthy men from Indiana in the same age group who only performed the activities of daily living with no history of structured exercise. The endurance athletes were cross-country skiers, including a former Olympic champion and several national/regional champions with a history of aerobic exercise and participation in endurance events throughout their lives. The athletes exercised four to six times a week, averaging 3,700 more steps per day than the non-exercisers. Members of the two study groups rode exercise bikes as researchers measured oxygen uptake. When the participants reached total exhaustion, they had reached maximum oxygen uptake (also known as VO2 max). Skeletal muscle biopsies were then taken to measure the capacity of their mitochondria, the aerobic base of their muscle and other cells. The study also found the endurance athletes established new upper limits for aerobic power in men 80-91 years old, including a maximum oxygen uptake that was nearly twice that of untrained men their age. "To our knowledge, the VO2 max of the lifelong endurance athletes was the highest recorded in humans in this age group, and comparable to nonendurance-trained men 40 years younger. We also analyzed the aerobic capacity of their muscles by examining biopsies taken from thigh muscles, and found it was about double that of typical men. In fact, the oldest gentleman was 91 years old, but his aerobic capacity resembles that of a man 50 years younger. It was absolutely astounding.""

Monday, February 25, 2013
The SENS Research Foundation works on the foundational biotechnologies that will be needed to create therapies capable of reversing aging: ways to make mitochondrial DNA damage irrelevant, removing harmful aggregates that build up with age within and between cells, and so forth. The Foundation staff kicked off the first phase of a major site redesign earlier this year, and rolled out the second stage this past weekend. So head over and take a look: "If this is your first time visiting our site, welcome. If you've been here before, you're no doubt noticing plenty that is new: an updated site design, a variety of new content, a new logo, and a new organizational name: "SENS Research Foundation". It all centers around a new tagline: reimagine aging. For a public charity, a tagline can be an enormously powerful thing. Our vision and mission statements remain the primary guides to our planning, but the tag is everywhere, on every business card and letter and web page. More than any other document or phrase, it naturally becomes the daily reminder of who we are and what we are about. Of course we are still "advancing rejuvenation biotechnologies" just as vigorously as when we carried that tagline over the last couple years. We still aim to introduce a new premise for the pharma and biotech industries. And now, our successes in our research, our collaborations, our conferences, and our educational programs have made us increasingly aware of the need to refocus our messaging to people being exposed to us for the first time."

Monday, February 25, 2013
An article on DNA methylation, which researchers have demonstrated to have the basis for a biomarker of aging; some of the patterns that tend to occur in the way in which these epigenetic decorations to DNA occur correlate well with biological age. This author is optimistic that manipulating DNA methylation can slow aging, which is something of a programmed aging point of view - that epigenetic changes are a root cause of aging and give rise to the damage of aging we can observe, rather than vice versa. It doesn't seem to me that the evidence rises to support that view and course of action over trying to repair the underlying damage of aging. If damage is the root cause, then when it is reverted the DNA methylation changes should also be restored to youthful levels. "How does the body know how old it is? Our metabolisms change as we get older, even though our DNA doesn't change. Different genes are activated at different times of life, and the timing of gene expression is what controls growth, development, sexual maturity, and perhaps aging as well. The body keeps accurate track of how old it is, though there has been no scientific agreement about where the clocks are, or how they work. Recently, some biologists have suggested that one such biological clock might reside in the epigenetic state of the DNA. If this is true, epigenetics will become an attractive, though challenging, target for anti-aging research. If we knew where the body kept its "clock", then perhaps we could target the clock itself with biochemical interventions. We would not just be able to slow the progress of aging, but reset the clock to an earlier age. DNA is decorated with methyl groups, small molecular add-ons that act like "Do Not Disturb" signs for the underlying gene. A gene that is decorated with methyl groups is passed over, and not expressed. Patterns of methylation are programmed into the genome at birth, and they are known to change over a lifetime. The new idea is that these changes can constitute a reference, like a clock face that informs the cell about the body's stage of life, so that it can appropriately adjust its gene expression, and thence its entire metabolism. If we're really lucky, it will turn out that humans, like flies, respond well to a dumb, across-the-board increase in methylation. [The] methyl transferase system in humans is more complicated, but it will still be far easier to engineer a general increase in methylation than to copy youthful methylation patterns in detail. This question could be posed in research project that we know how to do now."



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