Fight Aging! Newsletter, February 25th 2013

February 25th 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!



- The New SENS Research Foundation Site
- Noting the Inaugural Breakthrough Prize Awards
- The Old Have Been Persuaded to See Themselves as Worthless
- Rejuvenation Research for February 2013
- Incremental Advances in Machine-Nerve Interfaces
- Discussion
- Latest Headlines from Fight Aging!
    - Drugs to Slow Aging are a Matter of When, Not If
    - An Example of the Future of Stem Cell Therapies
    - Injectable Scaffold Gel to Spur Heart Regeneration
    - Bioengineering an Ear
    - Only Some Mitochondrial DNA Damage Contributes to Aging
    - Discussing Inflammation and Age-Related Disease
    - An Example of Scaffolds to Encourage Bone Regrowth
    - Aging is Emphatically Not an Inescapable Destiny
    - Adiponectin in Centenarians
    - DNA Damage and Reproductive Aging


The SENS Research Foundation staff launched a newly redesigned website a few days ago. It presents the Foundation mission to "reimagine aging" by building biotechnologies to repair the cellular and molecular damage that causes frailty, disease, and death. Take a look at the new videos and content by following the link below:


The Breakthrough Prize in Life Sciences is a new and narrowly focused Nobel-like initiative launched by a noteworthy Russian entrepreneur in collaboration with some of the high net worth individuals that the California start up community has produced over the past decade. The tagline is much as follows: "Breakthrough Prize in Life Sciences is founded by Art Levinson, Sergey Brin, Anne Wojcicki, Mark Zuckerberg and Priscilla Chan, and Yuri Milner to recognize excellence in research aimed at curing intractable diseases and extending human life. The prize is administered by the Breakthrough Prize in Life Sciences Foundation, a not-for-profit corporation dedicated to advancing breakthrough research, celebrating scientists and generating excitement about the pursuit of science as a career."

Note that "extending human life" in the middle there. It looks like we'll have to wait to see whether the ongoing prize initiative will place any real emphasis on that goal, however. The eleven inaugural awards of $3 million each went to researchers who don't have a great deal to do with longevity research. Cancer and its mechanisms form the dominant theme in this first set of awards. In some cases the scientists' work touches on aging, such as the telomere research of Titia de Lange, but then so do a great many other line items - it's quite possible to run a very successful career as a telomere researcher without contributing towards efforts to extend human life by intervening in the aging process.

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

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


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

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

In this post you'll find quoted the rather gloomy viewpoint of a near-70-year-old, informed by the Tithonus Error, the incorrect view that extended life achieved through biotechnology will result in more and increasingly decrepit old age rather than more vigor and youth as is in fact the case. As Aubrey de Grey asked in a recent editorial, why do people completely ignore what the research community says on this topic? Or for that matter, why do they ignore history? The incidental lengthening of human life achieved over the past two centuries through general improvement in medical technologies has been an extension of youth rather than an extension of old age. The public doesn't stick its head in the sand in the same way for heart disease or Parkinson's research. One might well ask why this happens for aging.

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


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

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

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


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

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

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


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, February 22, 2013
It is pleasing to see this sort of article emerging from a university publicity group - a part of the necessary trend within the scientific community towards making it acceptable and desirable to talk about extending human life through biotechnology. The silence of the research community on this topic across past decades was very harmful to the prospects for progress and funding in the field of aging research and longevity science. That said, it is problematic that the vast majority of resources and researchers presently focus on modestly slowing aging rather than trying to repair and reverse the causes of aging. Based on what we know today, it is probably harder to safely adjust metabolism to slow down aging than it is to repair the root causes of aging to restore a metabolism back to its youthful state. Further, slowing aging is of no use to old people, whereas repair based approaches are useful - and given that people in middle age today will be old by the earliest possible time that therapies might emerge, it won't be all that great if all those therapies can do is slow down the progression of aging. So more work on SENS and similar repair-based strategies, and less fiddling around with calorie restriction mimetics, longevity genes, and the like, is what we need to see if there is to be an effective near-term lengthening of human life. That result has to be based on rejuvenation, not slowing of aging. "Evidence is accumulating that not only is it possible to slow down aging, but that by doing so the onset and progression of multiple age-related diseases can be delayed. "Slowing aging should increase both lifespan and healthspan - the period of life spent in relatively good health, free from chronic disease or disability. A shared feature of most medically relevant diseases is that your risk of dying from them increases dramatically as you get older. Unlike traditional approaches, which tend to focus on a specific disease, targeting the aging process itself has a much greater potential to improve human health." Many experts in the biology of aging believe that pharmacological interventions to slow aging are a matter of 'when' rather than 'if'. A leading target for such interventions is the nutrient response pathway defined by mTOR, a protein that controls cell growth. "Inhibition of this pathway extends lifespan in model organisms and confers protection against a growing list of age-related pathologies. Characterized inhibitors of this pathway are already clinically approved, and others are under development. Although adverse side effects currently preclude use in otherwise healthy individuals, drugs that target the mTOR pathway could one day become widely used to slow aging and reduce age-related pathologies in humans.""

Friday, February 22, 2013
One major branch of future progress in stem cell therapy will discard transplantation of cells in favor of manipulating the signals that tell local cells what to do - which is generally what the transplanted cells are actually doing anyway. This will become more effective as researchers gain a better understanding of the intricacies of cell signalling relevant to growth and repair, but here is an early example of what can be done with this sort of approach: "In the first human study of its kind, researchers activated heart failure patients' stem cells with gene therapy to improve their symptoms, heart function and quality of life. [Researchers] delivered a gene that encodes a factor called SDF-1 to activate stem cells like a "homing" signal. SDF-1 is a naturally occurring protein, secreted by cells, that guides the movement of other cells. Previous research [has] shown SDF-1 activates and recruits the body's stem cells, allowing them to heal damaged tissue. However, the effect may be short-lived. For example, SDF-1 that's naturally expressed after a heart attack lasts only a week. In the study, researchers attempted to re-establish and extend the time that SDF-1 could stimulate patients' stem cells. Study participants' average age was 66 years. Researchers injected one of three doses of the SDF-1 gene [into] the hearts of 17 patients with symptomatic heart failure and monitored them for up to a year. Four months after treatment, they found: 1) Patients improved their average distance by 40 meters during a six-minute walking test. 2) Patients reported improved quality of life. 3) The heart's pumping ability improved. 4) No apparent side effects occurred with treatment. "We found 50 percent of patients receiving the two highest doses still had positive effects one year after treatment with their heart failure classification improving by at least one level. They still had evidence of damage, but they functioned better and were feeling better." Researchers are now comparing results from heart failure patients receiving SDF-1 with patients who aren't. If the trial goes well, the therapy could be widely available to heart failure patients within four to five years."

Thursday, February 21, 2013
Researchers are here working on an injectable gel scaffold material that appears to improve regeneration of heart damage: "[Researchers have] developed a protein-rich gel that appears to help repair cardiac muscle in a pig model of myocardial infarction. The researchers delivered the hydrogel via a catheter directly into the damaged regions of the porcine heart, and showed that the product promoted cellular regeneration and improved cardiac function after a heart attack. Compared to placebo-treated animals, the pigs that received a hydrogel injection displayed a 30% increase in heart volume, a 20% improvement in heart wall movement and a 10% reduction in the amount of scar tissue scar three months out from their heart attacks. [The researchers] developed their hydrogel by stripping muscle cells from pig hearts, leaving behind a network of proteins that naturally self-assembles into a porous and fibrous scaffold upon injection into heart tissue. They previously tested its safety and efficacy in rats, where they found increased cardiac function and no toxicity or cross-species reactivity."

Thursday, February 21, 2013
An application of 3-D printing and regenerative medicine: "[Researchers] described how 3-D printing and injectable gels made of living cells can fashion ears that are practically identical to a human ear. Over a three-month period, these flexible ears grew cartilage to replace the collagen that was used to mold them. A bioengineered ear replacement like this [would] help individuals who have lost part or all of their external ear in an accident or from cancer. [Replacement ears] are usually constructed with materials that have a Styrofoam-like consistency, or sometimes, surgeons build ears from a patient's harvested rib. This option is challenging and painful for children, and the ears rarely look completely natural or perform well. To make the ears, [researchers] started with a digitized 3-D image of a human subject's ear, and converted the image into a digitized "solid" ear using a 3-D printer to assemble a mold. [This] high-density gel is similar to the consistency of Jell-o when the mold is removed. The collagen served as a scaffold upon which cartilage could grow. The process is also fast: "it takes half a day to design the mold, a day or so to print it, 30 minutes to inject the gel, and we can remove the ear 15 minutes later. We trim the ear and then let it culture for several days in nourishing cell culture media before it is implanted.""

Wednesday, February 20, 2013
This research might be taken to illustrate the point that only some specific mutations in mitochondrial DNA (mtDNA) contribute to aging - those occurring in one of thirteen specific genes, per the SENS outline. So mice with accelerated mutation rates in all mitochondrial DNA exhibit accelerated aging, while mice with specific mitochondrial mutations that do not include those that contribute to aging do not exhibit accelerated aging. "It has been hypothesized that pathogenic mtDNA mutations that induce significant mitochondrial respiration defects cause mitochondrial diseases, and could also be involved in aging and age-associated disorders including tumor development. This hypothesis is partly supported by studies in mtDNA mutator mice: they possess a nuclear-encoded mtDNA polymerase with a defective proofreading function that leads to enhanced accumulation of random mutations in mtDNA with age, and the subsequent phenotypic expression of age-associated respiration defects and premature aging phenotypes, but not tumor development. On the contrary, our previous studies showed that transmitochondrial mito-miceΔ carrying mtDNA with a large-scale deletion mutation (ΔmtDNA) expressed age-associated respiration defects, but not express the premature aging phenotypes. Similar results were obtained in other transmitochondrial mito-miceCOIM, which have an mtDNA point mutation in the COI gene. Recently, we generated new transmitochondrial mito-miceND6M, which have an mtDNA point mutation in the ND6 gene that is derived from Lewis lung carcinomas, and confers respiration defects and overproduction of reactive oxygen species (ROS). Mito-miceND6M did not express premature aging phenotypes, but were prone to B-cell lymphoma development. Thus, it appears to be discrepant that premature aging phenotypes are exclusively observed in mtDNA mutator mice, but not in transmitochondrial mito-mice even though they all express mitochondrial respiration defects caused by mutated mtDNA."

Wednesday, February 20, 2013
Notes from a recent conference at the Impact Aging journal: "The workshop opened with [an] overview of the literature supporting the emergence a mild pro-inflammatory state that is closely linked to the major degenerative diseases of the elderly. The focus of the workshop was to better understand the origins and consequences of this low level chronic inflammation in order to design appropriate interventional studies aimed at improving healthspan. For many, inflammation is simply understood as a trajectory of biomarkers, for example the appearance of IL-6 or C-reactive protein (CRP), associated with a disease. However, inflammation is a very complex response to an injury, infection, or other stimulus, in which many different cells types and secreted factors orchestrate protective immunity, tissue repair, and resolution of tissue damage. Whereas acute inflammation limits tissue damage and resolves, chronic prolongation of the inflammatory state leads to progressive tissue damage. A central question, then, is how do we describe and begin to understand the mild pro-inflammatory state of aging. Among the causal pathways linked to the major diseases associated with aging, including physical frailty, are changes in body composition, energy imbalance, homeostatic dysregulation, and neurodegeneration. Chronic inflammation is strongly connected with each of these aging phenotypes. The inflammatory mediators IL-6, IL-18, and CRP increase with age in both women and men and are highly correlated with obesity and degenerative disease. Muscle strength, as measured by walking speed, also correlates with circulating IL-6 levels. Individuals with the lowest circulating levels had the highest walking speed. [These] data suggest that inflammation blocks critical metabolic signals that support muscle maintenance. In addition, [systemic] inflammation may predispose the microglia to a pro-inflammatory state that is associated with neurodegeneration. Although it is not clear what causes age-associated chronic inflammation, possible mechanisms include a disregulated NF-kB pathway, impaired mitochondrial function leading to excessive reactive oxygen species (ROS) the accumulation of senescent cells, and a decline in autophagy with age. Whether reducing inflammation will lead to beneficial effects on human health and function is the defining biological and medical challenge of the next decade."

Tuesday, February 19, 2013
The use of nanoscale-featured scaffold materials is common in regenerative medicine research. Here is an example that can be used to improve and guide the regrowth of bone: "Artificial bone, created using stem cells and a new lightweight plastic, could soon be used to heal shattered limbs. Researchers have developed the material with a honeycomb scaffold structure that allows blood to flow through it, enabling stem cells from the patient's bone marrow to attach to the material and grow new bone. Over time, the plastic slowly degrades as the implant is replaced by newly grown bone. Scientists developed the material by blending three types of plastics. They used a pioneering technique to blend and test hundreds of combinations of plastics, to identify a blend that was robust, lightweight, and able to support bone stem cells. Successful results have been shown in the lab and in animal testing with the focus now moving towards human clinical evaluation. "We were able to make and look at a hundreds of candidate materials and rapidly whittle these down to one which is strong enough to replace bone and is also a suitable surface upon which to grow new bone. We are confident that this material could soon be helping to improve the quality of life for patients with severe bone injuries, and will help maintain the health of an ageing population.""

Tuesday, February 19, 2013
An interview with Aubrey de Grey of the SENS Research Foundation in Tendencias21, a Spanish publication. The occasion is the publication of a Spanish language edition of Ending Aging: "[Tendencias21]: Do you think that aging and death are not an inescapable destiny of human being? [Aubrey de Grey]: What is this thing "aging and death" in the question? It is very instructive that there is so much fatalism about aging that people consider aging to be synonymous with death. Death - from any cause, including causes that are related to how long ago you were born and also causes that are not - is not what I am working to avert. I am working to avert aging, i.e. the ill-health that is currently an inescapable consequence of being alive for a long time. And yes, I think that aging is emphatically NOT an inescapable thing - I am sure that it will eventually be defeated with medicine. [Tendencias21]: What are the steps or progress made so far by the science that could prolong human life and improve its quality, despite the passage of time? [Aubrey de Grey]: All the therapies that we need for the control of aging are within reach. In some cases, such as stem cell therapies to replace cells that die and are not automatically replaced by cell division, we are very close - clinical trials are already in progress. In other cases we are still working with mice, or even just cells in a dish, but even there we have a clear way forward to the development of medicine for people. [Tendencias21]: Do you believe that, in the not too distant future, we could avoid the ballast of the degenerative diseases associated with aging? [Aubrey de Grey]: Yes I do. I think we have at least a 50% chance of developing truly comprehensive rejuvenation medicine within 25 years, just so long as the early-stage, proof-of-concept research that is going on right now is adequately funded."

Monday, February 18, 2013
Adiponectin shows up here and there in considerations of the relationship between metabolism and natural variations in longevity. Researchers here demonstrate an association for adiponectin in human centenarians: "The physiological mechanisms that promote longevity remain unclear. It has been suggested that insulin sensitivity is preserved in centenarians, whereas typical aging is accompanied by increasing insulin resistance. The oldest-old individuals display raised total adiponectin levels, despite the potential correlation between enhanced adiponectin and all-cause and cardiovascular mortality. A group of 58 Polish centenarians (50 women and 8 men, mean age 101±1.34 years) and 68 elderly persons (55 women and 13 men, mean age 70±5.69 years) as controls [were used] to evaluate the level of adiponectin and its isoforms in sera of centenarians and to assess associations between adiponectin and metabolic parameters. The concentrations of all adiponectin isoforms were significantly higher in the oldest-old participants. In the centenarian group, total adiponectin positively correlated with age and HDL-cholesterol, and HMW-adiponectin was negatively associated with insulin and triglycerides. The long-lived participants had a lower incidence of hypertension, type 2 diabetes, overweight and obesity, with lower concentrations of serum glucose and insulin, and reduced [insulin resistance]. Our findings support the thesis that centenarians possess a different adiponectin isoform pattern and have a favorable metabolic phenotype in comparison with elderly individuals. However, additional work is necessary to understand the relevance of these findings to longevity."

Monday, February 18, 2013
Researchers here dig into the mechanisms by which female capacity for reproduction diminishes with age. This produces an interesting data point to add to the debate over the degree to which nuclear DNA damage might be a contributing cause of aging: "A woman's eggs decline in quality and quantity as she ages, at least in part because an important DNA repair pathway becomes impaired. The pathway, which includes proteins encoded by the well-known BRCA genes, is supposed to repair double-strand breaks in DNA. But as women get older, the study found, repair mechanisms lose efficiency and reproductive cells accumulate damaged genes and often commit suicide. While women are born with 1 million oocytes, only about 500 turn into full-fledged eggs over their lifetime. By the time women reach their early 50s, the remaining oocytes have almost completely degraded. Why the oocytes degrade so rapidly in comparison to other body tissues was a mystery. [Researchers] first tested mouse and human oocytes for double-strand breaks and found that the damage increased significantly with age. They also looked at expression of several repair proteins in the cells. Expression of BRCA1 and a handful of other repair genes decreased with age. The results implied that dysfunction in DNA repair may lead to genomic damage seen in aging oocytes. The researchers studied both mice and women with mutations in the BRCA1 [gene]. People with mutations in BRCA1 had lower oocyte reserves in their ovaries than those without the mutations, and mice with BRCA1 mutations had smaller litters of pups than wild type mice. "



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