Fight Aging! Newsletter, May 28th 2012

May 28th 2012

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 Three Types of Aging Research
- An Interview on Radical Life Extension
- A Tale of Telomerase
- p16INK4A and Biological Age
- Discussion
- Latest Headlines from Fight Aging!


Here is an outline of the way in which I divide the aging research community:

"Class 1: Investigating Aging: By far the largest component of the aging science community is made up of researchers who are not working on ways to alter or repair the aging process. They investigate only, and thus the majority of funds devoted to the science of aging still go towards studies that aim to make no difference to the world beyond gathering data. This group include most of those who run demographic studies of human longevity, for example.

"Class 2: Working to Slow Aging: The larger minority class in aging research is made up of researchers and funding institutions who are working towards ways to slow aging, or working on related areas that will be used in constructing therapies to slow aging. The typical approach here is to reverse engineering the genetic and other low-level biochemical roots of known differences in longevity (such as the effects of calorie restriction, or the differences in life span between similar species), and then try to reproduce some of those differences using drugs, gene therapies, and other similar means. The view of these researchers is largely that we are a long way from any practical results, and those results will only offer incremental gains - a viewpoint I agree with.

"Class 3: Working to Reverse Aging: The smallest and most important cohort of researchers are those who are working on ways to repair, reverse, or work around the root causes of aging - the SENS Foundation research network being the archetype, though not the only set of researchers and laboratories involved in this work. This class are the most important because their approach is the only viable path we can see that has a good chance of producing rejuvenation biotechnology capable of greatly extending healthy life in the elderly - through restoring youthful function and vigor. This is the smallest cohort because we do not live in a particularly rational world.

"The sea change in the aging research community over the past decade or so has largely manifested as a transformation of researchers from the bulk of class 1 into up and coming enthusiasts of class 2. As it became respectable to talk about doing something about aging - thanks to the hard work of a comparatively small number of advocates and visionary scientists - there has been a steady shifting of research priorities. The investigators still outnumber research groups working on ways to alter the course of aging, but the trend is clearly towards a field that develops clinical applications in medicine rather than only informing the medical profession of what to expect in their patients.

"Now that the research community is essentially persuaded to the view that work on aging is good, interesting, and plausible, the next - and equally important - goal of advocacy is to persuade a great many more researchers to work on the SENS vision for rejuvenation biotechnology or equivalent scientific programs: to move in to class 3."


An interview with a philosopher on the topic of radical life extension was published recently at the Atlantic:

"Today I'll point out an interview with Bennett Foddy, the author of The Right and Wrong of Growing Old: Assessing the Argument from Evolution, who fits into the interesting - and possibly small - category of people who both (a) see the only viable way forward in longevity science as being the same old slow boat of small, expensive gains achieved by slowing aging through metabolic manipulation, and (b) think that we'll make good progress that way. ... From the blurb to his book: One argument which is frequently levelled against the enhancement of human biology is that we do not understand the evolved function of our bodies well enough to meddle in our biology without producing unintended and potentially catastrophic effects. In particular, this argument is levelled against attempts to slow or eliminate the processes of human ageing, or 'senescence', which cause us to grow decrepit before we die. In this article, I claim that even if this argument could usefully be applied against attempts to enhance other human traits, it cannot be valid in the case of attempts to enhance the various processes that constitute senescence.

"Now I completely agree with the argument noted in the first sentence above, if not the rest of it - that we don't understand enough about metabolism to make good progress in manipulating it to slow aging to a great enough degree to matter. By which I mean we'll be old and dying by the time that useful results are produced, at staggering cost - and those results won't do much at all for people who are already old and dying, because all they will do is slow down aging. It is far better to focus on the SENS vision of repairing damage rather than just slowing down the pace at which it occurs. For one, repair should be easier as it isn't anywhere near as large a swamp of unknowns: the list of biochemical damage that we need to repair is known, means of repair have been planned in some detail, and effective repair biotechnologies for these known forms of age-related damage will actually produce rejuvenation in the old.

"But on to the interview at the Atlantic, which makes for interesting reading. It would be pleasant to live in a world in which all we argued over was how exactly we should work to extend the healthy human life span and rescue the old from their degenerations. I should note that Foddy is a philosopher rather than a life scientist, so he's not quite as careful with his language as he should be - using 'life span' in place of 'life expectancy at birth', for example. But the general points he makes stand, and it is always good to see another member of the philosophy-slash-bioethics class explicitly place himself in opposition to the deathism of Fukuyama and Kass."


From the SENS Foundation, some more background and caveats on the recent study demonstrating an extension of life span in mice using telomerase gene therapy:

"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 MarĂ­a 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."


p16INK4A is a gene with many aliases, such as p16, CDKN2A, or cyclin-dependent kinase inhibitor 2A. This tends to happen for genes and the resulting protein products that are involved in numerous important mechanisms in the cell and were cataloged comparatively early on. Many different research groups will be working on the gene in isolation, and this results in a range of different names for the same thing. Levels of the protein produced by p16INK4A are associated with cellular senescence and the pace of aging:

"The link between levels of the protein p16INK4A and aging has been known for some years. In particular, it shows up in the senescent cells that accumulate with age, something that researchers have managed to make use of: you might recall last year's study that showed beneficial effects from destroying senescent cells in rats. That research group used p16INK4A as a basis for their method of selective destruction, targeting only those cells that had become senescent and thus removing their contribution to the aging process.

"In this study the researchers examined skin cells from middle aged people aged 43 to 63. They compared a group who had a strongly family history of extreme longevity to age-matched controls. They found that p16 expression in skin cells was significantly lower in the group that had the strong family history of longevity. They conclude 'a younger biological age associates with lower levels of p16INK4a positive cells in human skin.' This study supports the idea that p16 expressing cells are linked to age both from a chronological as well as biological perspective. Work needs to be done to find a way to remove p16 positive cells from all tissues of the body on a regular basis. Such a therapy, if it existed, may act to reduce aging.

"This all ties back in to cancer suppression versus tissue proliferation. Increased senescence in cells is one way of biasing the average over time to a lower rate of cancer - because the cells most likely to cause issues have been taken out of circulation and are no longer replicating. They should be destroyed by the immune system, but the immune system has its own age-related issues and falls down on that job, leaving the senescent cells to lurk and emit harmful signaling chemicals that damage surrounding tissue.

"The flip side of the coin is that less replication among cells translates to less resilient tissues and organs, and thus faster aging. As mammalian biochemistry is set up by default, you can either be generating lots of fresh cells with a higher cancer risk, or aging faster due to poor tissue maintenance, but with a lower cancer risk. Biotechnology will let us escape from this Hobson's choice in due course - a method for tweaking the system associated with another cancer suppression gene to generate both less cancer and slower aging has been demonstrated in mice, for example. More and better technologies will emerge in human medicine in the fullness of time.

"In particular, rather than focusing on metabolic tinkering to incrementally improve matters, the better approaches would be to (a) repair the ability of the immune system to eliminate senescent cells at a youthful level, and (b) develop therapies to regularly completely sweep senescent cells from the body. The effects of reducing senescent cell numbers in rats were sufficiently good that more work will be devoted to that sort of strategy in the future - and a good thing too."


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, May 25, 2012
A theory that has emerged in recent years points to forms of amyloidosis as the final limiting process for human life span. Extremely long-lived people, who have survived or evaded all the common fatal age-related conditions, appear to die because of amyloid buildup. The evidence is good enough for the SENS Foundation to start funding work on a therapy - like all the mechanisms of aging, this is something that can be fixed through appropriate use of biotechnology. Here's a little more on the topic (and a link to a PDF format research paper): "Supercentenarians are persons who have lived beyond the age of 110. Currently there are only about 80 such known individuals in the world whose age is verified. These people represent the limit of human lifespan. For a variety of reasons not fully understood but including lifestyle choices, genetic variants, and chance, these individuals have escaped the usual causes of death including cancer, heart disease and stroke. However, eventually they too die, with the world record holder being Jeanne Calment who survived until age 122. In a newly published review Drs. Stephen Coles and Thomas Young of the UCLA Gerontology Research Group point out what it may be that is killing supercentenarians: amyloidosis. Amyloidosis is a disease state hallmarked by the deposition of fibers of abnormally clumped masses of transthyretin. The protein transthyretin normally acts to carry thyroid and other hormones. Mutations in the gene make the fibers abnormally sticky and they tend to clump into long fibers which are deposited in multiple organs. Through early onset amyloidosis leads to disease, it is of interests that supercentanarians all seem to have significant amounts of it. Though not proven it is possible the amyloid is killing them. These persons have already escaped the typical causes of death however they have lived for so long, the normally innocuous amounts of amyloid that increase with age may actually become toxic to them because they have lived so many years. Where this line of reasoning gets exciting is that experimental drugs exist which may eliminate amyloid."

Friday, May 25, 2012
An example of the way in which the machinery of cells is very intertwined, components reused by evolution in many different mechanisms: "This was certainly an unexpected finding. It is rather uncommon for one gene to have two very different and very significant functions that tie together control of aging and inflammation. The two, if not regulated properly, can eventually lead to cancer development. It's an exciting scientific find. ... For decades, the scientific community has known that inflammation, accelerated aging and cancer are somehow intertwined, but the connection between them has remained largely a mystery ... What was known [was] that a gene called AUF1 controls inflammation by turning off the inflammatory response to stop the onset of septic shock. But this finding, while significant, did not explain a connection to accelerated aging and cancer. When the researchers deleted the AUF1 gene, accelerated aging occurred, so they continued to focus their research efforts on the gene. ... The current study reveals that AUF1, a family of four related genes, not only controls the inflammatory response, but also maintains the integrity of chromosomes by activating the enzyme telomerase to repair the ends of chromosomes, thereby simultaneously reducing inflammation, preventing rapid aging and the development of cancer. ... [Researchers are now] examining human populations for specific types of genetic alterations in the AUF1 gene that are associated with the co-development of certain immune diseases, increased rates of aging and higher cancer incidence in individuals to determine exactly how the alterations manifest and present themselves clinically."

Thursday, May 24, 2012
The underlying infrastructural methods and technologies for working with stem cells are consistently improving - which lowers cost, thus allowing more research and development to take place. Here is an example: "researchers have proven that a special surface, free of biological contaminants, allows adult-derived stem cells to thrive and transform into multiple cell types. Their success brings stem cell therapies another step closer. An embryo's cells really can be anything they want to be when they grow up: organs, nerves, skin, bone, any type of human cell. Adult-derived 'induced' stem cells can do this and better. Because the source cells can come from the patient, they are perfectly compatible for medical treatments. ... We turn back the clock, in a way. We're taking a specialized adult cell and genetically reprogramming it, so it behaves like a more primitive cell. ... Before stem cells can be used to make repairs in the body, they must be grown and directed into becoming the desired cell type. Researchers typically use surfaces of animal cells and proteins for stem cell habitats, but these gels are expensive to make, and batches vary depending on the individual animal. ... human cells are often grown over mouse cells, but they can go a little native, beginning to produce some mouse proteins that may invite an attack by a patient's immune system. ... [A] polymer gel created by [researchers] in 2010 avoids these problems because researchers are able to control all of the gel's ingredients and how they combine. ... [Researchers] had shown that these surfaces could grow embryonic stem cells, [but] the polymer surface can also support the growth of the more medically promising induced stem cells, keeping them in their high-potential state. To prove that the cells could transform into different types, the team turned them into fat, cartilage and bone cells. They then tested whether these cells could help the body to make repairs. Specifically, they attempted to repair five-millimeter holes in the skulls of mice. The weak immune systems of the mice didn't attack the human bone cells, allowing the cells to help fill in the hole. After eight weeks, the mice that had received the bone cells had 4.2 times as much new bone, as well as the beginnings of marrow cavities. The team could prove that the extra bone growth came from the added cells because it was human bone."

Thursday, May 24, 2012
Changes in the stem cell niche are a good part of the age-related decline in stem cell activity, which explains why old stem cells can perform like young stem cells if put into a young environment, and vice versa. Here researchers compensate for one of those niche changes: "Stem cells reside within a microenvironment of other cells - the niche - that is known to play a role in stem cell function. For example, after a tissue is injured, the niche signals to stem cells to form new tissue. It is believed that stem cells and their niche send signals to each other to help maintain their potency over a lifetime. But while the loss of tissue and organ function during aging has been attributed to decreases in stem cell function, it has been unclear how this decline occurs. [There are] a number of possible scenarios, such as whether the loss of tissue function is due to a decrease in the number of stem cells, to the inability of stem cells to respond to signals from their niche, or to reduced signaling from the niche. ... researchers discovered that as the stem cell niche [in flies] ages, the cells produce a microRNA (a molecule that plays a negative role in the production of proteins from RNA) known as let-7. This microRNA is known to exist in a number of species, including humans, and helps time events that occur during development. This increase in let-7 leads to a domino effect that flips a switch on aging by influencing a protein known as Imp, whose function is to protect another molecule, Upd, which is secreted from a key area of the niche. In short, Upd promotes the signaling that keeps stem cells active and in contact with the niche so that they can self-renew. And as aging advances, increasing expression of let-7 ultimately leads to lower Upd levels, decreasing the number of active stem cells in the niche. What leads to accumulation of let-7 in the niche of aged flies still remains an open question. The researchers also demonstrated they could reverse this age-related loss of stem cells by increasing expression of Imp."

Wednesday, May 23, 2012
Researchers are working on creating regeneration in mammals where it does not normally happen: "Researchers have long tried to get the optic nerve to regenerate when injured, with some success, but no one has been able to demonstrate recovery of vision. A team [now] reports a three-pronged intervention that not only got optic nerve fibers to grow the full length of the visual pathway (from retina to the visual areas of the brain), but also restored some basic elements of vision in live mice. ... [the mice were able to] regain some depth perception, the ability to detect overall movement of the visual field, and perceive light. ... Previous studies [have] demonstrated that optic nerve fibers can regenerate some distance through the optic nerve, but this is the first study to show that these fibers can be made to grow long enough to go from eye to brain, that they are wrapped in the conducting 'insulation' known as myelin, that they can navigate to the proper visual centers in the brain, and that they make connections (synapses) with other neurons, allowing visual circuits to re-form. ... [Researchers] combined three methods of activating the growth state of neurons in the retina, known as retinal ganglion cells: stimulating a growth-promoting compound called oncomodulin, [elevating] levels of cyclic adenosine monophosphate (cAMP) and deleting the gene that encodes the enzyme PTEN. ... these interventions have a synergistic effect on growth of optic nerve fibers. ... The eye turns out to be a feasible place to do gene therapy. The viruses used to introduce various genes into nerve cells mostly remain in the eye. Retinal ganglion cells are easily targetable."

Wednesday, May 23, 2012
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."

Tuesday, May 22, 2012
Researchers conclude that the extension of life in mice due to rapamycin is in fact a slowing of aging due to the breadth of its effects: "Rapamycin increases lifespan in mice, but whether this represents merely inhibition of lethal neoplastic diseases, or an overall slowing in multiple aspects of aging is currently unclear. We report here that many forms of age-dependent change, including alterations in heart, liver, adrenal glands, endometrium, and tendon, as well as age-dependent decline in spontaneous activity, occur more slowly in rapamycin-treated mice, suggesting strongly that rapamycin retards multiple aspects of aging in mice, in addition to any beneficial effects it may have on neoplastic disease. We also note, however, that mice treated with rapamycin starting at 9 months of age have significantly higher incidence of testicular degeneration and cataracts; harmful effects of this kind will guide further studies on timing, dosage, and tissue-specific actions of rapamycin relevant to the development of clinically useful inhibitors of TOR action." You might also look at recent research focused on separating the beneficial effects of rapamycin from the undesirable side-effects.

Tuesday, May 22, 2012
As an addendum to research showing that removal of visceral fat in mice extends life, here is work showing that it reduces risk of some cancers as well: "obesity increases the risk of heart disease, diabetes and cancer. But there have not been clinical studies to determine if the surgical removal of fat tissue would decrease cancer risk in humans. ... researchers found that surgical removal of abdominal fat from obese mice fed a high-fat diet had between 75-80 percent fewer UV-induced skin cancers than mice that did not undergo fat-removal surgery. Although scientists understand that tissue fat may play a role in tumor formation, there has been little research on the molecular mechanisms of how a high-fat diet increases the formation of skin cancer. This new study suggests that abdominal fat in mice secretes proteins that enhance the risk of cancer. Once the original fat tissue is removed, the biochemical properties of new fat tissue that appear after surgery are less harmful. ... It would be interesting to see if surgical removal of fat tissue in animals would prevent obesity-associated lethal cancers like those of the pancreas, colon and prostate. Whether removal of tissue fat in humans which has certain risks would decrease the risk of life-threatening cancers in humans is not known." A better approach is not to gain the fat tissue, and thus its unfortunate metabolic effects, in the first place - or work to lose it the traditional way, through improved diet and exercise, both of which have broad health benefits.

Monday, May 21, 2012
Cryonics provider Alcor gets a section in this Phoenix Magazine article on the industries associated with end of life management. It starts half way down the third page of the piece: "Max More, [the] CEO of the Alcor Life Extension Foundation is discussing the existential benefits of cryonics - i.e. the preservation of clinically-dead human beings at super-cold temperatures for the purpose of resuscitating them, presumably far in the future. Founded in 1972 by California couple Fred and Linda Chamberlain, Alcor relocated to Arizona in 1994 and currently hosts 110 cryopreserved patients in its hangar-like headquarters near the Scottsdale Airport. ... More isn't just the CEO of Alcor - he's also a longtime member. Known and respected as an advocate of transhumanist principles - a movement that proposes to eliminate aging and elevate the human condition to near godly heights - More first became hooked on cryonics as a 22-year-old undergraduate at the University of Oxford. At the time, Alcor was enjoying a surge in membership and positive international publicity. More, a young deep-thinker steeped in the science fiction classics of Philip K. Dick and Robert Heinlein, was intrigued. So he took out a life-insurance policy on himself ('At that age, it cost nothing...') to pay for his eventual one-time Alcor cryopreservation fee, which runs $200,000 for full-body patients and $80,000 for neuropatients. More chose the neuropatient option. 'To revive a cryopreserved patient, science and technology would have to advance to the point where minute repairs could be made to a hundred billion neurons. It seems to me that regenerating or cloning a new body would be relatively easy by comparison,' he says reasonably. 'No reason to preserve my broken down old body.' ... More's main focus is to bolster Alcor's membership rolls, which he concedes have stagnated in recent years, due both to the flagging economy and lax public-outreach efforts by previous CEOs. As of February 2012, Alcor had 957 members - still-living future 'patients' who had paid the one-time cryonics fee or taken out life insurance and made Alcor the beneficiary. The members sustain the nonprofit's day-to-day operations by paying $800 yearly dues until their legal deaths. (More is careful not to use the word 'death' without a qualifier; the foundation's entire doctrine is predicated on the idea that its patients aren't dead in the absolute sense.)"

Monday, May 21, 2012
A recent paper: "The biological aging process is commonly associated with increased risk of cardiovascular diseases. Several theories have been put forward for aging-associated deterioration in ventricular function, including attenuation of growth hormone (insulin-like growth factors and insulin) signaling, loss of DNA replication and repair, histone acetylation and accumulation of reactive oxygen species. Recent evidence has depicted a rather unique role of autophagy as another important pathway in the regulation of longevity and senescence. Autophagy is a predominant cytoprotective (rather than self-destructive) process. It carries a prominent role in determination of lifespan. Reduced autophagy has been associated with aging, leading to accumulation of dysfunctional or damaged proteins and organelles. To the contrary, measures such as caloric restriction and exercise may promote autophagy to delay aging and associated comorbidities. Stimulation of autophagy using rapamycin may represent a novel strategy to prolong lifespan and combat aging-associated diseases. Rapamycin regulates autophagy through inhibition of the nutrient-sensing molecule mammalian target of rapamycin (mTOR). Inhibition of mTOR through rapamycin and caloric restriction promotes longevity."



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