Fight Aging! Newsletter, February 18th 2013

February 18th 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!



- Intern at the SENS Research Foundation This Summer
- Much of Modern Aging Research in a Short and Pithy Nutshell
- Deconstructing Deathism, an Essay
- Protein Restriction Slows Alzheimer's Progression in Mice
- Discussion
- Latest Headlines from Fight Aging!
    - Nitric Oxide and Longevity in Nematodes
    - On Greater Longevity in Colder Environments
    - Searching for Commonalities in Cancer
    - Dietary Fatty Acids and Autophagy
    - Comments on Teaching an Ethical View of Life Extension
    - Arguing DNA Damage as a Cause of Aging
    - Relative Risk For Causes of Cognitive Decline
    - An Upcoming Oxford Debate With Aubrey de Grey and Richard Faragher
    - More on mTOR and Gender Longevity Differences
    - Blocking Development of Rheumatoid Arthritis in Mice


Here is a great opportunity for undergraduate and recently graduated life scientists: a chance to intern this coming summer at the SENS Research Foundation, an ambitious and well-connected organization that funds work on repairing the cellular and molecular damage that causes aging. If this is an area of applied medical biotechnology that interests you - and it should, as today you stand at the ground floor of a field that will expand in decades ahead to dwarf present behemoth research communities like the cancer establishment - then I encourage you to apply. If this isn't your cup of tea, then point it out to any biologist friends you might have.

SENS Research Foundation's summer internships are for undergraduates (students working towards a Bachelor's degree) and students who have just completed their undergraduate work. Interns in this program can expect to do a considerable amount of scientific research using various techniques in the biosciences, which can include PCR, western blotting, DNA purification, gel electrophoresis, and many others. Each intern will be working on a different project, so no two will be doing the exact same thing. Though interns will build their lab skills considerably during their internship period, the strongest applicants will already have laboratory experience.

In 2013, SENS Research Foundation will be placing summer interns at four different locations: SRF's own Research Center in Mountain View, California; the Buck Institute for Research on Aging in Novato, California; the Wake Forest Institute for Regenerative Medicine in Winston-Salem, North Carolina; and SUNY Upstate Medical University in Syracuse, New York. Note that the SRF Research Center and the Buck Institute are in the same metropolitan area: the San Francisco Bay Area.

The application deadline for the summer internship program is March 31, 2013 at 11:00 PM PST. However, there will be an early deadline for applicants who would like to be considered for the SUNY Upstate program: February 24th, 2013 at 11:00 PM PST. Each program will run on its own schedule, with its own stipend and arrangements.


As a nod to the oft-quoted evolutionary theorist George Williams, "It is remarkable that after a seemingly miraculous feat of morphogenesis, a complex metazoan should be unable to perform the much simpler task of merely maintaining what is already formed". How and why we age are mysteries of the ages.

The "how" of this mystery is the purview of experimental biologists who try to understand the basic processes that lead to system maintenance failure - from the level of molecules to that of entire organisms - that we term "aging".

The "why" of this mystery is the purview of evolutionary theorists whose ideas shape the questions that biogerontologists pose, on the basis of the premise put forth by another preeminent geneticist and evolutionary biologist, Theodosius Dobzhansky, that "[n]othing in biology makes sense except in the light of evolution".

These experimental and evolutionary perspectives converge in the modern science of aging, and its curious cousin "longevity", in an attempt to unify extensive findings from diverse areas of biology.


The essay linked in this Fight Aging! post was originally published back in 2004, but I have no recollection of reading it back then - so I'm going to assume that many of you folk also missed it the first time around. Another item lost to the mists of memory is exactly where and when I first heard the term "deathism," in the sense of an outlook that promotes death as a good thing rather than something to be avoided. You won't find much mention of it prior to 2007 here at Fight Aging!, for example. Deathism is usually put forward in the context of aging as an essentially conservative view: deathists are people who stand against change and for the continuation of the status quo, often without any great consideration, no matter how terrible it might be, and no matter that rampant change is underway in all aspects of human life and society nowadays.

Many similarities can be found when comparing the person who believes that everyone should live the same lives as their parents, aging to death at the same count of years, with the person who doesn't want a new train line built, or decries the latest addition to the downtown skyline, or waxes nostalgic for the foods of yesteryear. But there is an important difference here: people who advocate for the continuation of death and aging are also advocating destruction, pain, and suffering on a grand scale in a way that other conservatives are not. Destruction, pain, and suffering is invariably not their motivation, but it is what they call for nonetheless, and that fact should not be swept politely under the table.

Tens of millions of lives are lost every year, and hundreds of millions more are locked in terrible degenerative suffering and frailty - the human cost of death by aging year upon year is four times that of an eternally ongoing World War II, a horrific toll that our society does its best to ignore. Thus it is socially acceptable to say that aging should continue, and the average person in the street will claim to want to age and die on the same schedule as his or her parents - because that is the socially correct answer, the conforming answer, the one that seems to be taught at a young age by some form of educational osmosis. Sheep and cliffs spring to mind.


Lower protein levels are one of the triggers for metabolic changes that occur due to a calorie restricted diet. In past years researchers have shown that reducing proteins - especially methionine - in the diet of laboratory animals while keeping calorie levels constant can reproduce a portion of the benefits provided by full calorie restriction.

In this recently published research, mice with many of the pathologies of Alzheimer's Disease showed fewer signs of the disease when given a protein-restricted diet supplemented with specific amino acids every other week for four months. Upcoming studies [will] attempt to determine whether humans respond similarly - while simultaneously examining the effects of dietary restrictions on cancer, diabetes and cardiac disease. Researchers found that a protein-restricted diet reduced levels of IGF-1 circulating through the body by 30 to 70 percent, and caused an eight-fold increase in a protein that blocks IGF-1's effects by binding to it. IGF-1 helps the body grow during youth but is also associated with several diseases later in life in both mice and humans.

This quote is from the principal researcher: "We always try to do things for people who have the problem now. Developing a drug can take 15 years of trials and a billion dollars. Although only clinical trials can determine whether the protein-restricted diet is effective and safe in humans with cognitive impairment, a doctor could read this study today and, if his or her patient did not have any other viable options, could consider introducing the protein restriction cycles in the treatment - understanding that effective interventions in mice may not translate into effective human therapies."

You might take note of those remarks as indicative of one of the ways in which regulation steers researchers towards deliberately aiming to produce marginal benefits rather than revolutionary advances - slowing the pace of progress and shutting down promising avenues of medical science before they even get started.


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 15, 2013
Nitric oxide shows up in many places in the the biochemistry of longevity, the processes by which differences in the operation of metabolism influence the pace of aging. In this example, however, it isn't particularly clear that it has any great relevance to human biology: "Although humans and many other organisms have the enzyme needed to produce nitric oxide, C. elegans does not. Instead, [the] worm can "hijack" the compound from the soil-dwelling Bacillus subtilis bacterium that is not only a favored food but also a common colonist within its gut. This resourcefulness [partially] explains why worms fed B. subtilis live roughly 50 percent longer than counterparts fed Escherichia coli, which does not produce the compound. In the new study, the average C. elegans lifespan increased by nearly 15 percent, to about two weeks, when researchers fed the worms nitric oxide-producing B. subtilis bacteria, compared to worms fed mutant B. subtilis with a deleted nitric oxide production gene. The research group also used fluorescent sensors to show that C. elegans does not make its own nitric oxide gas. When the worms were fed normal B. subtilis bacteria, however, the fluorescent signal appeared in their guts. Fluorescent labeling and other tests also demonstrated that B. subtilis-derived nitric oxide penetrated the worms' tissues, where it activated a set of 65 genes. Some had been previously implicated in stress resistance, immune response, and increased lifespan, though others have unknown functions. Importantly, the researchers showed that two well-known regulatory proteins were essential for activating all of the genes. "What we found is that nitric oxide gas produced in bacteria inside the worms diffuses into the worm tissue and activates a very specific set of genes acting through two master regulators, hsf-1 and daf-16, resulting in a high resistance to stress and a longer life. It's striking that a small molecule produced by one organism can dramatically affect the physiology and even lifespan of another organism through direct cell signaling.""

Friday, February 15, 2013
Why do cold-blooded species live longer in colder environments? Researchers have a prospective mechanism that is shared by mammals: "Scientists have known for nearly a century that cold-blooded animals, such as worms, flies and fish all live longer in cold environments, but have not known exactly why. Researchers [have] identified a genetic program that promotes longevity of roundworms in cold environments - and this genetic program also exists in warm-blooded animals, including humans. "This raises the intriguing possibility that exposure to cold air - or pharmacological stimulation of the cold-sensitive genetic program - may promote longevity in mammals." Scientists had long assumed that animals live longer in cold environments because of a passive thermodynamic process, reasoning that low temperatures reduce the rate of chemical reactions and thereby slow the rate of aging. "But now, at least in roundworms, the extended lifespan observed at low temperature cannot be simply explained by a reduced rate of chemical reactions. It's, in fact, an active process that is regulated by genes." [Researchers] found that cold air activates a receptor known as the TRPA1 channel, found in nerve and fat cells in nematodes, and TRPA1 then passes calcium into cells. The resulting chain of signaling ultimately reaches DAF-16/FOXO, a gene associated with longevity. Mutant worms that lacked TRPA1 had shorter life spans at lower temperatures. Because the mechanisms [also] exist in a range of other organisms, including humans, the research suggests that a similar effect might be possible. The study also links calcium signaling to longevity for the first time and makes a novel connection between fat tissue and temperature response. Researchers have known that lowering the core body temperature of warm-blooded animals, such as mice, by 0.9 degrees Fahrenheit can extend lifespan by 20 percent, but it hasn't been practical for humans to attempt to lower the core body temperature." It's worth noting that past research has shown that not all methods of lowering core body temperature in mammals will extend life. It matters how it's done, which suggests that it isn't so much temperature as the particular mechanisms that are running that is driving the effect. For example, calorie restriction is associated with a lower core body temperature.

Thursday, February 14, 2013
The broad variety and rapid change in mechanisms within cancerous cells is one of the reasons that cancer is hard to tackle - every cancer is different and evolving. Circumventing this to find truly effective cancer therapies will require the discovery of some mechanistic commonality that can be targeted, some biological process that all cancers depend on and which distinguishes their cells from non-cancerous cells. The proposed SENS approach, for example, is to go right to the root and remove all ability to lengthen telomeres in the body, as all cancers depend on that. The mainstream research community aims to find markers for cancer stem cells, or low-level mechanisms shared between cancers to some degree and which can be sabotaged to slow down or reverse progression of the disease. Not all shared mechanisms are sufficient to build a true cure, unfortunately. Here is an example of one such lesser mechanism in the early stages of research and development: "Epithelial to mesenchymal transition is important to embryonic development, turning stationary epithelial cells into mobile mesenchymal cells to move them within the embryo. For example, a cell might be converted and then gather with other cells forming, for example, the kidney. Once there, it transitions back to an epithelial cell again and stays put. Research has shown that carcinomas, tumors that form in the epithelium (lining) of organs are able to reactivate EMT. About 85 percent of all solid tumors are carcinomas. "We found that FOXC2 lies at the crossroads of the cellular properties of cancer stem cells and cells that have undergone epithelial to mesenchymal transition (EMT), a process of cellular change associated with generating cancer stem cells. There are multiple molecular pathways that activate EMT. We found many of these pathways also activate FOXC2 expression to launch this transition, making FOXC2 a potentially efficient check point to block EMT from occurring." [Researchers believe] that targeting FOXC2 pathway [will] be an effective therapeutic strategy for inhibiting EMT and consequently reducing EMT/cancer stem cell-associated metastasis, relapse and therapy resistance."

Thursday, February 14, 2013
The cellular housekeeping processes of autophagy show up everywhere in considerations of metabolism and aging: better repair of cellular damage and removal of unwanted metabolic byproducts has a noticeable beneficial effect on the longevity of an organism. Many of the genetic manipulations that extend life in laboratory species have been shown to enhance autophagy, just as does the practice of calorie restriction. Here researchers find that the marginal benefits resulting from the inclusion of omega fatty acids in the diet may also result from increased autophagy: "Researchers have discovered that simple mutations in genetic pathways conserved throughout evolution can double or triple the lifespan of C. elegans and that similar mutations in the corresponding mammalian pathways also regulate lifespan. Many of these mutations also make animals resistant to starvation, suggesting that common molecular mechanisms may underlie both response to nutrient deprivation and the regulation of lifespan. To find these mechanisms [scientists] searched genomic databases covering many types of animals for shared genes that respond to fasting by changing their expression. She found that expression of the C. elegans gene lipl-4 increases up to seven times in worms not given access to nutrients. A transgenic strain that constantly expresses elevated levels of lipl-4, even when given full access to food, was found to have increased levels of arachidonic acid (AA), an omega-6, and eicosapentanoic acid (EPA), an omega-3 fatty acid and to resist the effects of starvation. Following the implication that omega fatty acids stimulate a process leading to starvation resistance, the researchers found that feeding AA and another omega-6 fatty acid, but not EPA, activated autophagy in non-transgenic C. elegans with full access to nutrients. Since activation of autophagy has been shown to increase lifespan in several genetic models, the authors tested the effect of omega-6 fatty acids on C. elegans lifespan and found that roundworms consuming a full normal diet supplemented with omega-6 fatty acids lived 20 to 25 percent longer than usual. Since dietary supplementation with both omega-3 and omega-6 fatty acids has been shown to prevent or improve several human health conditions, the researchers tested the response of cultured human cells to omega fatty acid supplementation. As in C. elegans, the human cells responded to supplementation with the omega-6 acids, but not to EPA, by activation of autophagy, measured by levels of marker proteins. That result suggests that omega-6 acids induce autophagy across the full range of multicellular animal species. The researchers then showed that the lifespan-increasing properties of omega-6 fatty acids in C. elegans depend on the presence of genes required for autophagy."

Wednesday, February 13, 2013
Some comments from a social studies professor with an interest in engineered human longevity: "This year I devote two whole classes to aging and the ethics of life extension. Last week was our first class on the topic and I asked my students, who are all graduate level students in the humanities and social sciences, how many of them had taken a course where aging was either the focus, or even just a topic covered in, the course. Not a single hand went up! This simply reinforced my conviction that it is absolutely essential to teach the course I am teaching, and to dedicate two weeks to aging and the ethics of life extension. I hope it helps to fill what is an unfortunate gap in the education our students receive. In my opinion, the aging of the world's populations is the most interesting and important development of the 21st century. And yet the education our students (many of whom will go on to be teachers, professors, politicians, work in public policy, law, medicine, etc.) receive is one that is completely blind to this reality. This neglect is itself an oddity worthy of serious reflection. Why do so many scholars in the humanities and social sciences appear to have "aging blinders" on? I think the answer to this question is complex, and many distinct cultural and institutional factors account for this neglect. I will write a longer post about this in a few weeks. I believe that one of the main reasons for this neglect is that scholars ignore the ultimate causation of morbidity, mortality and behaviour. While the proximate causation of mortality (such as poverty and war) is on the radar of many in the humanities and social sciences, they do not adopt as diverse an explanatory toolbox as they ought to. Once you add an evolutionary perspective into the mix, the questions, topics and debates to be discussed and pondered are wondrous and pressing. And doing this has profoundly altered the topics I work on, and the manner in which I approach them, in both ethics and political theory."

Wednesday, February 13, 2013
A stochastic accumulation of nuclear DNA damage progresses throughout life. This is definitely a cause of increased cancer risk, one of the reasons why cancer is predominantly a disease of the old, but is it also a contributing cause of degenerative aging in general? This is an arguable proposition, with some researchers suggesting that DNA damage doesn't meaningfully impact aging over the length of a human life span, while others consider it the most important cause of aging. Here is a review paper on the subject. It is always pleasant to see researchers openly discuss increasing life span through biotechnology, even if I don't necessarily agree with the likely effectiveness of the research path they choose. It is still the case that many scientists will not talk openly about the goal of extending human life. "Genome instability has long been implicated as the main causal factor in aging. Somatic cells are continuously exposed to various sources of DNA damage, from reactive oxygen species to UV radiation to environmental mutagens. To cope with the tens of thousands of chemical lesions introduced into the genome of a typical cell each day, a complex network of genome maintenance systems acts to remove damage and restore the correct base pair sequence. Occasionally, however, repair is erroneous, and such errors, as well as the occasional failure to correctly replicate the genome during cell division, are the basis for mutations and epimutations. There is now ample evidence that mutations accumulate in various organs and tissues of higher animals, including humans, mice, and flies. What is not known, however, is whether the frequency of these random changes is sufficient to cause the phenotypic effects generally associated with aging. The exception is cancer, an age-related disease caused by the accumulation of mutations and epimutations. Here, we first review current concepts regarding the relationship between DNA damage, repair, and mutation, as well as the data regarding genome alterations as a function of age. We then describe a model for how randomly induced DNA sequence and epigenomic variants in the somatic genomes of animals can result in functional decline and disease in old age. Finally, we discuss the genetics of genome instability in relation to longevity to address the importance of alterations in the somatic genome as a causal factor in aging and to underscore the opportunities provided by genetic approaches to develop interventions that attenuate genome instability, reduce disease risk, and increase life span."

Tuesday, February 12, 2013
Cognitive decline, like most of the consequences of aging, stems from a range of root causes. Here researchers look at which of these causes contribute the most to the harmful end result: "Vascular brain injury from conditions such as high blood pressure and stroke are greater risk factors for cognitive impairment among non-demented older people than is the deposition of the amyloid plaques in the brain that long have been implicated in conditions such as Alzheimer's disease, a study [has] found. The research was conducted in 61 male and female study participants who ranged in age from 65 to 90 years old, with an average age of 78. Thirty of the participants were clinically "normal," 24 were cognitively impaired and seven were diagnosed with dementia, based on cognitive testing. The researchers also sought to determine whether there was a correlation between vascular brain injury and the deposition of beta amyloid (Αβ) plaques, thought to be an early and important marker of Alzheimer's disease. [They] also sought to decipher what effect each has on memory and executive functioning. "We looked at two questions. The first question was whether those two pathologies correlate to each other, and the simple answer is 'no.' Earlier research, conducted in animals, has suggested that having a stroke causes more beta amyloid deposition in the brain. If that were the case, people who had more vascular brain injury should have higher levels of beta amyloid. We found no evidence to support that." "The second was whether higher levels of cerebrovascular disease or amyloid plaques have a greater impact on cognitive function in older, non-demented adults. Half of the study participants had abnormal levels of beta amyloid and half vascular brain injury, or infarcts. It was really very clear that the amyloid had very little effect, but the vascular brain injury had distinctly negative effects. The more vascular brain injury the participants had, the worse their memory and the worse their executive function - their ability to organize and problem solve.""

Tuesday, February 12, 2013
Via the SENS Research Foundation: "Dr. Aubrey de Grey, SENS Research Foundation's Chief Science Officer, will be debating Dr. Richard Faragher, Chair of the British Society for Research on Ageing and Professor of Biological Gerontology at the University of Brighton, at Oxford's Sheldonian Theatre on February 19. Dr. de Grey will argue that the diseases of aging can be treated comprehensively by SENS therapies, and that these therapies could be developed in the coming decades, given sufficient research and funding. Dr. Faragher will dispute these points. Most importantly, both researchers agree that aging research is critically underfunded, and is the key to a healthier future. SENS Research Foundation is proud to be a sponsor of this event, and looks forward to an insightful debate about the most direct and effective research strategies for addressing age-related disability and disease. We would like to thank the Oxford University Society of Biomedical Sciences for hosting the event."

Monday, February 11, 2013
This paper comes from a group that considers aging to be a programmed process involving later-life overactivity of processes vital to early-life development rather than the result of stochastic accumulation of unrepaired cellular and molecular damage. I think that this view isn't well supported by the balance of evidence, but it does illustrate the complexity of aging that such divergent interpretations of the same data exist. The researchers' views don't diminish the data they produce from animal studies, but do mean that you have to read their interpretations of the data with that bias in mind: "One of the most long-standing mysteries of gerontology is that the females of most species live longer than the males. Not only most mammals but also women of different nations and at most historical periods live longer. Ironically, it may seem that males do not age faster but simply are weaker at any age. In fact, the mortality rate is higher in young males and teenagers too. Importantly, however, old males die from age-related diseases, whereas young males mostly die from risky behavior and physical competition with each other. While risky competition increases chances of mating and offspring, this simultaneously results in high accidental mortality (from fights) and males die young. There is no reason for them to be naturally selected for slower aging. Therefore, animals with a high accidental death rate tend to age faster. It is exceptionally important for such males early in life to be bigger and stronger (even on the cost of accelerated aging). In brief, early in life, TOR drives growth, robustness and reproduction, while causing aging and age-related diseases later in life. This example of antagonistic pleotropy is in line with the evolutionary theory. We speculate that aging as a continuation of growth driven by the same mTOR pathway, leading to aging and diseases of aging culminating in organismal damage and death. In sum, mTOR may drive both growth and aging, associated with hyper-functions coupled with signal-resistance and malfunction, loss of homeostasis, leading to development of deadly diseases of aging such as cardiovascular and metabolic diseases, neurodegeneration, cancer and organ atrophy or failure. We hypothesize that males have a higher levels of mTOR activity, providing advantage (and bigger size) for young males even though accelerated aging and early death might follow."

Monday, February 11, 2013
Progress towards a different approach to therapies for autoimmune conditions such as rheumatoid arthritis, though still not one that addresses root causes directly: "Scientists have demonstrated a new strategy for treating autoimmune disease that successfully blocked the development of rheumatoid arthritis in a mouse model. They say it holds promise for improved treatment of arthritis and other autoimmune disorders in people. Infusing a highly specific type of cell that regulates immune responses into arthritis-prone mice shut down the cascade of inflammation that damages tissues and joints. The method worked best when the infusions of CD8+ Treg cells were given at the same time that the animals were injected with a protein that triggered the arthritis-causing autoimmune reaction. "We found we could almost completely inhibit the disease in this setting." Even when administered weeks after the disease was initiated, CD8+ Treg infusions combined with low doses of methotrexate - a commonly used drug for rheumatoid arthritis - were able to significantly slow the arthritis process. The new strategy also blocked disease progression when the scientists injected peptide antigens to expand the rodents' own pool of CD8+ Tregs, rather than infusing them from outside. Overall, the results "suggest that [these] strategies represent a promising therapeutic approach to autoimmune disorders.""



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