Fight Aging! Newsletter, November 5th 2012

November 5th 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!



- Considering Strategy in Aging Research
- A Review of "The Singularity"
- Not All Longevity Manipulations Play Nice Together
- A Possible Metabolic Signature of Biological Age in Mice
- Discussion
- Latest Headlines from Fight Aging!
    - Investigating the Mechanisms of Cellular Senescence
    - Creating Myelin-Producing Cells to Order
    - Promoting Remyelination by Blocking Hyaluronidase
    - Deepening the Puzzle
    - Considering Antagonistic Pleiotropy
    - More Mitochondrially Targeted Antioxidant Results
    - Exercise Improves Cognitive Function
    - Cartilage From Induced Pluripotent Stem Cells
    - Commenting on the Utility of AGE-Breakers
    - Histone Deacetylase Inhibitors Preserve Function in Aging Axons


The research community has as many opinions as researchers when it comes to how best to proceed with lengthening healthy human life spans. There are some clearly identifiable camps, however, such as slowing aging by manipulating metabolism versus reversing aging by repairing the damage that causes degeneration. Here are some thoughts on these camps and some of their subdivisions from Aubrey de Grey of the SENS Foundation:

The September 2012 issue of Scientific American includes a commentary contrasting two approaches to combating aging. Like almost all general-audience piece, and despite the best efforts of most experts in the field, it highlights the goal of life extension rather than stressing that any longevity benefits will be a side effect of health benefits ... The value of the article, though diminished thereby, is still substantial, in that it provides a clear description of the contrast between the "combat one disease at a time" approach generally taken by geriatricians and the holistic "combat aging itself" approach favored by most biogerontologists.

As those readers familiar with my work will know, I view both such approaches as highly unlikely to deliver substantial postponement of age-related ill health in the remotely foreseeable future, but not for the reasons generally given by the proponents of the other approach. Geriatricians reject combating of "aging itself" because they don't generally view aging as a medical condition at all, but instead merely view chronological age as a risk factor for various types of ill health. Biogerontologists, conversely, reject the "one disease at a time" approach because they believe that there will always be something - the very same "aging itself," of course - that will be a source of exponentially accelerating ill health however many specifics are defeated.

The SENS perspective is that it is inaccurate and misleading to draw a sharp distinction between "aging itself" and the specific aspects of age-related ill health, first because where one draws that distinction is arbitrary - Are foam cells atherosclerosis yet, for example? Are fatty streaks? - and second because the lifelong changes that drive ill health, and thus hold the the only logical claim to be lumped under the term "aging," are themselves not aspects of any meaningful unitary process, but are instead relatively independent processes occurring as side-effects of different aspects of metabolism.


A documentary film entitled The Singularity is the latest in a line of works from recent years to examine the near future of technology and its implications: a convergence of biotechnology, ever-increasing computing power, and molecular nanotechnology means that we will become capable of engineering ourselves to much the same degree as we presently choose to engineer our surroundings. Why would we stick with the flaky, error-prone, and short-lived evolved version of human biology when far better and more cost-effective replacements can be built? Here is a short review:

Doug Wolens' latest documentary captures the argument between the two sides. The Singularity takes the form of a series of intercut interviews, with animations illustrating various points ... Wolens' subjects include, unsurprisingly, people like Kurzweil himself, roboticist Cynthia Breazeal, and gerontologist Aubrey de Grey. But Wolens also interviews people not normally associated with the speculative edge of artificial intelligence and biomolecular engineering, such as Richard A. Clarke, the former chief counterterrorism advisor to the U.S. National Security Council, and the current U.S. secretary of defense, Leon Panetta.

While The Singularity doesn't cover a great deal of ground that's new to anyone already familiar with the concept, it does provide crisp snapshots of the current state of the debate and many of the main players.


One of the pleasant aspects of the repair approach to intervention in aging, such as that proposed in the Strategies for Engineered Negligible Senescence (SENS), is that all distinct forms of repair therapy can reasonably be expected to complement one another. Undergo a procedure to fix mitochondrial damage or break down an AGE such as glucospane, for example, and you are better off. Undergo both therapies and you will gain a commensurately greater benefit.

Unfortunately, this expectation of complementary therapies is very much not the case when it comes to attempts to slow down aging by genetic, epigenetic, or other metabolic manipulation. Metabolism is enormously complex, and even the well-studied phenomenon of calorie restriction isn't yet fully understood in terms of how the machinery of genes, proteins, and controlling signals all ties together to increase life span and improve health. Varied methods of extending life by slowing aging often turn out to operate on different portions of the same mechanism, or to be harmful when used together even though they are beneficial on their own.

One thing often tried by research groups that discover a novel way of slowing aging in laboratory animals is to try out the new method in calorie restricted animals: will the effects on life span complement one another and thus lead to a greater extension of life than is the case for either method on its own? Few presently known genetic alterations or other methods of slowing aging produce more than a 30% life extension in mice, and the standing record is 60-70% for growth hormone deficient mice - so at this point in time, it seems unlikely that any new life span record will be set through slowing aging without employing some complementary combination of techniques.

That this hasn't yet happened suggests that we shouldn't hold out much hope for the next five to seven years - there has, after all, been a lot of experimentation in mice over the past decade, and especially since the record set using growth hormone deficient mice. Unfortunately purely negative results don't tend to be published as often as positive results, so it's not a straightforward matter to find out which combinations of the various known methods to slow aging in mice have been tried only to fail.


A low-cost, reliable method of measuring biological age is greatly sought after by the research community. People and laboratory animals age at different rates - by which I mean that they accumulate damage and changes characteristic of aging at different rates. Thus two individuals of the same species and same chronological age might have different biological ages thanks to life style, environment, access to medicine, and so forth.

Some interventions, such as calorie restriction, can slow the pace at which an individual ages, but measuring this slowing is a challenging process. Biological age is a simple concept at the high level, but finding a quick and reliable way to actually measure it has yet to happen. Thus while researchers would like to have rapid answers as to how effective any given method of slowing aging might be, they must wait and run long-lasting studies. The bottom line measure for any slowing of aging is to wait for the individuals in question to live out their lives and thus measure by effect on life span. Even in short-lived mice this can require years and thus a great deal of money. In longer-lived animals, ourselves included, it is simply impractical to run the necessary studies.

When it comes to the forthcoming generation of therapies capable of limited rejuvenation - by repairing some of the damage that causes degenerative aging - the situation is much the same, as is the need for a quick and easy measure of biological age. A therapy that actually produces some degree of rejuvenation should make a laboratory animal biologically younger than peers with the same chronological age. But how to measure that change without employing the lengthy and expensive wait-and-see approach?

Given the present state of affairs, any quick measure of biological age will speed research, making it very much faster and cheaper to assess varied means of extending healthy life. Some experiments that would presently require a year or more could be conducted in a few weeks or months: apply the therapy and evaluate the resulting changes in measures of biological age.

Several lines of research look promising when it comes to yielding a way to reliably and consistently evaluate biological age. One involves measurement of DNA methylation levels, and despite initial setbacks it may yet prove possible to tease out a useful measure from changes in the dynamics of telomere length. There are others. Here, for example, is a recent paper in which researchers present a method based on measurement of metabolite levels.


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, November 2, 2012
Senescent cells are those that have left the cell cycle without being destroyed, either by the immune system or by one of the processes of programmed cell death. They remain active, however, exhibiting what is termed a senescence-associated secretory phenotype (SASP): these cells secrete all sorts of chemical signals that prove harmful to surrounding tissues and the body as a whole - through promotion of chronic inflammation, for example. The number of senescent cells in tissue grows with age, and this increase in numbers is one of the root causes of aging. Researchers have demonstrated benefits in mice through destroying senescent cells without harming other cells. Regular targeted destruction of senescent cells could be the basis for therapies that remove this contribution to degenerative aging. Any other approach would require understanding more about SASP and how to control or reverse the unpleasant effects of senescence - and here is an example of this sort of research, aimed at identifying controlling mechanisms with an eye to building therapies to reduce SASP: "With advancing age, senescent cells accumulate in tissues and the SASP-elicited proinflammatory state is believed to have a complex influence on age-related conditions. For example, two major SASP factors, IL-6 and IL-8, together with other SASP factors, attract immune cells to the tissue in which senescent cells reside; depending on the tissue context, this immune surveillance can promote processes such as wound healing, the resolution of fibrosis, and tumor regression. At the same time, SASP factors can compromise the integrity of the ECM, thus facilitating cancer cell migration. In addition, the systemic proinflammatory phenotype seen in the elderly is believed to affect a broad range of age-related pathologies, including diabetes, cancer, neurodegeneration and cardiovascular disease and contributes to an age-related decline of the adaptive immune system (immunosenescence). Despite the great potential impact of the SASP on the biology of senescence and aging, the mechanisms that regulate SASP are poorly understood. ... Here, we report the identification of NF90 as an RNA-binding protein that binds to numerous mRNAs encoding SASP factors (collectively named SASP mRNAs) and coordinately influences their post-transcriptional fate in a senescence-dependent manner. In young, early-passage, proliferating fibroblasts, high NF90 levels contributed to the repression of SASP factor production. This repression was elicited mainly via reduction in SASP factor translation ... By contrast, in senescent cells NF90 levels were markedly reduced, which allowed increased expression of numerous SASP factors. Our results are consistent with a role for NF90 as a coordinator of the inhibition of SASP factor production in early-passage, proliferating fibroblasts; in senescent cells, the lower levels of NF90 lead to SASP de-repression, permitting higher expression of SASP factors"

Friday, November 2, 2012
Myelin sheaths the axons of nerve cells, but the integrity of this sheathing degrades with age. Transplants of neural stem cells can be used to encourage myelin formation, and researchers are exploring this approach as a therapy for conditions involving more profound myelin loss. There is always a demand in this sort of research for better and cheaper ways to obtain cells that have the desired effect. It is not trivial, for example, to isolate the right sort of neural stem cell, or establish a protocol for producing these cells from embryonic or induced pluripotent stem cells. A great deal of stem cell research these days involves the discovery of chemical signals, growth environments, and other necessary items to guide the growth of specific cell types. Here is an example for myelin-forming cells, which will no doubt contribute to the next round of research and development of cell therapies aimed at regrowth of myelin: "Researchers have unlocked the complex cellular mechanics that instruct specific brain cells to continue to divide. This discovery overcomes a significant technical hurdle to potential human stem cell therapies; ensuring that an abundant supply of cells is available to study and ultimately treat people with diseases. "One of the major factors that will determine the viability of stem cell therapies is access to a safe and reliable supply of cells. This study demonstrates that - in the case of certain populations of brain cells - we now understand the cell biology and the mechanisms necessary to control cell division and generate an almost endless supply of cells." The study focuses on cells called glial progenitor cells (GPCs) that are found in the white matter of the human brain. These stem cells give rise to two cells found in the central nervous system: oligodendrocytes, which produce myelin, the fatty tissue that insulates the connections between cells; and astrocytes, cells that are critical to the health and signaling function of oligodendrocytes as well as neurons. One of the barriers to moving forward with human treatments for myelin disease has been the difficulty of creating a plentiful supply of necessary cells, in this case GPCs. Scientists have been successful at getting these cells to divide and multiply in the lab, but only for limited periods of time, resulting in the generation of limited numbers of usable cells. ... Overcoming this problem required that [researchers] master the precise chemical symphony that occurs within stem cells, and which instructs them when to divide and multiply, and when to stop this process and become oligodendrocytes and astrocytes."

Thursday, November 1, 2012
Myelin is the material sheathing axons in nerve cells. A number of conditions involve loss of myelin, such as multiple sclerosis (MS), but loss of myelin integrity occurs to a lesser degree for all of us as we age, and is thought to contribute to the characteristic cognitive decline of later years. Thus research into ways to regenerate myelin sheathing has broad potential application and is worth keeping an eye on: "We have identified a whole new target for drugs that might promote repair of the damaged brain in any disorder in which demyelination occurs. Any kind of therapy that can promote remyelination could be an absolute life-changer for the millions of people suffering from MS and other related disorders. In 2005, [researchers] discovered that a sugar molecule, called hyaluronic acid, accumulates in areas of damage in the brains of humans and animals with demyelinating brain and spinal cord lesions. Their findings at the time [suggested] that hyaluronic acid itself prevented remyelination by preventing cells that form myelin from differentiating in areas of brain damage. The new study shows that the hyaluronic acid itself does not prevent the differentiation of myelin-forming cells. Rather, breakdown products generated by a specific enzyme that chews up hyaluronic acid - called a hyaluronidase - contribute to the remyelination failure. This enzyme is highly elevated in MS patient brain lesions and in the nervous systems of animals with an MS-like disease. The research team [found] that by blocking hyaluronidase activity, they could promote myelin-forming cell differentiation and remyelination in the mice with the MS-like disease. Most significantly, the drug that blocked hyaluronidase activity led to improved nerve cell function. The next step is to develop drugs that specifically target this enzyme."

Thursday, November 1, 2012
One of the many oddities in the way in which the public at large approaches aging is captured by the existence of a thriving "anti-aging" marketplace, full of people selling fake silver bullets and fraudulent potions, alongside a pervasive lack of interest in scientific research aimed at extending human life, and outright rejection of the goal of extending human life in many quarters. One would think that a market claiming to sell ways to turn back the clock - or at least disguise the fact that the clock is ticking - could not thrive without interest in the supposed goal of their products, yet there is little manifestation of that interest when it comes to actually, really doing something about slowing or reversing aging, rather than just throwing money at faking it. Here is another data point to add to the existence of the "anti-aging" marketplace when trying to understand what is going on here: "A study [finds] that in 2011 spending on medications for aging conditions - such as mental alertness, sexual dysfunction, menopause, aging skin and hair loss - ranked third in annual prescription-drug costs of the commercially insured, surpassed only by the cost of treating diabetes and high cholesterol. The research found that among these insured individuals use of drugs to treat the physical impact associated with normal aging was up 18.5 percent and costs increased nearly 46 percent from 2006 to 2011. Increased use of these drugs was even more pronounced for the Medicare population (age 65+), up 32 percent from 2007 to 2011. The largest utilization jump among Medicare beneficiaries was from 2010 to 2011, up more than 13 percent and outpacing increases in the use of drugs for diabetes, high cholesterol and high blood pressure combined."

Wednesday, October 31, 2012
Antagonistic pleiotropy describes a situation in which a gene provides both benefit and drawback under different circumstances. In evolutionary considerations of aging the usual context for this situation is that a gene is selected because it provides competitive advantages in youth, when reproduction is taking place, and then becomes harmful later in life when evolutionary pressure is much reduced. Here researchers take a measure of the prevalence of this phenomenon in yeast: "The genes responsible for inherited diseases are clearly bad for us, so why hasn't evolution, over time, weeded them out and eliminated them from the human genome altogether? Part of the reason seems to be that genes that can harm us at one stage of our lives are necessary and beneficial to us at other points in our development. [Researchers now] report that antagonistic pleiotropy is very common in yeast, a single-celled organism used by scientists to provide insights about genetics and cell biology. "In any given environment, yeast expresses hundreds of genes that harm rather than benefit the organism, demonstrating widespread antagonistic pleiotropy. The surprising finding is the sheer number of such genes in the yeast genome that have such properties. From our yeast data we can predict that humans should have even more antagonistic pleiotropy than yeast." Yeast has about 6,000 genes, about 1,000 of which are essential - eliminate any of them and the organism dies. [Researchers] worked with a set of 5,000 laboratory strains of yeast in which one non-essential gene had been deleted from each strain. [They] grew all 5,000 strains together in a single test tube and compared the growth rates of each strain. This side-by-side comparison allowed them to determine which genes were beneficial (increased growth rate) and which ones were harmful (decreased growth rate) under the six environmental conditions. The researchers found that for each of the six conditions, on average, the yeasts expressed about 300 genes that slowed their growth and were therefore classified as harmful. Deleting those genes resulted in more rapid growth. But many of the genes that were harmful under one set of environmental conditions proved to be beneficial under another, demonstrating widespread antagonistic pleiotropy."

Wednesday, October 31, 2012
The mitochondria in our cells generate damaging oxidative byproducts as a result of their operation, and that is the first step in a long process that contributes to degenerative aging. Researchers have shown that localizing antioxidants to the mitochondria can reduce this damage and thus modestly slow aging and extend life in laboratory animals. Most antioxidants do not find their way to mitochondria, however, and have no effect on long term health or aging. Thus there has been some interest in recent years in designing compounds that do localize to mitochondria. One research group works on the mitochondrially targeted antioxidant SkQ1 and related compounds, and these scientists continue to conduct a range of studies in laboratory animals: "Here we evaluated the effect of the mitochondria-targeted antioxidant SkQ1 on markers of aging in the old OXYS rats, a unique animal model of accelerated senescence and age-related diseases, as well as normal Wistar rats. ... we compared effects of SkQ1 [on] age-dependent decline in blood levels of leukocytes, growth hormone (GH), insulin-like growth factor-1 (IGF-1), testosterone, dehydroepiandrosterone (DHEA). Our results indicate that when started late in life, treatment with SkQ1 [not] only prevented age-associated hormonal alterations but partially reversed them. These results suggest that supplementation with low doses of SkQ1, even in chronologically and biologically aged subjects seem to be a promising strategy to maintain health and retard the aging process."

Tuesday, October 30, 2012
Following on from a recent post on exercise and the aging brain, here is yet another study to show that improvements in cognitive function can be brought about by regular exercise and its consequent effects on body composition, metabolism, and other line items. Use it or lose it, as they say: "A regular exercise routine can make you fitter than ever - mentally fit. In a new study, previously sedentary adults were put through four months of high-intensity interval training. At the end, their cognitive functions - the ability to think, recall and make quick decisions - had improved significantly. Blood flow to the brain increases during exercise. The more fit you are, the more that increases. The pilot [study] looked at adults, average age 49, who were overweight and inactive. [Researchers] measured their cognitive function with neuropsychological testing, as well as their body composition, blood flow to the brain, cardiac output and their maximum ability to tolerate exercise. The subjects then began a twice-a-week routine with an exercise bike and circuit weight training. After four months - not surprising - their weight, body mass index, fat mass and waist circumference were all significantly lower. Meanwhile, their capacity to exercise (measured by VO2 max) was up 15 per cent. Most exciting, [cognitive function] had also increased, based on follow-up testing. These improvements were proportional to the changes in exercise capacity and body weight. Essentially, the more people could exercise, and the more weight they lost, the sharper they became."

Tuesday, October 30, 2012
Induced pluripotent stem cells (IPSCs) are reprogrammed cells - such as those obtained from a skin sample - and are similar to embryonic stem cells in the sense that it should be possible to generate any form of cell from them. They offer the capacity to easily generate unlimited numbers of patient-specific cells, or build tissue and organ structures from scratch. Each type of tissue or cell requires different chemical instructions, growth environments, and technical strategies to be discovered and then refined, however - and there are a few hundred types of cell in the human body. Here, researchers report on progress on generating cartilage from IPSCs: "[Researchers have] engineered cartilage from induced pluripotent stem cells that were successfully grown and sorted for use in tissue repair and studies into cartilage injury and osteoarthritis. ... [This] suggests that induced pluripotent stem cells, or iPSCs, may be a viable source of patient-specific articular cartilage tissue. Articular cartilage is the shock absorber tissue in joints that makes it possible to walk, climb stairs, jump and perform daily activities without pain. But ordinary wear-and-tear or an injury can diminish its effectiveness and progress to osteoarthritis. Because articular cartilage has a poor capacity for repair, damage and osteoarthritis are leading causes of impairment in older people and often requires joint replacement. One challenge the researchers sought to overcome was developing a uniformly differentiated population of chondrocytes, cells that produce collagen and maintain cartilage, while culling other types of cells that the powerful iPSCs could form. To achieve that, the researchers induced chondrocyte differentiation in iPSCs derived from adult mouse fibroblasts by treating cultures with a growth medium. They also tailored the cells to express green fluorescent protein only when the cells successfully became chondrocytes. As the iPSCs differentiated, the chondrocyte cells that glowed with the green fluorescent protein were easily identified and sorted from the undesired cells. The tailored cells also produced greater amounts of cartilage components, including collagen, and showed the characteristic stiffness of native cartilage, suggesting they would work well repairing cartilage defects in the body."

Monday, October 29, 2012
Advanced glycation endproducts (AGEs) are a class of undesirable metabolic byproduct. The level of AGEs in the body rises with age and causes harm through a variety of mechanisms, such as by excessively triggering certain cellular receptors or gluing together pieces of protein machinery by forming crosslinks, thus preventing them from carrying out their proper function. In past years a number of efforts were undertaken to develop drugs that can safely break down at least some forms of AGE. Early promising candidates in laboratory animals failed in humans because the most harmful forms of AGE are different for short-lived versus long-lived mammals - so what benefits a rat isn't of much utility for we humans. So far little progress has been made towards a therapy for the dominant type of AGE in humans, glucosepane, sad to say, as there is comparatively little interest in this field of research. Here is a recent paper commenting on the potential utility of AGE-beaker drugs: "Reducing sugars can react nonenzymatically with the amino groups of proteins to form Amadori products. These early glycation products undergo further complex reactions, such as rearrangement, dehydration, and condensation, to become irreversibly cross-linked, heterogeneous fluorescent derivatives, termed advanced glycation end products (AGEs). The formation and accumulation of AGEs have been known to progress in a normal aging process and at an accelerated rate under diabetes. Nonenzymatic glycation and cross-linking of proteins not only leads to an increase in vascular and myocardial stiffness, but also deteriorates structural integrity and physiological function of multiple organ systems. Furthermore, there is accumulating evidence that interaction of AGEs with a cell-surface receptor, receptor for AGEs (RAGE), elicits oxidative stress generation and subsequently evokes inflammatory, thrombogenic, and fibrotic reactions, thereby being involved in atherosclerosis, diabetic microvascular complications, erectile dysfunction, and pancreatic β-cell apoptosis. Recently, AGE cross-link breakers have been discovered. Therefore, removal of the preexisting AGEs by the breakers has emerged as a novel therapeutic approach to various types of diseases that develop with aging. This article summarizes the potential clinical utility of AGE cross-link breakers in the prevention and management of age- and diabetes-associated disorders."

Monday, October 29, 2012
Epigenetics has become an important component of the study of aging: how genetic regulation changes in response to cellular and molecular damage. One of the mechanisms of this regulation is the acetylation of histones: researchers evaluate the way in which this changes with aging, leading to changes in gene expression, altered levels of key protein machinery in tissues, and changes in the operation of biological systems in the body. Some research groups are in search of epigenetic alterations that might be reversed through therapy to produce beneficial effects: "Aging increases the vulnerability of aging white matter to ischemic injury. Histone deacetylase (HDAC) inhibitors preserve young adult white matter structure and function during ischemia by conserving ATP and reducing excitotoxicity. In isolated optic nerve from 12-month-old mice, deprived of oxygen and glucose, we show that pan- and Class I-specific HDAC inhibitors promote functional recovery of axons. This protection correlates with preservation of axonal mitochondria. The cellular expression of HDAC 3 in the central nervous system (CNS), and HDAC 2 in optic nerve considerably changed with age, expanding to more cytoplasmic domains from nuclear compartments, suggesting that changes in glial cell protein acetylation may confer protection to aging axons. Our results indicate that manipulation of HDAC activities in glial cells may have a universal potential for stroke therapy across age groups."



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