Fight Aging! Newsletter, February 6th 2012

February 6th 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!



- Intern at the SENS Foundation This Summer
- SENS5 Video: Immunotherapy Versus Tau
- Longevity Brings Economic Benefits
- Individual Molecules as Old as You Are
- Heterochromatin Levels Affect Lifespan in Flies
- Discussion
- Latest Headlines from Fight Aging!


Are you a life science student interested in the biology of aging? Here's a golden opportunity:

"In the summer of 2012, the Academic Initiative will bring as many as three students to the SENS Foundation Research Center in Mountain View, California to participate in SENS research for three months. These students will receive monthly stipends and, if they are not local to the San Francisco Bay Area, a credit towards airfare. Undergraduate, graduate, and medical students may apply, as may students who have graduated immediately prior to the summer. After an initial selection process, the most promising candidates will be interviewed over the phone by the SENS researchers they would work with. Each major research program at the Research Center will limit itself to one intern, such that each intern will be working on a different project and will be selected by different researchers. It will be important for applicants to have prior lab experience, and more experienced applicants are more likely to be accepted than relatively inexperienced ones. ... Applications are due by March 31, 2012. The most promising applicants will be interviewed in April. As always."


Tau is one of the proteins that aggregates with age, damaging nearby cells. When it happens more rapidly than usual it becomes one of the causes of Alzheimer's disease - but we all have tau building up in our brains. One of the potential ways to reverse this process is to manipulate the immune system into adding tau to its target list:

"One of the perils of aging is the accumulation of various protein/peptide aggregates throughout the body, some of which are associated with toxicity. In several age-related disorders, aggregates of certain amino acid sequences are much more prominent than under normal conditions, and define the disease. Harnessing the immune system has emerged in recent years as a promising approach to treat these conditions. My laboratory has worked in this field targeting the amyloid-β peptide, the prion protein, the tau protein, and more recently the islet amyloid polypeptide. The focus of my talk will be on our tau immunotherapy studies. We have shown in tangle mouse models that active or passive immunizations clear pathological tau aggregates from the brain with associated functional benefits."


As a population grows more long-lived, its members become wealthier:

"A common theme in past posts is that increased human longevity goes hand in hand with increased wealth: there are many economic benefits to living longer in good health beyond the immediately obvious ones. This has been demonstrated over and again in the past few centuries as, one after another, regions of the world have moved from poor to rich, and populations from shorter-lived to longer-lived. This bears repeating, and frequently, as the very vocal Malthusian and environmentalist camps claim that exactly the opposite will happen in the future - the Malthusian vision is of poverty and collapse brought on by longevity. This is, of course, ridiculous and just as wrong now as it has been at any time since Malthus first put forward his ideas. The world simply doesn't work that way, as human ingenuity driven by the urge to profit continually produces new and greater resources in response to the need for them.

"Nonetheless, with little regard for history, Malthusian adherents loudly oppose engineered human longevity - and their influence is grand and pervasive. When the average person on the street claims to be against longer lives and greater health, it is the hair-shirt Malthusian teachings of the environmentalist movement that inform that reaction: too many people, using too many resources, living too long, and not deserving any more of either. Yet the world does not work that way - there is no such thing as overpopulation, no such thing as limits on resources, and the arguments for more human death and suffering (and less striving for better medicine) are nothing less than evil. A banal and diffuse evil, with every person doing a little to build the monstrous whole, but still malign and terrible in its end result. Every day by which the development of rejuvenation biotechnology is slowed will cost at least 100,000 lives, and another day of suffering for tens of millions of people."


Some cells in your body are the very same cells you were born with; they will never be replaced, but nonetheless serve crucial functions in your nervous system and brain. They are just as vulnerable to damage and dysfunction as other cells, but must soldier on regardless, no matter how their capabilities are diminished. Now consider this: it may be the case that some of the individual vital proteins in the machinery of long-lived cells are also never replaced. Some of your complex individual proteins, important cogs and gears in important cells, might be as old as you are.:

"The scientists discovered that certain proteins, called extremely long-lived proteins (ELLPs), which are found on the surface of the nucleus of neurons, have a remarkably long lifespan. While the lifespan of most proteins totals two days or less, the Salk Institute researchers identified ELLPs in the rat brain that were as old as the organism. ... ELLPs make up the transport channels on the surface of the nucleus; gates that control what materials enter and exit. Their long lifespan might be an advantage if not for the wear-and-tear that these proteins experience over time. ... Most cells, but not neurons, combat functional deterioration of their protein components through the process of protein turnover, in which the potentially impaired parts of the proteins are replaced with new functional copies. Our results also suggest that nuclear pore deterioration might be a general aging mechanism leading to age-related defects in nuclear function, such as the loss of youthful gene expression programs."


The structure of DNA in the nucleus affects the operation of genes, and it turns out that there are aspects to that structural organization that can be controlled and alter life span in laboratory animals:

"Heterochromatin is the name given to the more tightly packaged structural forms of DNA and proteins found in the cell nucleus. It has been shown to be involved in cellular senescence, and is a part of the way in which genes are turned on or off, but like most things in the nucleus it is also involved in the deep, dark depths of many other mechanisms - down there in the basement clockwork of the tall towers of machinery that run a cell.

"To understand the role of heterochromatin in animal aging, and the underlying molecular mechanisms, we altered heterochromatin levels in [flies] by genetically manipulating Heterochromatin Protein 1 (HP1) levels ... we examined the life spans of flies with reduced or increased levels of HP1. These flies exhibit reduced or increased levels of heterochromatin, respectively, during development, as HP1 is an integral component of heterochromatin and controls heterochromatin levels.

"We found that reducing HP1 levels by half [caused] a dramatic shortening of life span compared to isogenic controls. ... Conversely, a moderate overexpression of HP1, caused by basal activity of the hsp70 promoter, significantly extended life span, resulting in a 23% increase in median life span and a 12% increase in maximum life span."


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 3, 2012
An advance in the methodologies of nerve repair: "scientists believe a new procedure to repair severed nerves could result in patients recovering in days or weeks, rather than months or years. The team used a cellular mechanism similar to that used by many invertebrates to repair damage to nerve axons. ... We have developed a procedure which can repair severed nerves within minutes so that the behavior they control can be partially restored within days and often largely restored within two to four weeks. If further developed in clinical trials this approach would be a great advance on current procedures that usually imperfectly restore lost function within months at best. ... nerve axons of invertebrates which have been severed from their cell body do not degenerate within days, as happens with mammals, but can survive for months, or even years. The severed proximal nerve axon in invertebrates can also reconnect with its surviving distal nerve axon to produce much quicker and much better restoration of behaviour than occurs in mammals. ... Severed invertebrate nerve axons can reconnect proximal and distal ends of severed nerve axons within seven days, allowing a rate of behavioural recovery that is far superior to mammals. In mammals the severed distal axonal stump degenerates within three days and it can take nerve growths from proximal axonal stumps months or years to regenerate and restore use of muscles or sensory areas, often with less accuracy and with much less function being restored. ... The team described their success in applying this process to rats ... The team were able to repair severed sciatic nerves in the upper thigh, with results showing the rats were able to use their limb within a week and had much function restored within 2 to 4 weeks."

Friday, February 3, 2012
To what degree does nuclear DNA damage contribute to aging? That remains a debated question. Here, researchers show that, at least in immune cells, there are perhaps more forms of large DNA damage than thought in the old: "researchers compared the DNA of identical (monozygotic) twins of different age. They could show that structural modifications of the DNA, where large or small DNA segments change direction, are duplicated or completely lost are more common in older people. The results may in part explain why the immune system is impaired with age. During a person's life, continuous alterations in the cells' DNA occur. The alterations can be changes to the individual building blocks of the DNA but more common are rearrangements where large DNA segments change place or direction, or are duplicated or completely lost. ... The results showed that large rearrangements were only present in the group older than 60 years. The most common rearrangement was that a DNA region, for instance a part of a chromosome, had been lost in some of the blood cells. ... Rearrangements were also found in the younger age group. The changes were smaller and less complex but the researchers could also in this case show that the number of rearrangements correlated with age. ... We were surprised to find that as many as 3.5 percent of healthy individuals older than 60 years carry such large genetic alterations. We believe that what we see today is only the tip of the iceberg and that this type of acquired genetic variation might be much more common. ... The researchers believe that the increased number of cells with DNA alterations among elderly can have a role in the senescence of the immune system. If the genetic alterations lead to an increased growth of the cells that have acquired them, these cells will increase in number in relation to other white blood cells. The consequence might be a reduced diversity among the white blood cells and thereby an impaired immune system." Compare that with the other explanations for reduced diversity that involve persistent and pervasive viruses like CMV.

Thursday, February 2, 2012
From the Wall Street Journal, a good example of the way in which much of present day research gravitates towards applications that patch over end-stage consequences of disease rather than addressing root causes and prevention: "Research into how iron, copper, zinc and other metals work in the brain may help unlock some of the secrets of degenerative diseases like Alzheimer's and Parkinson's. Iron and copper appear to accumulate beyond normal levels in the brains of people with these diseases, and a new [study] shows reducing excess iron in the brain can alleviate Alzheimer's-like symptoms - at least in mice. ... Research into the complicated, invisible roles these metals play in brain diseases has lagged behind study of the more-visible proteins that are damaged or clump together in the brains of Alzheimer's and Parkinson's sufferers. But better understanding metals' role in the brain could help shed light on a range of medical conditions and might offer a new route for developing treatments. ... [Researchers] examined the amount of iron in the brains of mice that were bred unable to produce the tau protein, which helps stabilize the structure of neurons. Tau damage is associated with Alzheimer's and Parkinson's. As the mice aged, they suffered symptoms similar to people with both diseases, including impaired short-term memory, and also exhibited an accumulation of iron in their brains. When the researchers gave them a drug removing excess iron, the symptoms reversed. This means normally functioning tau is necessary for removing iron in the brain ... The finding bolsters previous research showing that bringing down iron may be a path to new treatments. ... An accumulation of iron in neurons seems to be a final end-stage event in neurodegeneration, whether it be Alzheimer's or Parkinson's, [or] any [condition] related to tau abnormalities."

Thursday, February 2, 2012
Researches find another way in which the brain declines with age: "New findings [reveal] a novel mechanism through which the brain may become more reluctant to function as we grow older. ... researchers examined the brain's electrical activity by making recordings of electrical signals in single cells of the hippocampus, a structure with a crucial role in cognitive function. In this way they characterised what is known as "neuronal excitability" - this is a descriptor of how easy it is to produce brief, but very large, electrical signals called action potentials; these occur in practically all nerve cells and are absolutely essential for communication within all the circuits of the nervous system. ... The [researchers] identified that in the aged brain it is more difficult to make hippocampal neurons generate action potentials. Furthermore they demonstrated that this relative reluctance to produce action potential arises from changes to the activation properties of membrane proteins called sodium channels, which mediate the rapid upstroke of the action potential by allowing a flow of sodium ions into neurons. ... Much of our work is about understanding dysfunctional electrical signalling in the diseased brain, in particular Alzheimer's disease. We began to question, however, why even the healthy brain can slow down ... Previous investigations elsewhere have described age-related changes in processes that are triggered by action potentials, but our findings are significant because they show that generating the action potential in the first place is harder work in aged brain cells. Also by identifying sodium channels as the likely culprit for this reluctance to produce action potentials, our work even points to ways in which we might be able modify age-related changes to neuronal excitability, and by inference cognitive ability." You might compare this with past work on potassium channels and memory in aging.

Wednesday, February 1, 2012
The extracellular matrix (ECM) surrounds and supports cells, both structurally and in a range of other ways, such as by mediating cell signalling. With age, however, the ECM changes for a variety of reasons - it is damaged by the actions of senescent cells, for example. This has consequences, such as on the capacity of stem cells to maintain tissue. Here is a review paper: "Aging is characterized by reduced tissue and organ function, regenerative capacity, and accompanied by a decrease in tissue resident stem cell numbers and a loss of potency. The impact of aging on stem cell populations differs between tissues and depends on a number of non cell-intrinsic factors, including systemic changes associated with immune system alterations, as well as senescence related changes of the local cytoarchitecture. The latter has been studied in the context of environmental niche properties required for stem cell maintenance. Here, we will discuss the impact of the extracellular matrix (ECM) on stem cell maintenance, its changes during aging and its significance for stem cell therapy. ... It is concluded that a remodeled ECM due to age related inflammation, fibrosis or oxidative stress provides an inadequate environment for endogenous regeneration or stem cell therapies." The question of whether an old body can fully benefit from stem cell therapies continues to arise - eventually the stem cell research community will have to start addressing the damage of aging in order to assure the performance of their therapies when treating the old.

Wednesday, February 1, 2012
Autophagy is very important to long term health, and shows up again and again as a pivotal part of the way in which various genetic manipulations and lifestyle choices can improve health and extend life. Here is a good article that delves into the mechanisms of autophagy and the present limits of scientific understanding: "Cells live longer than their internal components. To keep their cytoplasm clear of excess or damaged organelles, as well as invading pathogens, or to feed themselves in time of nutrient deprivation, cells degrade these unwanted or potentially harmful structures, and produce needed food and fuel, using a process they have honed over millions of years. Known as autophagy, this catabolic process involves the selection and the sequestration of the targeted structures into unique transport vesicles called autophagosomes, which then deliver the contents to lysosomes where they are degraded by lytic enzymes. ... Experimental evidence indicates that autophagosome biogenesis is probably a very complex process on several levels, including its regulation in response to different cellular and environmental cues, and the factors governing the choice of membrane sources. Is there any therapeutic value in determining the origin of the autophagosomal membranes? We think that elucidating this process could ultimately provide new drug targets for the treatment of diseases that can be alleviated or cured by the activation of autophagy, including specific muscular dystrophies, persistent infections, and neurodegenerative disorders (ataxias, Huntington's, and Parkinson's diseases). Understanding the sources and processes by which the autophagosome's lipid bilayers are delivered will undoubtedly reveal critical new proteins and articulate their functions, allowing researchers to pinpoint specific parts of the pathway."

Tuesday, January 31, 2012
To what degree does the slow, expensive, and over-regulated institution of drug development - Big Pharma - contribute to the gentle upward trend in human life expectancy that has held over the past few decades? "This paper investigates the contribution of pharmaceutical innovation to recent longevity growth in Germany and France. The effect of the vintage of prescription drugs (and other variables) on the life expectancy and age-adjusted mortality rates of residents of Germany is examined, using longitudinal, annual, state-level data during the period 2001-7. The estimates imply that about one-third of the 1.4-year increase in German life expectancy during the period 2001-7 was due to the replacement of older drugs by newer drugs. The effect of the vintage of chemotherapy treatments on age-adjusted cancer mortality rates of residents of France is also investigated, using longitudinal, annual, cancer-site-level data during the period 2002-6. The estimates imply that chemotherapy innovation accounted for at least one-sixth of the decline in French cancer mortality rates, and may have accounted for as much as half of the decline."

Tuesday, January 31, 2012
Here is another good reason not to get fat and not to stay fat: "One of the largest studies to investigate lumbar spine disc degeneration found that adults who are overweight or obese were significantly more likely to have disc degeneration than those with a normal body mass index (BMI). Assessments using magnetic resonance imaging (MRI) show elevated BMI is associated with an increased number of levels of degenerated disks and greater severity of disc degeneration, including narrowing of the disc space. ... previous research has linked higher BMI to low back pain, which is often debilitating and can limit function, impact psychological well being, diminish overall quality of life, and is associated with substantial socioeconomic and health-care costs. ... The team recruited 2,599 participants aged 21 and older from Southern China between 2001 and 2009. Participants were from diverse social and economic backgrounds and were recruited regardless of whether they had lower back pain or not. The study group included 1,040 men and 1,559 women who had a mean age of 42 years. Researchers conducted radiographic and clinical assessments, and MRIs of the lumbar spine were obtained for all subjects. Study findings reveal that 73% of participants displayed disc degeneration, with men (76%) having a significantly higher prevalence of degeneration than women (71%). Not surprisingly, increasing age was found to increase the prevalence of disc degeneration. ... The authors suggest that with weight gain, physical loading on the disc and/or a chronic low-grade inflammation from the fat cells may play a role in disc degeneration."

Monday, January 30, 2012
Via ScienceDaily: researchers "are seeking to restore complete cardiac function with the help of artificial cardiac tissue. They have succeeded in loading cardiac muscle cells onto a three-dimensional scaffold, created using the silk produced by a tropical silkworm. Of all the body's organs, the human heart is probably the one most primed for performance and efficiency. Decade after decade, it continues to pump blood around our bodies. However, this performance optimisation comes at a high price: over the course of evolution, almost all of the body's own regeneration mechanisms in the heart have become deactivated. ... In their attempt to develop a treatment for the repair of cardiac tissue, scientists are pursuing the aim of growing replacement tissue in the laboratory, which could then be used to produce replacement patches for the repair of damaged cardiac muscle. The reconstruction of a three-dimensional structure poses a challenge here. Experiments have already been carried out with many different materials that could provide a scaffold substance for the loading of cardiac muscle cells. ... Whether natural or artificial in origin, all of the tested fibres had serious disadvantages. They were either too brittle, were attacked by the immune system or did not enable the heart muscle cells to adhere correctly to the fibres. ... the fibre produced by the tasar silkworm displays several advantages over the other substances tested. ... The surface has protein structures that facilitate the adhesion of heart muscle cells. It's also coarser than other silk fibres. ... This is the reason why the muscle cells grow well on it and can form a three-dimensional tissue structure. ... The communication between the cells was intact and they beat synchronously over a period of 20 days, just like real heart muscle."

Monday, January 30, 2012
An open access paper: "The amount of fat mass of an organism is emerging as key determinant in longevity. Too little or too much fat is associated with early mortality in rodents and humans, whereas leanness, intermediate with respect to these two extremes is associated with relative longevity, possibly reflecting an optimal amount of fat. ... Calorie restriction results in leanness, which is linked to metabolic conditions that favor longevity. We show here that deficiency of the triglyceride synthesis enzyme acyl CoA:diacylglycerol acyltransferase 1 (DGAT1), which promotes leanness, also extends longevity without limiting food intake. Female DGAT1-deficient mice were protected from age-related increases in body fat, tissue triglycerides, and inflammation in white adipose tissue. This protection was accompanied by increased mean and maximal life spans of ~25% and ~10%, respectively. Middle-aged Dgat1-/- mice exhibited several features associated with longevity, including decreased levels of circulating insulin growth factor 1 (IGF1) and reduced fecundity. Thus, deletion of DGAT1 in mice provides a model of leanness and extended lifespan that is independent of calorie restriction."



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