FIGHT AGING! NEWSLETTER
January 14th 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!
- Fat and Mortality Rates Again
- Rebuilding an Artery With Stem Cells
- Deuterium and Lifespan in Flies
- Latest Headlines from Fight Aging!
- Endurance Training Associated With Longer Telomeres
- Unpublished Reader's Digest Interview on Aging and Longevity
- Fat Tissue Knockout of Mitochondrial Transcription Factor A is Beneficial, and May Extend Life in Mice
- Regenerating Hair Cells to Restore Hearing
- Identifying a Mechanism for Nematode Longevity via Bifidobacteria in the Diet
- Towards Therapies for Regeneration of Dental Pulp
- News from the International Longevity Alliance
- Cell Transplants to Rebuild the Retina
- Comments on the State of Medical Biotechnology Development
- Data From the Genetics of Healthy Ageing Project
FAT AND MORTALITY RATES AGAIN
I'll preface this post by noting that one should always pay attention to the incentives operating behind any particular piece of news as it makes its way through the cultural landscape. In this case it is news about weight and mortality risk, and the incentive that always seems close to mind here is that, on balance, overweight people like to be told that they are not risking their health and longevity by being overweight. No one enjoys bad news, and bad news about general health always has that implied nagging edge of personal criticism. Good news is so much more welcome.
Thus there has been more press attention than usual given to the latest big metastudy on weight and mortality risk, as it claims that being slightly overweight is better than being of normal weight when it comes to mortality rates. Being obese still shows up as a bad lifestyle choice. The paper is open access and very readable, but here's the press release:
"The researchers found [a] 6 percent lower risk of death for overweight; a 18 percent higher risk of death for obesity (all grades); a 5 percent lower risk of death for grade 1 obesity; and a 29 percent increased risk of death for grades 2 and 3 obesity. The authors note that the finding that grade 1 obesity was not associated with higher mortality suggests that that the excess mortality in obesity may predominantly be due to elevated mortality at higher BMI levels."
I can roll out some of the obvious theorizing myself without trying too hard: average weight is increasing and thus more of the people of normal weight in fact have something wrong with them that causes weight loss and higher mortality; wealth effects and corresponding access to medical services have some relation to weight and are thus distorting the picture; overweight people have higher medical expenditures and are getting value for that expense; and so forth. Many versions of this sort of pseudo-explanation are doing the rounds, including the standard objections to working with BMI as a measure in the first place, as it isn't necessarily a great proxy for visceral fat mass.
Beyond the fact that people want to hear that they are just fine the way they are, the issue here is a collision of large masses of data. On the one side there is a huge, mountainous pile of evidence to show that excess visceral fat is very bad for you. Even a modest amount above a normal weight raises the risk of later age-related disease and shortens your life expectancy. Calorie restriction in humans, which necessitates leanness, is shown to be very, very positive for all measures of health. It goes on.
On the other hand we have this meta-study and other similar items from past years to claim that irrespective of all this data showing that fat is bad for health, people who are slightly overweight still live longer. There are no doubt some researchers out there who see this as an opportunity: how to reconcile these two collections of research. If there is a consensus among scientists with an interest in the field, I'd have to say it looks like one that leans towards the evidence that fat is bad, and therefore something has yet to be explained in the structure or underlying threads of causation in these mortality rate studies.
REBUILDING AN ARTERY WITH STEM CELLS
Researchers completely removed the cells that line the inside surface from a segment of artery, and then put cells that had been derived from embryonic stem cells inside the artery. They then connected both ends of the arterial segment to plastic tubing inside a device called a bioreactor which is designed to grow cells and tissues. The scientists then pumped fluid through the artery under pressure as if blood were flowing through it. The outside of the artery was bathed in another fluid to sustain the cells located there.
Three days later, the complex structure of the inner surface was beginning to regenerate, and by 14 days, the inside of the artery had been perfectly restored to its complex natural state. It went from a non-functional tube to a complex fully functional artery. "Just think of what this kind of treatment would mean to a patient who had just suffered a heart attack as a consequence of a damaged coronary artery. And this is the real potential of stem cell regenerative medicine - that is, a treatment with stem cells that regenerates a damaged or destroyed tissue or organ."
DEUTERIUM AND LIFESPAN IN FLIES
Every few years research on the effects of deuterium on life span in lower animals surfaces, by way of exposing them to heavy water, D2O rather than H2O. The presence of deuterium rather than hydrogen results in an uptake of deuterium atoms into biological molecules, subtly and slightly changing their behavior. Too much of that and you fall over dead - the mechanisms of life do not have a high tolerance for such tinkering, and heavy water is effectively toxic. At lower levels, however, species such as flies and nematodes live longer as a result of exposure to deuterium.
There is some skepticism and debate amongst various parties regarding the mechanisms by which deuterium uptake extends life span, but it's clear that exposure to heavy water at lower levels does in fact extend life in flies, worms, and so forth. Not too many people are working on this, so there is a lot of room for speculation and a lack of hard evidence that can rule out possibilities such as increased resistance to oxidative damage in important proteins. Given the evidence backing the membrane pacemaker theory of longevity, this is an attractive idea - there is plenty of support for the hypothesis that differences in the proteins that make up cell membranes are responsible for large differences in life span between various otherwise similar species. But robust evidence for the much smaller difference of a little extra deuterium substituted for hydrogen atoms - as opposed to completely different proteins - is lacking.
Hormesis is a possible (and disappointingly ordinary) explanation for this sort of result. Given the range of ways to make flies, worms, and rodents live longer by exposing them to adversity in early life, this almost seems like the first place to be looking. Perhaps lesser degrees of heavy water exposure, entirely separately from any deuterium uptake into proteins, have a hormetic effect, causing enough damage and disarray to spur repair mechanisms into greater efforts and leading to a net gain in life expectancy.
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!
LATEST HEADLINES FROM FIGHT AGING!
ENDURANCE TRAINING ASSOCIATED WITH LONGER TELOMERES
Friday, January 11, 2013
Exercise correlates with all sorts of better measures of health, but there is some debate and conflicting evidence on whether more is better past the point of moderate regular exercise. This ties in to questions of causation - to what degree are endurance athletes drawn to their activities because they are already more robust than their peers, for example? "Telomeres are the molecular caps on chromosomes. They shorten with each successive cell division and are thus linked to aging. The shortening rate also varies among people. Shorter telomeres have been linked to increased disease risk as well as shortening of lifespan. Chronic endurance training is at least modestly linked with long lifespan, though there are some controversies about whether it may increase the risk of some heart diseases. In the current study researchers sought to determine if chronic endurance training is associated with telomere length in older aged individuals. To perform the trial they measured the length of telomeres in four groups of individuals: young people and older people who did or did non engage in chronic endurance training. For the endurance training the researchers chose participation in a 58 km cross country ski competition. They found that indeed the older people who were chronic endurance trainers had significantly longer telomeres than moderately active older controls. There was no difference in telomere length in the younger subjects whether they did endurance training or not. There was also an association in older people between VO2 max and telomere length."
UNPUBLISHED READER'S DIGEST INTERVIEW ON AGING AND LONGEVITY
Friday, January 11, 2013
Over at In Search of Enlightenment you'll find an unpublished interview where the questions somewhat illustrate the point that most people don't look much beyond trivial matters when it comes to aging and longevity. Biotechnology like SENS and similar research projects are given no thought at all in most quarters, and even amongst advocates many favor the snail's pace path of trying to slow aging rather than working to repair its root causes to reverse it. This all means that there is much yet to accomplish in advocacy and education. "The field of research known as biogerontology, which studies the biology of aging, is a truly fascinating, though often misunderstood, area of scientific research. In 2011 the genome of the naked-mole rat was sequenced. This rodent is only the size of a mouse, and one might wonder what the significance of sequencing its genome could possibly be. But the naked-mole rate is the longest living rodent, it has a maximum lifespan exceeding 30 years and an exceptional resistance to cancer. Understanding the biology of this species could help unlock the mystery of healthy aging. A variety of experiments on fruit flies, mice and other species have demonstrated that the rate of aging can be manipulated, either by calorie restriction or by activating particular genes. Such research could eventually lead to the development of a drug that safely mimics the effects of caloric restriction (which delays the onset of disease) or actives the "longevity genes" that help protect against the diseases of late life. The lion's share of funding for medical research is spent on disease research, such as research on cancer, heart disease or Alzheimer's disease. This approach, which I call "negative biology", assumes that the most important question to answer is "what causes disease?". Unfortunately this is a severely limited approach, especially for older populations. Even if you cured all 200+ forms of cancer (and we have not yet eliminated even just one cancer despite investing enormous sums of money for decades now), one of the other diseases of aging would quickly replace cancer as the leading cause of death because most people in late life are vulnerable to multiple diseases. So "positive biology" takes a different intellectual starting point. It assumes that the puzzles of exemplar health are just as important to understand as the development of disease. How can some (very rare) humans live over a century of disease-free life? Understanding these exemplar examples of health might prove to be more significant than trying to understand, treat and cure every specific disease of late life."
FAT TISSUE KNOCKOUT OF MITOCHONDRIAL TRANSCRIPTION FACTOR A IS BENEFICIAL, AND MAY EXTEND LIFE IN MICE
Thursday, January 10, 2013
Mitochondrial transcription factor A (TFAM) plays a number of important roles and shows up in connection with protofection research aimed at mitochondrial repair. Separately, researchers observe benefits by removing it from the fat tissue of mice: "Mutations in genes involved in the electron transport chain that cause mitochondrial dysfunction can sometimes paradoxically lead to improved health and/or enhanced longevity. One example is the situation in mice with conditional knockout of the mitochondrial transcription factor A (TFAM) specifically in fat. These F-TFKO mice exhibit mitochondrial dysfunction with increased energy expenditure, but are protected from age- and diet-induced obesity, insulin resistance and hepatosteatosis, despite increased food intake. Mitochondrial DNA (mtDNA) is maternally inherited with multiple copies in each mitochondria. TFAM plays a critical role in maintenance and expression of mtDNA, and reductions of mtDNA copy number usually correlate with reduction of mitochondria content and function. So, how does a reduction in TFAM in fat have this beneficial effect? Upon high fat diet, [the F-TFKO] mice develop a build-up of long chain acyl carnitines in both adipose tissue and the circulation. In addition, markers of oxidative stress are observed at the level of DNA and lipids in adipose tissue of F-TFKO mice on high fat diet, indicating overload of the ROS protection system. Despite this mitochondria stress, the mice remain lean and insulin sensitive even at 10 months of age. Although no formal aging studies have been conducted in these mice, we also noted that by 18 months of age, an age at which the control mice have started to die, the F-TFKO mice are still thriving, suggesting this knockout may be beneficial to aging mice as well."
REGENERATING HAIR CELLS TO RESTORE HEARING
Thursday, January 10, 2013
In recent years a number of research groups have been investigating ways to restore the hair cells lost in some forms of deafness. Here is the latest example of success in laboratory mice: "Hair cell loss results from a variety of factors including noise exposure, aging, toxins, infections, and certain antibiotics and anti-cancer drugs. Although hearing aids and cochlear implants can ameliorate the symptoms somewhat, there are no known treatments to restore hearing, because auditory hair cells in mammals, unlike those in birds or fish, do not regenerate once lost. [Here, researchers] demonstrate for the first time that hair cells can be regenerated in an adult mammalian ear by using a drug to stimulate resident cells to become new hair cells, resulting in partial recovery of hearing in mouse ears damaged by noise trauma. This finding holds great potential for future therapeutic application that may someday reverse deafness in humans. The drug had been selected for its ability to generate hair cells when added to stem cells isolated from the ear. It acted by inhibiting an enzyme called gamma-secretase that activates a number of cellular pathways. The drug applied to the cochlea inhibited a signal generated by a protein called Notch on the surface of cells that surround hair cells. These supporting cells turned into new hair cells upon treatment with the drug. Replacing hair cells improved hearing in the mice, and the improved hearing could be traced to the areas in which supporting cells had become new hair cells."
IDENTIFYING A MECHANISM FOR NEMATODE LONGEVITY VIA BIFIDOBACTERIA IN THE DIET
Wednesday, January 9, 2013
One line of longevity science involves linking known ways to extend life in laboratory species with known mechanisms of longevity. In nematode worms, for example, it costs comparatively little to create groups with a range of the various genetic alterations shown to extend life in recent years, and then test strategies with those groups. If a strategy for extending life in nematodes doesn't have much effect on a particular long-lived mutant strain, then it's likely that it works through the same underlying mechanism - though of course it's rarely as cut and dried as that: multiple mechanisms and varying degrees of effect can be involved. Here is an example of this sort of work: "Lactobacilli and bifidobacteria are probiotic bacteria that modify host defense systems and have the ability to extend the lifespan of the nematode Caenorhabditis elegans. Here, we attempted to elucidate the mechanism by which bifidobacteria prolong the lifespan of C. elegans. When the nematode was fed Bifidobacterium infantis (BI) mixed at various ratios with the standard food bacterium Escherichia coli strain OP50 (OP), the mean lifespan of worms was extended in a dose-dependent manner. Worms fed BI displayed higher locomotion and produced more offspring than control worms. The growth curves of nematodes were similar regardless of the amount of BI mixed with OP, suggesting that BI did not induce prolongevity effects through caloric restriction. Notably, feeding worms the cell wall fraction of BI alone was sufficient to promote prolongevity. The accumulation of protein carbonyls and lipofuscin, a biochemical marker of aging, was also lower in worms fed BI; however, the worms displayed similar susceptibility to heat, hydrogen peroxide, and paraquat, an inducer of free radicals, as the control worms. As a result of BI feeding, loss-of-function mutants of daf-16, jnk-1, aak-2, tol-1, and tir-1 exhibited a longer lifespan than OP-fed control worms, but BI failed to extend the lifespan of pmk-1, skn-1, and vhp-1 mutants. As skn-1 induces phase 2 detoxification enzymes, our findings suggest that cell wall components of bifidobacteria increase the average lifespan of C. elegans via activation of skn-1, regulated by the p38 MAPK pathway, but not by general activation of the host defense system via DAF-16."
TOWARDS THERAPIES FOR REGENERATION OF DENTAL PULP
Wednesday, January 9, 2013
Dental regenerative medicine is closer to commercial application than many other areas of this field: "The traditional root canal procedure involves removing decayed root tissue, or dental pulp, from the tooth's canal and filling that space with gutta percha, an artificial rubber-like substance. With Huang's new approach, the canals that have been cleared would be injected with stem cell tissue to stimulate healthy tissue growth, essentially rebuilding the tooth, and eliminating the need for gutta percha. "Our group has been able to demonstrate that we can isolate stem cells from the pulp tissue, let them expand or grow in culture dishes, seed them onto artificial or natural scaffolding materials, and then insert them into the canal space. Using a small animal model, we were able to demonstrate that we can entirely regenerate pulp tissue in the empty canal space." "The dentin can also be regenerated. The natural function of the pulp tissue is to maintain the homeostasis of the tooth and lay down the dentin structure to sustain the architecture of the tooth." Similar research in other countries has been successful. Testing has now moved to larger animals, including pigs and dogs, and clinical trials on humans could begin in the next 10 years."
NEWS FROM THE INTERNATIONAL LONGEVITY ALLIANCE
Tuesday, January 8, 2013
Here is news from the newly formed International Longevity Alliance, the umbrella group for the brace of single issue political party initiatives that have arisen in the past year in Europe and Russia: "On January 5, the second general meeting of the leaders and activists of the International Longevity Alliance (ILA) took place. [The] meeting took place in an extremely cooperative and constructive atmosphere. About 18 collaborative projects were initiated right there and then. The exact organizational structure, goals and ways to join the projects will be elaborated and announced soon, in the "Projects" section of the ILA website. To facilitate the collection of knowledge, exchange and distribution of free and accessible information about longevity, a Wikipedia project was initiated. A related item is the Collaborative Knowledge Management project that will provide a repository of information on aging and longevity researchers and research centers, as well as providing linking tools. And yet another form of knowledge collection and sharing will be the creation of Educational Platforms on longevity, for different audiences, lay and more academic. There is an overarching "Linking Researchers" project, initiated to facilitate the interaction with and between researchers in the field. [The] Denigma project will be the main IT platform in the creation of the repository of information on research of aging, and linking of researchers."
CELL TRANSPLANTS TO REBUILD THE RETINA
Tuesday, January 8, 2013
An example of the sort of work presently taking place aimed at retinal regeneration: "The researchers worked with mice that are blind due to complete loss of the light-sensing photoreceptor cells in their retinas. This is the most relevant mouse model for treating patients who are blind from retinitis pigmentosa. After two weeks, the researchers showed the cells transplanted into the eye had re-formed a full light-detecting layer on the retina and the mice could see. The cells used were mouse 'precursor' cells that are on an initial path towards developing into retinal cells. A pupil constriction test showed that, of the 12 mice that received the cell transplant, 10 showed improved pupil constriction in response to light. This shows that the retinas of the mice were sensing the light once more, and this was being transmitted down the optic nerve to the brain. "We found that if enough cells are transplanted together, they not only become light sensing but they also regenerate the connections required for meaningful vision. Stem cells have been trialled in patients to replace the pigmented lining of the retina, but this new research shows that the light-sensing layer might also be replaced in a similar way. The light-sensing cells have a highly complex structure and we observed that they can resume function as a layer and restore connections after transplantation into the completely blind retina.""
COMMENTS ON THE STATE OF MEDICAL BIOTECHNOLOGY DEVELOPMENT
Monday, January 7, 2013
Via FuturePundit, some comments on the development of medical biotechnology: "My suspicion: most of the remaining problems that chemical drugs haven't cured or slowed down are problems that chemical drugs can't fix. For most of what goes wrong as we age we need gene therapies, cell therapies, and other techniques that are powerful enough to repair or replace aged tissue. Chemical drugs are just too simple in structure and in potential effects. They can't do much tissue repair. The slow rate of cancer drug testing and the regulatory environment that causes the snail's pace is tragic. [If] I was dying of cancer and had months to live I'd volunteer to take a large dose of an experimental drug to find out its toxicity. If I was really lucky I'd be cured. If I was only moderately lucky the drug would kill me quickly so I wouldn't have to spend months in pain slowly dying. I bet if dying cancer patients were given the choice of whether to risk a fast death due to aggressive testing of new drugs enough would say yes that drug testing could be sped up substantially. The regulators who create this slow drug development environment also place high hurdles in the way of trying stem cell therapies and gene therapies for fatal illnesses. The US FDA has won a court case that gives it broad power to regulate stem cell therapies. Well, FDA regulation basically means "spend hundreds of millions of dollars and spend a decade getting approval". Got a disease that'll kill you 5 or even 10 years from now? Time to get a passport if you don't already have one. When the biotech revolution finally starts arriving with great clinical treatments you'll have to go abroad to get the latest treatments. We need a faster rate of progress in biotechnology."
DATA FROM THE GENETICS OF HEALTHY AGEING PROJECT
Monday, January 7, 2013
Research into genetic contributions to longevity rolls onwards. APOE remains one of the few genes with variants associated with longevity in many populations. For the rest, it is expected that there are many different contributing variations, different by population, and each only causing a small change in life expectancy. It is still the case that genes are not as important as good lifestyle choices, and neither of those are anywhere near as important as progress in medical technology when it comes to the prospects for living a long life. Here are the results from a recent study that again point to APOE. You might also look at an introduction to gene locations for an overview of how researchers label locations in a chromosome such as 17q12-q22: "Clear evidence exists for heritability of human longevity, and much interest is focused on identifying genes associated with longer lives. To identify such longevity alleles, we performed the largest genome-wide linkage scan thus far reported. Linkage analyses included 2118 nonagenarian Caucasian sibling pairs that have been enrolled in fifteen study centers of eleven European countries as part of the Genetics of Healthy Ageing (GEHA) project. In the joint linkage analyses we observed four regions that show linkage with longevity; chromosome 14q11.2, chromosome 17q12-q22, chromosome 19p13.3-p13.11 and chromosome 19q13.11-q13.32. To fine map these regions linked to longevity, we performed association analysis using [genome-wide association study] data in a subgroup of 1,228 unrelated nonagenarian and 1,907 geographically matched controls. [By] combined modeling of linkage and association we showed that association of longevity with APOEε4 and APOEε2 alleles explain the linkage at 19q13.11-q13.32. In the largest linkage scan thus far performed for human familial longevity, we confirm that the APOE locus is a longevity gene and that additional longevity loci may be identified at 14q11.2, 17q12-q22 and 19p13.3-p13.11. Since the latter linkage results are not explained by common variants, we suggest that rare variants play an important role in human familial longevity."