Fight Aging! Newsletter, December 3rd 2012

December 3rd 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!



- Reminder: Eurosymposium on Healthy Aging, December 12th
- A Bioprinting Infographic
- The Lifespan Observations Database
- Associations Between Reduced Thyroid Function and Longevity
- Discussion
- Latest Headlines from Fight Aging!
    - A Protein Map for Mitochondrial Function
    - A Method of Determining Lobster Age
    - Kynurenine-Tryptophan Metabolism and Fly Longevity
    - Rejuvenation in the Jellyfish Turritopsis Dohrnii
    - Visceral Fat Associated With Decreased Bone Strength
    - Mild Early Hypoxia Produces Life-long Benefits in Rats
    - Reducing Alzheimer's Progression By Blocking Cytokines
    - FGF21 as Calorie Restriction Mimetic
    - Dihydrolipoamide Dehydrogenase as Longevity Gene


A few weeks from now, Heales, the Healthy Life Extension Society will host a Eurosymposium on Healthy Ageing in Brussels, Belgium. Heales sets its claim as the largest European longevity advocacy group: "Heales is the largest non-profit organisation in Continental Europe promoting and advocating scientific research into longevity and biogerontology (the science of aging). We are a group of biologists, biochemists, medical doctors and diverse other professions throughout Europe."

The December symposium will be a three day affair, and you may recognize some of the names in the program - noted folk from the longevity science community. The presentation abstracts make for good reading, and there is still time to register online if you plan to be in that part of the world later this month. From the symposium website:

"Having followed the evolution of the European Innovation Partnership on Active and Healthy Ageing we have reached the conclusion that biology of ageing needs to be highlighted more clearly as an important solution. Innovations based on biology of ageing can contribute to improve healthy life in a very significant way and we want to address this message to the European Union through this conference.

"In this conference, we will let scientists explain how their research contributes or can contribute to extend the healthy lifespan of European citizens; we will put scientists, entrepreneurs, medical doctors and other key actors together to build the business of long term health, towards a living Europe rather than a dying Europe. We hope that policy makers and people who work for the European Union will be interested and will further help biology of aging reach concrete implementations."


Bioprinting is one of the many applications of 3D printing, a family of automation technologies for building three-dimensional structures from a blueprint. Living tissue is only different from other forms of automated fabrication by virtue of being much more complicated and somewhat more fragile. On the other hand, cells in a structure can self-assemble to some degree if the initial printed structure, chemical signals, and types of cell used are close enough to the final goal. So the challenges in printing tissue - and eventually in printing organs - are focused on trying to produce structures sufficiently close to living tissue for the cells involved to finish up on their own and close the gap. Creating a sufficiently comprehensive network of blood vessels to allow printed tissue to sustain itself is a big issue, for example.

At the end of this road, not so many years away, lies the goal of organ printing: producing complex organs for transplant on demand, grown from a patient's own cells. What effect this will have on life span remains to be seen, but on its own it is unlikely to be as large as we would like: probably incremental rather than revolutionary. You might look on it more in the way of taking conventional medicine for organ damage to the next level: expanding the number of people who can be treated, increasing the success rate of treatments, but suffering from many of the same limitations when it comes to the ability to successfully treat very elderly and frail people. There will probably be modest incidental benefits to life expectancy, just as there are for most broad improvements in medical technology. But you can have organs replaced as much as you like, and still age to death if there is no way to treat mitochondrial damage, build up of aggregates, aging in the brain, and so forth.

Surgery is never a desirable thing to have happen to you, especially if you are frail enough to need a transplant. This is one of the reasons why I suspect that stem cell medicine will ultimately gravitate to methods for inducing repair, regeneration, and rejuvenation in situ. They will either manipulate existing stem cells or infuse cultured stem cells taken from the patient, but these will be minimally invasive procedures that produce little to no trauma in the way that a transplant does.


Over the years a great many studies have been conducted using laboratory animals with the aim of recording changes in life span that result from drugs, genetic alterations, and environmental conditions. The shorter-lived and less costly to maintain the species, the more studies there are - probably thousands for nematode worms, for example.

If you feel like browsing through the stacks to gain an impression of the work that has taken place over the past few decades, allow me to point you to the Lifespan Observations Database, which "collects published lifespan data across multiple species." It isn't a complete reference, but contains thousands of entries.


The thyroid gland carries out a number of important functions, responding to changing conditions by varying its production of thyroid hormones that alter the behavior of metabolism elsewhere in the body. The behavior of the thyroid changes with age, but in a sufficiently subtle and varying manner to make its role in aging a challenging thing to study. Nonetheless, there is at this point enough data to conclude that some forms of reduced thyroid function tend to associate with increased longevity in a number of species.

This also ties in with other lines of research. Calorie restriction, for example, reduces thyroid hormone levels in the course of extending life and improving health. A predisposition to low thyroid hormone levels appear to be inherited in long-lived families. And so forth. Here is a short and very readable open access review paper that looks at thyroid function in the context of aging and longevity.


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 30, 2012
Mitochondria and the damage they accumulate as a result of their operation are important in the process of degenerative aging. Further, declining mitochondrial function is a feature in many age-related conditions. Many researchers focus their studies on mitochondrial function, differences in mitochondria between species and how that determines life span, alterations in mitochondrial operation that occur in connection with life-extending interventions in laboratory animals, and similar areas. These days that often involves producing a great deal of data for later analysis: "In efforts to understand what influences life span, cancer and aging, scientists are building roadmaps to navigate and learn about cells at the molecular level. To survey previously uncharted territory, a team of [researchers] created an "atlas" that maps more than 1,500 unique landmarks within mitochondria that could provide clues to the metabolic connections between caloric restriction and aging. The map, as well as the techniques used to create it, could lead to a better understanding of how cell metabolism is re-wired in some cancers, age-related diseases and metabolic conditions such as diabetes. "It's really a dynamic atlas for regulatory points in mitochondrial function - there are many interesting avenues that other scientists can follow up on. It could take years for researchers to understand what it all means, but at least now we have a list of the most important players." [The scientists] conducted earlier research on the mitochondrial protein Sirt3, where they suggested a link between Sirt3 and the benefits of caloric restriction in situations such as the prevention of age-related hearing loss. The new research [more] broadly identifies pathways in mitochondria that could be behind the rewiring of metabolism. Their work uncovered regulatory processes that maintain mitochondrial health, control cells' ability to metabolize fat and amino acids, as well as stimulate antioxidant responses."

Friday, November 30, 2012
Lobsters are one of the small number of species that might be ageless, or at the very least age very slowly and exhibit little to no decline until very late life. There is little money for aging research in lobsters, however: until now researchers possessed no way to accurately determine the age of a lobster, and no good estimate as to average or maximum life span in these species. This new development should hopefully lead to a better grasp of the degree to which lobsters do or do not age, and pin down numbers for life span: " For the first time, scientists have figured out how to determine the age of a lobster - by counting its rings, like a tree. Nobody knows how old lobsters can live to be; some people estimate they live to more than 100. Scientists already could tell a fish's age by counting the growth rings found in a bony part of its inner ear, a shark's age from the rings in its vertebrae and a scallop or clam's age from the rings of its shell. But crustaceans posed a problem because of the apparent absence of any permanent growth structures. It was thought that when lobsters and other crustaceans molt, they shed all calcified body parts that might record annual growth bands. [Researchers] took a closer look at lobsters, snow crabs, northern shrimp and sculptured shrimp. They found that growth rings, in fact, could be found in the eyestalk - a stalk connected to the body with an eyeball on the end - of lobsters, crabs and shrimp. In lobsters and crabs, the rings were also found in the so-called "gastric mills," parts of the stomach with three teeth-like structures used to grind up food."

Thursday, November 29, 2012
Metabolism is a very complex set of overlapping mechanisms, feedback loops, and networks of protein interactions. So even if there are only a few core methods of extending life by altering metabolism in a species, we should expect to see scores of different ways to trigger some or all of that alteration - and with widely varying side-effects. This is one of the present challenges facing those researchers who focus on how metabolism and genes determine natural variations in longevity: mapping it all for any one species is a vast task. Here is one example of ongoing research drawn from among the many ways to make flies live longer: "Up-regulation of kynurenine (KYN) pathway of tryptophan (TRP) was suggested as one of the mechanisms of aging and aging-associated disorders. Genetic and pharmacological impairment of TRP - KYN metabolism resulted in prolongation of life span in Drosophila models. Minocycline, an antibiotic with anti-inflammatory, antioxidant and neuroprotective properties independent of its antibacterial activity, inhibited KYN formation from TRP. Since minocycline is the only FDA approved for human use medication with inhibitory effect on TRP - KYN metabolism, we were interested to study minocycline effect on life- and health-spans in Drosophila model. Minocycline prolonged mean, median and maximum life span of wild-type Oregon Drosophila melanogaster of both genders [and] might be a promising candidate drug for anti-aging intervention. [The] role of TRP - KYN metabolism in the mechanisms of minocycline-effect on life- and health-span might be elucidated by the future assessment of minocycline effects in Drosophila mutants naturally or artificially knockout for genes impacting the key enzymes of KYN pathway of TRP metabolism."

Thursday, November 29, 2012
Aging has evolved despite its terrible effects on the individual because over the long run it is highly effective in the evolutionary competition that takes place in most ecological niches - any amount of hardship and pain can be selected for if it means that genes are more effectively propagated. There are exceptions, however, in the form of successful species that do not appear to age; especially in the case of lower animals we can find life histories that look nothing like our own. Take the hydra, for example, or here the tiny jellyfish Turritopsis dohrnii: "[An individual Turritopsis dohrnii appears to reverse its life cycle], growing younger and younger until it reached its earliest stage of development, at which point it began its life cycle anew. ... We now know [that] the rejuvenation of Turritopsis dohrnii and some other members of the genus is caused by environmental stress or physical assault. We know that, during rejuvenation, it undergoes cellular transdifferentiation, an unusual process by which one type of cell is converted into another - a skin cell into a nerve cell, for instance. But we still don't understand how it ages in reverse. There are several reasons for our ignorance, all of them maddeningly unsatisfying. There are, to begin with, very few specialists in the world committed to conducting the necessary experiments. ... The genus, it turns out, is extraordinarily difficult to culture in a laboratory. It requires close attention and an enormous amount of repetitive, tedious labor; even then, it is under only certain favorable conditions, most of which are still unknown to biologists, that a Turritopsis will produce offspring."

Wednesday, November 28, 2012
Visceral fat is strongly associated with most common age-related conditions and frailties, and mice have been shown to live longer if you remove their visceral fat. Maintaining excess fat tissue appears to be bad for you in many ways: more disability, more disease, a shorter life expectancy. So it's no surprise to see research results like this: "Visceral, or deep belly, obesity is a risk factor for bone loss and decreased bone strength in men. [Not] all body fat is the same. Subcutaneous fat lies just below the skin, and visceral or intra-abdominal fat is located deep under the muscle tissue in the abdominal cavity. Genetics, diet and exercise are all contributors to the level of visceral fat that is stored in the body. Excess visceral fat is considered particularly dangerous, because in previous studies it has been associated with increased risk for heart disease. [Researchers] evaluated 35 obese men with a mean age of 34 and a mean body mass index (BMI) of 36.5. The men underwent CT of the abdomen and thigh to assess fat and muscle mass, as well as very high resolution CT of the forearm and a technique called finite element analysis (FEA), in order to assess bone strength and predict fracture risk. ... FEA can determine where a structure will bend or break and the amount of force necessary to make the material break. In the study, the FEA analysis showed that men with higher visceral and total abdominal fat had lower failure load and stiffness, two measures of bone strength, compared to those with less visceral and abdominal fat. There was no association found between age or total BMI and bone mechanical properties. "We were not surprised by our results that abdominal and visceral fat are detrimental to bone strength in obese men. We were, however, surprised that obese men with a lot of visceral fat had significantly decreased bone strength compared to obese men with low visceral fat but similar BMI.""

Wednesday, November 28, 2012
Hormesis is the process by which a little stress or damage actually improves health. It spurs greater repair, growth, and regeneration than would otherwise have taken place, with the net effect being positive. This is an example with life-long benefits: "Whereas brief acute or intermittent episodes of hypoxia have been shown to exert a protective role in the central nervous system and to stimulate neurogenesis, other studies suggest that early hypoxia may constitute a risk factor that influences the future development of mental disorders. We therefore investigated the effects of a neonatal "conditioning-like" hypoxia on the brain and the cognitive outcomes of rats until 720 days of age (physiologic senescence). We confirmed that such a short hypoxia led to brain neurogenesis within the ensuing weeks, along with reduced apoptosis in the hippocampus. During aging, previous exposure to neonatal hypoxia was associated with enhanced memory retrieval scores specifically in males, better preservation of their brain integrity than controls, reduced age-related apoptosis, larger hippocampal cell layers, and higher expression of glutamatergic and GABAergic markers. These changes were accompanied with a marked expression of synapsin proteins, mainly of their phosphorylated active forms which constitute major players of synapse function and plasticity. Thus, early non-injurious hypoxia may trigger beneficial long term effects conferring higher resistance to senescence in aged male rats, with a better preservation of cognitive functions."

Tuesday, November 27, 2012
Researchers here demonstrate a much reduced progression of the signs of Alzheimer's disease in mice by altering immune signaling: "Alzheimer's disease is one of the most common causes of dementia. [The] accumulation of particular abnormal proteins, including amyloid-ß (Aβ) among others, in patients' brains plays a central role in this disease. [Researchers] were able to show that turning off particular cytokines (immune system signal transmitters) reduced the Alzheimer's typical amyloid-ß deposits in mice with the disease. As a result, the strongest effects were demonstrated after reducing amyloid-ß by approximately 65 percent, when the immune molecule p40 was affected, which is a component of the cytokines interleukin (IL)-12 and -23. Follow-up experiments [showed] that substantial improvements in behavioral testing resulted when mice were given the antibody blocking the immune molecule p40. This effect was also achieved when the mice were already showing symptoms of the disease. Based on the current [study], the level of p40 molecules is higher in Alzheimer's patients' brain fluid, which is in agreement with a recently published [study] demonstrating increased p40 levels in blood plasma of subjects with Alzheimer's disease. The significance of the immune system in Alzheimer's research is the focus of current efforts. [Researchers] suspect that cytokines IL-12 and IL-23 themselves are not causative in the pathology, and that the mechanism of the immune molecule p40 in Alzheimer's requires additional clarification."

Tuesday, November 27, 2012
Boosting levels of fibroblast growth factor 21 (FGF21) has been shown to extend life in mice. Here, researchers classify it as a calorie restriction mimetic treatment: "Dietary or caloric restriction (DR or CR), typically a 30-40% reduction in ad libitum or "normal" nutritional energy levels, has been reported to extend lifespan and healthspan in diverse organisms, including mammals. Although the lifespan benefit of DR in primates and humans is unproven, preliminary evidence suggests that DR confers healthspan benefits. A serious effort is underway to discover or engineer DR mimetics. The most straightforward path to a DR mimetic requires a detailed understanding of the molecular mechanisms that underlie DR and related lifespan-enhancing protocols. Increased expression of FGF21, a putative mammalian starvation master regulator, promotes many of the same beneficial physiological changes seen in DR animals, including decreased glucose levels, increased insulin sensitivity, and improved fatty acid/lipid profiles. Ectopic over-expression of FGF21 in transgenic mice (FGF21-Tg) extends lifespan to a similar extent as DR in a recent study. FGF21 may achieve these effects by attenuating GH/IGF1 signaling. Although FGF21 expression does not increase during DR, and therefore is unlikely to mediate DR, it does increase during short-term starvation in rodents which is a critical component of alternate day fasting, a DR-like protocol that also increases lifespan and healthspan in mammals. Various drugs have been reported to induce FGF21 [but] of these, only metformin has been reported to extend lifespan in mammals, and the extent of benefit is less than that seen with ectopic FGF21 expression. Perhaps the most parsimonious explanation is that high, possibly unphysiological, levels of FGF21 are needed to achieve maximum life- and healthspan benefits and that sufficiently high levels are not achieved by the identified FGF21 inducers. More in-depth studies of the effects of FGF21 and its inducers on longevity and healthspan are warranted."

Monday, November 26, 2012
It's no longer remarkable for researchers to discover ways to alter genes or the level of proteins produced through gene expression that extend life in laboratory animals. Many new interventions of this sort are discovered every year, and most go largely unremarked now. With the falling cost and increasing capacity of DNA sequencing and related biotechnologies it is becoming ever easier to find new connections or poke and prod at DNA and protein machinery in living organisms. That trend speeds the pace of progress in this field, and here is a recent example: "Mit mutations that disrupt function of the mitochondrial electron transport chain can, inexplicably, prolong Caenorhabditis elegans lifespan. In this study we use a metabolomics approach to identify an ensemble of mitochondrial-derived α-ketoacids and α-hydroxyacids that are produced by long-lived Mit mutants but not by other long-lived mutants or by short-lived mitochondrial mutants. We show that accumulation of these compounds is dependent upon concerted inhibition of three α-ketoacid dehydrogenases that share dihydrolipoamide dehydrogenase (DLD) as a common subunit, a protein previously linked in humans with increased risk of Alzheimer's disease. When the expression of DLD in wild type animals was reduced using RNA interference we observed [that] as RNAi dosage was increased lifespan was significantly shortened but, at higher doses, it was significantly lengthened, suggesting DLD plays a unique role in modulating length of life."



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