Fight Aging! Newsletter, May 14th 2012

May 14th 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!



- Maintain Yourself
- A Report from the Genetics of Aging and Longevity Conference
- Metformin, a Review
- Learning from the Regrowth of Feathers and Hair?
- Discussion
- Latest Headlines from Fight Aging!


A reminder that it is a good plan to put in the effort on basic health maintenance:

"The human body needs to be taken care of in a variety of ways for best performance over the long term. Exercise, keep the weight off, try to avoid stabbing yourself. It's a considerable disadvantage that in our formative years that sort of maintenance just happens as a natural consequence of being a child - so the additional work that has to go into maintaining health as an adult comes as an unexpected chore.

"So: many of us get successful, then get fat, and then suffer age-related conditions more frequently and sooner, and then on average die younger. This isn't rocket science - most people know what they are doing to themselves, even if they aren't up to speed on the details of the biochemistry involved. But the siren song of life in a time of wealth and plenty lures you in. Maybe medical science will save you from yourself ... but I wouldn't count on it.

"So maintain yourself. You stand on the verge of a golden age in biotechnology, one that will offer unlimited healthy, youthful lifespans to those who claw their way over the threshold. Slacking on your health is turning your back on that future, it is making it harder for you to live long enough to benefit from rejuvenation biotechnologies that can be clearly envisaged today."


Maria Konovalenko recently reported on her attendance at the Moscow conference on the genetics of aging and longevity, held last month. The post includes a great many photographs of folk from the aging research community; browse through if you are interested in putting faces to the names you read about in the science press:

"It has been a while since I've posted my blog updates. The reason was the Genetics of Aging and Longevity conference. I have been involved in preparations of this meeting since December and the last month before the event was especially tough. Anyway, the conference turned out to be pretty good. I was surprised to hear so many good responses and impressions from the attendees and the speakers, so I am proud to say that the meeting was a success. The talks were superb, a lot of new and even unpublished data, a lot of discussions during the breaks and meals. I saw quite many people walking around with burning eyes - from excitement of science, of course) Some of those eyes are in the photos below. I believe this was a ground braking event on life extension topic in Russia, a truly unique gathering of minds. The more meetings like this we have, the more attention they get in the media, the better chances we have to live longer."


There are a few established drugs shown to modestly extend life in laboratory animals, with varying degrees of certainty. Rapamycin is probably the most concrete of those drugs at this time. Metformin is another, but the results there are far more ambiguous:

"Metformin is a drug that shows up in discussion here every so often. It is thought to be a calorie restriction mimetic, recapitulating some of the metabolic changes caused by the practice of calorie restriction. Its effects on life span in laboratory animals are up for debate and further accumulation of evidence - the results are on balance more promising than the generally dismal situation for resveratrol, but far less evidently beneficial than rapamycin. Like rapamycin, metformin isn't something you'd want to take as though it were candy, even if the regulators stood back to make that possible, as the side effects are not pleasant and potentially serious.

"I should note as an aside that while ongoing research into the effects of old-school drugs of this nature is certainly interesting, it doesn't really present a path to significantly enhanced health and longevity. It is a pity that such research continues to receive the lion's share of funding, given that the best case outcome is an increase in our knowledge of human metabolism, not meaningful longevity therapies. Even if the completely beneficial mechanism of action is split out from the drug's actions - as seems to be underway for rapamycin - the end results will still only be a very modest slowing of aging. You could do better by exercising, or practicing calorie restriction.

"For the billions in funding poured into these drug investigation programs, there should be a better grail at the end of the road - such as that offered by the SENS vision of rejuvenation biotechnology. Targeted repair of the biological damage of aging is a far, far better strategy than gently slowing the pace of damage accumulation through old-style drug discovery programs. This is a biotechnology revolution: time to start acting like it.

Anyway, aside done, let me point you to a recent open access review on metformin: the interesting work that won't really be in any way relevant to the future of your longevity, but which I'll wager has raised more funding as an object of study than the entire present extant SENS program and directly related scientific studies. ... See what you think; it makes for an interesting read - and includes a table of results from a number of life span studies that are, indeed, all over the map. It somewhat reinforces the point that unambiguous success in extending healthy life is not going to arrive from this quarter. Think SENS, not drug discovery - what will come from the drug discovery clade is a slow, grinding, and expensive cataloging of the fine details of genetics, metabolism, and aging in mammals."


The animal kingdom is rife with species that do a far better job of regeneration than we humans. What can be learned from the details of their biochemistry?

"For some years researchers have been investigating the mechanisms of limb and organ regrowth in lower animals like salamanders, with an eye to finding out how easy or hard it would be to recreate those same capabilities in mammals - such as we humans. Do we retain the core mechanisms, lying dormant in our biochemistry, or have they been completely lost? Time and ongoing research will tell.

"But these are not the only areas of regrowth wherein researchers might learn something of interest to regenerative medicine. Consider that elk regularly regrow their antlers, for example - not a simple organ by any means. Further down the scale of impressiveness, we might consider the many higher animals that regularly regrow feathers or coats of hair. Is there anything in their biochemistry that might be discovered and adapted to cause humans to regenerate in situations where they normally do not? If you buy into the argument that salamander biochemistry is worth investigation, then it's hard to reject similar investigations in other species capable of the lesser forms of regrowth mentioned above."


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, May 11, 2012
In recent years resveratrol has clearly fallen below the dividing line for work that is useful from a longevity perspective - if it could extend life significantly in mice, that would have been demonstrated by now. You might compare with the size of the effects on mouse lifespan for rapamycin to provide an example of a compound that is worth investigating. There is, however, a lot of money sunk into work on resveratrol and the underlying mechanisms of sirtuins, so don't expect that to halt any time soon. Research and developer institutions are prone to inertia, just like all other fields of human endeavor. In any case, here is some of the latest work on SIRT1: "If resveratrol needs SIRT1 to improve health, then animals lacking the gene should not get any benefits from the chemical. His lab published that experiment in yeast in 2003. But mice lacking SIRT1 die in the womb, or they are born with developmental defects such as blindness. To get around that problem, [researchers] engineered 'conditional knockout' mice whereby SIRT1 can be inactivated in adulthood. ... It took us two weeks to do the experiment in yeast, and five years in mouse, but finally we're there ... In normal mice, resveratrol combated the effects of a high-fat diet by boosting the efficiency of energy-generating organelles called mitochondria in skeletal muscle tissue. This effect vanished in adult mice without a working version of SIRT1. Yet SIRT1 wasn't responsible for all the beneficial effects of resveratrol ... Resveratrol stabilized the blood glucose levels of both normal and SIRT1-lacking mice on fatty diets. The chemical also improved liver health in mice without SIRT1. [The researchers also contend] that a lot the confusion over how resveratrol works comes down to dosage. At very high doses it binds other proteins besides SIRT1 ... For instance, a signalling protein called AMPK is also important to resveratrol's beneficial effects on metabolism. ... low doses of resveratrol boosted AMPK levels in various cells that expressed SIRT1, but not cells without the sirtuin. Much higher doses of resveratrol, however, activated AMPK irrespective of whether the cells expressed SIRT1."

Friday, May 11, 2012
Singularity Hub looks at the tissue engineering of teeth: "For years, researchers have investigated stem cells in an effort to grow teeth made for a person's own cells. Toward this end, [scientists] have developed methods to control adult stem cell growth toward generating dental tissue and 'real' replacement teeth. [The] researchers' approach is to extract stem cells from oral tissue, such as inside a tooth itself, or from bone marrow. After being harvested, the cells are mounted to a polymer scaffold in the shape of the desired tooth. The polymer is the same material used in bioreabsorable sutures, so the scaffold eventually dissolves away. Teeth can be grown separately then inserted into a patient's mouth or the stem cells can be grown within the mouth reaching a full-sized tooth within a few months. So far, teeth have been regenerated in mice and monkeys, and clinical trials with humans are underway, but whether the technology can generate teeth that are nourished by the blood and have full sensations remains to be seen. Teeth present a unique challenge for researchers because the stem cells must be stimulated to grow the right balance of hard tissue, dentin and enamel, while producing the correct size and shape."

Thursday, May 10, 2012
An article from the Wellcome Trust: "Researchers have been engineering cartilage in the laboratory for 15 years or more, but as yet the tissues they have created don't function properly in human joints. [Researchers] are taking a new approach to try to bridge the gap between laboratory-created cartilage and the tissue our bodies make. ... Biological texts show that these lab-grown tissues have the appearance, texture, and protein and mineral components of bone and cartilage. But once they are tested in an animal, these tissues simply don't behave quite like the natural tissues they are supposed to replicate. ... Joints are remarkable feats of engineering, but efforts to grow them in the lab have focused mostly on their biology. ... Biologists attempting to create cartilage and bone over the past 15 years have typically tested the mechanical properties of their laboratory-grown tissue - for example, whether it is rubbery and resilient enough when pressure is applied. ... Just because biological tests indicate a tissue looks like bone and feels like bone, doesn't actually mean it is bone ... This is where an engineering perspective becomes important. To look at how close a match these laboratory-generated tissues really are to native bone and cartilage, [researchers] supplemented the biological analyses with engineering tests, such as bio-Raman microspectroscopy. ... You shine a laser on the material, and the way the light scatters gives you an idea of the bonds between its components. Different mineral types form different bonds, so you get a much more precise picture of what is actually present. ... If a lab-grown tissue seems from some tests to be the real thing but isn't really, then it won't behave like it once it has been implanted in a human body. ... [The researchers aim] to use an engineering approach to create a whole osteochondral interface in which bone and cartilage transition seamlessly into each other like they do in the body. ... That's the only way it will effectively transmit loads to the underlying bone. And because bone will heal, it will heal the construct into the joint."

Thursday, May 10, 2012
Following on from a recent post on the involution of the thymus in adults, the process by which it ceases to generate immune cells and atrophies, here is a another paper that considers some of the possible paths to interventions that maintain the thymus into old age. Given experiments in mice showing that transplant of a young thymus extends life, this seems worthy of further investigation: "The thymus is the primary organ for T-cell differentiation and maturation. Unlike other major organs, the thymus is highly dynamic, capable of undergoing multiple rounds of almost complete atrophy followed by rapid restoration. The process of thymic atrophy, or involution, results in decreased thymopoiesis and emigration of naïve T cells to the periphery. Multiple processes can trigger transient thymic involution, including bacterial and viral infection(s), aging, pregnancy and stress. Intense investigations into the mechanisms that underlie thymic involution have revealed diverse cellular and molecular mediators, with elaborate control mechanisms. This review outlines the disparate pathways through which involution can be mediated, from the transient infection-mediated pathway, tightly controlled by microRNA, to the chronic changes that occur through aging."

Wednesday, May 9, 2012
An update on the LysoSENS research project from the SENS Foundation, which aims to discover and adapt bacterial enzymes to break down the damaging buildup of unwanted metabolic byproducts in the aging body: "SENS Foundation-funded research shows that expression of a modified microbial enzyme protects human cells against 7-ketocholesterol toxicity, advancing research toward remediation of the foam cell and rejuvenation of the atherosclerotic artery. ... Atherosclerotic cardiovascular disease is the principal cause of ischaemic heart disease, cerebrovascular disease, and peripheral vascular disease, making it the root of the leading cause of morbidity and mortality worldwide. Atherosclerosis begins with the entrapment and oxidation of low-density lipoprotein (LDL) cholesterol in the arterial endothelium. As a protective response, the endothelium recruits blood monocytes into the arterial wall, which differentiate and mature into active macrophages and engulf toxic oxidized cholesterol products (oxysterols) such as 7-ketocholesterol (7-KC). Although initially protective, this response ultimately leads to atherosclerotic plaque: oxidized cholesterol products accumulate in the macrophage lysosome, and impair the processing and trafficking of native cholesterol and other materials, leading macrophages to become dysfunctional and immobilized ... more and more of these disabled "foam cells" progressively accumulate in the arterial wall, generating the fatty streaks that form the basis of the atherosclerotic lesion. Rejuvenation biotechnology can be brought to bear against this disease of aging through the identification, modification, and therapeutic delivery of novel lysosomal enzymes derived from microbes to the arterial macrophage - enzymes which are capable of degrading oxidized cholesterol products. SENS Foundation-funded researchers have been making steady progress in the identification and characterization of candidate enzymes for several years now, and a new report represents a substantial advance in the research: the rescue of cellular oxysterol toxicity by an introduced microbial lysosomal enzyme."

Wednesday, May 9, 2012
You might recall research published last near on NRG-1 levels in naked mole-rats. Here is an update: "The typical naked mole rat lives 25 to 30 years, during which it shows little decline in activity, bone health, reproductive capacity and cognitive ability. ... Naked mole rats have the highest level of a growth factor called NRG-1 in the cerebellum. Its levels are sustained throughout their life, from development through adulthood. ... NRG-1 levels were monitored in naked mole rats at different ages ranging from a day to 26 years. The other six rodent species have maximum life spans of three to 19 years. The cerebellum coordinates movements and maintains bodily equilibrium. The research team hypothesized that long-lived species would maintain higher levels of NRG-1 in this region of the brain, with simultaneous healthy activity levels. Among each of the species, the longest-lived members exhibited the highest lifelong levels of NRG-1. The naked mole rat had the most robust and enduring supply. ... In both mice and in humans, NRG-1 levels go down with age ... The strong correlation between this protective brain factor and maximum life span highlights a new focus for aging research, further supporting earlier findings that it is not the amount of oxidative damage an organism encounters that determines species life span but rather that the protective mechanisms may be more important."

Tuesday, May 8, 2012
The thymus is the source of immune cells, but involutes in adults - it shrinks and loses its functionality. Restoring the thymus is one possible way around some of the built-in limitations of the immune system that contribute to age-related immune failure and a shorter life: "Emerging evidence indicates that the immune and metabolic interactions control several aspects of the aging process and associated chronic diseases. Among several sites of immune-metabolic interactions, thymic demise represents a particularly puzzling phenomenon because even in metabolically healthy middle-aged individuals the majority of thymic space is replaced with ectopic lipids. The new T cell specificities can only be generated in a functional thymus and, peripheral proliferation of pre-existing T cell clones provides limited immune-vigilance in the elderly. Therefore, it is hypothesized that the strategies that enhance thymic-lymphopoiesis may extend healthspan. Recent data suggest that byproducts of thymic fatty acids and lipids result in accumulation of 'lipotoxic DAMPs' (damage associated molecular patterns), which triggers the innate immune-sensing mechanism like inflammasome activation which links aging to thymic demise. The immune-metabolic interaction within the aging thymus produces a local pro-inflammatory state that directly compromises the thymic stromal microenvironment, thymic-lymphopoiesis and serves a precursor of systemic immune-dysregulation in the elderly. [This has] implications for developing future therapeutic strategies for living well beyond the expected."

Tuesday, May 8, 2012
Long-lived naked mole-rats appear to have more effective housekeeping and maintenance activity in their cells: the naked mole-rat "maintains robust health for at least 75% of its 32 year lifespan, suggesting that the decline in genomic integrity or protein homeostasis routinely observed during aging, is either attenuated or delayed in this extraordinarily long-lived species. The ubiquitin proteasome system (UPS) plays an integral role in protein homeostasis by degrading oxidatively-damaged and misfolded proteins. In this study, we examined proteasome activity in naked mole-rats and mice in whole liver lysates as well as three subcellular fractions to probe the mechanisms behind the apparently enhanced effectiveness of UPS. ... We found that when compared with mouse samples, naked mole-rats had significantly higher [activity]. ... the 20S proteasome was more active in the longer-lived species and that 26S proteasome was both more active and more populous. Western blot analyses revealed that both 19S subunits and immunoproteasome catalytic subunits are present in greater amounts in the naked mole-rat suggesting that the observed higher specific activity may be due to the greater proportion of immunoproteasomes in livers of healthy young adults. It thus appears that proteasomes in this species are primed for the efficient removal of stress-damaged proteins. Further characterization of the naked mole-rat proteasome and its regulation could lead to important insights on how the cells in these animals handle increased stress and protein damage to maintain a longer health in their tissues and ultimately a longer life."

Monday, May 7, 2012
Extensive studies of the genetics of human longevity are growing more common - the flow of data is becoming a flood. Here is an example: "we chose to investigate 1,200 individuals of the Danish 1905 birth cohort, which have been followed since 1998 when the members were 92-93 years old. The genetic contribution to human longevity has been estimated to be most profound during the late part of life, thus these oldest-old individuals are excellent for investigating such effect. The follow-up survival data enabled performance of longitudinal analysis, which is quite unique in the field of genetic epidemiology of human longevity. ... However, this study explores the genetic contribution to survival during the ninth decade of life, hence, in order to investigate the genetic contribution to survival in younger elderly we also included 800 individuals of the Study of Middle-aged Danish twins (MADT). ... The analyses of the data set verified the association [with longevity of] SNPs in the APOE, CETP and IL6 genes, [and] pointed to new candidate genes of human longevity: especially SNPs in the INS, RAD52 and NTHL1 genes appeared promising. As part of these investigations, replication studies of the single-SNP level findings were conducted in German case-control samples of 1,613 oldest-old (ages 95-110) and 1,104 middle-aged individuals and in a Dutch prospective cohort of 563 oldest-old (age 85+). ... Interesting aspects of the study were that the majority of the rare alleles of the identified SNPs were longevity variants, not mortality variants, indicating that at least in our study population, longevity is primarily affected by positively acting minor alleles. ... Furthermore, the genotype data generated were used for a number of replication studies on variation in the FOXO3A, TERT and TERC genes. These studies were performed in response to new data being published on the association of genetic variation in the genes with longevity (FOXO3A and TERT) and with telomere length (TERT and TERC). Our studies verified a role of TERC in human telomere length and of FOXO3A in human longevity (survival from middle age to old age), while a novel role of TERC in human longevity was found."

Monday, May 7, 2012
Tissue engineering is steadily advancing into the easier areas of growing replacement parts: "Other groups have tried to tackle nose replacement with implants but we've found they don't last. They migrate, the shape of the nose changes. But our one will hold itself completely, as it's an entire nose shape made out of polymer. ... Inside this nanomaterial are thousands of small holes. Tissue grows into these and becomes part of it. It becomes the same as a nose and will even feel like one. ... When the nose is transferred to the patient, it doesn't go directly onto the face but will be placed inside a balloon inserted beneath the skin on their arm. After four weeks, during which time skin and blood vessels can grow, the nose can be monitored, then it can be transplanted to the face. At the cutting edge of modern medicine, [researchers] are focusing on growing replacement organs and body parts to order using a patient's own cells. There would be no more waiting for donors or complex reconstruction - just a quick swap. And because the organ is made from the patient's own cells, the risk of rejection should, in theory, be eliminated. ... We seed the patient's own cells on to the polymer inside a bioreactor. ... This is a sterile environment mirroring the human body's temperature, blood and oxygen supply. ... As the cells take hold and multiply, so the polymer becomes coated. The same methods could be applied to all parts of the face to reconstruct those of people who have had severe facial traumas."



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