Fight Aging! Newsletter, July 30th 2012

July 30th 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!



- An Interview With David Gobel, Methuselah Foundation CEO
- Pharmaceutical Innovation and Longevity Gains
- Biochemistry (Moscow)'s Programmed Aging Issue
- Discussion
- Latest Headlines from Fight Aging!
    - A Single-Issue Political Party for Longevity Science
    - FDA Reaches to Regulate (i.e. Block) Simple Stem Cell Therapies
    - A Review of Skeletal Muscle Mitochondria in Aging
    - Towards Functional Blood Vessels Grown From Fat Cells
    - A Review: Physical Activity Increases Life Expectancy
    - Regenerating Bone With Scaffolds and Gene     - Assessing mTOR Signaling in Human Aging
    - Modifying Old Heart Stem Cells to Boost Regenerative Capacity
    - Enhanced Energy Metabolism Contributes to Extended Lifespan Through Calorie Restriction
    - Identifying Genetic Changes that Reduce Stem Cell Aging


David Gobel here discusses some of the aims of the Methuselah Foundation's New Organ initiative:

"By promoting extension of the statistical healthy lifespan, Methuselah has been a major influence on the public and scientific community's perception of the acceptability and value of increasing the maximum human lifespan and health-span. Starting in 2003 via the Methuselah Mouse Prize (four winners to date) and the tireless work of Methuselah volunteers - notably, Dr. Aubrey de Grey - the concept of engineering the delay of the human 'expiration date' went from a ridiculous sci-fi fantasy to a non-controversial goal that serious scientists can now pursue without destroying their careers. The only controversy today is not if it will happen, but how soon it will happen.

"On the second point of personal longevity, Methuselah has initiated a New Organ Prize that will incent the creation of something blindingly obviously needed. New parts for people. If a car can run perfectly well as if it had just come off the assembly line 110 years after being built because of replacement parts, why should humans be second class citizens to cars? Why should the 30,000 people who need new hearts at any given time be stuck with death as the likely outcome when your old corvair can easily get a rebuilt fuel pump? It is completely ridiculous, and we intend to do all we can to end the horror of the 'Dialysis Matrix,' for those needing kidneys currently suffer year after year in silence. So, New Parts For People is our current focus, because no one dies statistically - we die one unique and irreplaceable person at a time. Often because we just need a new part."


One researcher has been crunching numbers for the past decade or so to illustrate the correlation between measures of the pace of progress in medicine and the pace of increasing human longevity:

"We examine the impact of pharmaceutical innovation, as measured by the vintage of prescription drugs used, on longevity, using longitudinal, country-level data on 30 developing and high-income countries during the period 2000-2009. We control for fixed country and year effects, real per capita income, the unemployment rate, mean years of schooling, the urbanization rate, real per capita health expenditure (public and private), the DPT immunization rate, HIV prevalence and tuberculosis incidence.

"Life expectancy at all ages and survival rates above age 25 increased faster in countries with larger increases in drug vintage. The increase in drug vintage was the only variable that was significantly related to all of these measures of longevity growth. ... Pharmaceutical innovation is estimated to have accounted for almost three-fourths of the 1.74-year increase in life expectancy at birth in the 30 countries in our sample between 2000 and 2009, and for about one third of the 9.1-year difference in life expectancy at birth in 2009 between the top 5 countries (ranked by drug vintage in 2009) and the bottom 5 countries (ranked by the same criterion)."


The Biochemistry (Moscow) journal has provided open access to the English-language version of its latest issue on programmed aging:

"Some debate continues within the scientific community over the degree to which aging is programmed, which aspects of aging are programmed, and whether it is fair to call the body's characteristic responses to accumulated stochastic damage a form of programmed aging. Patterns of gene expression clearly change in fairly defined ways with aging, for example, and it is well known that stem cell populations decline and become less active - but is that just a reaction to levels of damage, or something else? This feeds into discussion over strategy when it comes to how to approach development of therapies for aging. Is it sufficient to repair all cellular and molecular damage caused by the operation of metabolism, because all forms of programmed aging are just reaction to that damage? Or even after researchers realize the SENS vision of rejuvenation biotechnology, would they then have to build further genetic therapies to block forms of decline that proceed independently of damage? From my view of what is known, I think the evidence leans more towards the former than the latter situation - and either way, we should still be working to realize rejuvenation biotechnology."


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, July 27, 2012
In a number of countries one plausible path to advocacy for a cause is the establishment of a single issue political party - see, for example, the original Green Party or Pirate Party as successful examples of the type in Europe. The Russian longevity science community is beginning to take this approach: "On July 19, we made the first step towards the creation of the Longevity Party. The initiative group of 10 people gathered together in Moscow to establish the first political party aimed at extending human lifespan using technological advances. ... Among these 10 people were Mikhail Batin, Alexey Turchin, Leonid Kaganov and Elena Milova. This is the very first step in the long and hard process of legally registering a political party. I believe this is one of the most important things that happened in the past few years in fighting aging. Nowhere in the world ever before have people expressed their desire to live longer in the form of a political movement. ... The main goal of the Longevity Party is to increase human lifespan so that people could live for as long as they would like to and remain young and healthy. We would like to achieve this goal by promoting scientific research and technological advances in regenerative medicine, genetics of aging and longevity, neuroscience, computer modeling of biological processes and other areas of life extension. ... The next big thing we need to do is to finalize the Program of the Party. Then we have to have at least 2 people in 42 regions of Russia as representatives of the Party and have the founding meeting after which the Party can be registered and eventually appear in the voting ballots. Our goal is to influence the authorities to support life extension technologies and increase funding for research aimed at improving people's health and extending longevity."

Friday, July 27, 2012
The FDA seems to be succeeding in the courts with regard to shutting down the few groups in the US trying to offer first generation stem cell therapies, and placing a heavy burden of regulation upon them. This most likely means that for another decade or so the only realistic way to access most of the present variety of stem cell therapies will continue to be medical tourism: "It's official: stem cells are drugs. At least, that's the opinion of the US district court in Washington DC, which has ruled that the Food and Drug Administration (FDA) has the authority to regulate clinics offering controversial stem cell therapies. Treatments in which stem cells are harvested from bone marrow and injected straight back into the same patient are deemed part of routine medical practice - not regulated by the US government. But if the cells are subjected to more than 'minimal manipulation', the FDA maintains that the therapy becomes a 'drug', which must be specifically approved for use. It was on this basis that in 2008 the FDA began moves to shut down Regenerative Sciences, a clinic in Broomfield, Colorado, that treats orthopaedic problems using a stem cell therapy called Regenexx. ... Regenexx consists of mesenchymal stem cells, which give rise to tissues including bone and cartilage, taken from a patient's bone marrow and grown in culture for about two weeks. Centeno has published a series of case reports describing its use to treat joint problems - but no controlled clinical trials. ... Regenerative Sciences challenged the FDA's authority to regulate its activities, setting the stage for a legal fight. In 2010, the FDA sought an injunction to take Regenexx off the market. This has now been granted in the court's ruling. Christopher Centeno, medical director of Regenerative Sciences, vows to appeal. 'This is really round one. Our position remains that a patient's cells are not drugs.'"

Thursday, July 26, 2012
An open access paper: "Aging is characterized by a progressive loss of muscle mass and muscle strength. Declines in skeletal muscle mitochondria are thought to play a primary role in this process. Mitochondria are the major producers of reactive oxygen species, which damage DNA, proteins, and lipids if not rapidly quenched. Animal and human studies typically show that skeletal muscle mitochondria are altered with aging, including increased mutations in mitochondrial DNA, decreased activity of some mitochondrial enzymes, altered respiration with reduced maximal capacity at least in sedentary individuals, and reduced total mitochondrial content with increased morphological changes. However, there has been much controversy over measurements of mitochondrial energy production, which may largely be explained by differences in approach and by whether physical activity is controlled for. These changes may in turn alter mitochondrial dynamics, such as fusion and fission rates, and mitochondrially induced apoptosis, which may also lead to net muscle fiber loss and age-related sarcopenia. Fortunately, strategies such as exercise and caloric restriction that reduce oxidative damage also improve mitochondrial function. While these strategies may not completely prevent the primary effects of aging, they may help to attenuate the rate of decline."

Thursday, July 26, 2012
Another of the numerous different efforts to build blood vessels from a patient's own cells: "Researchers have grown small blood vessels in a lab using stem cells from fat gathered through liposuction. Such cultured blood vessels might someday play a role in transplant operations, including heart bypass surgery. ... Many more steps are involved before heart surgery patients can benefit from this technique. ... First, we will need to make a fully functional vessel. Ours works, but does not yet achieve physiological mechanical properties. [Then] we will need to show that stem cells obtained from old, sick people can also be used to make a functional vessel and that this works in an animal model. ... All in all, [we] are still five to 10 years away from seeing this being tested in people. ... For the study, researchers using liposuction extracted adult stem cells from fat and turned them into smooth muscle cells. Adult stem cells are considered to be undifferentiated, which means they hold the potential to morph into specialized cell types. ... The extracted cells were 'seeded' onto a very thin collagen membrane. As they multiplied, researchers rolled them into tubes with the diameter of small blood vessels (3 millimeters). In three to four weeks, they were able to grow usable blood vessels."

Wednesday, July 25, 2012
An open access review: "Physical activity reduces many major mortality risk factors including arterial hypertension, diabetes mellitus type 2, dyslipidemia, coronary heart disease, stroke, and cancer. All-cause mortality is decreased by about 30% to 35% in physically active as compared to inactive subjects. The purpose of this paper was to synthesize the literature on life expectancy in relation to physical activity. A systematic PubMed search on life expectancy in physically active and inactive individuals was performed. In addition, articles comparing life expectancy of athletes compared to that of nonathletes were reviewed. Results of 13 studies describing eight different cohorts suggest that regular physical activity is associated with an increase of life expectancy by 0.4 to 6.9 years. Eleven studies included confounding risk factors for mortality and revealed an increase in life expectancy by 0.4 to 4.2 years with regular physical activity. Eleven case control studies on life expectancy in former athletes revealed consistently greater life expectancy in aerobic endurance athletes but inconsistent results for other athletes. None of these studies considered confounding risk factors for mortality. In conclusion, while regular physical activity increases life expectancy, it remains unclear if high-intensity sports activities further increase life expectancy."

Wednesday, July 25, 2012
Another group working on bone regeneration: "researchers have developed an innovative scaffold material (made from collagen and nano-sized particles of hydroxyapatite) which acts as a platform to attract the body's own cells and repair bone in the damaged area using gene therapy. The cells are tricked into overproducing bone producing proteins known as BMPs, encouraging regrowth of healthy bone tissue. This is the first time these in-house synthesised nanoparticles have been used in this way and the method has potential to be applied to regenerate tissues in other parts of the body. ... Previously, synthetic bone grafts had proven successful in promoting new bone growth by infusing the scaffold material with bone producing proteins. These proteins are already clinically approved for bone repair in humans but concerns exist that the high doses of protein required in clinical treatments may potentially have negative side effects for the patient such as increasing the risk of cancer. Other existing gene therapies use viral methods which also carry risks. By stimulating the body to produce the bone-producing protein itself, using non-viral methods these negative side effects can be avoided and bone tissue growth is promoted efficiently and safely."

Tuesday, July 24, 2012
The target of rapamycin (TOR) gene is widely studied by researchers working on the mechanisms of aging and enhanced longevity provided by calorie restriction. Here a team pull in more data from human populations: "Interventions which inhibit TOR activity (including rapamycin and caloric restriction) lead to downstream gene expression changes and increased lifespan in laboratory models. However, the role of mTOR signaling in human aging is unclear. We tested the expression of mTOR-related transcripts in two independent study cohorts; the InCHIANTI population study of aging and the San Antonio Family Heart Study (SAFHS). ... 8 genes were robustly associated with age in both cohorts. Genes involved in insulin signaling (PTEN, PI3K, PDK1), ribosomal biogenesis (S6K), lipid metabolism (SREBF1), cellular apoptosis (SGK1), angiogenesis (VEGFB), insulin production and sensitivity (FOXO), cellular stress response (HIF1A) and cytoskeletal remodeling (PKC) were inversely correlated with age, whereas genes relating to inhibition of ribosomal components (4EBP1) and inflammatory mediators (STAT3) were positively associated with age in one or both datasets. We conclude that the expression of mTOR-related transcripts is associated with advancing age in humans. Changes seen are broadly similar to mTOR inhibition interventions associated with increased lifespan in animals. Work is needed to establish whether these changes are predictive of human longevity and whether further mTOR inhibition would be beneficial in older people." It is worth recalling that we humans are unusually long-lived for mammals of our size; it is certainly possible that we evolved to consistently use some of the same mechanisms that are only turned on with calorie restriction in smaller mammals.

Tuesday, July 24, 2012
The stem cell research community is increasingly headed in the direction of finding ways to reverse or work around the age-related decline in regenerative capacity, driven by changes in stem cells and their niches: "Since patients with heart failure are normally elderly, their cardiac stem cells aren't very healthy. We modified these biopsied stem cells and made them healthier. It is like turning back the clock so these cells can thrive again. ... Modified human stem cells helped the signaling and structure of the heart cells, which were biopsied from elderly patients. Researchers modified the stem cells in the laboratory with PIM-1, a protein that promotes cell survival and growth. Cells were rejuvenated when the modified stem cells enhanced activity of an enzyme called telomerase, which elongates telomere length. Telomeres are 'caps' on the ends of chromosomes that facilitate cell replication. Aging and disease results when telomeres break off. ... There is no doubt that stem cells can be used to counter the aging process of cardiac cells caused by telomere degradation. ... The technique increased telomere length and activity, as well as increasing cardiac stem cell proliferation, all vital steps in combating heart failure. While human cells were used, the research was limited to the laboratory. Researchers have tested the technique in mice and pigs and found that telomere lengthening leads to new heart tissue growth in just four weeks. ... Modifying aged human cardiac cells from elderly patients adds to the cell's ability to regenerate damaged heart muscle, making stem cell engineering a viable option."

Monday, July 23, 2012
Here is an open access paper that looks at some of the mechanisms of calorie restriction in nematode worms - and you'll note that PEPCK-C manipulation, shown to extend life and improve health in mice, also works in the same way in this lower species: "Caloric restriction (CR) markedly extends lifespan and improves the health of a broad number of species. Energy metabolism fundamentally contributes to the beneficial effects of CR, but the underlying mechanisms that are responsible for this effect remain enigmatic. A multidisciplinary approach that involves quantitative proteomics, immunochemistry, metabolic quantification and lifespan analysis was used to determine how CR, which occurs in the C. elegans eat-2 mutants, modifies energy metabolism of the worm, and whether the observed modifications contribute to the CR-mediated physiological responses. A switch to fatty acid metabolism as an energy source and an enhanced rate of energy metabolism by eat-2 mutant nematodes was detected. Lifespan analyses validated the important role of these previously unknown alterations of energy metabolism in the CR-mediated longevity of nematodes. As observed in mice, the over-expression of the gene for the nematode analogue of the cytosolic form of phosphoenolpyruvate carboxykinase (PEPCK-C) caused a marked extension of lifespan in C. elegans, presumably by enhancing energy metabolism ... We conclude that an increase, not a decrease in fuel consumption, via an accelerated oxidation of fuels in the TCA cycle is involved in lifespan regulation; this mechanism may be conserved across phylogeny."

Monday, July 23, 2012
Here researchers note a genetic alteration that reduces age-related changes in one stem cell population: "Upon aging, the number of hematopoietic stem cells (HSCs) in the bone marrow increases while their repopulation potential declines. Moreover, aged HSCs exhibit lineage bias in reconstitution experiments with an inclination towards myeloid at the expense of lymphoid potential. The adaptor protein Lnk is an important negative regulator of HSC homeostasis, as Lnk deficiency is associated with a 10-fold increase in HSC numbers in young mice. However, the age-related increase in functional HSC numbers found in wild type (WT) HSCs was not observed in Lnk-deficient animals. Importantly, HSCs from aged Lnk null mice possess greatly enhanced self-renewal capacity and diminished exhaustion, as evidenced by serial transplant experiments. In addition, Lnk deficiency ameliorates the aging-associated lineage bias. Transcriptome analysis revealed that WT and Lnk-deficient HSCs share many aging-related changes in gene expression patterns. Nonetheless, Lnk null HSCs displayed altered expression of components in select signaling pathways with potential involvement in HSC self-renewal and aging. Taken together, these results suggest that loss of Lnk partially mitigates age-related HSC alterations."



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