Fight Aging! Newsletter, September 24th 2012

September 24th 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!



- Thoughts on Aging Research in Canada
- Between Zeus and the Salmon
- A Hole-Based Taxonomy for Theories of Aging
- Articles on Plastination
- Discussion
- Latest Headlines from Fight Aging!
    - Genetic Hotspots for Diseases of Aging
    - A Look at the Allen Institute for Brain Science
    - Correlating Progressive Frailty in Aging With Parental Longevity
    - Using Fruit Flies to Study Immune System Aging
    - Calorie Restriction Greatly Slows Protein Turnover
    - A Different View of Aging
    - Longevity in Mammals as a Way to Extend Life of Male Offspring
    - A Review of Vascular Aging
    - 3rd World Congress on Targeting Mitochondria, November 2012
    - Progress in Tailor-Made Organs


From the In Search of Enlightenment blog:

"I attended [an] interesting talk on the 5 year priorities and vision of Canada's Institute of Aging. Many interesting issues arose in the talk and the discussion that followed that illustrate the ongoing challenges which the field of biogerontology faces. ... For a population to approach a life expectancy near 100 years we would have to eliminate most cancers, heart disease and stroke. Considering we have not yet eliminated any one of these diseases, the suggestion that we will continue to increase life expectancy at the same rate as we have in the past is simply unfounded. Take mice in the laboratory. On average, they could life about 2 years if they are fed, protected from predators, etc. Can we get them to live significantly longer by trying to treat all the diseases that afflict them in late life? No. ... We should invest more research dollars into the biology of aging than we do into any one specific disease of aging (e.g. cancer, heart disease, etc.). Unfortunately my sense is that we don't come even close to this. Biogerontology continues to be disadvantaged as a field of scientific inquiry.

"My sense of things, from hearing about the vision of the Institute and the new priorities it has identified, is that the Institute of Aging in Canada still struggles to get the respect, funding and support it deserves. This is no doubt due to many factors, such as the dominance of disease research, misconceptions about the true causes of health disparities, misguided sensibilities of fairness, ageist attitudes, and a general ignorance of the biology of aging and evolutionary biology in general. This makes selling the science to politicians and the general public a really tough sell. But I believe it is something that must be done if we hope to add healthy years to late life. So we must soldier on...."


Here are pointers to an overview of recent advances, present strategy, and dominant viewpoints in the mainstream of aging research - those researchers who are interested only in investigation of the mechanisms of aging or gently slowing aging through genetic and metabolic alterations:

"This is a goodly amount of reading material, and will probably keep you busy for a weekend or two. It's written from the conservative mainstream point of view, which is to say that it expresses the assumptions that (a) any future change in human longevity will be incremental and small, because (b) no radical advances in biotechnology applicable to aging are waiting in the wings, and (c) manipulation of longevity-related genes to slow aging is the best way forward, even though it will be slow, hard, challenging work. This is wrong, wrong, wrong - but that's always the way of the mainstream. They are there to be surprised and disrupted by suddenly rushing technological advancement, discontinuities in the pace of progress that occur increasingly frequently in this age of ours. If you want to understand this mainstream of longevity research and its viewpoints on present day and near future challenges in the field, however, then this is a great resource."


There are, it has to be said, a great many theories of aging. It occurs to me that we can classify most theories of aging according to where they stand with respect to the hole we find ourselves in - that hole being the inconvenient fact that we're all aging to death, and progressively increasing suffering and pain lies in each of our personal futures:


Plastination is the basis for a technology platform that might, in the years ahead, compete with low-temperature vitrification as a way to preserve a brain sufficiently well to also preserve the mind it contains. Preservation, such as that presently offered by the cryonics industry, gives an individual a shot at waiting out the future development of molecular nanotechnologies that could restore him to active life. This is the best chance on offer for those born too soon to benefit from the rejuvenation biotechnology that will emerge over the next few decades:

"Assuming that brain plastination eventually comes into practice, the first step, regrettably, is that you have to die. This could be in or near a hospital, hospice, or your home. Moments after your death, a response team will start the process of emergency glutaraldehyde perfusion (EGP) for protein fixation (a kind of advanced embalming process). This has to happen within 15 minutes of your death, otherwise the first phase of neural degradation will start to set in; brain cells start to die on account of oxygen deprivation. The infusion of this molecule by the response team basically freezes your brain into place, creating a snapshot of your identity and your long term memories - though you might lose some short-term memories when you resume life after reanimation, just as sometimes happens after brain trauma today. ... After this, your body will be moved to a centralized facility where, over the course of several months, your brain will be carefully removed and placed into a bath. ... It's at this point that a chemical called osmium tetroxide fixes all the fats and fluid membranes in the brain cells. Then, a series of acetone-like solvents are used to convert the brain into plastic where it can be stored at room temperature. ... All the water gets leached, out, but all the protein (and presumably, the other critical features) is still there, and so are all the neural connections, as are all the neural weightings - including the three dimensional structure."


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, September 21, 2012
Some interesting results from genetic research: scientists "have shown definitively that a small number of places in the human genome are associated with a large number and variety of diseases. In particular, several diseases of aging are associated with a locus which is more famous for its role in preventing cancer. For this analysis, [researchers] cataloged results from several hundred human Genome-Wide Association Studies (GWAS) from the National Human Genome Research Institute. These results provided an unbiased means to determine if varied different diseases mapped to common 'hotspot' regions of the human genome. This analysis showed that two different genomic locations are associated with two major subcategories of human disease. ... More than 90 percent of the genome lacked any disease loci. Surprisingly, however, lots of diseases mapped to two specific loci, which soared above all of the others in terms of multi-disease risk. The first locus at chromosome 6p21, is where the major histocompatibility (MHC) locus resides. The MHC is critical for tissue typing for organ and bone marrow transplantation, and was known to be an important disease risk locus before genome-wide studies were available. Genes at this locus determine susceptibility to a wide variety of autoimmune diseases ... The second place where disease associations clustered is the INK4/ARF (or CDKN2a) tumor suppressor locus [also known as p16]. This area, in particular, was the location for diseases associated with aging: atherosclerosis, heart attacks, stroke, Type II diabetes, glaucoma and various cancers. ... The finding that INK4/ARF is associated with lots of cancer, and MHC is associated with lots of diseases of immunity is not surprising - these associations were known. What is surprising is the diversity of diseases mapping to just two small places: 30 percent of all tested human diseases mapped to one of these two places. This means that genotypes at these loci determine a substantial fraction of a person's resistance or susceptibility to multiple independent diseases. ... In addition to the MHC and INK4/ARF loci, five less significant hotspot loci were also identified. Of the seven total hotspot loci, however, all contained genes associated with either immunity or cellular senescence. Cellular senescence is a permanent form of cellular growth arrest, and it is an important means whereby normal cells are prevented from becoming cancerous. It has been long known that senescent cells accumulate with aging, and may cause aspects of aging. This new analysis provides evidence that genetic differences in an individual's ability to regulate the immune response and activate cellular senescence determine their susceptibility to many seemingly disparate diseases."

Friday, September 21, 2012
A comprehensive understanding of the brain is an important line item for future medical development, as the research community will have to develop ways to repair the brain and reverse aspects of its aging while preserving the structures that encode the mind. Here is a look at one of the higher profile projects of recent years: "Paul Allen, the 59-year-old Microsoft cofounder [has] plowed $500 million into the Allen Institute for Brain Science, a medical Manhattan Project that he hopes will dwarf his contribution as one of the founding fathers of software. The institute, scattered through three buildings in Seattle's hip Fremont neighborhood, is primarily focused on creating tools, such as the mouse laser, which is technically a new type of microscope, that will allow scientists to understand how the soft, fleshy matter inside the human skull can give rise to the wondrous, mysterious creative power of the human mind. ... His first $100 million investment in the Allen Institute resulted in a gigantic computer map of how genes work in the brains of mice, a tool that other scientists have used to pinpoint genes that may play a role in multiple sclerosis, memory and eating disorders in people. Another $100 million went to creating a similar map of the human brain, already resulting in new theories about how the brain works, as well as maps of the developing mouse brain and mouse spinal cord. These have become essential tools for neuroscientists everywhere. Now Allen, the 20th-richest man in America, with an estimated net worth of $15 billion, has committed another $300 million for projects that will make his institute more than just a maker of tools for other scientists, hiring several of the top minds in neuroscience to spearhead them. One effort will try to understand the mouse visual cortex as a way to understand how nerve cells work in brains in general. Other projects aim to isolate all the kinds of cells in the brain and use stem cells to learn how they develop. Scientists think there may be 1,000 of these basic building blocks, but they don't even know that. 'In software,' Allen says, 'we call it reverse engineering.'"

Thursday, September 20, 2012
A nice demonstration of the degree to which the pace of aging is inherited - but remember that for the vast majority of us, lifestyle choices have more influence than genes, while progress in medical technology trumps all such concerns: "Various measures incorporated in geriatric assessment have found their way into frailty indices (FIs), which have been used as indicators of survival/mortality and longevity. Our goal is to understand the genetic basis of healthy aging to enhance its evidence base and utility. We constructed a FI as a quantitative measure of healthy aging and examined its characteristics and potential for genetic analyses. Two groups were selected from two separate studies. One group (OLLP for offspring of long-lived parents) consisted of unrelated participants at least one of whose parents was age 90 or older, and the other group of unrelated participants (OSLP for offspring of short-lived parents), both of whose parents died before age 76. FI(34) scores were computed from 34 common health variables and compared between the two groups. The FI(34) was better correlated than chronological age with mortality. The mean FI(34) value of the OSLP was 31% higher than that of the OLLP. The FI(34) increased exponentially, at an instantaneous rate that accelerated 2.0% annually in the OLLP and 2.7 % in the OSLP consequently yielding a 63% larger accumulation in the latter group. The results suggest that accumulation of health deficiencies over the life course is not the same in the two groups, likely due to inheritance related to parental longevity. Consistent with this, [sibling pairs] were significantly correlated regarding FI(34) scores, and heritability of the FI(34) was estimated to be 0.39. ... Variation in the FI(34) is, in part, due to genetic variation; thus, the FI(34) can be a phenotypic measure suitable for genetic analyses of healthy aging."

Thursday, September 20, 2012
An open access review paper that looks at the use of fruit flies in studying the details of immune system aging: "Aging is a complex process that involves the accumulation of deleterious changes resulting in overall decline in several vital functions, leading to the progressive deterioration in physiological condition of the organism and eventually causing disease and death. The immune system is the most important host-defense mechanism in humans and is also highly conserved in insects. Extensive research in vertebrates has concluded that aging of the immune function results in increased susceptibility to infectious disease and chronic inflammation. Over the years, interest has grown in studying the molecular interaction between aging and the immune response to pathogenic infections. The fruit fly Drosophila melanogaster is an excellent model system for dissecting the genetic and genomic basis of important biological processes, such as aging and the innate immune system, and deciphering parallel mechanisms in vertebrate animals. Here, we review the recent advances in the identification of key players modulating the relationship between molecular aging networks and immune signal transduction pathways in the fly. Understanding the details of the molecular events involved in aging and immune system regulation will potentially lead to the development of strategies for decreasing the impact of age-related diseases, thus improving human health and life span."

Wednesday, September 19, 2012
Examination of the sweeping low-level changes in biochemistry brought on by calorie restriction continues apace: "Calorie restriction (CR) promotes longevity. A prevalent mechanistic hypothesis explaining this CR effect suggests that protein degradation, including mitochondrial autophagy, is increased, thereby removing damaged proteins. At steady state, increased catabolism must be balanced by increasing mitochondrial biogenesis and protein synthesis, resulting in faster protein replacement rates. To test this hypothesis, we measured replacement kinetics and concentrations of hundreds of proteins in vivo in long-term CR and ad libitum -fed mice ... CR reduced absolute synthesis and breakdown rates of almost all measured hepatic proteins and prolonged half-lives of most (~80%), particularly mitochondrial proteins ... Proteins with related functions exhibited coordinated changes in concentration as well as replacement rates. ... In summary, our combination of dynamic and quantitative proteomics suggest that long-term CR reduces mitochondrial biogenesis and mitophagy are reduced. Our findings contradict the theory that CR increases mitochondrial protein turnover, and provide compelling evidence that cellular fitness is accompanied by reduced global protein synthetic burden."

Wednesday, September 19, 2012
This author defines aging as "an age-dependent trajectory of interacting system states - the sum of all molecular and physiological states and their interaction networks, many but not all of which shift in a consistent direction over time. This definition broadens our focus to include components that do not themselves depend on age, but which cohabit networks containing components that do. Gene-environment interactions are a case in point, wherein environmental variation can help to shape the age-structure of a population despite being quite obviously independent of age. Perhaps the best-established genetic pathway to influence lifespan is insulin-like signaling, believed to have evolved at least in part for its ability to maximize reproduction under favorable environments while postponing both reproduction and individual mortality under conditions of crowding or insufficient food ... Since natural populations are polymorphic for ostensibly rate-limiting components of this pathway, it is likely that individuals genetically predisposed to low insulin-like signaling should survive famine better than those geared for higher signaling and shorter lifespan. This is a conclusion of some import for population biologists, since the age-composition of any population must then be modified by the availability of food. A particularly instructive example is the near-ubiquitous evolutionary requirement for species or their constituent populations to survive extended periods of famine. Groups experiencing more prolonged famines (or just over-wintering, if their lifespans are measured in weeks) will have more diverse age structures, including an increased number of individuals for whom reproduction has been delayed. ... The same potential also exists for gene-gene interactions (including genes that dictate dietary preferences) to affect long-term survival. For example, only one component of a gene network may actually be age-dependent, while other genes create the background context of homeostatic states and their oscillations within which age-dependent genes must function. An increased probability of death with age could then arise from components undergoing essentially monotonic age-dependent declines, confronting extreme-value system states (in variable but age-independent parameters) to which they cannot respond adequately in any essential tissue or organ. Alternatively, an age-dependent increase in the variance of system oscillations may exceed the response range of one or more age-independent gene functions. In either case, the precise cause of death or debility will vary in a stochastic way, appearing as the 'weakest link' in any one tissue or organism, although the underlying age-associated changes may be common to many or all cell types and individuals."

Tuesday, September 18, 2012
The members of a number of mammal species, ourselves included, live long past their reproductive years. The question would be why this postreproductive longevity has evolved: what advantage does it confer? For humans, the grandmother hypothesis suggests that it has something to do with enhancing the survival of grandchildren, but this is debated. Here, researchers look at killer whales to argue that the advantage lies in enhanced survival of the male children of long-lived mothers: "Prolonged life after reproduction is difficult to explain evolutionarily unless it arises as a physiological side effect of increased longevity or it benefits related individuals (i.e., increases inclusive fitness). There is little evidence that postreproductive life spans are adaptive in nonhuman animals. By using multigenerational records for two killer whale (Orcinus orca) populations in which females can live for decades after their final parturition, we show that postreproductive mothers increase the survival of offspring, particularly their older male offspring. This finding may explain why female killer whales have evolved the longest postreproductive life span of all nonhuman animals." Male mammals are capable of siring offspring far later in life than females, so if a longer-lived mother can increase the number of years in which a male child continues to mate, that would constitute an advantage even if the mother can no longer reproduce.

Tuesday, September 18, 2012
An open access paper: "'Man is as old as his arteries.' This old aphorism has been widely confirmed by epidemiological and observational studies establishing that cardiovascular diseases can be age-related in terms of their onset and progression. Besides, with aging come a number of physiological and morphological changes that alters cardiovascular function and lead to subsequently increased risk of cardiovascular disease, even in health asymptomatic individuals. Even though different adaptive mechanisms to protect blood vessels against mild stress have been described, the aging process induces a progressive failure of protective mechanisms, leading to vascular changes. The outcomes of the aging-related modifications are the impairment of homeostasis of the irrigated organs and resultant target organ damage. The increasing mean age of the population in industrialized countries has turned out to be an economic and public health problem, as the increase in life expectancy goes in parallel with high incidence of several pathological conditions, despite unprecedented advances in prevention, diagnostics, and treatment. Of all aging-related illness, cardiovascular diseases remain the leading cause of morbidity and mortality in the elderly, and thus it is imperative to understand the mechanism underlying cardiovascular senescence."

Monday, September 17, 2012
Progress towards ways to repair mitochondria is very important: a way to fix our age-damaged mitochondria is a necessary part of any toolbox of therapies capable of reversing aging. An upcoming conference provides some insight into the present state of research: "After the success of the two first editions held in 2010 & 2011, the Scientific Committee of the International Society of Antioxidants in Nutrition and Health (ISANH) decided to organize the 3rd World Congress on Targeting Mitochondria which will be held in Berlin in November 8-9, 2012. Mitochondrial dysfunctions are associated with hundred of pathologies such as cancer, diabetes, neurodegenerative diseases, migraine, infertility, kidney diseases, liver diseases, toxicity of HIV drugs, aging... It is becoming a necessity and an urge to know why and how to target mitochondria with bioactive molecules, drugs or nutrients in order to treat and prevent pathologies and chronic diseases. This 3rd World Congress on Targeting Mitochondria will cover a variety of new strategies and innovations as well as clinical applications in Mitochondrial Medicine. ... The Scientific Committee has selected two hot topics for this year's meeting. The first topic involves Mito-Devices, which are novel tools for probing mitochondrial function under physiological and pathological conditions. The second topic focuses on Mito-Engineering, i.e. novel strategies and means towards manipulations of mitochondrial function. Mito-devices and Mito-engineering are essential for making mitochondria-targeted therapeutics clinical feasible, therefore clinical applications are the underlying theme of the 3rd edition of Targeting Mitochondria."

Monday, September 17, 2012
A popular science article on recent progress in organ engineering: "Implanting such a 'bioartificial' organ would be a first-of-its-kind procedure for the field of regenerative medicine, which for decades has been promising a future of ready-made replacement organs - livers, kidneys, even hearts - built in the laboratory. For the most part that future has remained a science-fiction fantasy. Now, however, researchers like Dr. Macchiarini are building organs with a different approach, using the body's cells and letting the body itself do most of the work. ... So far, only a few organs have been made and transplanted, and they are relatively simple, hollow ones - like bladders and [windpipes] ... But scientists around the world are using similar techniques with the goal of building more complex organs. At Wake Forest University in North Carolina, for example, where the bladders were developed, researchers are working on kidneys, livers and more. Labs in China and the Netherlands are among many working on blood vessels. The work of these new body builders is far different from the efforts that produced artificial hearts decades ago. Those devices, which are still used temporarily by some patients awaiting transplants, are sophisticated machines, but in the end they are only that: machines. Tissue engineers aim to produce something that is more human. They want to make organs with the cells, blood vessels and nerves to become a living, functioning part of the body. Some, like Dr. Macchiarini, want to go even further - to harness the body's repair mechanisms so that it can remake a damaged organ on its own."



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