Longevity Meme Newsletter, June 28 2010

June 28 2010

The Longevity Meme 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 the Longevity Meme.



- Decellularized Lungs Demonstrated in Rats
- The Slow Boats to China
- Theories on Gender Longevity Differences
- The Genetics of Longevity Will Be Extremely Complex
- Discussion
- Latest Healthy Life Extension Headlines


Lung tissue engineering has lagged behind work on other organs in recent years: lungs are complex and inaccessible, and despite advances in early regenerative medicine, survival rates for lung injuries remain low. Here, however, researchers have taken a large step forward:


"Decellularization, or recellularization, is a fairly new technique in tissue engineering wherein a donor organ is chemically stripped of its cells, leaving behind the intricate structure of the extracellular matrix. That structure is then repopulated by stem cells drawn from a patient, which use the matrix as a guide to rebuild the fine structure of the organ. When transplanted, a recellularized organ has few of the issues of immune rejection associated with a normal donor organ transplant, as it is essentially built from a patient's own cells."

"The team started with decellularized adult rat lungs, which retain the organs' branching airways and blood vessel network, and added a mixture of lung cells from newborn rats. Niklason says that the crucial step was nurturing the would-be lungs in a bioreactor that circulates fluid - simulating what would happen during fetal development - or air through them. The cells stuck to the scaffold in the right locations and multiplied. After up to 8 days in the bioreactor, they had coalesced into what the researchers' tests indicated was functional lung tissue. To determine whether the new organs worked, the researchers removed rats' left lungs and stitched in lab-grown replacements. X-rays showed that the implanted lungs were inflating, though not fully. Tests of gas levels in blood flowing to and from the replacement organs showed that they were taking in oxygen and releasing carbon dioxide at 95% of normal efficiency."


Here is an examination of the mainstream of aging research, which is focused on a very long and arduous process of learning to safely alter human metabolism so as to modestly slow down aging:


"One boat is red, one is green. The sails are a different shape. One has a cook, the other a raconteur. But they're both going to China, and both are going to take a long time in doing so. This little scene is what springs to mind when I see people debating the merits of different attempts to develop drugs that can slow aging. Slowing aging is the slow and expensive path to a poor end result. ... We who are middle aged have a few decades of leeway - in which one development path or another will be pursued. If at the end of the day, when we are old and damaged, the result is a therapy that only slows aging, then we are out of luck. Thanks for playing. But today, the vast majority of longevity research is focused on the slow boats to China - on producing ways to change human metabolism to modestly slow down age-related degeneration. This state of affairs will be the death of us all, unless the focus shifts to the Strategies for Engineered Negligible Senescence and other repair-based approaches to reversing the damage of aging."


"Following on from a recent post on defining aging as a disease, I see that an article from Proto Magazine looks at the same question. This is really an examination of the slow boat mainstream of aging research: scientists who are careful to say in public that they are not in fact working towards greater maximum human longevity, but rather trying to achieve what is known as 'compression of morbidity,' wherein the period of illness at the end of life is shortened, but life span is not lengthened."


Why do women tend to live longer than men? A definitive answer is not yet established, but the pile of theories and evidence grows ever higher:


"Differing smoking rates, stem cell effectiveness, mitochondrial effectiveness, and the possible effects of hormones on the immune system are all on the list. [As well as the theory] that hormones influence the expression and activity of known longevity genes. ... I recently pointed out a paper suggesting that men age faster for evolutionary reasons. Today I'll direct your attention to another evolutionary examination: University of Michigan researcher Daniel Kruger offers this explanation: It is all about sex. Women invest more physiologically in reproduction than men, thus men compete with other men for mating partners and try to make themselves attractive to women. This competition leads to strategies that are riskier for men both behaviorally and physiologically, and these result in higher levels of mortality."

It is possible that all the better theories are true at the same time: evolutionary history and mating strategies favor the establishment of a male biochemistry that ages more rapidly, and thus we see the stem cell, mitochondrial, hormonal, and gene expression differences.


Researchers will be working for decades if they want to untangle all of the genetic contributions to human longevity:


"The effects on life expectancy of known single gene variants may be enhanced or diminished by other variations that do not themselves directly contribute to longevity. Combinations of genetic variants are probably just as important as single gene differences, in other words. We humans have a lot of genes, which means there is a very, very large number of potential interactions between gene variants - even within a subset of genes associated with a specific biological system. Discovery and understanding in the face of this complexity represents an enormous amount of work, which is one of the reasons that researchers who favor the metabolic manipulation approach to aging believe that we are a long way from any significant slowing of aging or extension of the healthy human life span.

"This is why those of us who want to see that progress happen in our lifetimes should favor approaches like Aubrey de Grey's SENS: don't try to find, test, and debug ways to alter human metabolism, but rather work on repair technologies that can remove the known forms of biochemical damage that build up in the metabolism we have now."


The highlights and headlines from the past week follow below.

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THE YOUTH PILL (June 25 2010)
A new popular science book on the manipulation of metabolism to slow aging, the author inspired by the Longevity Dividend initiative: "No scientific advances inspire more media hype than ones in gerontology, the study of aging. Even the crustiest editors have been known to turn giddy when new light is shed on the topic and take to blowing raspberries at the Reaper with headlines suggesting immortality elixirs are just around the corner. Biologists aren't so easily wowed, though, and before the mid-1990s they generally saw gerontology as a dismal bog where once-promising peers sank out of sight, or worse, re-emerged clutching beakers of snake oil. ... Studying the details of this inexorable, chaotic decay seemed a waste of time to most life scientists. ... Then in 1988 a miracle happened - the University of Colorado's Thomas Johnson reported that a gene mutation in nematodes could more than double their life spans. Five years later, Cynthia Kenyon at the University of California, San Francisco, nailed a similar worm 'gerontogene' dubbed daf-2. These flabbergasting discoveries revealed that not everything about aging is intractable chaos - worms, at least, apparently possessed gene-encoded modules poised to oppose the ravages of advancing age when activated by a single mutation. Optimists soon speculated that similar modules exist in mammals."

From the MIT Technology Review: "Rats genetically engineered to lose their sight can be protected from blindness by injections of human neural stem cells ... a startup in Palo Alto, CA, plans to use the positive results to file for approval from the U.S. Food and Drug Administration to begin human trials. The company is already testing the cells in children with a rare, fatal brain disorder called Batten's disease. ... The company's cells are isolated from human fetal tissue and then grown in culture. To determine whether these cells can protect against retinal degeneration, scientists studied rats that were genetically engineered to progressively lose their photoreceptors - cells in the retina that convert light into neural signals. These animals are commonly used to model macular degeneration and retinitis pigmentosa, two major causes of blindness that result from cell loss in the retina. Researchers injected about 100,000 cells into the animals' eyes when the rats were 21 days old. ... the cells migrate over time, forming a layer between the photoreceptors and a layer of tissue called the retinal pigment epithelium, cells which nourish and support the photoreceptors. ... the cells protected vision in the part of the retina in which they were implanted."

Scientific American looks at the state of viral cancer therapies: "The adapted virus that immunized hundreds of millions of people against smallpox has now been enlisted in the war on cancer. Vaccinia poxvirus joins a herpesvirus and a host of other pathogens on a growing list of engineered viruses entering late-stage human testing against cancer. ... After a decade of development of so-called oncolytic viruses, the newest strains hold the most promise yet ... In a two-pronged attack, these viruses specifically target tumor cells while delivering a cargo of immune-boosting genes. In contrast, viruses that cause cancer, such as the human papillomavirus that is responsible for most cases of cervical cancer, disrupt a cell's genome, thereby triggering out-of-control growth. When the engineered viruses recognize and infect cancer cells, they replicate and sometimes destroy their hosts. Several of the viruses also release the gene for granulocyte-macrophage colony-stimulating factor (GM-CSF) an immune system protein. The GM-CSF attracts a swarm of white blood cells and other immune system operatives that mount a further attack on the tumor. ... The vaccinia virus has been developed by the biotechnology company Jennerex ... Later this year, the company plans to launch a phase III clinical trial in advanced liver cancer patients, in which the virus will be added to standard antibody treatment."

A novel methodology in regenerative medicine: "The objective was to evaluate the utility of cryo-preserved human amniotic membrane (HAM) as a support for repairing human articular cartilage injuries, which have a very limited capacity for self-healing ... The results [show] that cryo-preserved HAM is useful as a scaffold for growing human chondrocytes in cell therapy and for repairing human cartilage injuries. ... It provides a more regular surface and fills in the cavities and fissures ... The authors cultivated the chondrocytes (cells that form part of the cartilaginous tissue), isolated from human articular cartilage, on the amniotic membrane over a period of three and four weeks. The amniotic membranes were used to develop 44 repair models of arthritic human articular cartilage in vitro, which was assessed between four and 16 weeks later. The HAM also bonds well with the native cartilage. ... In some models, we could not differentiate between where the native tissue stopped and the neo-synthesised tissue began. ... This tissue had a fibrous appearance and high cellular density (cellularity), which in some cases was greater than that of the actual native cartilage."

Another reason why you really don't want to live a lifestyle that makes you overweight: "For individuals 65 years of age and older, obesity, excess body fat around the waist and gaining weight after the age of 50 are associated with an increased risk of diabetes. ... Adiposity [body fat] is a well-recognized risk factor for type 2 diabetes among young and middle-aged adults, however, the relationships between different measures of body composition and diabetes in older adults [65 years of age or older] are not well described ... [researchers] examined the relationship between measures of overall body fat, fat distribution, changes in these measures, and diabetes risk among 4,193 men and women 65 years of age and older. ... The researchers found that BMI at baseline, BMI at 50 years of age, weight, fat mass, waist circumference, waist-hip ratio, and waist-height ratio were all strongly related to the risk of diabetes. ... For each measure, there was a graded increase in the risk of diabetes with increasing quintiles of adiposity. Participants in the highest category of adiposity had an approximately 2- to 6-fold increased risk of developing diabetes compared with those in the lowest category."

A review paper from Italian researchers who have been working on understanding inflammaging for a number of years: "Ageing is an inexorable intrinsic process that affects all cells, tissues, organs and individuals. Due to a diminished homeostasis and increased organism frailty, ageing causes a reduction of the response to environmental stimuli and, in general, is associated to an increased predisposition to illness and death. Actually, it is characterized by a state of reduced ability to maintain health and general homeodynamics of the organism. A large part of the ageing phenotype is explained by an imbalance between inflammatory and anti-inflammatory networks, which results in the low grade chronic pro-inflammatory status of ageing, 'inflamm-ageing'. It is strictly linked to immunosenescence, and on the whole they are the major contributory factors to the increased frequency of morbidity and mortality among elderly. Inflamm-ageing is compatible with longevity; even if centenarians have an increased level of inflammatory mediators in comparison to old subjects and they are very frail, they also have high level of anti-inflammatory cytokines together with protective genotypes. Actually, data on case control studies performed in Italian centenarians suggest that a pro-inflammatory genotype is unfavourable to reach extreme longevity in good health and likely favours the onset of age-related diseases such as cardiovascular diseases and Alzheimer's disease."

Here, researchers investigate one of a number of mechanisms that may explain degeneration in the aging brain: "A common way of describing the behavior of older adults is that they are more rigid and set in their ways. The wide range in sensory and cognitive functional changes that accompany normal, healthy aging are suggestive of widespread cortical dysfunction. Neurobiological studies are beginning to link these functional changes and common descriptions with a loss of experience-dependent plasticity that reflects age-related changes in synaptic plasticity mechanisms. ... many changes occur at the aging synapse and it is likely that more than just one synaptic mechanism contributes to visual deficits in aging. Recent studies have highlighted the important role of ubiquitin-mediated degradation of proteins at the synapse as a potent mechanism for changing synaptic structure and function. ... Ube3A, an E3 ubiquitin ligase that is absent in Angelman's syndrome, is required for experience-dependent plasticity during development of the visual cortex. We found that Ube3A expression declines across the lifespan in human, monkey, and cat cortex. The losses were substantial (50–80%) in all areas studied."

This should be an expected result: "Cellular aging is characterised by telomere shortening, which can lead to uncapping of chromosome ends (telomere dysfunction) and that activation of DNA damage responses. There is some evidence the DNA damage accumulates during human aging and that lifestyle factors contribute to the accumulation of DNA damage. Recent studies have identified a set of serum markers that are induced by telomere dysfunction and DNA damage and these markers showed an increased expression in blood during human aging. Here, we investigated the influence of lifestyle factors (such as exercise, smoking, body mass) on the aging associated expression of serum markers of DNA damage [in] comparison to other described markers of cellular aging (p16(INK4a) upregulation and telomere shortening) in human peripheral blood. The study shows that lifestyle factors have an age-independent impact on the expression level of biomarkers of DNA damage. Smoking and increased body mass indices were associated with elevated levels of biomarkers of DNA damage independent of the age of the individuals. In contrast, exercise was associated with an age-independent reduction in the expression of biomarkers of DNA damage in human blood. The expression of biomarkers of DNA damage correlated positively with p16(INK4a) expression and negatively with telomere length in peripheral blood T-lymphocytes. Together, these data provide experimental evidence that both aging and lifestyle impact on the accumulation of DNA damage during human aging."

Every year something on the order of 50 million people die, and the fine structure of the brain that houses their minds is allowed to decay, destroying them forever. It does not have to be this way: the technology exists to plastinate and store the newly deceased, preserving the data of the mind until such time as medical technology can work a restoration. "The Open Letter on Brain Preservation seeks to raise awareness regarding the science, ethics and legality surrounding the emerging scientific process of chemical, whole-brain preservation. ... We, the undersigned, hereby publicly profess our human right to undergo a high-quality elective chemical brain preservation procedure immediately upon our physical death, and demand that such a procedure be made legal and accessible within the existing medical system in our countries of residence. We further demand that if medical evidence exists that an individual's brain is being substantially damaged by Alzheimer's, tumors, or other disease processes that elective brain preservation be available prior to that individual's natural death."

A Newsweek article runs through some of the standard foolish objections to greater human longevity. There is no change so beneficial that people will refrain from protesting it - it is human nature to be vehemently against a new idea before being grudgingly for it: "When we consider the problem of aging, and imagine that we might be able to cure it, that alternating current we feel consists of longings and dread. We are afraid of what we wish for; and most of our fears, like our hopes, have always cycled in us. Dreams of immortality have led to terrible nightmares of boredom ever since people began writing down their thoughts. ... What happens when we have real antiaging pills that pass the tests of clinical trials? As bioethicists have begun to note, this is a problem that would make all our bioethical debates to date look small. What are the bioethical problems that have exercised us in the last 10 or 20 years? Stem cells. Cloning. Gene therapy. The privacy of genetic information. Steroids. All these problems matter in themselves, but all of them would be subsumed in the transformations of society and human nature that would be wreaked by a significant success with the human life span. And then will come the option of changing the genome itself. We will add or subtract genes to lengthen our lives, until there is no going back, because no human beings alive (however long they may live) will ever be human in the same way again. If we are going to survive to enjoy a good portion of the future, our health and happiness depend on a great deal of luck. The trouble with immortality is endless." There is no objection to longevity that comes close to touching the present horror of aging - the more than 100,000 people who die each and every day.



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