Longevity Meme Newsletter, October 11 2010

October 11 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.



- "I refuse the invitation to my grave"
- The Rational Use for Excess Money
- Faking the Appearance of Rejuvenation
- The Prevailing Double Standard
- Discussion
- Latest Healthy Life Extension Headlines


Maria Konovalenko of the Science Against Aging initiative recently discussed the mainstream gerontology focus on slowing aging only. These are researchers who reject repair strategies such as SENS and the possibility of greatly extending the human life span, but not, I think, for entirely good reasons.


"I fundamentally disagree with the following idea made by [researcher Tom Kirkwood in a recent issue of Scientific American]: 'The goal of gerontology research in humans, however, is always improving health at the end of life, rather than achieving Methuselean life spans.' This is a traditional stance taken by the hawks of the conservative wing of gerontologists: to [set quality of life and longevity as distinct research goals that are in opposition]. This is the biggest mistake in gerontology. The quality of life and longevity are closely related. If the quality of life is high in the biomedical sense, then why would the person suddenly die? Besides, many experiments on model animals show that the interventions leading to life extension also led to improved reproduction and increased activity. Essentially, an improved quality of life for the animal.

"The reasoning behind such statements is based on an 'acceptance of one's own death', which the author is calling for. Since we cannot radically increase longevity right now, then let's consider it as 'unnecessary'. ... Denial of the radical life extension idea amounts to intellectual cowardice or fear to be perceived as a 'black sheep', and ignoring the advances of modern science."

You might read more in the Fight Aging! archives about the divide between advocates of slowing aging to improve health in later life and advocates of repairing and reversing aging to create large gains in life span:



Time can buy money, but it is only now that money can possibly buy time:


"A hundred years ago, additional time was a limited commodity. You could spend resources to have a little more of it - doctors, a good life, the learning needed to take advantage of these items - but after a certain point there was no amount you could spend that would let you live for even one additional day.

"This is no longer the case. A sufficiently massive directed research program could, for example, realize the SENS program for rejuvenation within a couple of decades, to produce the planned and presently understood methods for repairing the biochemical and cellular damage that causes aging. Say $2 billion spent at $100 million a year, and you'll have working rejuvenation in mammals in the laboratory, ready to move to development in humans. It really is that cheap to go from where the research community stands now to completed proof of concept, and that would fund the full spectrum of development: replacement of mitochondrial DNA, safe breakdown of AGEs, amyloids, lipofuscin, and other unwanted chemical gunk, replacement of damaged stem cell populations, immune system restoration, and so forth. Cures for all cancers are in that list as well, but I'm actually fairly confident that will happen anyway before 2040 rolls around.

"If you have time and health, you can always make more money. If you have neither time nor health, then money is worthless. So it seems fairly obvious where a rational person should direct the money not needed to get by. It should all go to longevity science: increasing the chance of you personally living into an age of indefinite healthy, youthful life spans, brought about by medical technologies of maintenance and repair that can reverse the course of aging."


The common meanings and baggage attached to language by moneyed interests are there to trip you up and hinder you when advocating longevity science:


"When we advocate engineered human longevity by using the word rejuvenation, to make young again is exactly what we mean. We are being precise, and using rejuvenation to mean 'a hypothetical reversal of the aging process.' The problem here is that 'rejuvenation' has long been a term of art and marketing brand for cosmetics manufacturers, the horrid 'anti-aging' marketplace, dermatologists, and plastic surgeons - four communities with a significant overlap. They also boast very significant revenues, meaning their voices are loud and their presence hard to miss.

"What all of these groups have in common is that they develop and sell products and services claiming to restore the appearance of youth to some degree: fake rejuvenation, in other words. At best it's a matter of papering over the cracks - but these folk use the term rejuvenation without qualification or reservation. In their eyes and publicity materials, 'rejuvenation' means exactly 'faking the appearance of rejuvenation.' ... Every technical artifice, none of which do anything to intervene in the actual process of aging, is labeled as rejuvenation - because in their field, rejuvenation means artifice. It means fakery, deception, and alteration of appearance. ... As I mentioned, this is a rich field. Throw enough money into marketing and the meanings you ascribe to words will spread into common usage."


Why do people object to longevity science while they are enthusiastically in favor of other attempts to save lives?


"We don't call other efforts to save human life 'denial' when they don't work in some cases, and not just in a medical context. The effort to rescue those trapped miners in Chile may not work, for example; but nobody I know of calls the rescue project 'denial,' wants to stop it as a waste of resources, and admonishes the doomed miners to 'Get over yourselves' ... The same goes for medicine in general. How would we react if authority figures scolded us for seeking health care for serious illnesses or injuries, saying that we should instead deal with our 'denial' and 'fear of death' issues through, say, strength of character, rather than trying to stay alive and functional through modern medicine?

"A person who ages to frailty is no less suffering and no less dead in the end than one who dies through accident or disease at a younger age. So many people are instinctively hostile to the prospect of anyone managing to live longer, just as they are instinctively hostile to those who make far more money - and this jealousy is, sadly, an important aspect of human nature. We primate hunter-gatherers are hardwired to hate and stamp out inequality wherever we see it, a tendency that isn't helpful at all in this day and age of great cities and complex economies. When acted upon, these urges help to hold back improvement for all."


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!




Via FuturePundit, the estimates for recent research funding: "The U.S. invested $139 billion last year in health research from all public and private sources, according to Research!America's latest annual estimate. That amount represents only 5.6% of the $2.47 trillion overall U.S. health spending in 2009 [which] varies no more than 0.2% from 2005 levels. ... We are all growing old. We are all aging and our parts are breaking down and wearing out. A portion of those billions of dollars flows toward science technologies that will eventually put an end to aging. Human bodies will become as repairable as cars. Replacement organs, cell therapies, gene therapies, and even nanobots will, at some point in the 21st century, halt and reverse the process of aging. Will you still be alive when that day is reached?" As has always been the case, funding for research is a tiny percentage of the flows of money in our culture. Funding for aging research is a tiny fraction of the figures given above, and funding for engineered longevity is in turn a tiny fraction of aging research. To fully realize the Strategies for Engineered Negligible Senescence in mice in the laboratory would probably cost in the vicinity of $1-2 billion over a decade or two. Food for thought.

From the Australian: "Generating new body organs in the lab is the stuff of Hollywood fantasy. But judging by the latest experimental findings, science fiction may soon be science fact. ... Already, a bio-printer is cranking out three-dimensional tissues and Australian researchers are hard at work growing spare parts, with designer tissues proving their stuff in animal - and even human - trials. ... In animal experiments, [researchers have] made breast, fat, muscle and even pancreatic tissue that secretes insulin. They've also created tissue of a specialised immune system organ, the thymus, opening the way for multiple applications in immunology. That's because the thymus schools T-cells that help the immune system identify and fight infections and foreign cells. Using mice bred with no immune system, [researchers] found that after the mice received newly grown tissue they developed effective immune responses. ... the institute is engaged in a small number of human clinical trials with fat and breast tissue. The goal is to establish whether tissue can be created and used to replace tissue removed due to cancer. The trials have about six months to run. While creating living tissue is important, the larger aim is creation of functioning human organs."

Mitochondrially targeted antioxidants - such as gene engineering of increased amounts of catalase - are shown to extend life in mice, but here researchers find no such effect (or a negative effect) in flies: "The simultaneous overexpression of multiple copies of Mn superoxide dismutase (SOD) and ectopic catalase (mtCat) transgenes in the mitochondria of the fruit fly, Drosophila melanogaster, was shown previously to diminish the life span. The hypothesis tested in the present study was that this effect was due primarily to the presence of one or the other transgene. An alternative hypothesis was that both transgenes have additive, negative effects. Crosses were performed between five pairs of transgenic lines containing single-copy insertions of either mtCat, Mn SOD, or P element vector control transgenes at unique loci, and the life spans of progeny containing two mtCat, Mn SOD or vector insertions were determined. Increasing amounts of mitochondrial catalase activity tended to be associated with decreases in mean life span. Overexpression of two copies of the genomic Mn SOD transgene had no effect on life span. The results do not support the hypothesis that enhanced mitochondrial SOD or catalase activity promotes longevity in flies." This suggests that it's possible to set up a situation in mammals wherein mitochondrially targeted antioxidants are harmful to life span, but I'm not aware of any examples.

CALERIE is the largest present study of calorie restriction in humans: "In a robust and consistent manner, sustained caloric restriction (CR) has been shown to retard the aging process in a variety of animal species. Nonhuman primate studies suggest that CR may have similar effects in longer-lived species. The CALERIE (Comprehensive Assessment of the Long-term Effects of Reducing Intake of Energy) research program is the first systematic investigation of CR in nonobese human beings. In the phase 2 study, it is hypothesized that 2 years of sustained CR, involving a 25% reduction of ad libitum energy intake, results in beneficial effects similar to those observed in animal studies. ... The study is a multicenter, parallel-group, randomized controlled trial. A sample of 225 participants [is] being enrolled with 2:1 allocation to CR. ... An intensive dietary and behavioral intervention was developed to achieve 25% CR and sustain it over the 2 years. Adherence is monitored using a doubly labeled water technique. Primary outcomes are resting metabolic rate and core temperature, and are assessed at baseline and at 6-month intervals. Secondary outcomes address oxyradical formation, cardiovascular risk markers, insulin sensitivity and secretion, immune function, neuroendocrine function, quality of life and cognitive function. ... The results will provide insight into the detrimental changes associated with the human aging process and how CR mitigates these effects."

Inevitably, researchers who focus on slowing aging through metabolic manipulation will uncover ingested compounds that alter metabolism in beneficial ways, and thus very modestly raise life expectancy. Here is an example in mice: "Recent evidence points to a strong relationship between increased mitochondrial biogenesis and increased survival ... Branched-chain amino acids (BCAAs) have been shown to extend chronological life span in yeast. However, the role of these amino acids in mitochondrial biogenesis and longevity in mammals is unknown. Here, we show that a BCAA-enriched mixture (BCAAem) increased the average life span of mice. BCAAem supplementation increased mitochondrial biogenesis and sirtuin 1 expression in primary cardiac and skeletal myocytes and in cardiac and skeletal muscle, but not in adipose tissue and liver of middle-aged mice, and this was accompanied by enhanced physical endurance. Moreover, the reactive oxygen species (ROS) defense system genes were upregulated, and ROS production was reduced by BCAAem supplementation. All of the BCAAem-mediated effects were strongly attenuated in [mice engineered to lack] endothelial nitric oxide synthase." Nitric oxide is important to stem cell and blood vessel function; it is interesting that this effect depends upon that component of metabolism.

A brief summary of recent research into risk factors for disease and human longevity: "A set of currently known alleles increasing the risk for coronary artery disease, cancer, and type 2 diabetes as identified by genome-wide association studies was tested for compatibility with human longevity. Here, we show that nonagenarian siblings from long-lived families and singletons older than 85 [years] of age from the general population carry the same number of disease risk alleles as young controls. Longevity in this study population is not compromised by the cumulative effect of this set of risk alleles for common disease." The way in which you choose to lead your life is a more important determinant - for example, being sedentary and fat raises your risk of suffering the common diseases of aging far more than most known genetic variants. It is true that there are many gene variants associated with exceptional human longevity, but it still seems to be the case that environment and choice trumps small variations in your biology.

Your cells are constantly creating and destroying the protein components of their machinery. All of the known metabolic alterations that enhance longevity affect these processes in some way: "Cellular homeostasis, which is needed for the cells to survive, requires a well-controlled balance in protein turnover. Both protein synthesis and degradation are influenced by distinct genetic pathways that control aging in divergent eukaryotic species. ... In addition to providing building blocks for generation of new proteins and fuelling the cell with energy under starvation, the protein degradation processes eliminate damaged, nonfunctional proteins, the accumulation of which serves as the primary contributory factor to aging. Interestingly, a complex, intimate regulatory relationship exists between mechanisms promoting protein synthesis and those mediating protein degradation: under certain circumstances the former downregulate the latter. Thus, conditions that favor protein synthesis can enhance the rate at which damaged proteins accumulate. This may explain why genetic interventions and environmental factors (e.g., dietary restriction) that reduce protein synthesis, at least to tolerable levels, extend lifespan and increase resistance to cellular stress in various experimental model organisms of aging."

Looking back at historical data on life span in human lineages, researchers find the result you might expect from centenarian studies - the most long-lived families tend to have more long-lived offspring, while for everyone else lifestyle choices and accident are more important determinants: "Although genetic factors are known to influence the human aging process, the proportion of life span and longevity variation explained by them is still controversial. We evaluated the genetic contribution to life span using historical data from three Alpine communities in South Tyrol, Italy. We estimated the heritability of life span and survival to old age (longevity), and we assessed the hypothesis of a common genetic background between life span and reproduction. The heritability of life span was [low], whereas the heritability of longevity [increased] as the longevity threshold increased. Heritability estimates were little influenced by shared environment, most likely due to the homogeneity of lifestyle and environmental factors in our study population. Life span showed both positive association and genetic correlation with reproductive history factors. Our study demonstrates a general low inheritance of human life span, but which increases substantially when considering long-living individuals, and a common genetic background of life span and reproduction, in agreement with evolutionary theories of aging."

ETS-4 AND WORM LIFE SPAN (October 04 2010)
An open access paper that is representative of much of the present day investigation of the genetics of longevity: "Animal life span is regulated in response to developmental and environmental inputs through coordinate changes in gene expression. Thus, longevity determinants include DNA-binding proteins that regulate gene expression by controlling transcription. Here, we explored the physiological role of the transcriptional regulator, ETS-4, in the roundworm Caenorhabditis elegans. Our data showed that worms that lack ETS-4 lived significantly longer, revealing ETS-4's role in the transcription network that regulates life span. We identified 70 genes whose expression was modulated by ETS-4 that function in lipid transport, lipid metabolism and innate immunity. Some of the ETS-4-regulated genes were also controlled by two other regulators of aging, the FOXO and GATA factors. We concluded that a common set of transcriptional targets orchestrate the network of physiological factors that affect aging. ETS-4 is closely related to the human ETS protein SPDEF that exhibits aberrant expression in breast and prostate tumors. Because the genetic pathways that regulate aging are well conserved in other organisms, including humans, our findings could lead to a better understanding of SPDEF function and longevity regulation in mammals."

As a companion piece to recent work on histones and aging in yeast, these researchers investigate further the connections between cell aging and histones: "as cells count down to senescence and telomeres wear down, their DNA undergoes massive changes in the way it is packaged. These changes likely trigger what we call 'aging'. ... Prior to this study we knew that telomeres get shorter and shorter as a cell divides and that when they reach a critical length, cells stop dividing or die. Something must translate the local signal at chromosome ends into a huge signal felt throughout the nucleus. But there was a big gap in between. ... [researchers compared] levels of proteins called histones in young cells - cells that had divided 30 times - with 'late middle-aged' cells, which had divided 75 times and were on the downward slide to senescence, which occurs at 85 divisions. Histone proteins bind linear DNA strands and compress them into nuclear complexes, collectively referred to as chromatin. ... aging cells simply made less histone protein than do young cells. ... These proteins are required throughout the genome, and therefore any event that disrupts this production line affects the stability of the entire genome. ... Comparisons of histone patterns in cells taken from human subjects-a 9- versus a 92-year-old-dramatically mirrored histone trends seen in cell lines. ... These key experiments suggest that what we observe in cultured cells in a laboratory setting actually occurs and is relevant to aging in a population." This might be thought of as another line of evidence in the debate over the degree to which nuclear DNA damage contributes to aging.



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