Fight Aging! Newsletter, April 4th 2011

April 4th 2011

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!



- Regeneration of the Pancreas Demonstrated in Mice
- Respectable Manias and Well-Thought-Of Delusions
- Commercial Services to Measure Telomere Length
- Bacteria Complicate the Picture in AGEs and Aging
- Discussion
- Latest Headlines from Fight Aging!


Good news from the regenerative medicine research community:

"We demonstrate that intravenous delivery of human, or rat, pancreas-derived pathfinder (PDP) cells can totally regenerate critically damaged adult tissue and restore normal function across a species barrier. ... One of the more interesting aspects of this demonstration is that rat or human pathfinder cells introduced into mice spur rapid regeneration that produces overwhelmingly mouse tissue rather than rat or human tissue - and all without causing immune issues. ... the [therapy] is able to completely reverse diabetes in a mouse model. ... With only two treatments with [pathfinder cells], just days after induction of diabetes, we were able to quickly regenerate critically damaged pancreatic tissue, restoring and maintaining normal glucose levels and healthy body weight. ... Immunohistochemical analyses of animal tissues confirmed [that] treatment lead to regeneration of pancreatic beta-cells and formation of functional islets, which displayed normal architecture. Further examination determined that the regenerated islets consisted overwhelmingly of mouse cells."


We do not live in the most ideal of worlds:

"It is unfortunately the case that we live in a world in which a great many people choose to hold self-evidently incorrect and harmful beliefs. It really doesn't matter where you yourself stand in the grand spectrum of ideas, there is still at least one vast group of people who hold beliefs - and undertake actions based on those beliefs - that you would consider nothing short of madness. Take the comparative few of us who rationally value human life and scientific progress, for example: our view is of the other 99.9% of humanity clearly and deliberately walking a path of individual self-destruction. The masses reject or shun or remain in deliberate ignorance of every available path that might lead to longer healthy lives or a chance at avoiding oblivion at death.

"The world is populated with people who fail to take care of their health, who avoid thinking about progress in medicine, who laugh at cryonics, and who declare that they want to age and die. Every year, more than fifty million of them do die, decay, and the data that makes up their minds, encoded in the fine structure of the brain, is lost to oblivion. Every year, hundreds of millions suffer in terrible pain and frailty caused by age. And yet we know, from our everyday experience with the human nature of those around us, that after the advent of working rejuvenation therapies, the vast majority of people will use those technologies."


It looks like the commercial DNA analysis companies (such as 23andMe) are about to be joined by a group of startups providing telomere length measurement services:

"'Knowing whether our telomeres are a normal length or not for a given chronological age will give us an indication of our health status and of our physiological 'age' even before diseases appear,' says Maria A. Blasco, who heads the Telomeres and Telomerase Group at the Spanish National Cancer Research Center and who co-founded the company Life Length in September. Telomere research pioneer Calvin B. Harley, who co-founded Telome Health last spring with Nobel laureate Elizabeth H. Blackburn, considers telomere length 'probably the best single measure of our integrated genetics, previous lifestyle and environmental exposures.' Beginning as early as this spring, the companies will offer telomere-measurement tests to research centers and companies studying the role of telomeres in aging and disease; the general public may have access by the fall through doctors and laboratories, perhaps even directly."

I think that this is more important as a marker of a continuing trend than in and of itself: the marketplace for personal biochemical information supplied on demand, via mail and internet, will only grow as the underlying technologies become cheaper, more reliable, and possible to run at scale.


New research and new knowledge usually means the existing picture is becoming more complex, even as it becomes more comprehensible. On this theme, we come to the role of bacteria in the link between aging and the buildup of compounds known as AGEs:

"The many types of advanced glycation endproducts, or AGEs, build up with age. These are forms of sugary gunk that glue together important components in your cellular machinery, and enough of that going on would ultimately become a fatal problem. AGE levels are probably (for most people) more of a contributory cause than principle cause of age-related degeneration, however. The other things kill you first - but it's all a matter of accumulation, and every form of unrepaired biological damage plays its part in hastening the end.

"It is likely that the way in which AGEs cause issues has just as much to do with making cells act in counterproductive ways as it does with outright destruction of essential mechanisms. An important focus of research is RAGE, the cellular receptor for AGEs, which is involved in the inflammatory response. As I'm sure you know by now, chronic inflammation is very bad for you over the long term, and goes a long way towards degrading health and remaining longevity. If your body is flooded with AGEs, then one consequence is inflammation - and that in turn will cause harm over time in many different ways.

"The picture of AGEs and aging is already complicated by diet - some AGE levels are very variable, and depend on what you happen to be eating - and metabolic conditions such as diabetes wherein the overall behavior of human metabolism is quite different from that of an aged but otherwise normal person. Much of the modern populace eats far too much, and far too much sugar as well, which leads to these sorts of conditions of overnutrition.

"Today I noticed an open access paper that adds another layer of complexity to the picture of AGEs and aging. Bacteria produce AGEs, and RAGE and its connection to the inflammatory response may be a component part of the immune system - a mechanism that evolved long before we humans had ready access to the damaging levels and types of food we presently consume."


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, April 1, 2011
The liver has the greatest capacity for regeneration amongst human organs - but there's always room for improvement. Here, cancer researchers incidentally uncover a potential mechanism to safely boost regenerative capacity: "During chronic liver damage repetitive waves of hepatocyte cell death and compensatory proliferation take place, eventually culminating in chronic liver failure and often in the development of hepatocellular carcinoma (HCC). A misregulated regenerative response to chronic liver injury may represent the base for development of HCC. Therefore, a more detailed understanding of signaling pathways involved in proliferation control of hepatocytes not only holds the great promise of informing new therapies to increase the hepatic regenerative potential but also to deduce new strategies for the treatment of HCC. We have established a unique system to perform in vivo RNAi screens to genetically dissect cellular signaling networks regulating hepatocyte proliferation during chronic liver damage. ... we identified shRNAs which showed strong enrichment during regeneration, therefore pinpointing new regulators of liver regeneration. Our top scoring candidate represents a kinase, which is accessible to pharmacological inhibition. Functional in vivo validation studies show that stable knockdown of the candidate gene by different shRNAs can significantly increase the repopulation efficiency of mouse hepatocytes and also increases the regenerative capacity of chronically damaged mouse livers. Despite the fact that some human HCCs show focal deletion of the candidate gene, a therapeutic window for regenerative therapy exists, as mice stably repopulated with shRNAs against the candidate did not develop liver tumors."

Friday, April 1, 2011
Type 2 diabetes is a lifestyle disease, avoidable for vast majority of people. If you overeat, become fat, and live a sedentary life then the odds are good you'll develop the condition, or at least its precursor, metabolic syndrome. The cost of this neglect of health basics is measurable: "Middle-aged adults with diabetes are much more likely to develop age-related conditions than their counterparts who don't have diabetes, according to a new study ... Adults between 51 and 70 with diabetes developed age-related ailments like cognitive impairment, incontinence, falls, dizziness, vision impairment and pain at a faster rate than those without diabetes, the study found. ... Our findings suggest that middle age adults with diabetes start to accumulate these age-related problems. Because diabetes affects multiple organ systems, it has the potential to contribute significantly to the development of a number of issues that we associate with aging ... For adults aged 51-60 with diabetes, the odds of developing new geriatric conditions were nearly double those of their counterparts who didn't have diabetes, the researchers found. By the time people with and without diabetes reach 80, the overall effects of aging and impact of other diseases start to reduce the disparities between the two groups. ... The findings suggest that adults with diabetes should be monitored for the development of these conditions beginning at a younger age than we previously thought." Though of course your odds of making it to 80 to be compared to your healthier cohorts are not as good if you're diabetic. So don't get fat, don't stay fat, and exercise sounds like good advice.

Thursday, March 31, 2011
A recent review: "The function of adult tissue-specific stem cells declines with age, which may contribute to the physiological decline in tissue homeostasis and the increased risk of neoplasm during aging. Old stem cells can be 'rejuvenated' by environmental stimuli in some cases, raising the possibility that a subset of age-dependent stem cell changes is regulated by reversible mechanisms. Epigenetic regulators are good candidates for such mechanisms, as they provide a versatile checkpoint to mediate plastic changes in gene expression and have recently been found to control organismal longevity. Here, we review the importance of chromatin regulation in adult stem cell compartments. We particularly focus on the roles of chromatin-modifying complexes and transcription factors that directly impact chromatin in aging stem cells. Understanding the regulation of chromatin states in adult stem cells is likely to have important implications for identifying avenues to maintain the homeostatic balance between sustained function and neoplastic transformation of aging."

Thursday, March 31, 2011
Another hit in the search for compounds that extend life in lower animals: "Basic Yellow 1, a dye used in neuroscience laboratories around the world to detect damaged protein in Alzheimer's disease - [also] known as Thioflavin T, (ThT) - extended lifespan in healthy nematode worms by more than 50 percent and slowed the disease process in worms bred to mimic aspects of Alzheimer's. The research, conducted at the Buck Institute for Research on Aging, could open new ways to intervene in aging and age-related disease. The study highlights a process called protein homeostasis - the ability of an organism to maintain the proper structure and balance of its proteins, which are the building blocks of life. Genetic studies have long indicated that protein homeostasis is a major contributor to longevity in complex animals. Many degenerative diseases have been linked to a breakdown in the process. ... this study points to the use of compounds to support protein homeostasis, something that ThT, did as the worms aged. ThT works as a marker of neurodegenerative diseases because it binds amyloid plaques - the toxic aggregated protein fragments associated with Alzheimer's. In the nematodes ThT's ability to not only bind, but also slow the clumping of toxic protein fragments, may be key to the compound's ability to extend lifespan ... We have been looking for compounds that slow aging for more than ten years and ThT is the best we have seen so far. But more exciting is the discovery that ThT so dramatically improves nematode models of disease-related pathology as well. ThT allows us to manipulate the aging process, it has the potential to be active in multiple disease states and it enhances the animal's innate ability to deal with changes in its proteins."

Wednesday, March 30, 2011
An introductory article at h+ Magazine looks at the role of telomeres and telomerase in aging: "Several thousand studies have been published on telomeres and telomerase, which are now known to maintain genomic stability, prevent the inappropriate activation of DNA damage pathways, partially determine disease susceptibility/resistance and regulate cellular and organism-wide viability and aging. Telomerase expression [in conjunction with other genetic alterations] also extends the lifespan and reverses senescence-associated pathologies in mice. ... In humans telomere length and integrity plays a role in some diseases, disease susceptibility, aging and even in mediating the deleterious effects of long-term psychological stress. Several human genetic diseases are caused by alterations in telomerase function. For example, individuals with dyskeratosis congenita (DC) ... Many aspects of DC resemble normal aging, although at an accelerated rate. Individuals with DC are born with unusually short telomeres and not surprisingly, the expression of unmutated telomerase in DC cells corrects many of their molecular defects and lengthens their telomeres. ... Normal cellular telomerase expression is insufficient to prevent telomere shortening with each cell division and hence, telomeres shorten with aging, eventually causing age-related changes. The process is complex, and different cell types and organs show different rates of telomere shortening, although overall telomere shorten most rapidly in growing cell populations. Interestingly, high telomere stability correlates with human longevity while caloric restriction (the only known intervention that increases the [maximum] mammalian lifespan), reduces the rate of telomere shortening, although it does not increase telomerase expression. Last, malignant tumors overexpress telomerase, allowing them to grow indefinitely. One reason why most normal cells of the human body do not express high levels of telomerase might be to prevent cancer."

Wednesday, March 30, 2011
One approach to developing targeted therapies is to co-opt existing biological structures, such as cells and bacteria: "Scientists have developed bacteria that serve as mobile pharmaceutical factories, both producing disease-fighting substances and delivering the potentially life-saving cargo to diseased areas of the body. ... [Researchers] chose the term 'bacterial dirigibles' because the modified bacteria actually have the fat-cigar look of blimps and zeppelins, those famous airships of yesteryear. ... We're building a platform that could allow bacterial dirigibles to be the next-generation disease fighters. ... traditional genetic engineering reprograms bacteria so that they produce antibiotics, insulin, and other medicines and materials. The bacteria grow in nutrient solutions in enormous stainless steel vats in factories. They release antibiotics or insulin into vats, and technicians harvest the medicine for processing and eventual use in people. The bacterial dirigible approach takes bioengineering a step further. Scientists genetically modify bacteria to produce a medicine or another disease-fighting substance. Then, however, they give the bacteria a biochemical delivery address, which is the locale of the disease. Swallowed or injected into the body, the bacteria travel to the diseased tissue and start producing substances to fight the disease. ... We have created a genetic circuit that endows E. coli with targeting, sensing and switching capabilities. ... The 'targeting' molecule is attached to the outer surface of the bacteria. It gives the bacteria an ability to 'hone in' on specific cells and attach to them - in this instance, the intestinal cells where other strains of E. coli cause food poisoning symptoms. Inside the bacteria is a gene segment that acts as 'nanofactory.' It uses the bacteria's natural cellular machinery to make drugs, such as those that can fight bacterial infections, viruses, and cancer. The nanofactory also could produce signaling molecules that enable the dirigible to communicate with natural bacteria at the site of an infection. Some bacteria engage in a biochemical chit-chat, termed 'quorum sensing,' in which they coordinate the activities needed to establish an infection. Bacteria dirigibles could produce their own signaling molecules that disrupt quorum sensing."

Tuesday, March 29, 2011
Optimizing health, measuring progression of age-related change in metabolism, and detecting disease are far more challenging today than they will be in the future. We can envisage sophisticated implanted devices that cheaply and continuously measure aspects of our biology that are presently expensive to test - and the first steps in the development of such implanted monitors are already underway. "Michael Cima and his team developed an implantable sensor that uses antibodies attached to nanoparticles to detect cancer related biomarkers. In 2009 Cima showed that he could implant these devices into human tumors in mice and then 'read' the cancer growth using MRI. No biopsies need. Over the past few years, Cima and his team have adapted their work to create a very similar device that measures biomarkers related to heart damage. ... This work is very exciting, but still very early in development. As we've said many times before, successes with mice experiments and successes with human experiments can be miles apart. The 5mm cylindrical cancer implant and the 8mm heart monitoring disk both need more time to be perfected. The antibodies used to detect biomarkers have a limited lifetime in the body. Currently an implant probably wouldn't last much longer than two months. ... If MIT continues to see good results with these early prototypes, there's a good chance we'll see similar devices in clinical trials in the near future. Cima thinks that such experiments could be as little as five years away. The lowest hanging fruit are implants that could monitor for pH levels - acidity is often a hallmark of cancer cells. After that, we may see versions that can accurately detect hormone levels and drug responses."

Tuesday, March 29, 2011
A very readable editorial on recent research into the connection between germ cells and longevity: " For reasons still unknown, a roundworm without its germ cells lives 60% longer than one with those cells intact. And you don't even need to actually remove them - mutations that impair their proliferation also extend life. ... The authors began their exploration by searching for nuclear receptors that were required for the life-extension effect, reasoning that one or more such receptors were likely to play a key role in controlling longevity pathways. Using RNAi in long-lived worms with a known germline proliferation mutation, they shut down hundreds of receptors, looking for those that would reverse the lifespan extension. They found only one, called nhr-80, which they showed acted specifically within the germline-mediated longevity pathway, and not any of the several other pathways known to extend lifespan. This result provided the first experimental evidence that lifespan extension through ablation of the germline can occur in the absence of insulin signaling, one of the best characterized pathways affecting lifespan. Mutation of nhr-80 to prevent expression of the gene prevented the longevity effect, while overexpression increased it, in both cases only when germline cells were absent. ... As a transcription factor, NHR-80 regulates gene expression. Its known targets include a group of enzymes involved in lipid metabolism called desaturases. Desaturases convert saturated fatty acids, such as stearic acid, into unsaturated fatty acids, such as oleic acid, a conversion that significantly alters the physical and biological properties of the fats made from them. The authors show that genes for several desaturases are highly expressed in long-lived germline mutants. ... While worms are not humans, we share many of the same cellular mechanisms, and it is possible the same life-extending effects of this germline-loss/fatty acid increase pathway will be found in us."

Monday, March 28, 2011
From a recent review paper: "Naked mole rats (NMRs; Heterocephalus glaber) are the longest-living rodents known, with a maximum lifespan of 30 years— - 5 times longer than expected on the basis of body size. These highly social mouse-sized rodents, naturally found in subterranean burrows in the arid and semiarid regions of the horn of Africa, are commonly used in behavioral, neurological, and ecophysiological research. Very old NMRs (>28 years), like humans, show signs of age-associated pathologies (e.g., muscle loss) as well as the accumulation of lipofuscin pigments, but no signs of tumorigenesis. Indeed, for at least 80% of their lives NMRs maintain normal activity, body composition, and reproductive and physiological functions with no obvious age-related increases in morbidity or mortality rate. Their long lifespan is attributed to sustained good health and pronounced cancer resistance. Clearly physiological and biochemical processes in this species have evolved to dramatically extend both their good health and lifespan. We and others have tested various current theories using this species as an exceptionally long-lived animal model of successful abrogated aging. Surprisingly, NMRs have high levels of oxidative stress and relatively short telomeres, yet they are extremely resilient when subjected to cellular stressors and appear capable of sustaining both their genomic and protein integrity under hostile conditions. The challenge is to understand how these animals are able to do this. Elucidating these mechanisms will provide useful information for enhancing human life- and healthspan, making the naked mole rat a true “supermodel” for aging research and resistance to chronic age-associated diseases."

Monday, March 28, 2011
Long running studies of calorie restriction in primates remain promising: "In the 75 years since the seminal observation of Clive McCay that restriction of calorie intake extends the lifespan of rats, a great deal has been learned about the effects of calorie restriction (CR; reduced intake of a nutritious diet) on aging in various short-lived animal models. Studies have demonstrated many beneficial effects of CR on health, the rate of aging, and longevity. Two prospective investigations of the effects of CR on long-lived nonhuman primate (NHP) species began nearly 25 years ago and are still under way. This review presents the design, methods, and main findings of these and other important contributing studies, which have generally revealed beneficial effects of CR on physiological function and the retardation of disease consistent with studies in other species. Specifically, prolonged CR appears to extend the lifespan of rhesus monkeys, which exhibited lower body fat; slower rate of muscle loss with age; lower incidence of neoplasia, cardiovascular disease, type 2 diabetes mellitus, and endometriosis; improved insulin sensitivity and glucose tolerance; and no apparent adverse effect on bone health, as well as a reduction in total energy expenditure. In addition, there are no reports of deleterious effects of CR on reproductive endpoints, and brain morphology is preserved by CR. ... More research is needed to delineate the mechanisms of the desirable outcomes of CR and to develop interventions that can produce similar beneficial outcomes for humans. This research offers tremendous potential for producing novel insights into aging and risk of disease."



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