Longevity Meme Newsletter, August 31 2009

August 31 2009

The Longevity Meme Newsletter is a weekly e-mail containing news, opinions, and happenings for people interested in healthy life extension: making use of diet, lifestyle choices, technology, and proven medical advances to live healthy, longer lives.



- Twelve Ways to Extend Healthy Life in Mice
- Immortality Institute Members Debating the Name Once Again
- An Introduction to the Importance of Autophagy
- Discussion
- Latest Healthy Life Extension Headlines


Researchers have discovered a fair number of ways to extend healthy life in mice over the past fifteen years, and the pace is picking up. You can read about some of the more interesting methods in this Fight Aging! post:


The greatest benefit with no apparent side-effects or drawbacks is presently about a 50% addition to mouse life span. Two entirely different genetic alterations achieved this level of life extension, both leading to mice that are more active, healthier, and suffer far less age-related disease.


Over at the Immortality Institute, the members are once again debating the name, this time looking for a compromise position between a name change or no name change. It's one facet of the broader discussion over strategies for advocacy and progress:


"The name of the Immortality Institute is a bold statement - part and parcel of a strategy of shifting the debate about longevity science by planting a flag as far out as possible. It is one and the same with talking about the 1000 or so years an ageless person could expect to live under reasonable assumptions of accident-based mortality rates, or arguing the plausible science behind the complete elimination of aging through ongoing repair strategies. If there is no effort made to plant flags far out in the field and shift the debate, then all that is left are the cautious, institution-bound people whose idea of ambition is to talk about extending life expectancy by seven years - at some fuzzy future date - through working to gently slow down aging.

"I, personally, am very much on the side of bold statements and bounds shifting. We won't get more than one chance to build an entirely new research community and see the results it produces in our lifetimes. This is the work of decades. If we don't try to shoot for the moon, then we may as well resign ourselves to those seven extra years and little more, because no-one will be trying to do any better."


Autophagy, a cellular housekeeping and recycling process, is increasingly considered to be important in how the operation of metabolism determines longevity:


"The weight of evidence points to more and better autophagy as beneficial overall, most likely because it leads to fewer lingering damaged components inside a cell. Repeated throughout all your cells, this should result in better functioning tissue, fewer errant biological systems, and a longer life - remember that aging itself is nothing more than accumulated damage and the thrashing of systems trying to adapt to that damage.

"The mechanisms by which autophagy mediates lifespan extension are not yet understood. However, one possibility is that the increase in lifespan is mediated through the autophagy-dependent nonspecific or selective removal of damaged mitochondria, decrease in levels of intracellular reactive oxygen species, and subsequent protection against oxidative damage."


The highlights and headlines from the past week follow below.

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This study shows centenarians to more often carry a variant gene that affects exonuclease 1 (EXO1), involved in some forms of DNA repair - adding some fuel to the debate over the significance of nuclear DNA damage in aging. At this stage researchers are turning up longevity-associated differences in genes at a much faster rate than progress in understanding how it all ties together and how important specific genetic differences might be. From the paper: "Human longevity is heritable with a genetic component of 25-32%. Variation in genes regulating the levels of somatic maintenance and DNA repair functions is thought to modulate the aging process and to contribute to survival at advanced age. We tested 92 non-synonymous SNPs in 49 DNA repair genes for a possible association with longevity in a sample of 395 German centenarians and 411 controls. The obtained association signal in exonuclease 1 (EXO1) was further investigated by fine-mapping and mutation detection, leading to the identification of the functionally relevant SNP rs1776180. Our detailed analyses revealed that the common allele (C) of this promoter SNP is significantly enriched in female centenarians. This finding replicated in 455 female French centenarians and 109 controls. ... Given the survival advantage that is associated with the C allele of rs1776180, EXO1 can be considered a candidate for a novel longevity-enabling gene."

Via ScienceDaily: "We wanted to uncover the workings of skin health in order to see why older people don't deal well with skin infections and are prone to skin cancers also. ... In the past, the reduction in skin health was put down to potential defects in the white blood cells called T-cells that would usually help to identify and clear infection. However, when experiments were carried out with healthy young individuals under the age of 40 years and older individuals over the age of 70 years in this study, it was shown that in fact there is nothing wrong with the T-cells in the older group; instead it is the inability of their skin tissue to attract T-cells where and when they are needed that is the source of reduced immunity. ... Knowing this now raises the question of whether the same defect also occurs in other tissues during ageing. Is it possible that, for example, lung tissues also fail to give out the right message to T-cells to bring them into the tissue to do their job? This may explain, in part, the higher rates of lung cancer, chest infections and pneumonia in older people, perhaps. ... at least in the test tube, it is possible to make older skin express the missing signals that attract T cells. This indicates that, in principle, the defect is entirely reversible."

Excess visceral fat, the insulin resistance of type 2 diabetes and metabolic syndrome, and chronic, damaging inflammation all go together. But why? Looking at the fat tissue tells us that macrophages seem to be involved, but here researchers dive in deeper, finding "in cultured cells and mouse experiments that Fox01 stimulates inflammatory white blood cells called macrophages, which migrate to the liver and adipose, or fat, tissue in insulin-resistant states, to increase production of a cytokine called interleukin-1 beta (IL-1B). The cytokine in turn interferes with insulin signaling. Insulin typically inhibits Fox01, setting up a feedback loop in healthy tissues that helps regulate insulin levels. ... The findings suggest that when there is a lack of insulin or when cells such as macrophages are resistant to its presence, there are no brakes on Fox01's stimulation of IL-1B and its further interference with insulin signaling. That might explain why chronic inflammation often is coupled with obesity and type 2 diabetes." All the more reason to take better care of your health so that you don't find yourself experiencing this firsthand.

The interesting thing about longevity science is that the end result - a much longer, healthier life - is so compelling that even communities traditionally opposed to free and rapid development of new technologies on ideological grounds (such as prioritizing equality so highly that universal poverty and death is preferable to inequality) find their members coming around eventually. See this, for example, from an ethicist steeped in the social justice viewpoint: "A fair system of social cooperation is one that is both rational and reasonable (John Rawls, 2001). Is it rational and reasonable for societies that (1) are vulnerable to diverse risks of morbidity (e.g. cancer, heart disease) and mortality, and (2) are constrained by limited medical resources, to prioritize aging research? In this paper I make the case for answering 'yes' on both accounts. Focusing on a plausible example of an applied gerontological intervention (i.e. an anti-aging pharmaceutical), I argue that the goal of decelerating the rate of human aging would be a more effective strategy for extending the human healthspan than the current strategy of just tackling each specific disease of aging. Furthermore, the aspiration to retard human aging is also a reasonable aspiration, for the principle that underlies it (i.e. the duty to prevent harm) is one that no one could reasonably reject."

By now I'd hope you know that the evidence points to excess visceral fat being very bad for you over the long term. Is it the visceral fat or something else correlated with visceral fat, however? "New findings [suggest] that it's not whether body fat is stored in the belly that affects metabolic risk factors for diabetes, high blood triglycerides and cardiovascular disease, but whether it collects in the liver. ... For years, scientists have noted that where individuals carried body fat influences their metabolic and cardiovascular risk. Increased fat inside the belly, known as visceral fat, is associated with an increased risk of diabetes and heart disease. ... Data from a large number of studies shows that visceral fat is associated with metabolic risk, which has led to the belief that visceral fat might even cause metabolic dysfunction. However, visceral fat tracks closely with liver fat. We have found that excess fat in the liver, not visceral fat, is a key marker of metabolic dysfunction. Visceral fat might simply be an innocent bystander that is associated with liver fat." On the other hand, mouse studies show that surgically removing visceral fat extends life.

Closely following reprogramming of bone marrow cells into retinal cells, researchers have now demonstrated that induced pluripotent stem cells (iPS cells) can turn out retinal cells as well: the scientists have "grown multiple types of retina cells from two types of stem cells - suggesting a future in which damaged retinas could be repaired by cells grown from the patient's own skin. Even sooner, the discovery will lead to laboratory models for studying genetically linked eye conditions, screening new drugs to treat those conditions and understanding the development of the human eye. ... This is an important step forward for us, as it not only confirms that multiple retinal cells can be derived from human iPS cells [but] also shows how similar the process is to normal human retinal development. That is quite remarkable given that the starting cell is so different from a retinal cell and the whole process takes place in a plastic dish. We continue to be amazed at how deep we can probe into these early events and find that they mimic those found in developing retinas. Perhaps this is the way to close the gap between what we know about building a retina in mice, frogs and flies with that of humans."

Protein misfolding is a form of damage that accumulates with age. Here researchers show that some misfolds are more important than others: "Misfolded and damaged proteins spell trouble and are common to all human neurodegenerative diseases and many other age-associated diseases. But when during a lifespan do proteins start to misbehave? A new [study] reports that protein damage can be detected much earlier than we had thought, long before individuals exhibit symptoms. But the study also suggests if we intervene early enough, the damage could be delayed. In studying seven different proteins of the worm C. elegans, the researchers discovered that each protein misfolds at the same point: during early adulthood and long before the animal shows any behavioral, or physiological, change. ... The misfolding coincided with the loss of a critical protective cellular mechanism: the ability to activate the heat shock response, an ancient genetic switch that senses damaged proteins and protects cells by preventing protein misfolding." You might recall that enhanced heat shock response is how SIRT1 is thought to influence health and longevity, and there is a growing interest in manipulating the heat shock response as the basis for longevity and cancer therapies.

More on the link between obesity and increased risk of dementia from the New Scientist: "Brain regions key to cognition are smaller in older people who are obese compared with their leaner peers, making their brains look up to 16 years older than their true age. As brain shrinkage is linked to dementia, this adds weight to the suspicion that piling on the pounds may up a person's risk of the brain condition. Previous studies suggested that obesity in middle age increases the risk of dementia decades later, which is accompanied by increased brain shrinkage compared with leaner people. Now brain scans of older people have revealed the areas that are hardest hit, as well as the full extent of brain size differences between obese people and those of average weight. ... High insulin levels and type 2 diabetes tend to accompany being overweight and are risk factors for brain tissue loss and dementia. However, the relationship between brain size and body mass index still stood when the researchers accounted for these conditions, indicating that body fat levels may be linked directly to brain shrinkage. Thompson suggests that as increased body fat ups the chances of having clogged arteries, which can reduce blood and oxygen flow to brain cells."

Researchers here describe chronic kidney disease as essentially an accelerated form of mitochondrial damage as described in the mitochondrial free radical theory of aging: "Chronic kidney disease (CKD) has been linked to oxidative stress caused by dysregulation of the genes that control mitochondria. A study [has] revealed alterations in respiration gene expression in the white blood cells of CKD patients. ... The researchers found 44 genes that were up-regulated in the peripheral blood mononuclear cells of CKD patients, compared to normal controls. Of these, 11 were genes were involved in the oxidative phosphorylation system. Further tests revealed that the levels reactive oxygen species (ROS) were significantly higher in the CKD group. [Researchers] suggest that these species are part of a vicious circle of respiration dysregulation that ultimately results in CKD ... Our hypothesis is that an increased production of ROS, due to the effect of pro-inflammatory mediators, may cause a profound inhibition of the oxidative phosphorylation system leading to a compensatory 'hypertrophy' of its components. In addition, a hypertrophic and impaired oxidative phosphorylation system may prime a vicious circle, causing a continuous release of ROS."

News from a UK research charity supportive of the Strategies for Engineered Negligible Senescence (SENS): "The Biogerontology Research Foundation in collaboration with the Institute for Biology of Aging funds research in hematopoietic stem cell transplantation in telomerase-knockout mice. Mammals must finely balance stimulation and suppression of cell division: over-permissive cellular proliferation promotes cancer, whereas over-restrictive cell division promotes degeneration. This is especially true in tissues with a high cell turnover, such as the blood. Genetic manipulation of the machinery that maintains the ends of our chromosomes, combined with cell therapy, is potentially a very powerful way to alleviate this problem. However, such an approach is highly complex; as a result, researchers have been reluctant to investigate its components. In this new project, the blood will be used as an example to demonstrate the feasibility of such a manipulation. ... This project will be the first ever test of whether intrinsically mortal stem cells can maintain a proliferating tissue indefinitely if periodically replenished. If the answer is yes, this will motivate exploring such treatments as part of an exceptionally robust cancer-prevention therapy." You will recognize this as an early test of WILT, the SENS strategy for eliminating cancer by destroying its most fundamental required mechanism.



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