Fight Aging! Newsletter, January 9th 2012

January 9th 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!



- SENS5 Video: Rejuvenating B-Cells
- Research and Development Must Become Global in Reach
- The Development of Exercise Mimetics
- An Update on Uncoupling and Human Longevity
- Discussion
- Latest Headlines from Fight Aging!


Video of presentations from the SENS5 conference continue to formatted up and posted to YouTube in high definition:

"Aging is associated with a decline in B-lymphopoiesis in the bone marrow and accumulation of long-lived B-cells in the periphery. These changes decrease the body's ability to mount protective antibody responses. The mechanisms underlining these alterations are poorly understood. We found that the age-related alterations in the B-lineage reflect homeostatic pressures that are imposed by the accumulating long-lived B cells. Thus, a continuous demand for peripheral B cells renders the [bone marrow] devoid of senescence, and depletion of B cells in old mice revives B cell production in the bone marrow and rejuvenates the peripheral B cell compartment. Collectively, our studies suggest that immunosenescence in the B-lineage can be reversed to enhance immune responsiveness in aging."


The most viable way to work around the roadblock of regulation that prevents the application of longevity science - and so much other medical progress - is for industries and research communities to reach beyond their own regions:

"If research and development in medicine is to move at anywhere near the pace it is capable of, given the rapid progress in all forms of underlying biotechnology, it must find a way to extend beyond the most heavily regulated regions. The most capable and largest research communities, like that based in the US, are also those with the least ability to locally develop their advances into medical products, thanks to the straitjacket of regulation from government bodies like the FDA.

"The way out of this mess, short of a revolution or collapse of government, is a systemic extension of the industry of clinical application of longevity science to include regions outside the US. The logical end result of the growing medical tourism industry is better defined roadway of connections and multinational organizations that will usher scientific developments from regions like the US into other parts of the world where they can be offered as clinical treatments. What has happened for stem cell therapies and medical tourism in the past decade is just a tiny beginning, a few first steps towards what must become a much more systematic, high-bandwidth, highly visible, reliable transfer of knowledge and funds - such that the US government can't just shut it down with a few threats of prosecution, such that every life scientist in the US knows how to monetize their research outside the US by shopping around for deals with offshore developers, and such that a large enough and competitive enough marketplace exists to make that shopping around a viable process."


The next decade will see work on the development of drugs to mimic the benefits of exercise, just as the past decade has seen efforts to develop drugs to mimic the benefits of calorie restriction:

"Exercise mimetics are drugs that can replicate some fraction of the beneficial effects of exercise; their development is in the early stages. I don't think it's too far-fetched to suggest that the next ten years of exercise mimetic development will look a lot like the last ten years of calorie restriction mimetic development. In other words there will be a couple of well-funded, well-hyped lines of research that fizzle out with nothing to show for it, some solid advances towards identifying mimetics that, for one reason or another, aren't terribly practical for clinical development, and all of that against a backdrop of across-the-board progress in understanding metabolic processes that relate to exercise and its long-term effects. But, you'll note, no actual products that are legally available for use by healthy people. Absent the straitjacket regulation it would be a whole other story when it came to products and product development, of course, but we live in a world of centralized control and socialism for medicine for those regions that also boast the most active and capable research communities. It's unfortunate, and it needs to change."


Mitochondrial uncoupling, like many aspects of mitochondrial biochemistry, has been implicated in longevity in a range of species - including we humans.

"Uncoupling proteins (UCPs) govern the process of mitochondrial uncoupling, which changes the operation of the mitochondria in our cells ... Mitochondria are the power plants of your cells: they toil to turn food into ATP, used as fuel by the cell. In recent years, the eye of the research community has turned towards the process of mitochondrial uncoupling, whereby the processing of food is uncoupled from the generation of ATP. The result is less ATP and more energy in the form of heat - this is a part of the temperature regulation process in mammals, for example.

"Data from experimental models have previously suggested that UCPs may play an important role on aging rate and lifespan. We analyzed the genetic variability of human UCPs in cohorts of subjects ranging between 64 and 105 years of age (for a total of 598 subjects), to determine whether specific UCP variability affects human longevity. Indeed, we found that the genetic variability of UCP2, UCP3 and UCP4 do affect the individual's chances of surviving up to a very old age."


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, January 6, 2012
From CTV News: "Researchers say they have discovered a new source of stem cells at the back of the eye, which they hope may one day provide a way to repair the damage from age-related macular degeneration, or AMD. ... [Researchers] identified the central nervous system stem cells in a single layer called the retinal pigment epithelium, or RPE, which lies behind the retina. ... The researchers salvaged the stem cells from the RPE layer in the eyes of more than 100 deceased donors, who ranged in age from 22 to 99. But the cells can also be isolated from the fluid surrounding the retina at the back of the eye, meaning they're also accessible in living people. ... You can literally go in and poke a needle in the eye and get these cells from the sub-retinal space. It sounds awful, but retinal surgeons do it every day. ... In culture dishes in the lab, the researchers were able to coax about 10 per cent of the RPE-derived stem cells to grow in the lab. Further prodding caused the cells to differentiate into, or give rise to, a variety of cell types - those that make bone, fat or cartilage. [The researchers] also generated a progenitor cell that carries some characteristics of one type of nervous system cell, although it was not fully differentiated. ... But the fact that we could make these cells that were part-way, that were immature, indicates to us that if we keep on manipulating them, going forward in the future, we should be able to find ways to create other types of central nervous system cells."

Friday, January 6, 2012
One of the predictions of reliability theory as applied to aging is that we are all born with an existing level of damage. One of the ways in which that damage might occur - and "damage" here is a very broad term, which might include suboptimal epigenetic changes - stems from maternal influence while in the womb. For example, researchers "have shown one way in which poor nutrition in the womb can put a person at greater risk of developing type 2 diabetes and other age-related diseases in later life. This finding could lead to new ways of identifying people who are at a higher risk of developing these diseases and might open up targets for treatment. ... The research shows that, in both rats and humans, individuals who experience a poor diet in the womb are less able to store fats correctly in later life. Storing fats in the right areas of the body is important because otherwise they can accumulate in places like the liver and muscle where they are more likely to lead to disease. ... One of the ways that our bodies cope with a rich modern western diet is by storing excess calories in fat cells. When these cells aren't able to absorb the excess then fats get deposited in other places, like the liver, where they are much more dangerous and can lead to type 2 diabetes. ... The team found that this process is controlled by a molecule called miR-483-3p. They found that miR-483-3p was produced at higher levels in individuals who had experienced a poor diet in their mother's wombs than those who were better nourished."

Thursday, January 5, 2012
Type 2 diabetes (T2D) is a lifestyle disease for the vast majority of people - you avoid it by refraining from overeating, becoming fat, and giving up exercise to turn sedentary. But some folk are more likely to succumb than others, given the same lifestyle choices, and different people descend into metabolic syndrome and then type 2 diabetes at different rates. It won't be too many more years before clinics will be able to tell you exactly where you stand on the downward spiral, and what your risks are: research "has provided the first proof of molecular risk factors leading to type 2 diabetes, providing an 'early warning' sign that could lead to new approaches to treating this and other human disease conditions. ... Taking an innovative research direction, [the] research team decided to map DNA methylation variations rather than DNA sequence variations, as was traditionally done. The team undertook a proof-of-concept study among 1,169 type 2 diabetes patients and non-diabetic controls. The results demonstrated the unique abilities of this novel research approach by revealing a clear-cut, disease-predisposing DNA methylation signature. This is a first report in the scientific literature of epigenetic risk factor for T2D. DNA methylation is a naturally occurring mechanism used to regulate genes and protect DNA from some types of cleavage. It is one of the regulatory processes that are referred to as epigenetic, in which an alteration in gene expression occurs without a change in the nucleotide sequence of the DNA. Defects in this process cause several types of disease that afflict humans. ... telltale methylation signature marks were also shown to appear on the DNA of young individuals who latter developed impaired glucose metabolism, even before the appearance of clinical diabetic manifestations."

Thursday, January 5, 2012
The onset of Alzheimer's is not a sudden thing, which reinforces the view of it as a lifestyle disease: "The first changes in the brain of a person with Alzheimer's disease can be observed as much as ten years in advance - ten years before the person in question has become so ill that he or she can be diagnosed with the disease. [Researchers] are studying biomarkers - substances present in spinal fluid and linked to Alzheimer's disease. The group has studied close to 140 people with mild memory impairment, showing that a certain combination of markers (low levels of the substance beta-amyloid and high levels of the substance tau) indicate a high risk of developing Alzheimer's disease in the future. As many as 91 per cent of the patients with mild memory impairment who had these risk markers went on to develop Alzheimer's within a ten-year period. In contrast, those who had memory impairment but normal values for the markers did not run a higher risk of getting Alzheimer's than healthy individuals. ... This is a very important finding with regard to the development of new therapies against the disease. All prospective therapies have so far shown to be ineffective in stopping the disease, and many people are concerned that the pharmaceutical companies will give up their efforts in this field. But these failures may depend on the fact that the new therapies were initiated too late. When a patient receives a diagnosis today, the damage has already gone too far." I'm not sold on this last comment, given the evidence suggesting that Alzheimer's symptoms are reversible.

Wednesday, January 4, 2012
From Big Think: "The loss of a human limb is a tragedy. We know that once they're gone, mammalian arms and legs can't ever be restored. But if you cut off a salamander's leg - or tail - it will reappear in just a few weeks. ... Now, a new generation of longevity-seekers hopes to apply the power of amphibians like the salamander, the axlotl, and the worm to human medicine. ... In the future, if we had the ability to grow a brand new heart or parts of hearts with that person's very own adult stem cells, then when we know that they have heart disease, we could just replace the heart. All of those [costly] visits to the hospital, all of the drugs, won't be required. ... Better tools will enable us to repair people rather than just sort of patching them up for a little while until they get sicker and sicker. ... Over the past few decades, scientists have begun to understand exactly how the regeneration process works in nature. When a salamander is injured, a clump of cells called a blastomea forms at the site of the wound. Like embryonic stem cells, the blastomea are especially plastic. These cells are then triggered to de-differentiate and re-initiate growth. ... Debate remains over whether they're fully pluripotent, meaning that they have the ability to form any type of tissue, or whether the cellular dynamics merely have to be reprogrammed. ... The trick, of course, is applying this knowledge to human anatomy."

Wednesday, January 4, 2012
Two supercentenarian genomes have been sequenced, and suggest that - as always - the roots of variations in human longevity are more complex than we'd like them to be: "Supercentenarians (age 110+ years old) generally delay or escape age-related diseases and disability well beyond the age of 100 and this exceptional survival is likely to be influenced by a genetic predisposition that includes both common and rare genetic variants. In this report, we describe the complete genomic sequences of male and female supercentenarians, both age >114 years old. We show that: (1) the sequence variant spectrum of these two individuals' DNA sequences is largely comparable to existing non-supercentenarian genomes; (2) the two individuals do not appear to carry most of the well-established human longevity enabling variants already reported in the literature; (3) they have a comparable number of known disease-associated variants relative to most human genomes sequenced to-date; (4) approximately 1% of the variants these individuals possess are novel and may point to new genes involved in exceptional longevity; and (5) both individuals are enriched for coding variants near longevity-associated variants that we discovered through a large genome-wide association study. These analyses suggest that there are both common and rare longevity-associated variants that may counter the effects of disease-predisposing variants and extend lifespan. The continued analysis of the genomes of these and other rare individuals who have survived to extremely old ages should provide insight into the processes that contribute to the maintenance of health during extreme aging."

Tuesday, January 3, 2012
The proteasome is a cellular repair system that seems to be important in the evolution of longevity; here researchers show that impairing it causes accelerating aging. This is expected - aging is damage. Even if it fits with the established view, however, we should be wary of putting too much weight on studies that show shortened life span. There are all too many ways to reduce life span that have no application to extending life span, and the true proof of an interesting mechanism is to demonstrate increased maximum life span in mammals. Still, this is interesting work when held up against the broader context of what is known about the proteasome and the role of low level biochemical damage in aging: "The proteasome is a multicatalytic enzyme complex responsible for the degradation of both normal and damaged proteins. An age-related decline in proteasomal activity has been implicated in various age-related pathologies, including obesity and hepatic steatosis. The relevance of decreased proteasomal activity to aging and age-related diseases remains unclear, however, because suitable animal models are not available. In the present study, we established a transgenic (Tg) mouse model with decreased proteasomal chymotrypsin-like activity. Tg mice exhibited a shortened life span and developed age-related phenotypes. In Tg mice, polyubiquitinated and oxidized proteins accumulated. ... Our results provide the first in vivo evidence that decreased proteasomal chymotrypsin-like activity affects longevity and aggravates age-related metabolic disorders, such as obesity and hepatic steatosis."

Tuesday, January 3, 2012
Researchers are applying the most modern tools of biotechnology in efforts to better understand the evolution of longevity: "The genetic basis of the large species differences in longevity and aging remains a mystery. Thanks to recent large-scale genome sequencing efforts, the genomes of multiple species have been sequenced and can be used for cross-species comparisons to study species divergence in longevity. By analyzing proteins under accelerated evolution in several mammalian lineages where maximum lifespan increased, we identified genes and processes that are candidate targets of selection when longevity evolves. We identified several proteins with longevity-specific selection patterns, including COL3A1 that has previously been related to aging and proteins related to DNA damage repair and response such as DDB1 and CAPNS1. Moreover, we found that processes such as lipid metabolism and cholesterol catabolism show such patterns of selection and suggest a link between the evolution of lipid metabolism, cholesterol catabolism, and the evolution of longevity. Lastly, we found evidence that the proteasome-ubiquitin system is under selection specific to lineages where longevity increased and suggest that its selection had a role in the evolution of longevity. These results provide evidence that natural selection acts on species when longevity evolves, give insights into adaptive genetic changes associated with the evolution of longevity in mammals, and provide evidence that at least some repair systems are selected for when longevity increases."

Monday, January 2, 2012
One of the needed shifts in our culture is to move away from the dominant themes of apologism and acceptance of aging - this is a necessary precursor for widespread support of longevity science, to the level needed to raise up rejuvenation biotechnology research to match cancer research or regenerative medicine in funding and enthusiasm. So more of this sort of thing is welcome: "In 1981, five days before cancer killed him, the life-loving writer William Saroyan told the Associated Press: 'Everybody has to die, but I always believed an exception would be made in my case. Now what?' There it is: 'Now what?' That is the great question growing all the greater for being asked by the biggest, most self-conscious and possibly most self-deluded generation in American history, the baby boomers. The youngest of them are middle-aged now, taking a hard-headed look at old age and asking: Now what? Some are also taking a soft-headed look, as if they were already demented beyond grappling with reality. Some of them like to think of old age as 'elderhood,' which is thinking of old age as just another stage of life, like childhood or adulthood. But then what? Surely not deathhood. Or afterhood, or oblivionhood. No, a lot of people are making a lot of money promising immortality. But I digress. Then again, digression is the essence of William Ian Miller's book about old age. It answers the question of 'Now what?' with its title: 'Losing It.' ... The point, if I may dare to sum up: Old age is an annoying, ridiculous and pathetic decline toward the state of a turnip softening in a compost heap, if death is not kind enough to intervene first. But why write a book about it? ... Mr. Miller wants to express his contempt for the positivity crowd that echoes 'grow old along with me, the best is yet to be,' in the words of Robert Browning, one of the softer turnips of 19th-century English poetry."

Monday, January 2, 2012
An example of the sort of research work undertaken by cryonics provider Alcor: "During the month of November the research and development team made a field trip to a local medical CAT scanning service, taking with them two recent neuro patients. Due to circumstances surrounding their death, one patient was cryoprotected and the other was not. ... Having safely returned from our trip and taking care of returning the patients to the patient care bay, Steve Graber opened up the first of the patient scan files in our 3-D visualization software. This is where the team could really see some interesting things. ... looking into the brain cavity we could make out the sensor wires which were previously placed into the brain cavity during surgery. Through the slice we can see variations in brain density ... When one compares these identically composed, sectioned and displayed images of a cryoprotected brain [vs] non-cryoprotected brain it is clear that there is a big difference in overall density between these two brains. A-1546 displays a significantly greater electron density than A-1088 throughout the majority of the brain. Overall the A-1546 brain is much more electron dense and we believe this to be evidence that perfusion [of cryoprotectant] did occur, at least in certain areas. ... A future test of a variety of substances under the CAT scanner [is] expected to help to identify electron density specifics of cryoprotectants, which in turn will make our analysis that much more complete. We also expect to test a locally pronounced patient vs an out of state pronounced patient to determine the quality differences in cryoprotection caused by the time-lag to cryoprotection between these two scenarios.... We also expect to test a locally pronounced patient vs an out of state pronounced patient to determine the quality differences in cryoprotection caused by the time-lag to cryoprotection between these two scenarios."



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