Fight Aging! Newsletter, April 23rd 2012

April 23rd 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!



- Managing Expectations
- Fully Functional Hair Regeneration Demonstrated
- Sitting Time and Mortality
- Discussion
- Latest Headlines from Fight Aging!


There is work ahead of us, and foundations behind us - benefits to longevity have not yet been realized:

"If you are around 40 years of age and basically average in terms of genes and health, the odds are good that in your first few decades you gained little in the way of longevity advantages over someone 20 years your senior, living in the same location. Medical science is progressing, but the young in wealthier regions of the world don't really use or need all that much medical technology once past the point of vaccinations and the standard - and diminishing - brace of infectious childhood diseases. The point here is that the bulk of any technology-dependent difference in your life span has yet to be engineered: it depends on how well you take care of the health basics from here on out, and far more on how rapidly medical technology progresses towards working rejuvenation biotechnology. If that medical technology isn't researched, isn't developed, isn't made available in a competitive marketplace, then the life trajectory of your parents is not an unreasonable model for your life.

"If medical technology stopped moving forward now, then, sad to say, most people would not live a great deal longer than their parents. Gains due to medical technology are all in the future - they can be seen, discussed, and worked on in detail, but they are not here yet. What does that mean? It means that if you are 40, you're half-way done. You have half of the hour-glass left in which to make a difference - to help build the technologies that will smash this limitation of the human condition.

"Life expectancy at birth is an artificial construct - it is a measure of quality of health and medical technology, useful for comparisons, not a number that corresponds to what will happen to people born now or who are alive now. It reflects the life expectancy of a person born now if every statistical measure of health and mortality derived from the present population remained the same into the future. So in an age of advancing technology you would expect life expectancy figures to be lower than what will turn out to be the average age attained by your peers.

"But still, it should be clear that unless progress in extending healthy life becomes more radical and less incremental, there are fair odds of 40-year-old you not living to see 80. This is not what anyone wants to hear, but it is what it is - the only way to make this different is to work to make it different. Support the work of the SENS Foundation, for example, or other causes that are involved in the science of extended human longevity and repair of aging."

On a related note, you might look at a recently posted SENS5 video in which Caleb Finch presents his view of the future of human longevity:

"The historical improvements in life expectancy that accompany lower levels of chronic disease are an excellent illustration of aging as an accumulation of damage - that data fits well with the application of reliability theory to aging, for example. Find a way to reduce exposure to damage at the level of cells and molecular machinery and life will lengthen. Researchers like Finch - epidemiologist S. Jay Olshansky being another with similar views - see the most plausible future as an extension of this gradual improvement from the past. It won't be the same processes at work, because the easy gains accruing from control over infectious disease have been achieved, but it will be another gradual shifting of the chart of life expectancy, just a little progress achieved with each passing year of modestly longer lives. In this view of the world, growing levels of obesity form a very serious threat that may reduce life expectancy by causing more harm than incremental medical progress will prevent.

"This sort of viewpoint is, I think, harmful to the prospects for significant advances to arise from initiatives like the Strategies for Engineered Negligible Senescence. When gradualism is institutionally entrenched, radical investigations with radical goals are discouraged at every level, from student education through to the funding rat race, and cautious predictions in public do not attract the sort of supporters and researchers who can make bold strides. This is why we need philanthropists willing to back those who can credibly think outside the box and shoot for the moon. Big risks and potentially very large payoffs. In this time of revolution and progress in biotechnology, when better to break out of the straightjacket vision of incremental progress and tinkering with metabolism?"


Structure turns out to be very important in tissue engineering, and here researchers seem to have found a solution to guiding structure in hair follicles:

"Researchers have been manipulating stem cells to cause hair follicles to form and hair to grow for a few years now. ... Bald skin and haired skin have the same cell populations needed to grow hair, as it turns out, so this sort of cell-based approach has merit. The end of the story will likely be some form of cell signalling treatment to instruct cells already present in the body to form hairs in an area of skin rather than cell transplants - but transplants are first in line for development. The process is not exactly straightforward, unfortunately. Much like the tissue engineering of teeth, some form of guiding technology must be established to ensure that the cells grow as they should - without it, you end up with misshapen or broken structures.

"On this subject, the work of a Japanese group on hair regeneration has been in the news of late, and they seem to have established a proof of principle for guiding correct hair growth. ... In the new work, the team transplanted a group of the engineered follicles into the skin on the backs of hairless mice. After about two weeks, hairs began to sprout. Under the microscope, the hair grown from the bioengineered mouse follicles resembled normal hair, scientists found. And the mouse follicles went through the normal cycle of growing hair, shedding and making new hair.

"When researchers injected the region around the bioengineered follicle with acetylcholine, a drug that causes muscles to contract, the hairs perked up. This suggests that the transplanted follicles had integrated with surrounding muscle and nerves like normal hair follicles do. Importantly, the researchers were able to ensure hair didn't become ingrown or point in the wrong direction by attaching a nylon thread to the engineered follicles and guiding the hair to grow outward."


A recent analysis of study data concludes that sitting correlates with increased mortality, but separately and independently from levels of physical activity - and on that point I am dubious:

"One has to wonder what the mechanism is here - my suspicion is that it actually does all come back down to the level of physical activity in the end. In these massive studies the level of exercise and activity is reported by the participants. A person who stands and works is going to be somewhat more active than a person who sits and works, even though that time may not be categorized as physical activity, or reported differently. Exercise is much like calorie restriction - the effects are so large in comparison to other factors we have easy access to that they are likely to creep into any study.

"You might look at a recent study on activity and Alzheimer's disease that was one of the few to use measuring devices rather than reports of activity. One point that emerges is that a fair degree of ongoing low level activity and exercise won't be classified as such by the participants of study without machine measurement. Housework, taking out the trash, the small increase in energy expenditure from standing while waiting versus sitting while waiting, that sort of thing repeated day in and day out. How much you are sitting really does sound a lot like a proxy for how much activity you are undertaking when you are doing things that most people don't really count as activity."


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 20, 2012
Researchers continue to investigate the genetics of natural variations in aging, such as those that can be generated through diet (e.g. calorie restriction) in mice: "Dietary interventions are effective ways to extend or shorten lifespan. By examining midlife hepatic gene expressions in mice under different dietary conditions, which resulted in different lifespans and aging-related phenotypes, we were able to identify genes and pathways that modulate the aging process. We found that pathways transcriptionally correlated with diet-modulated lifespan and physiological changes were enriched for lifespan-modifying genes. Intriguingly, mitochondrial gene expression correlated with lifespan and anticorrelated with aging-related pathological changes, whereas peroxisomal gene expression showed an opposite trend. Both organelles produce reactive oxygen species, a proposed causative factor of aging. This finding implicates a contribution of peroxisome to aging. Consistent with this hypothesis, lowering the expression levels of peroxisome proliferation genes decreased the cellular peroxide levels and extended the lifespan of Drosophila melanogaster and Caenorhabditis elegans. These findings show that transcriptional changes resulting from dietary interventions can effectively reflect causal factors in aging and identify previously unknown or under-appreciated longevity pathways, such as the peroxisome pathway."

Friday, April 20, 2012
Another aspect of aging slowed by calorie restriction: "Caloric restriction (CR) retards aging in laboratory rodents. [Little] information is available on the effects of long-term CR on physiologic markers of aging and longevity in humans. Heart rate variability (HRV) is a marker for cardiac autonomic functioning. The progressive decline in HRV with aging and the association of higher HRV with better health outcomes are well established. HRV assessment is a reliable tool by which the effects of CR on autonomic function can be assessed. Time and frequency domain analyses compared 24-hr HRV in 22 CR individuals aged 35-82 yrs and 20 age-matched controls eating Western diets (WD). The CR group was significantly leaner than the WD group. Heart rate was significantly lower, and virtually all HRV significantly higher in the CR than in the WD group. HRV in the CR individuals was comparable to published norms for healthy individuals 20 years younger. In addition, when differences in HR and HRV between CR and WD were compared with previously-published changes in HRV induced in healthy adults given atenolol, percent differences in each measure were generally similar in direction and magnitude and suggested declines in sympathetic and increases in parasympathetic modulation of HR and increased circadian variability associated with CR. These findings provide evidence that CR has direct systemic effects that counter the expected age-associated changes in autonomic function so that HRV indexes in CR individuals are similar to those of individuals 20 years younger eating WDs,"

Thursday, April 19, 2012
Nature comments on recent advances: "At the turn of the twentieth century, the promise of regenerating damaged tissue was so far-fetched that Thomas Hunt Morgan, despairing that his work on earthworms could ever be applied to humans, abandoned the field to study heredity instead. Though he won the Nobel Prize in 1933 for his work on the role of chromosomes in inheritance, if he lived today, the advances in regenerative medicine may have tempted him to reconsider. Three studies published this week show that introducing new cells into mice can replace diseased cells - whether hair, eye or heart - and help to restore the normal function of those cells. These proof-of-principle studies now have researchers setting their sights on clinical trials to see if the procedures could work in humans. ... You can grow cells in a Petri dish, but that's not regenerative medicine. You have to think about the biology of repair in a living system. ... Japanese researchers grew different types of hair on nude mice, using stem cells from normal mice and balding humans to recreate the follicles from which hair normally emerges. ... A second study using regenerative techniques helped to restore some vision to mice with congenital stationary night blindness, an inherited disease of the retina. ... [Researchers reprogrammed] cardiac fibroblasts into cardiomyocytes - the muscle cells of the heart that are permanently lost after a heart attack. The team used a retrovirus to deliver three transcription factors that induced the reprogramming in adult mice, and improved their cardiac function. ... These three papers are just the tip of the iceberg. By the time we grow old, doctors are going to look back and say, 'Can you believe people used to go bald, go blind or even have their leg cut off from vascular disease?' - and then the doctor will treat the problem with an injection of cells."

Thursday, April 19, 2012
Via EurekAlert!: "Daily physical exercise may reduce the risk of Alzheimer's disease, even in people over the age of 80 ... The study showed that not only exercise but also activities such as cooking, washing the dishes and cleaning are associated with a reduced risk of Alzheimer's disease. These results provide support for efforts to encourage physical activity in even very old people who might not be able to participate in formal exercise but can still benefit from a more active lifestyle. ... For the study, a group of 716 people with an average age of 82 wore an actigraph, a device that monitors activity, on their non-dominant wrist continuously for 10 days. All exercise and non-exercise was recorded. They also were given annual tests during the four-year study that measured memory and thinking abilities. During the study, 71 people developed Alzheimer's disease. ... The research found that people in the bottom 10 percent of daily physical activity were more than twice as likely to develop Alzheimer's disease as people in the top 10 percent of daily activity. The study also showed that those people in the bottom 10 percent of intensity of physical activity were almost three times as likely to develop Alzheimer's disease as people in the top 10 percent of intensity of physical activity."

Wednesday, April 18, 2012
From Queen Mary, University of London, investigation of the mechanisms of periodontitis in aging: "New research [sheds] light on why gum disease can become more common with old age. The study, published in Nature Immunology, reveals that the deterioration in gum health which often occurs with increasing age is associated with a drop in the level of a chemical called Del-1. The researchers say that understanding more about Del-1 and its effects on the body's immune system could help in the treatment or prevention of serious gum disease. ... As people age they are more likely to suffer from inflammatory diseases, including gum disease. The new research investigated gum disease in young and old mice and found that an increase in gum disease in the older animals was accompanied by a drop in the level of Del-1. This protein is known to restrain the immune system by stopping white blood cells from sticking to and attacking mouth tissue. Mice that had no Del-1 developed severe gum disease and elevated bone loss and researchers found unusually high levels of white blood cells in the gum tissue. When they treated the gums of the mice with Del-1, the number of white blood cells dropped, and gum disease and bone loss were reduced. The researchers say their findings could be the basis for a new treatment or prevention of gum disease."

Wednesday, April 18, 2012
Researchers are not having as much success as they'd like in finding unambiguous associations between specific genes and human longevity - studies are turning up results, but few are similar between populations, indicating that the genetics of natural variations in longevity are probably very complex: "It has long been thought that related individuals share a familial predisposition to longevity, and for more than a century numerous studies have investigated the degree to which human longevity might be an inherited characteristic. Most studies of this type have reported small (∼10%) to moderate (∼30%) heritability of human longevity, amid differences in definitions of longevity, methods of measuring it, ascertaining individuals who demonstrate it, and in various behavioral and environmental settings. These methodological differences likely account for much of the variation in the resulting estimates of the heritability of longevity. ... We identified individuals from a large multigenerational population database (the Utah Population Database) who exhibited high levels of both familial longevity and individual longevity. This selection identified 325 related 'affected individuals', defined as those in the top quartile for both excess longevity (EL=observed lifespan - expected lifespan) and familial excess longevity (FEL=weighted average EL across all relatives). A whole-genome scan for genetic linkage was performed on this sample using a panel of 1100 microsatellite markers. A strongly suggestive peak was observed in the vicinity of D3S3547 on chromosome 3p24.1, at a point nearly identical to that reported recently by an independent team of researchers from Harvard Medical School (HMS). ... Corroboration of the linkage of exceptional longevity to 3p22-24 greatly strengthens the case that genes in this region affect variation in longevity and suggest, therefore, an important role in the regulation of human lifespan. Future efforts should include intensive study of the 3p22-24 region."

Tuesday, April 17, 2012
Breakout Labs is a part of Peter Thiel's vision of radical philanthropy in science and technology funding, modeled on the venture capital industry and aiming to invest in high risk, high reward programs: "The Thiel Foundation announced today the first grants awarded through Breakout Labs, its revolutionary revolving fund to promote innovation in science and technology. ... it provides teams of researchers in very early-stage companies with the means to pursue their most radical goals in science and technology. Breakout Labs has awarded six grants, of up to $350,000 each, to the following recipients: ... 3Scan, to develop 3-D digital reconstruction of brain tissue, using a novel, faster, less expensive microscope technology. Building a map of connections in the brain-the connectome-is a critical step to understanding what makes the human brain unique. ... Arigos Biomedical, to develop methods of cooling organs for long-term storage. When combined with emerging advances in cryopreservation, tissue engineering, and stem cell therapies to eliminate graft rejection, this technology would make banked organs immediately available to anyone needing a transplant. ... Immusoft, to re-program human immune cells to produce therapeutics in the body. This technology could dramatically improve the ability to treat a range of diseases, as well as enhance human health and longevity. ... Longevity Biotech, to develop an entirely new class of therapeutics via artificial protein technology ("Hybridtides"). Hybridtides are targeted biologic-like molecules which are highly-resistant to breakdown by natural digestive enzymes and tunable to very stable molecular structures. These features have demonstrated potent therapeutic activity with the possibility of oral biologic delivery. ... In the past, people dreamed of the future as a radically better, more technologically advanced place: you might live for centuries, delegate work to your robots, and take your vacations on the moon. Now, many people expect their children to inherit a world worse than today's. With Breakout Labs, we want to rekindle dreams of an amazing future. That's why we're supporting researchers who dream big and want to build a tomorrow in which we all want to live."

Tuesday, April 17, 2012
A research group is claiming that fullerenes (C60, ingested and injected) greatly extend life span in rats; this is meeting with some considerable skepticism, given the degree of life extension and the lack of a plausible mechanism. "In the current study researchers fed the molecule dissolved in olive oil to rats and compared outcomes to a control group of rats who got plain olive oil. The main question they wanted to answer was whether chronic C60 administration had any toxicity, what they discovered actually surprised them. ... Here we show that oral administration of C60 dissolved in olive oil (0.8 mg/ml) at reiterated doses (1.7 mg/kg of body weight) to rats not only does not entail chronic toxicity, but it almost doubles their lifespan. ... The estimated median lifespan (EML) for the C60-treated rats was 42 months while the EMLs for control rats and olive oil-treated rats were 22 and 26 months, respectively. Using a toxicity model the researchers demonstrated that the effect on lifespan seems to be mediated by 'attenuation of age-associated increases in oxidative stress'." So what might be going on here? The average life span of the Wistar rats used is 2-3 years (24 - 36 months). This was a small study size, but that's not so important in determining whether you have an actual means of life extension if you can show that any of your study group lived much longer than usual - but it is important when it comes to the degree of life extension. If the study group is small, as it is here, using only a handful of rats, then the size of the effect can be much more readily distorted by chance. This line in the paper jumped out at me: "Before C60 administration, the rats were fasted overnight but with access to water." If they failed to fast the control group, then we're looking at yet another study that failed to control for calorie restriction, and this is actually largely an intermittent fasting study - which has certainly been shown to extend life in rats.

Monday, April 16, 2012
Following on from a recent presentation on cost-effectiveness in longevity research, here's an interview with Aubrey de Grey of the SENS Foundation at 80,000 hours: "ZR: Back to matters financial... How much funding would your programme actually need to complete its goals? Paraphrasing your talk again, you guesstimated '$50,000,000 allocated appropriately would be 'enough for the next while''. Can you be a bit specific about what 'the next while' means? ... AdG: I think I said $50M per year. 20M/year would be a good start, and I think above $100M/year we'd be reaching diminishing returns. This is tiny compared to (for instance) the NIH budget, but that's because it's only the budget for the next several years, when the key work will be on mice rather than humans. ... It's pretty clear that a dollar makes more difference when spent on early-stage biomedical research (which is what we'd spend it on) than on the delivery of existing therapies. ... ZR: How confident are you about the success of your program? I'll paraphrase a couple of off-the-cuff remarks on the subject you made in your 80K talk: 'We'll get to robust human rejuvenation - within the next 25 years with 50% probability.' 'I'd give a 10% chance we won't get there for 100 years.' Would you modify these now you're not on the spot? What exactly do you mean by robust human rejuvenation? Is that the same thing as reaching what you call the ageing escape velocity? (for the benefit of readers: the point at which progress in our ability to extend our lifespans surpasses the rate at which we age, effectively making us immune to age-related death) ... AdG: I still stand by both those statements, but please note that I always add the caveat that the former depends on adequate funding, especially in the coming decade. I define 'robust human rejuvenation' (RHR) as the addition of 30 years of extra healthy life to those who are already 60 when the therapies are first given. Longevity escape velocity is different - it's the postponement of aging faster than time is passing, which results from continued progress in improving the comprehensiveness of the therapies. The moment at which we reach LEV, which we call the Methuselarity (and we're pretty sure there will be inly one such moment, i.e. that once we exceed LEV we will never fall below it again), will probably occur at around the same time when we achieve RHR - maybe a little sooner, maybe a little later."

Monday, April 16, 2012
Researchers manage to make an immunotherapy work well in aged immune systems - which is important, as most of the potential uses for immune therapies will target older people: "a new study [shows] that some types of immunotherapy previously thought to work only in younger patients can be used to help the elderly, with less toxic effects than many common therapies, if combined in ways that account for age-related changes in the immune system. ... We've shown that immunotherapy for cancer not only works in aged mice, but actually can work better in aged hosts than in young counterparts by capitalizing on the immune changes that happen with age ... As you age, most parts of your body begin to wear out. They keep doing what they're made to do [but] over time, they don't do it as well. The general perception is that the immune system also simply declines with age. ... That's really too simplistic. That's really not the full picture of what's happening. ... The body's immune system does weaken with age, but it also changes, and that changes the rules for fighting disease within the body. [The researchers] started by examining an immune therapy that they previously had shown to work in younger hosts, including cancer patients. It's designed to eliminate regulatory T cells (called Tregs), which are cells that turn off immune responses, allowing cancer to progress. Tregs increase in cancer. In young hosts, the drug turns off Treg activity, allowing the immune system to function better. In older hosts, even though the drug turns off the Tregs, it has no clinical benefit. ... In older mice, when the drug turned off the Tregs, the researchers found that another type of immune suppressor cell (a myeloid-derived suppressor cell or MDSC) exploded in number to take the Tregs' place, hampering clinical efficacy. That did not happen in young mice. The team added a second drug that targets the MDSC, and found that with those tools to help immunity, the older hosts can combat cancer just as well as the younger hosts."



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