Debating Compression of Morbidity

The latest two podcasts at SAGE Crossroads look at either side of views on compression of morbidity:

Fries' hypothesis is that the burden of lifetime illness may be compressed into a shorter period before the time of death, if the age of onset of the first chronic infirmity can be postponed before the age of death. In order to confirm this hypothesis, the evidence must show that it is possible to delay the onset of infirmity, and that corresponding increases in longevity will be modest.

On the one side:

Longevity will continue to increase under hopeful scenarios for the human future, and morbidity will continue to decrease. The question is the relative rate of those, and I’m just telling you and anybody else who would make such an argument that in fact the data is in. The mortality rates are going down 1 percent a year. That’s a substantial decline in mortality rates. That’s been continuing for a century, that’s almost a straight line, at 1 percent a year. The morbidity rates are going down 2 percent a year. It’s the story.

And on the other side:

KYLE JENSEN: Now do you feel that the compression of morbidity theory should be the focus of biomedical gerontology?

AUBREY DE GREY: No, not really I don’t. It’s important first of all to remember that the original description of compression of morbidity by Jim Fries in 1990 did not even propose this. What he proposed was that actually it would be easier to implement changes in lifestyle that would postpone the onset of morbidity than it would be to develop medical technologies to postpone death. In other words, he felt that by changes of lifestyle we could compress the period between the two, but he never suggested that we would actually compress morbidity by intervening in the biology of aging. Indeed, he felt that intervening in the biology of aging was essentially impossible. What we are actually seeing is failure to implement those changes of lifestyle that Jim Fries suggested. We are seeing increase in lifespan and also [delay in] onset of morbidity. Not much change in the rates of those two so the interval between the two [remains the same]. There is not progress being made in compressing morbidity. There is a bit of variation. In some statistics we see a little bit of compression in some people; in some places we see a little bit of expansion. By in large what we are seeing is exactly what you would expect from postponing aging. In other words, you postpone the onset of morbidity and you also postpone death by about the same amount.

As they say, you can do all sorts of things with statistics and definitions, and I'm far from qualified to put forward any sort of firm opinion as to whether present statistics better support one side or another. Compression of morbidity is something of the declared goal of those in the mainstream of aging research who don't want to talk about extending life span, however, which makes it a little more than a matter of statistical interpretation. When a researcher talks about compression of morbity, that is something of a cipher, an identifying mark as to where he stands on the topic of engineered longevity: possibly in favor, but not willing to risk offending conservative funding organizations, possibly against. Either case has much the same result - a researcher who isn't working as freely as he might to extend human longevity.

From my reductionist viewpoint, I find it hard to reconcile an existence of compression of morbidity with the performance of reliability theory as applied to aging, amongst other things. Theories of aging based upon accumulation of biochemical damage and incremental system failure are very convincing, and have a great deal of experimental support, but don't predict that compression of morbidity is possible to any great degree. The only way to push out health life span is to prevent or repair damage, and that will also push out overall life span.

On Compression of Morbidity

The basic idea behind compression of morbidity is to reduce the span of time spent frail in old age without extending life span. This is an incoherent goal from the point of view of any theory of aging that presents degeneration as a result of accumulated damage, and it is a pity that compression of morbidity is so firmly entrenched in the research philosophy of mainstream aging research. The only way to ensure more years of health is to repair or prevent damage, which will also lead to a longer life. This SAGE Crossroads podcast is a discussion with Aubrey de Grey on the topic: "In some statistics we see a little bit of compression in some people; in some places we see a little bit of expansion. By in large what we are seeing is exactly what you would expect from postponing aging. In other words, you postpone the onset of morbidity and you also postpone death by about the same amount. ... the compression of morbidity theory as you call is not really a theory, it's more of an aspiration. People say 'well wouldn't it be a good thing if we could compress morbidity,' but they don't really say how we would expect to be able to do it. ... [the focus of research should be on] postponing morbidity so much that there is a much higher probability that people will die of causes that have nothing to do with aging just because they've got longer to do it before they become frail and decrepit."


On Artificial Retinas

A general interest piece from "Tests of a relatively crude artificial retina [called Argus One] began on six patients in 2002. With the aid of these devices, people who'd been totally blind were able to read foot-high letters, tell a plate from a cup, find doors and windows, and navigate around large objects ... Argus One is still in use, but it's being succeeded by Argus Two, a smaller, more sophisticated device with an array of 60 electrodes, providing a much sharper image to its users. The newer device is being tested on 17 blind people in the U.S. and Europe, and more patients are being enrolled. At a retina conference in October, patients reported improvements in orientation and mobility. They were able to find a door from 20 feet away and to follow a line on the floor for 20 feet ... Meanwhile, researchers [are] creating a third-generation artificial retina. Much smaller than its predecessors, the device will contain 200 or more electrodes on a thin, flexible film that curves to fit the shape of the retina. Human tests are scheduled to begin in 2011. ... We're aiming for a 1,000-electrode array ... Such a device would 'let a blind patient recognize objects and read large-scale newsprint.'"


Interesting Mortality Data

I noticed a mortality study that illustrates some of the common wisdom regarding the common diseases of aging:

The remaining lifetime risk of cancer at age 40 was 45.1% and at age 90 was 9.6%. The remaining lifetime risk of major cardiovascular disease at age 40 was 34.8% and at age 90 was 16.7%.


The remaining lifetime risk of both diseases approached a plateau in the 10th decade. This may be due to decreased detection of disease and reporting of symptoms and increased resistance to disease in those who survive to old age.

The older a person becomes - or rather, the more capable a person is of achieving longevity - the less likely he or she is to suffer from the major diseases of aging. As the authors point out, however, it's a challenge to build reliable data:

The measurement and interpretation of the incidence of disease in advanced age is complex. Lower incidence in late life may reflect decreased screening and medical surveillance rather than decreased risk. ... This cohort of health conscious doctors has several advantages for studying the incidence of disease in men of advanced age, as it has a large proportion of participants surviving to age 90 and beyond, as well as a higher level of screening for disease and diagnosis than in a general population.

This and other collections of data on mortality risk consistantly show that incidence of cancer and cardiovascular disease is lower for those who live longer. Other research shows that living longer within the present state of medical science is a matter of making consistently sensible choices in life for most of us - not a matter of good genes to any great degree. Join the dots: all that exercise and good diet really does make a difference in the long term.

Now if you have a good few decades left before getting to the point at which you have to start worrying in earnest about your heart and runaway cells killing you from the inside, it's probably the case that the future trajectory of your life will be far more determined by progress in medical science than living well. Absent progress, your life will look much like that of your parents. With exceptional progress, the sky is the limit - aging itself might be defeated before you reach the point at which it will kill you. So while you're on the execise machine, or pondering a good diet, spare some thought for how you can support the future of medical research as well. There is where the real difference lies.

Seventy-Five Percent

A reminder of the degree of control you have over your future health and longevity, even absent advances in medical science: "Seventy-five percent of the variation in lifespan can be attributed to a modification of risk factors during early old age. The modifiable behaviors that can positively affect longevity included smoking abstinence, weight management, blood pressure control and regular exercise. ... Smoking, diabetes, obesity and hypertension significantly reduced the likelihood of a 90-year life span, while regular vigorous exercise substantially improved it. Furthermore, men with a lifespan of 90 or more years also had better physical function, mental well-being and self-perceived health in later life compared with men who died at a younger age. ... Restricting caloric intake and daily exercise positively lowered most of the risk factors noted in the study. Many illnesses such as diabetes and high blood pressure can be eliminated or reduced through maintaining an active lifestyle."


Neurodegeneration and Excess Blood Sugar

While too little blood sugar appears to contribute to Alzheimer's, too much - as in diabetes - also brings on degeneration of the brain: "This research used imaging in both human volunteers and in animal models to help us better understand the basic mechanisms behind hippocampal dysfunction in the aged ... The research found that decreasing activity in the dentate gyrus only correlated with levels of blood glucose. ... Beyond the obvious conclusion that preventing late-life disease would benefit the aging hippocampus, our findings suggest that maintaining blood sugar levels, even in the absence of diabetes, could help maintain aspects of cognitive health. ... By improving glucose metabolism, physical exercise also reduces blood glucose. It is therefore possible that the cognitive enhancing effects of physical exercise are mediated, at least in part, by the beneficial effect of lower glucose on the dentate gyrus. Whether with physical exercise, diet or through the development of potential pharmacological interventions, our research suggests that improving glucose metabolism could be a clinically viable approach for improving the cognitive slide that occurs in many of us as we age."


Doing the Right Things Does Help

We can never know absolutely and for sure whether doing the "right things" for our health will make a significant difference to our own healthy longevity. You have to wait and see, one chance to get it right, no going back to fix things up. We do, however, have a wealth of evidence that actions long commonly regarded as the "right things" for good health will indeed be good for our future healthy longevity. This evidence is quite separate from the comparatively recent investigations of medical science into the biochemical roots of good health and longevity.

What is this evidence? That wealthier, higher IQ people tend to live longer and suffer less age-related illness. For example:

Lower scores on measures of IQ at two time points were associated with [cardiovascular disease] and, particularly, total mortality, at a level of magnitude greater than several other established risk factors.

I don't think that it's ever been a grand mystery that regular exercise, a good physician relationship, and eating sanely are going to be good for you; the common wisdom for good health long predated the scientific studies showing that it was the case. The grand mystery is why so few people keep up with those efforts in their own lives, and suffer because of that negligence. I've been inclined to interpret results like the research above to mean that more intelligent people tend to get wealthier but also tend to do more of the right things for their health - you can be as rich as you like, but if you weren't exercising all that time you were making money, you're still going be at a higher risk for suffering cardiovascular disease at the end of the day.

Smarter people have a greater tendency to keep up with common sense health practices and gain a benefit by doing so. That's my thesis. As to why that is the case - well, that gets back to what IQ actually measures, whether time preference is very different between individuals, and so forth.

Prospects for Repairing the Brain

From Nanowerk: "In order for neural prostheses to augment or restore damaged or lost functions of the nervous system they need to be able to perform two main functions: stimulate the nervous system and record its activity. To do that, neural engineers have to gain a full understanding of the fundamental mechanisms and subtleties of cell-to-cell signaling via synaptic transmission, and then develop the technologies to replicate these mechanisms with artificial devices and interface them to the neural system at the cellular level. A group of European researchers has now shown that carbon nanotubes may become the ideal material for repairing damaged brain tissue. ... The new carbon nanotube-based interface technology discovered together with state of the art simulations of brain-machine interfaces is the key to developing all types of neuroprosthetics - sight, sound, smell, motion, vetoing epileptic attacks, spinal bypasses, as well as repairing and even enhancing cognitive functions."


Autophagy Genes and Aging

A review: "Ageing in divergent animal phyla is influenced by several evolutionarily conserved signalling pathways, mitochondrial activity and various environmental factors such as nutrient availability and temperature. Although ageing is a multifactorial process with many mechanisms contributing to the decline, the intracellular accumulation of damaged proteins and mitochondria is a feature common to all aged cells. Autophagy (cellular self-eating) - a lysosome-mediated catabolic process of eukaryotic cells to digest their own constituents - is a major route for the bulk degradation of aberrant cytosolic macromolecules and organelles. Indeed, genetic studies show that autophagy-related genes are required for lifespan extension in various long-lived mutant nematodes and promote survival in worms and flies exposed to prolonged starvation. These data implicate autophagy in ageing control. Furthermore, results in Drosophila demonstrate that promoting basal expression of the autophagy gene Atg8 in the nervous system extends lifespan by 50%, thereby providing evidence that the autophagy pathway regulates the rate at which the tissues age."


A Novel View of Inflammaging

Inflammaging is a term coined to describe one way in which the immune system runs awry with age. Like a malfunctioning thermostat, the level of inflammatory response is consistantly too high, leading to damage to aged tissue:

Inflammation is necessary to cope with damaging agents and is crucial for survival, particularly to cope with acute inflammation during our reproductive years. But chronic exposure to a variety of antigens, especially to some viruses such as cytomegalovirus, for a period much longer than that predicted by evolution, induces a chronic low-grade inflammatory status that contributes to age-associated morbidity and mortality. This condition carries the proposed name "inflammaging".

I noticed a paper today which contains an interesting take on how inflammation leads to damage. It's not just the inflammatory response, per this theory, but also the anti-inflammatory systems evolved to shut off an inflammatory response after it has served its purpose. If inflammation is constantly jammed on, then so is the anti-inflammatory system - based on the hormone cortisol - that is trying to shut it down. So you have at once all the downsides of both a constantly active immune system, and an immune system that is constantly damped down: damage from constant activity yet poor immune response when you do need it to fight off disease:

"Inflamm-aging" denotes the up-regulation of certain pro-inflammatory cytokines at older ages, and associated chronic diseases. It is well known that blood levels of cortisol also increase with age, an increase commonly considered to be due to activation of the Hypothalamus-Pituitary-Adrenal (HPA) axis by many non-specific stressors.

On the contrary, herein I describe how the activation of Hypothalamus-Pituitary-Adrenal (HPA), far from being unspecific, constitutes: a) the main specific response and counterbalance to "Inflammaging" ('anti-inflammaging'), b) an explanation for the well known paradox of immune-senescence: i.e. the coexistence of inflammation and immunodeficiency, as well as c) a complex mechanism of remodelling elicited by inflammaging, explaining the long and winding pathophysiological road that goes from robustness to frailty.

Indeed, the phenomenon of anti-inflammaging, mainly exerted by cortisol, with the passage of time becomes the cause of a marked decline of immunological functions, and its coexistence with the increased levels of pro-inflammatory cytokines of inflammaging, ultimately have negative impacts on metabolism, bone density, strength, exercise tolerance, the vascular system, cognitive function, and mood. Thus inflammaging and anti-inflammaging together determine many of the progressive pathophysiological changes that characterize the "aged-phenotype", and the struggle to maintain robustness finally results in frailty.

The author points to cortisol, and if you look at the Wikipedia entry you will see touches upon a wide range of vital systems in the body. If inflammation is always on, then excess cortisol is constantly trying to turn it off, causing harm along the way.

Fortunately solutions to prevent the immune system from getting into this state in the first place are within sight. If the medical research community makes a sane shift from a philosophy of futile attempts to patch up the end results of aging to preventing and reversing specific degenerations earlier in life, then I imagine we'll see a range of ways to restore a damaged immune system in the clinic by 2030. Have a look back in the Fight Aging! archives for some pointers:

Another Example of Veterinary Stem Cell Therapies

Thanks to less regulation, veterinary medicine is years ahead of human medicine in putting stem cell therapies into practice. There's no sane reason why this should be the case; why do humans suffer needlessly when the technology works and is ready for use? From the Daily Gazette: "Charlie is one of 15 dogs that have undergone stem cell therapy [since] June, and one of 1,000 around the country since May who have been helped by the procedure. Most of the animals were suffering from hip displasia or some other kind of arthritic condition that severly limited their mobility, and in most cases, about 87 percent nationally, the dogs became rejuvenated soon after receiving their injections. ... I understand the science behind it, but it's still amazing to think that we can harvest these cells, inject them into a joint, and a couple of days later we have a dog that is running around and is pain free. It's incredible that it works, and it's incredible that it works so well. ... The general public really isn't aware yet of what's going on. They think all of this work is still in the research stage. Somedays I feel like an evangelist, and I have to continue to get out the word. There are places in the world where they're doing this on humans, not dogs. It works, and it's a dramatic new tool that we can all be pretty excited about."


Corrupting Influences

Here is an example of the sort of damage done to research endeavors by the highly dubious business-as-usual practices of the "anti-aging" marketplace. Science is the search for truth and, far more so than reputable fields of business, the anti-aging marketplace is based upon whatever lies you can get away with. That is the prevalent culture there - selling snake oil with hype and glitter, with those who've convinced themselves that their product in fact works doing the best job of salesmanship. When the two meet, trust in scientific progress suffers. That doesn't happen in a dozen other fields of business intimately connected with scientific medical research, so why should it do so here? Is resveratrol junk and nonsense, just like a thousand products that don't do what their sellers promise? Many more people now think so on the back of this news. Is research into calorie restriction biology worth funding? Many more people now think not, putting it in the same category as cremes from Revlon and feel-good supplements from fly by night providers. The anti-aging marketplace is a noxious cloud hanging about the scientific quest for healthy life extension. The sooner it either goes away or reforms itself the better.


An Interview With the Supercentenarian Research Foundation Chairman

An item of interest on an otherwise slow day:

In this podcast, you’ll hear Dr. Platika review the accomplishments of the Pittsburgh Life Sciences Greenhouse, and he’ll talk about his new job: helping to get funding to study the world's oldest people.

Dr. Platika is the chairman of the Supercentenarian Research Foundation, a new organization designed to raise funding for studies of supercentenarians, or people who have lived more than 110 years. Dr. Platika wants to know: Why have the very aged survived as long as they have? Are they less susceptible to the common diseases that slow down the rest of us? Ultimately, Dr. Platika hopes the foundation will contribute to the discovery of products that help people fight degenerative and other conditions associated with aging and maintain their mobility and quality of life.

The SRF has fairly close ties to the Methuselah Foundation, as I recall. Certainly, amyloidosis is a condition that interests both parties: a buildup of different types of clumping biochemicals in different tissues that leads to loss of function and eventually death. It is thought to be an important cause of death in supercentenarians who have evaded all the other common killers.

"The superseniors deviate from the norm not just in how long they live but in how they die," says Coles, who arranges autopsies of the oldest old as part of his work with the recently established Supercentenarian Research Foundation. Only nine Supercentenarians have undergone postmortems - Calment, for example, never agreed to one - and Coles and colleagues have performed six of these procedures, including one earlier this year in Cali, Colombia, on a man who died at age 111.

Coles argues, based on these autopsies, that supers aren't perishing from the typical scourges of old age, such as cancer, heart disease, stroke, and Alzheimer's Disease. What kills most of them, he says, is a condition, extremely rare among younger people, called senile cardiac TTR Amyloidosis. TTR is a protein that cradles the thyroid hormone thyroxine and whisks it around the body. In TTR Amyloidosis, the protein amasses in and clogs blood vessels, forcing the heart to work harder and eventually fail. "The same thing that happens in the pipes of an old house happens in your blood vessels," says Coles.

The Methuselah Foundation is funding development of biomedical remediation as a technology platform to safely remove amyloid and other forms of aggregate from tissues, which should prevent that process from contributing to degenerative aging.

Catalase-Based Longevity Not Replicated In Mice

Never a straight road in the life sciences. The extension of mouse life span by genetic modification to target the antioxidant catalase to the mitochondria is a result I've considered important for years, but another study finds no benefit to life span: "We evaluated the effect of overexpressing antioxidant enzymes on the lifespans of transgenic mice that overexpress CuZnSOD, catalase, or combinations of either CuZnSOD and catalase or CuZnSOD and MnSOD. Our results show that the overexpression of these major antioxidant enzymes, which are known to scavenge superoxide and hydrogen peroxide in the cytosolic and mitochondrial compartments, is insufficient to extend lifespan in mice." So something more complex is going on here; back to square one, and more studies to try and understand how it is that earlier results of extended healthy life were in fact produced.


A Different View of Alzheimer's and Blood Flow

Researchers how produced evidence suggesting that reduced blood flow to the brain prevents amyloid beta from being carried away, thereby worsening the progression of Alzheimer's - which explains why exercise seems to help resist this age-related condition. Here is a different view of why reduced blood flow is bad, and a reminder that Alzheimer's a complex, many-faceted degeneration: "when the brain doesn't get enough sugar glucose - as might occur when cardiovascular disease restricts blood flow in arteries to the brain - a process is launched that ultimately produces the sticky clumps of protein that appear to be a cause of Alzheimer's. [Researchers] discovered a key brain protein is altered when the brain has a deficient supply of energy. The altered protein, called elF2alpha, increases the production of an enzyme that, in turn, flips a switch to produce the sticky protein clumps. ... What we are talking about here is a slow, insidious process over many years where people have a low level of cardiovascular disease or atherosclerosis in the brain. It's so mild, they don't even notice it, but it has an effect over time because it's producing a chronic reduction in the blood flow."


The Young Biochemistry of Centenarians

When compared to a random selection of folk in their middle ages and younger, centenarians have biochemistries that seem better adapted to long term survival. That makes sense, given that few of those random folk would make it to 100 under the same life circumstances as the centenarians. Hopefully researchers can use the identified differences to make faster progress in longevity science. Here is an example:

OBJECTIVES: To analyze several functions and antioxidant parameters of peripheral blood neutrophils from healthy centenarians (men and women) and compare them with those of healthy young (aged 25-35) and middle-aged (aged 65-75) men and women.


PARTICIPANTS: Twenty-one healthy centenarians (8 men), 30 young adults (15 men), and 30 middle-aged adults (15 men).


RESULTS: Neutrophil functions of the middle-aged group were worse than those of young adults and centenarians ... The neutrophil functions of the centenarians were closer to those of the young adults. ... With normal aging, total glutathione levels decrease, but the centenarians in this study showed levels similar to those of young adults. Centenarians showed the highest catalase activity of the three groups.

CONCLUSION: Progressive impairment of the immune system accompanies aging. The better preservation of function and antioxidant systems in the neutrophils of centenarians could play a key role in the longevity of these subjects.

The catalase data is interesting, given the work of Rabinovitch showing that increased catalase expression in mice - if targeted to the mitochondria - extends healthy life. It seems that there might be a fair degree of difference within the human species as to how genetically resistant people are to aging. For more on why catalase - an antioxidant - likely works to extend life when introduced to the mitochondria, you might look back into the Fight Aging! archives.

The catalase soaks up some portion of free radicals before they can attack your vulnerable mitochondrial DNA. Damage to this [DNA] leads to an unfortunate chain of events that causes entire cells to rabidly produce damaging free radicals and export them throughout the body. But stop a fraction of the original mitochondrial free radicals from attacking their birthplace, and you have slowed the rate at which one cause of aging happens - you have slowed down aging, and extended healthy life.

Towards a Way to Block Metastasis

Researchers are making progress towards identifying specific mechanisms that cause metastasis in cancer, and thereby find ways to shut it down, preventing the spread of cancer in the body and giving more time for the original tumor to be destroyed. From ScienceDaily: "Essential to our understanding of how metastasis develops is identification of the molecules, and characterisation of the mechanisms that regulate cell motility. Hitherto, these mechanisms have been poorly understood. ... [researchers have now] shown not only that the enzyme phospholipase C-gamma-1 (PLC-gamma-1) plays a crucial role in metastasis formation, but that down regulation of PLC-gamma-1 expression is able to revert metastasis progression. ... This is an exciting discovery. He has shown that turning off this molecule prevents metastasis. The simple fact is that if you stop metastasis, you stop cancer from killing people. We now need to focus on developing drugs that can block PLC-gamma-1."


Biomedical Remediation Versus Aging

The Biodesign Institute has posted a good article and video on biomedical remediation, a search for bacterial enzymes to break down damaging waste biochemicals that contribute to aging by damaging the operation of our cells: "The same principles that a Biodesign Institute research team has successfully applied to remove harmful contaminants from the environment may one day allow people to clean up the gunk from their bodies - and reverse the effects of aging. The Biodesign Institute, along with partner, the Methuselah Foundation, is working to vanquish age-related disease by making old cells feel younger. ... The mainstream approach to curing aging diseases is to delay them a little bit, which is great for pharmaceutical sales, but not so good for fixing people. What's different about the Methuselah Foundation is that their approach is to directly repair the damage that the passage of time does to our bodies and eventually causes disease."


A Little Mitochondrial Science of Aging

Not to sound like a broken record, but the state of the mitochondria inside your cells is very important. The level of damaged suffered by these mitochondria is a determinant of your future health and longevity because of the further damaging processes set in motion by faulty mitochondria. Furthermore, we can point to some known ways to extend longevity - such as calorie restriction - and show that they cause changes in biochemical processes that act to eliminate damaged mitochondria before they cause significant harm or prevent that damage from occuring in the first place. As this recent abstract points out for one small facet of aging:

The mechanisms by which caloric restriction preserves skeletal muscle health with aging continue to be explored; however, mounting evidence points toward a convergence of effects at the level of the mitochondrion. Specifically, caloric restriction reduces mitochondrial reactive oxygen species production and promotes mitochondrial renewal via enhanced drive on mitochondrial biogenesis and autophagy.

The mitochondrial free radical theory of aging describes in detail how it is proposed that increasing numbers of damaged mitochondria lead to the slow breakdown of systems within the body. A crucial point here is that each of your cells contains thousands of mitochondria, a population constantly in flux with members being broken down when damaged and replaced through binary fission of remaining mitochondria, dividing in two like bacteria. Mitochondria have their own internal DNA, separate from nuclear DNA in your cells, and when that mitochondrial DNA gets damaged then every future generation of mitochondria carry the damage with them.

The core of the mitochondrial free radical theory of aging is an explanation as to how certain forms of mitochondrial DNA damage, such as large deletions, can subvert the normal processes that check for damaged mitochondria to recycle. These damaged mitochondria will be recycled more slowly than their pristine counterparts and will thus soon replicate unchecked to take over the entire mitochondrial population of a cell. Things start to go downhill for that cell and all other nearby cells soon thereafter as the mechanisms of metabolism run awry. Here is a paper providing solid evidence for that concept:

Age-dependent accumulation of partially-deleted mitochondrial DNA (DeltamtDNA) has been suggested to contribute to aging and the development of age-associated diseases including Parkinson's disease. However, the molecular mechanisms underlying the generation and accumulation of DeltamtDNA have not been addressed in vivo.

In this study [we] obtained in vivo evidence that DeltamtDNAs with larger deletions accumulate faster than those with smaller deletions, implying a replicative advantage of smaller mtDNAs. These findings identify DSB, DNA repair systems and replicative advantage as likely mechanisms underlying the generation and age-associated accumulation of DeltamtDNA.

More damage means more replication of damaged mitochondria. This isn't all idle research, of course: having identified damage to mitochondrial DNA as a significant contributer to degenerative aging, there are a wealth of potential ways to reverse or eliminate it through medical science, some already demonstrated in laboratory animals. Look back in the Fight Aging! archives to see some of them:

More Control Over Health Than You Think

Most people have far more control over their health than they think they do or take advantage of. Take metabolic syndrome, for example, a precursor to diabetes and all sorts of other common age-related degenerations linked to excess visceral fat. The evidence suggests that metabolic syndrome is just another name for "not exercising and getting fat" - a state of affairs that can be remedied. For example: researchers examined "the effects of a 24-week lifestyle intervention prescribed by family doctors on carotid artery stiffness in metabolic syndrome (MS) subjects with pre-hypertension and/or pre-diabetes. ... Sixty-three middle-aged and older subjects with pre-hypertension and/or pre-diabetes were divided into subjects without MS (MS-) and with MS (MS+). ... Family doctors prescribed an individually customized lifestyle prescription for aerobic exercise and Mediterranean-style diet. ... Carotid artery distensibility significantly increased in MS+ following the 24 weeks of intervention compared with baseline. Similarly, beta stiffness index decreased in MS+ following the 24 weeks of intervention. Following the intervention, waist circumference, BP and fasting glucose levels reduced in MS+, and 13 MS+ subjects were free from MS." Why let yourself become run down and damaged when you can prevent that from happening?


Creating Artificial Bone Marrow

From ScienceDaily: "This is the first successful artificial bone marrow. It has two of the essential functions of bone marrow. It can replicate blood stem cells and produce B cells. The latter are the key immune cells producing antibodies that are important to fighting many diseases ... Bone marrow is a complicated organ to replicate ... Vital to the success of this new development is the three-dimensional scaffold on which the artificial marrow grows. This lattice had to have a high number of precisely-sized pores to stimulate cellular interaction. The scaffolds are made out of a transparent polymer that nutrients can easily pass through. To create the scaffolds, scientists molded the polymer with tiny spheres ordered like billiard balls. Then, they dissolved the spheres to leave the perfect geometry of pores in the scaffold. The scaffolds were then seeded with bone marrow stromal cells and osteoblasts, another type of bone marrow cell."


The Terrible Urge to Tear Down the Successful

Fairness and equality, much like communism, are concepts that pull at the hardwired nature of we humans. For reasons no doubt much to do with the evolutionary success of our ancestors, we instinctively seek to tear down those who have more than we do. Fairness and equality, again much like communism, turn into a race for the bottom when put into practice:

Creating "equality" by taking from the successful ruins the creation of wealth - very much a non-zero sum game - for all. It takes away the vital incentives and rewards for success. At the end of the process, as demonstrated by all that transpired in the Soviet Union, you are left with the same old inequalities, but now taking place amongst ruins, starvation and disease.

I noticed an exploration of one manifestation of this human urge today:

The fair innings argument maintains that for healthcare resources to be distributed fairly every person should receive sufficient healthcare to provide them with the opportunity to live in good health for a normal span of years. What constitutes a normal span of years is often defined as life expectancy at birth, but this criterion fails to provide adequate grounds for the equal distribution of healthcare across and between generations. A more suitable criterion for the normal life span is the idea that the human life span is biologically limited. Many current gerontological theories argue that the biological limit to human life spans is related to the ageing process. If technological advances in medicine can retard the ageing process by treating and preventing the diseases and disorders associated with it, human longevity will be limited only by the developments in and the successful application of medicine. In consequence, the fair innings argument will no longer be able to justify denying people healthcare resources because they have lived longer than the normal life span.

The very existence of the fair innings argument - the term coming from cricket, I imagine, refering to a decent time spent at bat, a good life lived, time to get out of the pool - is a terrible end manifestation of the urge to equality. That people talk about denying medical care to those who need it the most, and that they establish an idea of what length of life should be in defense of that aim, demonstrates that any attempt to impose equality is also a retreat from compassion and a refutation of progress.

An older paper runs along much the same lines and is open access: the basics of the fair innings argument haven't changed.

The fair innings argument (FIA) is frequently put forward as a justification for denying elderly patients treatment when they are in competition with younger patients and resources are scarce. In this paper I will examine some arguments that are used to support the FIA. My conclusion will be that they do not stand up to scrutiny and therefore, the FIA should not be used to justify the denial of treatment to elderly patients, or to support rationing of health care by age.

The whole debate has to be put in context, however. This is related to the operation of the universal health care system in the UK, a system that has long been in the doleful steady state of all such socialist, centralized systems: waste, terrible services, and - most importantly - rationing. Every taxpayer involuntarily funding this behemoth feels that they own a piece of it, and everyone has that tug on their human nature urging them to make sure that no-one gets more than they do. It's ugly, and it's why socialism fails. Along the way to failure, however, it produces dangerous ideas, such as "human beings have a fixed length of life, after which they should be cut off and left to die."

I much prefer the vanishing alternate path for health provision: a free market of competing service providers, and people taxed less, free to save and plan for their own medical needs. In that environment progress and longevity are welcome, and increased need for medicine is a market opportunity to excel in providing services.

I say if this were a privatized system, we would all say “gee it’s wonderful. All these people want more health care, this industry is thriving”. Let me put one other analogy. Suppose we made cars a government entitlement. Instead of cheering when auto production went up, we’d say, "Oh my God, we can’t afford this!". How you finance it may greatly affect the psychology and actually the freedom of the economy to take advantage of these new opportunities.

Sadly, freedom in medical choice is not the zeitgeist of this age. Worse looks more likely than better for the years immediately ahead.

Alzheimer's and Blood Flow

From ScienceDaily, indicators as to why it is that exercise improves resistance to Alzheimer's - by increasing blood flow to the brain: "there's a great deal of evidence to suggest that Alzheimer's disease is a problem having much to do with the vascular plumbing. ... . It's not simply that reduced blood supply hurts brain cells by causing a shortage of oxygen and other nutrients. Rather, deterioration of blood flow seems to gum up the brain's ability to remove toxic amyloid beta. Normally, amyloid is picked up efficiently by blood vessels that then whisk the toxic trash away. But in Alzheimer's disease, the system no longer is able to keep up with the body's production of the substance. The molecular trash accumulates, and [researchers] believe the buildup kills brain cells." The researchers here show that two proteins linked to the cardiovascular system change both blood flow and the ability to clear amyloid beta. It's worth remembering that Alzheimer's is a multifaceted, complicated condition with numerous contributing issues: see for example the convincing evidence for involvement of degeneration in the choroid plexus, diabetes-like lifestyle conditions, a herpes simplex virus, and so forth.


A Look at the Buck Institute

The Sacramento Bee is running an article on the Buck Institute for Age Research. It's representatives of the mainstream aging research approach to talking about their work: slowly, slowly, and never any prospects for large gains in healthy longevity. Which is probably the case given their approach to the problem of aging, to change our hugely complex metabolic processes and genetic programming so as to slow down the rate at which damage accumulates. As usual, I'm much more interested in researchers who advocate keeping the metabolism we have, developing near-term ways to repair the biochemical damage we know a great deal about, and aim to reverse aging rather than just slow it down. The under the hood battle over how the research community moves forward is the most important scientific debate of our time, for it will determine how long we can live in good health.


More Evidence For Methionine as the Primary Driver of Calorie Restriction

You'll recall that experiments restricting intake of the dietary amino acid methionine - without restricting calories - demonstrate some of the same beneficial health effects as calorie restriction. This suggests that the level of methionine ingested is primarily what cues our biochemistry to produce the benefits it does under a low calorie diet that still supplies the right levels of micronutrients. See, for example:

Now here's a reversal of these experiments, in which researchers restrict all the other dietary amino acids except methionine, and come to much the same conclusion:

Previous studies have shown that the decrease in mitochondrial reactive oxygen species (mitROS) generation and oxidative damage to mitochondrial DNA (mtDNA) that occurs during life extending dietary restriction also occurs during protein or methionine restriction, whereas it does not take place during carbohydrate or lipid restriction.

In order to study the possible effects of other amino acids, in this investigation all the dietary amino acids, except methionine, were restricted by 40% in male Wistar rats (RESTAAS group). After 6-7 weeks, experimental parameters were measured in the liver.


[The] results, together with previous ones, strongly suggest that the decrease in mitROS generation and oxidative damage to mtDNA that occurs during dietary restriction is due to restriction of a single amino acid: methionine. They also show for the first time that restriction of dietary amino acids different from methionine decreases mitochondrial protein oxidative modification [and] increases SIRT1, in rat liver.

Meaning that while methionine restriction accounts for much of calorie restriction, it doesn't account for all of it. There may be multiple parallel mechanisms operating, which in turn suggests that building calorie restriction mimetic drugs that capture anywhere near the entire effect of actual calorie restriction will be challenging. Meanwhile, while research groups are spending hundreds of millions to billions of dollars on research an development, you can obtain the whole benefit of calorie restriction for just about free. Just start eating less, sensibly, while ensuring that your intake of micronutrients remains optimal.

Exercise, the Immune System, and Cancer

As you might know, one of the roles of the immune system is to hunt down and destroy cancerous cells before they can grow into tumors. That the immune system becomes damaged and dysfunctional in later life is one of the many reasons why cancer risk increases with age. Here is a paper that shows that exercise boosts the capacity of immune cells to kill cancer - as though you needed another reason to regularly exercise, given its many benefits to healthy longevity. "Natural killer cells (NK) induce the death of tumor cells [by] cytotoxicity, whereas platelets reduce the capacity of NK to destroy tumor cells. Physical exercise affects both immune function and platelet activity because responses depend on type, intensity, and duration of exercise. This investigation explores how various exercise regimens influence platelet-impeded cytotoxicity of NK to [tumor cells] ... Thirty sedentary men performed on three occasions moderate exercise), severe exercise and severe exercise after warm-up exercise ... Severe exercise enhances the cytotoxicity of NK to [tumor cells] and simultaneously promotes the platelet-impeded apoptosis of [tumor cells] induced by NK. However, warm-up exercise reduces the resistance of platelet to NK-[tumor cell] interaction, increasing the efficiency [of] cytotoxicity by NK after severe exercise."


More on Adult Brain Plasticity

Researchers are getting closer to inducing the adult brain to reconfigure and repair itself in response to damage: "The [study] identified a set of proteins - calpain and cortactin, which regulate and control the sprouting of neurons - a mechanism known as neural plasticity. ... During development, growing neurons are relatively plastic and can sprout new connections, however their plasticity levels drop rapidly as they mature and become integrated into neuronal networks. ... as a consequence, the central nervous system is unable to reorganize itself in response to injury or disease. ... This discovery is exciting because we now know that neurons haven't lost their capacity to re-grow connections, but instead are under constant repression by the protein calpain. If we can target therapies that block this mechanism, then neurons should be able to sprout new connections, therefore stimulating the brain's ability to repair its wiring network. ... The next step is to find a way to enhance neural plasticity without interfering with the good connections that are already in place."


On Consuming AGEs

Regular readers will know that advanced glycation endproducts (AGEs) are not a good thing; they're one of the types of biochemical gunk that accumulate in our tissues to degrade function and cause follow-on issues relating to that lost functionality.

Problems caused - or not helped - by AGE buildup include kidney disease, and the many variations of blood pressure and heart conditions caused by a lack of elasticity in the tissues of heart and blood vessels. Diabetics in particular suffer due to more rapid accumulation of AGEs based on their metabolic biochemistry (e.g. high blood sugar, inflammation, free radicals).

You might also recall some of my posts on RAGE, the receptor for AGEs and how that fits in to the way in which AGEs damage the workings of your biochemistry.

At least some of the degenerations brought on by AGE buildup can be laid at the feet of the interaction with RAGE, and the resulting actions then taken by your cells. Cell receptors are like keyboards or buttons - hit them with the right sort of molecules and you're instructing the cell to take action.

There is, however, some debate over the role of AGEs ingested with food - cooked meat is comparatively high in AGEs, for example, and pretty much anything else that involves the Malliard reaction. Do these AGEs contribute to damage in the same way as those generated inside the body as a side effect of the operation of human metabolism? Here's a recent paper on the topic:

Effects of high-AGE beverage on RAGE and VEGF expressions in the liver and kidneys

BACKGROUND: The formation and accumulation of advanced glycation end products (AGEs) increase in some lifestyle-related diseases as well as in aging; however, little is known about the relationship between food-derived AGEs and the pathology of such diseases.

AIM OF THE STUDY AND METHODS: To explore whether food items containing high levels of AGEs are involved in the development of lifestyle-related diseases, rats were orally administered a commercial high-AGE beverage (LB-A) ... With a particular focus on angiogenesis-associated diseases, the gene expressions of vascular endothelial growth factor (VEGF) and the receptor for AGEs (RAGE) were examined in the liver and kidneys using real-time reverse transcription-polymerase chain reaction. Moreover, AGE deposition was immunohistochemically investigated in these tissues.

RESULTS AND CONCLUSIONS: Hepatic VEGF expression was significantly increased in rats administered LB-A ... Furthermore, immunohistochemical analysis detected glucose-derived AGE-positive cells in the liver from the LB-A group. These results suggest that AGE-rich beverages increase hepatic VEGF expression and AGE accumulation, bringing about early events associated with lifestyle-related diseases.

Fair evidence to suggest that reducing your AGE intake in addition to reducing your overall calorie intake might be a good idea over the long term.

Cell Polarity and Aging

Another good find from Ouroboros, an outline of differential distribution of damage to daughter cells and the origins of aging: "Let's pretend you are a unicellular organism - what would be the best strategy to ensure the long-term multi-generational survival of your lineage? One approach is to distribute everything equally amongst your two offspring. ... A second approach is to give all the crap to one of the two new cells and keep the other one pristine. Lets call these two cells the crap cell and the pristine cell. What's the result of this second strategy? Using our crap metric from above, the first cell accumulates 10 units of garbage over its lifetime and then gives it all to one offspring, the crap cell, and none to the other offspring, the pristine cell. Those cells then grow and by the time they divide each second generation cells have made 10 units of additional crap each. The crap cell has 20 units the pristine cell 10. The two cells divide and dump all their garbage on one of their offsprings. One cell starts with 20 units of crap, one cell with 10 units and two cells are again crap free. The end result of this strategy? Part of your descendents will become more and more decrepit as they fill up with crap, while others remain pristine."


Ouroboros on AGEs and Senenscence

From Ouroboros: "Advanced glycation endproducts (AGEs) have been implicated in age-related disease and aging itself, convincingly enough that significant effort has gone into finding compounds that can 'break' or reverse them. Among many unresolved questions: Are specific proteins AGEylated, and if so, which proteins are being modified within cells? Unterluggauer et al. report that in [senescent cells], the chaperone Hsc70 is modified by AGE ... If a major chaperone is modified by AGEs, and the modification is deleterious to its function, this could dramatically decrease the efficiency of protein folding, which (given that chaperones are proteins too) could dramatically decrease the number of chaperones, which [leads to a] garbage catastrophe ... (Then again: senescent cells persist in culture for a long time, implying that they have some way to deal with the admittedly hypothetical protein-folding death spiral implied in the previous paragraph.)"


Longevity Meme Folding@Home Team Hits the Top 100

I'm pleased to note that the volunteer folders-at-home who gather at the Immortality Institute forum have pushed the Longevity Meme Folding@Home team into the top 100 list - it's sitting right at rank 100 as I type this. I'd love to say I helped, but the steady climb through the ranks and increasing donation of computational resources is really all due to the hard work of those who organizated, encouraged, and recruited to grow the team to its present size. Well done all. There is a celebratory discussion thread underway over at the Immortality Institute.

Feel free to set off some fireworks or eat some cake or something to mark the occasion.

When the team hit rank 200 at the start of this year, I donated a small chunk of change to the Methuselah Foundation as an incentive for the folders. The team has sprinted ahead to rank 100 faster than I had anticipated given the competition - and so has caught me without a plan as to what to do to mark the occasion. Since you can't go far wrong by offering money, I think I'll donate a further $2000 to the Methuselah Foundation this year in support of Strategies for Engineered Negligible Senescence research.

Keep up the good work!

Evidence For Cancer Stem Cells

Evidence both for and against the cancer stem cell hypothesis is arriving rapidly these days. Scientists "have answered a central question in cancer biology: whether normal stem cells can give rise to tumors. Stem cells are immature cells that can renew themselves and give rise to mature differentiated cells that compose the range of body tissues. In recent years, researchers have developed evidence that cancers may arise from mutant forms of stem cells. Like a brand-name product instantly identifiable by its trademarked logo, normal and cancerous stem cells display on their surface characteristic proteins, including Prominin1 or CD133. A key question in cancer biology has been whether these so-called cancer stem cells arise from normal stem cells or more mature cancer cells that somehow reacquire the characteristics of stem cells. ... investigators show that Prominin1 marks normal intestinal stem cells and that these cells, when mutated, give rise to intestinal tumors. The finding could also aid in identifying the source of cancer stem cells in the lung, kidney, brain, pancreas and other tissues." If cancer stem cells are in fact the root of a majority of cancers, then targeted therapies presently in development will ensure that cancer becomes a lot rarer a decade from now.


Aging: Genetic Program Versus Stochastic Damage

Via EurekAlert!: "Aging yeast cells accumulate damage over time, but they do so by following a pattern laid down earlier in their life by diet as well as the genes that control metabolism and the dynamics of cell structures such as mitochondria, the power plants of cells. These research findings [support] the theories that old age is the final stage of a developmental program AND the result of a lifelong accumulation of unrepaired cellular and molecular damage. ... The scientists first identified a mechanism closely linking life span to the dynamics of such lipids as cholesterol, triglycerides and fatty acids ... These fatty acids are constantly synthesized in the endoplasmic reticulum (ER), the cell's protein manufacturing factory. ... Low-calorie diets, which have been shown to increase lifespan and delay age-related disorders in nonhuman primates and other organisms, altered the way fats were processed in the yeast cells. The researchers assessed calorie restriction along with a number of known mutations that extend yeast lifespan against a variety of age-related changes in fat metabolism and lipid transport. ... Through the yeast model, [researchers] identified five groups of novel anti-aging small molecules that significantly delayed aging."


A Short Editorial on the Limits of Longevity

The mailing list of the Gerontology Research Group is something of a watering hole for many of the interesting folk in the pro-longevity gerontology community and related supporters of medical intervention to extend healthy life. Members include the Supercentenarian Research Foundation board, Methuselah Foundation volunteers, calorie restriction researchers, transhumanist writers, and so forth. L. Stephen Coles of the GRG recently penned a short editorial on the limits of longevity which closes with:

We should appreciate that the really-important parameters of longevity operate at the molecular level, such as the accumulation of sticky amyloid compounds which relentlessly infiltrate all our organs, the mechanism for which we have yet to decipher. When we do figure it out (science) and when we learn what to do about it (medicine), "all bets (on life-insurance-policy planning) will be off." We will be on the road to a real revolution in the human condition.

It being that time of year, I should note that the Supercentenarian Research Foundation is soliciting donations:

We seek to further scientific research into to why Supercentenarians live as long as they do? (And, conversely, why they don't live longer still?) We are incorporated and have held many meetings of our Board of Directors. We have received approval for our 501(c)(3) non profit, tax-exempt status from the US Internal Revenue Service. Nevertheless, we are urgently in need of "seed money" to fund the formation of an international team of physicians and investigators who could travel to visit each of our living Supercentenarians around the world in person before they are no longer with us. Obviously, the data that we plan to obtain is a precious resource that could disappear from our radar screens unless we get started soon.

An Update on Progress in Treating Progeria

We should be at least a little interested in the accelerated aging condition Progeria (or HGPS), for as this ScienceDaily article points out: "Recent research indicates that all people, not just children with HGPS, produce small amounts of [the truncated Lamin A protein called]progerin, and that this mutant protein may play roles in aging or longevity ... The discovery of the gene responsible for the disease five years ago led scientists to the experimental drug that is now being evaluated in 28 children ... The 2003 discovery of the HGPS gene, named lamin A (LMNA), laid the groundwork for the clinical trial. ... scientists found that the minute change in the LMNA gene's DNA sequence dramatically changed the way in which the sequence was spliced by the cell's protein-making machinery. The end result was the production of an abnormal lamin A protein that is missing a stretch of 50 amino acids near one of its ends. ... Years of basic research studies showed that the Lamin A protein production depends on the farnesyl group molecules' attaching themselves to the pre-lamin A protein. This attachment - and progerin production - can be blocked by a FTI drug."


Continued Cataloguing of Stem Cells

ScienceDaily provides a good example of the sort of work taking place in the stem cell field at the moment. Near future applications are as much about understanding how to correct problems in human tissue as about building replacement tissue: researchers "have discovered stem cells in the esophagus of mice that were able to grow into tissue-like structures and when placed into immune-deficient mice were able to form parts of an esophagus lining. ... The immediate implication is that we'll have a better understanding of the role of these stem cells in normal biology, as well as in regenerative and cancer biology ... Down the road, we will develop a panel of markers that will define these stem cells and use them in replacement therapy for diseases like gastroesophogeal reflux disease [GERD] and also to understand Barrett's esophagus, a precursor to esophageal adenocarcinoma and how to reverse that before it becomes cancer."


A Brace of Stem Cell Advances

Biotechnology and life science research is forging ahead despite the steadily worsening situation in bringing medical advances to market - stifling regulation that seems to do little but get worse year after year, and now an ongoing economic collapse that looks set to continue for some time. Here are a couple of examples from the field of regenerative medicine in the past few days:

Single Adult Stem Cell Can Self Renew, Repair Tissue Damage In Live Mammal

The transplanted adult stem cell and its differentiated descendants restored lost function to mice with hind limb muscle tissue damage. ... Unlike tumor cells, the transplanted stem cells achieved homeostasis, growing to a stable, constant level and ceasing replication. After demonstrating that the transplanted stem cells proliferated and fully restored the animal's lost function, Sacco and Blau recovered new stem cells from the transplant with full stem cell potency, meeting the final "gold standard" test for adult multipotent stem cells.

Single virus used to convert adult cells to embryonic stem cell-like cells

Researchers have greatly simplified the creation of so-called induced pluripotent stem (iPS) cells, cutting the number of viruses used in the reprogramming process from four to one. Scientists hope that these embryonic stem-cell-like cells could eventually be used to treat such ailments as Parkinson's disease and diabetes.

New Way To More Rapidly Generate Bone Tissue Developed

Using stem cell lines not typically combined, researchers [have] designed a new way to "grow" bone and other tissues.


The inability to foster angiogenesis - a physiological process involving the growth of new blood vessels from pre-existing vessels - has been a major roadblock in tissue regeneration. Previous approaches have included the use of angiogenic growth factors and the fabrication of artificial blood vessels. However, there are problems associated with these approaches. Among these problems: artificially fabricated blood vessels do not readily branch out and network with host blood vessels, and blood vessels induced by angiogenic growth factors tend to be immature and "leaky."

To overcome these obstacles, a team of Columbia researchers has co-transplanted hematopoietic and mesenchymal stem/progenitor cells to promote the regeneration of vascularized tissues. What they found was that the tissue regenerated in bone more rapidly than when either type of stem cell was used alone.

It is encouraging to have seen a steady stream of improvements to new techniques this past year. Researchers are moving rapidly to build a sound basis for the near-future construction of replacement organs and directed regrowth of damaged tissue inside the body.

The Masses Who Don't Have To Die

From Overcoming Bias: "More likely than not, most folks who die today didn't have to die! Yes, I am skeptical of most medicine because on average it seems folks who get more medicine aren't healthier. But I'll heartily endorse one medical procedure: cryonics, i.e., freezing folks in liquid nitrogen when the rest of medicine gives up on them. Yes even with modern anti-freezes, freezing does lots of damage, perhaps more than whatever else was going to kill you. But bodies frozen that cold basically won't change for millennia. So if whole brain emulation is ever achieved, and if freezing doesn't destroy info needed for [constructing an emulation based on scanning brain structure], if we think more likely than not, future folks could make an [emulation] out of your frozen brain. Since most folks who die today have an intact brain until the rest of their body fails them, more likely than not most death victims today could live on as (one or more) future [emulations]. And if future folks learn to repair freezing damage plus whatever was killing victims, victims might live on as ordinary humans." Those of us more in favor of continuity theories of identity prefer the latter option, and cutting edge cryonics now uses vitrification rather than freezing, which causes far less damage. But the point still stands: we have the technology to prevent irreversible death in a majority of cases, yet it is scarely used at all.


Methuselah Foundation Newsletter

The latest Methuselah Foundation newsletter is available, including a progress report on Methuselah Foundation Undergraduate Research Initiative (MFURI), and an interesting overview of anti-cancer OncoSENS and telomere research: "Cancer is one of the leading causes of death and thus one of the key targets of SENS. Our approach aims to tackle cancer by making it impossible for tumor cells to become immortal, rendering them harmless. Telomeres, the ends of chromosomes, play a key role in this process; specifically, we want to prevent them from being lengthened - a precondition of cellular immortality. In humans two mechanisms of telomere lengthening exist, of which the telomerase enzyme is the most well known; in my work, I focus on the less understood form called 'alternative lengthening of telomeres' (ALT). ... In the near future, I see OncoSENS taking two main directions; understanding ALT and - at first independently, but later in conjunction with that - providing a proof-of-principle in mice that telomerase-deficient stem cells can be successfully transplanted and largely prevent the emergence of malignant tumors."


Predicting Longevity Genes

Here's an open access paper for those of you interested in bioinformatics: using network theory and existing data on genes and proteins to predict new longevity genes and targets for further investigation. This is an example of the modern nuts and bolts of efforts to fully understand longevity from a reductionist point of view - a long road ahead there.

Identification of genes that modulate longevity is a major focus of aging-related research and an area of intense public interest. In addition to facilitating an improved understanding of the basic mechanisms of aging, such genes represent potential targets for therapeutic intervention in multiple age-associated diseases, including cancer, heart disease, diabetes, and neurodegenerative disorders.


We have utilized a shortest-path network analysis to identify novel genes that modulate longevity in Saccharomyces cerevisiae. Based on a set of previously reported genes associated with increased life span, we applied a shortest-path network algorithm to a pre-existing protein-protein interaction dataset in order to construct a shortest-path longevity network.


we report the identification of previously unknown longevity genes, several of which function in a conserved longevity pathway believed to mediate life span extension in response to dietary restriction.

I happen to think that the best near-term result - over the next decade, say - to come out of efforts aimed at complete understanding of our biochemistry will be a speeding of medical engineering for increased longevity. Engineering comes before science, and is improved by increased understanding provided by science, but you don't have to wait for full understanding to make progress. Bridge building was a fine art long before architectural and materials science became mature fields, and so too could longevity therapies be developed well in advance of a full understanding of metabolism. Medicine is, after all, a branch of engineering.

For an more detailed explanation as to why this is so, you might read up on the Strategies for Engineered Negligible Senescence. We already know more than enough to work at repairing our age-damaged biochemistry through medical science, as we can identify the precise ways in which old biochemistry differs from young biochemistry. Further understanding why these differerences exist will make the task of repairing them easier, but is not strictly necessary to progress. You don't need to know the chemistry of rust in order to perform the maintenance work of removing it from machinery - you just need to know how to remove rust.

Notes on the 4th Terasem Movement Colloquium

You find a lot of interesting speculation on the future intersection of law and cryonics in this lengthy report from Accelerating Future: "this is a legally focused gathering, and addresses legal issues related to cryonics patients, cyborgs, artificial biological intelligent beings, enhanced human beings, and artificial intelligences. ... Martine invites the first speaker, John Didon, to the podium. He has contributed more than any other attorney to the rights of people in biostasis. As many of you may know, people in biostasis are sometimes at risk of their rights being denied, treated as objects rather than the people they are. John points out that there is no legal status of suspended persons, so any discussion of such is merely (unfortunately) of ideas. Historically, people have tried to do things like will money to themselves for revival after biostasis, and these efforts have run into trouble with family members. John quotes William Goldman: 'Nobody knows anything'. Law is based on precedent, which is both a blessing and a curse. Because cryonic suspension is so new, there is little precedent, but we have to try to shape the law by being there first. He will present four arguments to support shaping the law in favor of persons upon their suspension." From where I stand, law is far less important than incentives - worry about arranging the incentives first, because incentives shape laws and the way people interact with those laws. Potential material gain beats ink on paper every time.


Gene Therapy Versus Periodontitis and Arthritis

Via EurekAlert!: "Using gene therapy, [researchers] found a way to help certain cells using an inactivated virus to produce more of a naturally-produced molecule soluble TNF receptor. This factor is under-produced in patients with periodontitis. The molecule delivered by gene therapy works like a sponge to sop up excessive levels of tumor necrosis factor, a molecule known to worsen inflammatory bone destruction in patients afflicted with rheumatoid arthritis, joint deterioration and periodontitis. ... Targeted Genetics released human trial results that showed the same gene therapy approach [had] positive affects in human patients with rheumatoid arthritis ... The company tested 127 human subjects and showed a 30 percent improvement in pain relief, and gain of function, among other enhancements using the gene treatment. ... The gene also delivers quite a bit of genetic bang for the buck. The periodontal tissues were spared from destruction by more than 60-80 percent with the use of gene therapy. ... If you deliver the gene into the target cells once, it keeps producing in the cells for a very long period of time or potentially for the life of the patient. This therapy is basically a single administration, but it could have potentially life-long treatment effects in patients who are at risk for severe disease activity."


Confirming the Importance of Autophagy to Longevity

Autophagy is the process by which cells break down damaged components and replace them with newly created ones. The quality and degree of ongoing autophagy - and most importantly autophagy of damaged mitochondria in your cells - appears to be important for longevity. See past posts here at Fight Aging! for example:

Autophagy researchers are amassing a heavy weight of evidence pointing to autophagy as a key process that boosts healthy longevity, most likely by cycling out damaged mitochondria before those damaged mitochondria can replicate to wreck havoc in your tissues.

Scientists generally concur that accumulated damage throughout the body due to free radicals is one important root cause of age-related degeneration - but the devil is in the details. The vast, overwhelming majority of those free radicals are generated by your [mitochondria] as an unavoidable byproduct. The rate of free radical generation increases greatly with age as the [mitochondria] are themselves damaged by the free radicals they created.

Continuing in this vein, a great post over at Ouroboros analyzes research that provides more and better confirmation of the role of autophagy in extending healthy life span through calorie restriction:

Mitochondria are central to many theories of aging because they produce damaging reactive oxygen species (ROS) as a by-product of normal function. Over time, ROS can degrade mitochondrial DNA (mtDNA), interfering with cellular energy production. The cell’s strategy for dealing with this damage is to recycle its mitochondria on a regular basis.


The main result of this paper is that calorie restriction makes mitochondria turn over a substantial 35% faster, at least in mouse liver. This provides another explanation for the recent finding that [calorie restriction] protects mtDNA from age-related damage.

It's worth a few moments to stop and think about the deep biochemical damage your body is accumulating because of the extra calories you consume.

Manipulating Heart Cells Into Regeneration

Via EurekAlert!: "Up until today scientists assumed that the adult heart is unable to regenerate. Now, researchers and cardiologists [have] been able to show that this dogma no longer holds true. [They] were able to show that the body`s own heart muscle stem cells do generate new tissue and improve the pumping function of the heart considerably in an adult organism, when they suppress the activity of a gene regulator known as beta-catenin [which] plays an important role in the development of the heart in embyros. [Researchers] could now show that beta-catenin is also important for the regeneration of the adult heart. They suppressed this factor in the nucleus of the heart cells in mice. This way they activated heart precursor cells (stem cells) to turn on the regeneration of heart in adult mice. Four weeks after blocking beta-catenin, the pumping function of the heart of the animals had improved and the mice survived an infarction much better than those animals with a functioning beta-catenin gene."


New Methuselah Foundation Website Launches

The long awaited redesign of the Methuselah Foundation website has lauched - and very impressive it is too. "We are very excited to announce a new chapter in the future of the Methuselah Foundation, and in our collective efforts to fight aging. Today we launched a new website,, that will serve as a platform for the groundbreaking research and ideas generated from the Methuselah Foundation. Visitors to will be able to interact with the Foundation's pioneering researchers, and learn about the work they are doing to better understand and reduce the degenerative effects of aging. In other Methuselah Foundation news, we are announcing the creation of the 300 Monument, a monument dedicated to our visionary donors who are supporting, and who will continue to support the Methuselah Foundation's fight for longer, healthier human lifespans. For $1,000 a year, for 25 years, which amounts to $85 a month or $2.75 a day, committed donors will be immortalized on the monument. We are at a critical juncture in our fundraising efforts. We thank you for your continued support, and encourage you to explore our dynamic new website and our vision for the 300 Monument."


The Era of Unifying Theories

Scientific progress goes through cyclic periods of fragmentation followed by synthesis. During fragmentation, many different groups toil away at their own little pieces of the great unknown. Each group generates data that, at first, appears to have little to do with other efforts. As the data piles higher, correlations start to appear - and so do the efforts at synthesis. Gradually, the focus in a field shifts from finding new information to making sense of what is known, pulling it all together such that links, correlations, and chained mechanisms are understood. Then they next great unknown beckons and the process of fragmentation starts once more.

At present the grand study of human biochemistry is moving from fragmentation to synthesis. It is still the case that some different specialties know little of one another's work. Researchers look at the same mechanisms and compounds, giving them different names and assuming different dominant roles in biochemical processes, all the while missing out on the enlightenment that a complete picture can bring. But that state of affairs is generally on the way out, helped by modern information technology. The cost of knowledge is dropping precipitously, and so the process of synthesis becomes easier and starts earlier:

In past years, I was fond of comparing biogerontology to the tale of the blind men and the elephant: everyone was approaching the problem from different directions, unable to see the big picture - and reaching conclusions that had more to do with the direction of approach (i.e., initial biases) than the fundamental importance of any given observation.

But this analogy is becoming increasingly less apt, and we may be on the verge of the era of unifying theories in the biology of aging.

What causes aging? The various subfields of biogerontology answer this question in very different ways. To vastly oversimplify: In one corner we have metabolism, including the related stories of sirtuins and calorie restriction; in another corner, we have DNA damage and stochasticity of gene expression. (Already we're seeing the unifying tendency of recent findings: a few years ago I might have put those four items in four separate corners, but on the basis of recent reports I feel comfortable starting to bin them together. There are those, however, who would argue I'm being premature if not outright inaccurate in so doing.) In both corners, one could make a legitimate claim that the phenomenon in question has serious explanatory power regarding a fundamental mechanism of aging or longevity assurance - but is there a connection between the two?

This is a view within the mainstream focus on metabolism, DNA damage and the like - quite different from the Strategies for Engineered Negligible Senescence approach to aging science - but you should read the rest; it's very interesting.

CR Mimetics Are Not CR

By way of a reminder that there's still a world of difference between calorie restriction (CR) and a CR mimetic drug that reproduces some of the same observed biochemical changes: "resveratrol may produce calorie restriction-like effects on metabolic and longevity endpoints in mice. In this study, we sought to determine whether resveratrol treatment elicited other hallmark changes associated with calorie restriction, namely bradycardia and decreased body temperature. We found that during short-term treatment, wild-type mice on a calorie-restricted diet experienced significant decreases in both heart rate and body temperature after only 1 day whereas those receiving resveratrol exhibited no such change after 1 [week]. We also used [obese] mice to study the effects of long-term treatment because previous studies had indicated the therapeutic value of resveratrol against the linked morbidities of obesity and diabetes. After 12 [weeks], resveratrol treatment had produced no changes in either heart rate or body temperature. Strikingly, and in contrast to previous findings, we found that resveratrol-treated mice had significantly reduced endurance in a treadmill test. ... we conclude that the bradycardia and hypothermia associated with calorie restriction occur through mechanisms unaffected by the actions of resveratrol."


Another Approach to Restoring Hair Cells

Researchers are exploring a range of options to restore the hair cells of the ear that are lost with age, leading to deafness: "Damage to hair cells in the inner ear due to ageing and overstimulation is a major cause of deafness, affecting 10% of the worldwide population. The cell loss is irreversible because the cells have a limited capacity to regenerate. However, a new study suggests that the ependymal layer of the lateral ventricle of the brain contains stem cells which share characteristics with inner ear hair cells and which have the potential to reproduce. According to the scientists, these cells could potentially be transplanted from a person's brain into their ear, where they would undergo a functional switch to enable them to replace the damaged ones. ... The authors concluded that transplanted cells could alter their functions to work as inner ear hair cells and thus restore hearing. They suggested their findings on the flexible function of certain cells could also be extended to offer treatment for other problems affecting the nervous system."


An Article on Cryonics and Alcor

I noticed a press article on cryonics and the Alcor Life Extension Foundation today:

With medical advances, many put faith in freezing

Leis studies geosciences at the University of Arizona and works in the school's Lunar and Planetary Laboratory, helping study high-resolution images of Mars. Meanwhile, he's paying $22 a month into a life insurance policy that would provide $250,000 if he dies young.

That's enough freeze his body at minus 196 degrees Celsius and store it indefinitely at the Alcor Life Extension Foundation here, waiting for medical advances that could bring him back to life.


Leis, the University of Arizona student, said he's happy to have the option to be preserved until someone figures out how to revive and cure him.

"The technological breakthroughs in cryopreservation suggest that we at least have the ability to preserve biological matter relatively well for a longer period of time," he said. "Whether or not we will be able to do anything with that biological matter down the road remains unseen."

Alcor uses vitrification these days, a process that is very different from freezing and which causes far less damage to tissue.

There's the standard humbug from a bioethicist in the middle of the piece, sticking with the party line of pulling nonsense objections from thin air in response to every endeavor in medicine. If they couldn't at least make the pretense of finding fault, they wouldn't have a job, after all. It's just a pity that bioethicists aren't engaged in more useful work, such as actually getting something accomplished:

Arthur Caplan, a professor of bioethics at the University of Pennsylvania, said those considering being frozen should think about what it would be like to come back. For example, a person revived in the future wouldn't have any relationships or ties to that time.

"Who we are isn't just defined by what's in our heads; it's also by our relationships,"


Rafal said he disagrees with Caplan's concerns about a revived person fitting into a future culture. "A reasonable person would find a place in society and have a new life with no difficulty," he said.

Which is exactly the case. You can go through life making up dumb reasons not to forge ahead, or you can forge ahead. I know which approach I prefer.

Hourglass VI

The sixth edition of the Hourglass blog carnival on aging and longevity science is up at Ouroboros. One of the linked posts is a series of thoughts on the way in which we humans cut ourselves short by discounting the future: "The best example of human’s irrational dealing with the future is what is called hyperbolic discounting (also called: temporal discounting, or future discounting). Hyperbolic discounting is the human preference for small immediate reward over larger future payoffs. The further the time in the future of the reward the greater the discounting ... Humans are generally bad at delaying rewards and hence we too easily take the immediate smaller reward rather than delaying our immediate gratification for a greater reward in the future. ... I propose here that unless humans soon become better at thinking about the future - and not discounting it so much - we might not be able to make the changes we need for a better world and society. ... The same could be said about longevity research - if we can not imagine ourselves living longer and healthier lives - and not imagine it as only happening to a 'stranger' we [are] unlikely as a society to invest in this imagined future."


Another Survey on Attitudes to Longevity Science

Australian universities seem to be turning out a fair few surveys on attitudes to longevity science. Here is another: "Some researchers in the field of ageing claim that significant extension of the human lifespan will be possible in the near future. While many of these researchers have assumed that the community will welcome this technology, there has been very little research on community attitudes to life extension. This paper presents the results of an in-depth qualitative study of community attitudes to life extension across age groups and religious boundaries. There were 57 individual interviews, and 8 focus groups (totalling 72 focus group participants) conducted with community members in Brisbane, Australia. Community attitudes to life extension were more varied and complex than have been assumed by some biogerontologists and bioethicists. While some participants would welcome the opportunity to extend their lives others would not even entertain the possibility. This paper details these differences of opinion and reveals contrasting positions that reflect individualism or social concern among community members. The findings also highlight the relationship between Christianity, in particular belief in an afterlife, and attitudes to life extension technology." Which is much what you'd expect.


Visceral Fat, Exercise, and Your Future Health

I don't think it's any great secret that failing to exercise regularly and accumulating visceral fat around the organs are both bad for your long term health - but I suspect that most people don't realise just how bad it is. Either that or it's the way in which we are hardwired to discount the future and cause harm to the person we will one day be - time preference at work. In any case, here is a reminder from the scientific community:

Adiposity and Alzheimer's disease

Alzheimer's disease is the most common form of dementia. There are no known preventive or curative measures. There is increasing evidence for the role of total adiposity, usually measured clinically as BMI, and central adiposity [or visceral abdominal fat], in Alzheimer's disease.


Salient publications in 2007 and 2008 showed that (a) central adiposity in middle age predicts dementia in old age; (b) the relation between high adiposity and dementia is attenuated with older age; (c) waist circumference in old age, a measure of central adiposity, may be a better predictor of dementia than BMI; (d) lower BMI predicts dementia in elderly people; and (e) weight loss may precede dementia diagnosis by decades, which may explain seemingly paradoxical findings.

All a long way of saying if you get fat and stay fat, your biochemistry is more likely to destroy the structure and function of your mind. And those thinner old people who are suffering as well? Their developing dementia - partially caused by earlier excess fat - led them to lose weight during their decline. There are easier ways through life than this, and unlike many of the slings and arrows we suffer, for the vast majority of us our level of body fat is a choice.

Newsweek on Mainstream Longevity Science

Newsweek has a general interest article up online on the topic of mainstream longevity science: projects aimed at the hard target of metabolic manipulation to slow aging. "Since the days of Ponce de Leon, if not before, people have been seeking the elusive Fountain of Youth. Until recently, such pursuits were the realm of quacks and charlatans. And there are still plenty of snake-oil salesmen out there on the Internet and in so-called anti-aging clinics, hawking everything from longevity-bestowing Ecuadoran waters (which are probably harmless) to growth hormones (which could be downright dangerous for adults). But serious scientists are now bringing respectability to the field, unraveling the secrets of aging on a cellular level and looking for ways to slow it down. And while the science is still young (so to speak), legitimate longevity-boosting treatments could be available in 10 to 15 years - although the gains would be [modest]. ... Some critics of the scientific quest for longevity say it's God's will that we should die when our time comes. But in the past century, a clean water supply, antibiotics, vaccines and improved medical care have boosted life expectancy at birth by roughly 50 percent in the United States - from 48 for men and 51 for women in 1900 to 75 for men and 80 for women today. No one seems to object to that."


A Viral Cause for Alzheimer's?

This release via EurekAlert! is very compelling - but how does it fit in with the good evidence that Alzheimer's is a form of diabetes? "The virus behind cold sores is a major cause of the insoluble protein plaques found in the brains of Alzheimer's disease [AD] sufferers ... [researchers] investigated the role of herpes simplex virus type 1 (HSV1) in AD ... Most people are infected with this virus, which then remains life-long in the peripheral nervous system ... HSV1 DNA is located very specifically in amyloid plaques: 90% of plaques in Alzheimer's disease sufferers' brains contain HSV1 DNA, and most of the viral DNA is located within amyloid plaques. The team had previously shown that HSV1 infection of nerve-type cells induces deposition of the main component, beta amyloid, of amyloid plaques. Together, these findings strongly implicate HSV1 as a major factor in the formation of amyloid deposits and plaques, abnormalities thought by many in the field to be major contributors to Alzheimer's disease."


Insight Into Sierra Sciences

Sierra Sciences is one of a number of small companies working on telomeres and telomerase with an eye to engineering therapies for age related disease or perhaps even rejuvenation of some form.

Sierra Sciences, LLC. (Sierra) is a biotech research company located in Reno, Nevada. Our mission is to discover a medicine to prevent and/or reverse cellular senescence (the phenomenon where cells lose the ability to divide).

We believe that cellular senescence is an underlying cause of many conditions in cells which are related to the diseases of human aging, including aging itself.

Senescent cells are almost certainly not good: they build up with age, and secrete unwanted biochemicals that contribute to cancer risk in surrounding tissue, amongst other bad behavior. I've written about Sierra Sciences before, back when I wasn't so sold on the efficacy of this line of research.

The past few years have not been kind to the telomere theory of aging as it originally stood - that telomere shortening alone causes aging. The contribution of shortened telomeres to the plot is more complex and not yet well understood; a great deal is yet to be learned about the underlying biochemistry and genetics. Scientists are still obtaining apparently contradictory results in telomere and telomerase research, which indicates that the fundamentals are not yet clear.

Fortunately, the possibilities of science are not bounded by my opinions and things have a way of coming back into focus. Recently research strongly suggests that telomeres and telomerase are very connected to the age-related decline of mitochondria, and that progress in understanding how and why this is so may ultimately lead to longevity-enhancing interventions on that front.

In any case, you'll find an presentation by Laura Briggs of Sierra Sciences over at Future Current, given at the Understanding Aging conference earlier this year. It's an eye opener for those folk who are under the impression that there's any such thing as "simple science":

In cells, in cell culture anyway, preventing telomere shortening will extend the healthspan and lifespan of those cells. Unfortunately, we do not know if that is going to apply to humans. Can we extrapolate what we know about cell cultures to humans? That is a question that has not been answered yet. That is the fundamental question that Sierra Sciences is attempting to answer. We would love to get to this point and answer this question.


There are a number of diseases that could be helped by the prevention of telomere shortening. With that I will start with what I came here to talk about, which are some of the tools that we are using in the struggle to keep our telomeres long. Sierra Sciences has been in existence for about nine years. We have worked really hard trying to figure out all we can about telomerase. ... We now have a 300,000 compound library and are searching for compounds that will turn on telomerase.

The Life Expectancy Puzzle of Left-Handedness

Many identified differences in human longevity between groups lack conclusive explanations, such as why women have a greater life expectancy. Differences in life expectancy due to handedness are another puzzle: "Many studies report that left-handers have a shorter longevity than right-handers, and the present study may provide a possible explanation for that finding. In a Cardiac Rehabilitation Unit for the elderly with a mean age of 75.2 years the prevalence of left-handers was 16.7%. This latter value was significantly different from the 6.7% in controls of similar age. These data suggest that heart disease may be one reason for a reduced longevity among left-handers. Left-handers use the right hemisphere for movement, and unilateral activation of that hemisphere in the form of EEG desynchronization and deactivation in the form of EEG slow waves are both related to cardiac abnormalities." In the grand scheme of things these differences are unimportant: the greatest determinant of our future longevity is progress in the application of aging research.


On Immunosenescence

Researchers discuss the failing, age-damaged immune system: "At present, individuals can live up to 80-120 years, a time much longer than that of our ancestors, as a consequence of the improvements in life conditions and medical care. Thus, the human immune system has to cope with a lifelong and evolutionarily unpredicted exposure to a variety of antigens, which are at the basis of profound age-related changes globally indicated as immunosenescence, a multifaceted phenomenon that increases morbidity and mortality due to infections and age-related pathologies. The major changes occurring during immunosenescence are the result of the accumulation of cellular, molecular defects and involutive phenomena (such as thymic involution) occurring concomitantly to a hyperstimulation of both innate and adaptive immunity (accumulation of expanded clones of memory and effector T cells, shrinkage of the T cell receptor repertoire, progressive activation of macrophages), and resulting in a low-grade, chronic state of inflammation defined as inflammaging. It is unknown whether inflammaging, which represents a risk factor for most age-related pathologies, is a cause or rather an effect of the aging process. ... centenarians seem to be equipped with gene variants that allow them to optimize the balance between pro- and anti-inflammatory molecules, and thus to minimize the effects of the lifelong exposure to environmental insults and stressors."


Nearly In Situ Retinal Regrowth

One ideal end result of stem cell research would be the ability to provoke cells within the body into controlled regeneration, replicating the world they did during early development to repair any cell loss suffered by the body. Easier said than done, but technology demonstrations over the past few years have shown that the potential is there: controlling signals exist to direct cellular behavior. They are very complex, and still poorly understood, but progress is being made. This report is an example of the sort of work presently taking place:

mammals can be stimulated to regrow inner nerve cells in their damaged retinas. Located in the back of the eye, the retina's role in vision is to convert light into nerve impulses to the brain.


Other scientists have shown before that certain retina nerve cells from mice can proliferate in a laboratory dish. This new report gives evidence that retina cells can be encouraged to regenerate in living mice.

This is a demonstration only, as the regenerated cells are created after artificial biochemical signals are issued into the bodies of mice, but don't last long. It's not enough to just create new cells: they must be created in such a way as to integrate with their functional systems they are to support.

Dormant Emergency Stem Cells

An intriguing discovery from a cancer research group that I suspect has more promise for the field of regenerative medicine: "Up to now, scientists have assumed that adult stem cells have a low division rate. According to theory, they thus protect their DNA from mutations ... [Researchers] have now discovered a group of stem cells in mouse bone marrow that remain in a kind of dormancy [and] divide only about five times throughout the life of a mouse. Translated to humans, this would correspond to only one cell division in 18 years. ... In contrast, stem cells of the larger group, the 'active' stem cells, divide continuously about once a month. However, in an emergency such as an injury of the bone marrow or if the messenger substance G-CSF is released, the dormant cell population awakes. Once awakened, it shows the highest potential for self-renewal ever to be observed in stem cells. If transplanted into irradiated mice, these cells replace the destroyed bone marrow and restore the whole [blood] system. It is possible to isolate new dormant stem cells from the transplanted animals and these cells are able to replace bone marrow again - this can be done several times in a row. The situation is different with 'active' stem cells, where bone marrow replacement can successfully be carried out only once."


Call for Submissions for Hourglass VI

Your submissions are wanted for the sixth Hourglass blog carnival on aging and longevity science: "Topics of posts should have something to do with the biology of aging, broadly speaking - including fundamental research in biogerontology, age-related disease, ideas about life extension technologies, your personal experience with calorie restriction, maybe even something about the sociological implications of increased longevity. Opinions expressed are not necessarily those of the management, so feel free to subvert the dominant paradigm. If in doubt, submit anyway. ... In the meantime, feel free to check out previous editions of the carnival. By the way, if you'd like to volunteer to host, please email me directly - basically all of 2009 is wide open. If you've already hosted before, don't let that hold you back; while the carnival is young, some repeat hosting is going to be par for the course."


A Listing of CIRM-Sponsored Published Research

My attention was directed today to the list of research publications from scientists awarded grants by the California Institute for Regenerative Medicine. Regardless of your views on the heavy-handed entry of government into research funding, it provides a interesting snapshot of the state of stem cell research; scientists making progress in reverse engineering the ways the body builds and repairs itself. Take a look:

Researchers at UC, Los Angeles have created cells that go on to form normal T cells out of human embryonic stem cells.


Researchers at UC, Irvine identified the true location of adult stem cells in the brain.


Researchers at UC, Berkeley identified a signaling molecule that interferes with the ability of older skeletal muscle to regenerate. After injury, adult skeletal muscle regenerates by activating muscle stem cells that fuse with the existing muscle cells to repair the damage. This ability to regenerate diminishes with age, not because of a decline in the number of resident stem cells, but because stem cells in the older muscle don’t respond when damage occurs. It turns out that older muscles release molecules that actively inhibit the resident stem cells. In this study, the team identified one of those molecules and showed that interfering with that molecule’s function restores the ability of muscle in older mice to regenerate after injury.


Researchers at UC, Los Angeles discovered a series of mutations that can convert normal blood stem cells into cancer stem cells. It is believed that many types of cancer result from cancer stem cells created by such mutations. ... The team hopes that by studying these pathways they will find ways to block them with small molecule drugs and cure the often fatal disease.

Our stem cells are complex machinery; in between the scientific successes that have immediate application, much of present research is the biochemical equivalent of tracing wires and dismantling clockwork to understand how it works. The pace of basic research is fast, however, and the field is comparatively well funded. Ten years from now, I would not be at all surprised to see the research community to possess a fairly complete picture of the biochemistry of stem cells: how they work, and what signals and genes control each step of the processes that take place inside our bodies. From there on in, it's all application of that knowledge.

Evidence Against the Cancer Stem Cell Theory

It would be good for all of us if the cancer stem cell theory turns out to be true for even a majority of cancer types - as this would mean that a side-effect of stem cell research will be a cure for cancer. Unfortunately, there are good reasons to believe that this will not be the case; nothing in human biochemistry is as simple as we'd like. From EurekAlert!: "the cancer stem-cell model [must] be reassessed because it is based largely on evidence from a laboratory test that is surprisingly flawed when applied to some cancers ... I think the cancer stem-cell model will, in the end, hold up for some cancers. But other cancers, like melanoma, probably won't follow a cancer stem-cell model at all. ... Scientists previously estimated that only one in 1 million melanoma cells has the ability to run wild, exhibiting the kind of unchecked proliferation that leads to new tumors. These aggressive interlopers are the cancer stem cells, according to backers of the model. But after updating and improving the laboratory tests used to detect these aberrant cells, [researchers] determined that at least one-quarter of melanoma cells [have] the ability to form new tumors. ... The assay on which the field is based misses most of the cancer cells that can proliferate to form tumors. Our data suggest that it's not going to be possible to cure melanoma by targeting a small sub-population of cells."


Senescent Cells and Cancer

One of the consequences of an aging immune system is that it stops removing senescent cells - certainly, senescent cells increase dramatically with age. Here is a look at why that process is likely to increase your cancer risk: "Although 'cellular senescence' can suppress tumor formation from damaged cells by blocking the cell division that underlies cancer growth, it has also been implicated in promoting cancer and other age-related diseases. To understand how this might happen, we measured proteins that senescent human cells secrete into their local environment and found many factors associated with inflammation and cancer development. ... Senescent cells promote the growth and aggressiveness of nearby precancerous or cancer cells ... Our findings support the idea that cellular senescence can be both beneficial, in preventing damaged cells from dividing, and deleterious, by having effects on neighboring cells; this balance of effects is predicted by an evolutionary theory of aging." Senescent cells are a prime target for the same sorts of discerning therapies being developed to kill cancer cells with no side-effects.


From Understanding Aging: Destroying Lipofuscin and Destroying Cancer

We should all thank Jeriaska of Future Current for providing such a fine service in writing up and publishing presentations, interviews, and lectures from conferences of interest to the transhumanist and healthy life extension communities. Two of the latest are from the Understanding Aging conference hosted earlier this year by the Methuselah Foundation:

Natural Cancer Resistance in Mice and in Humans

The main concept for this project is very simple. This idea, that we may have natural resistance to cancer present in our body at all times, is not a new idea. It has been proposed for over a hundred years. In other words, the reason that we are sitting here cancer-free is not because we’re lucky, it is because we may have an innate system in our body to protect us - in other words, to get rid of cancer cells. As we get older, this protection may get weaker. That balance between the generation of cancer cells on a continuous basis can overtake the ability of your body to get rid of them

If you are already familiar with Zheng Cui's work, this presentation provides some very interesting additional data. If not, you might want to read the excellent introduction posted at the Methuselah Foundation blog.

Unfocused Pulsed Lasers Selectively Destroy Lipofuscin

The idea is lipofuscin is this aggregate of oxidized lipids and proteins that accumulates in autophagosomes or lysosomes. Lipofuscin itself we think is the problem. We think lipofuscin is sufficient to knock down autophagy as it accumulates. Eventually you get cells that are loaded with lipofuscin and the lysosomes cannot do their job of rejuvenating the cell. We think many aspects of aging are the result. If that is true, this is where the whole idea of "removing the garbage" comes in. We think the garbage itself is the problem, and if you can get rid of it we can make some serious inroads into conquering aging.

If you found these items interesting, then I recommend you look over the online videos from the Understanding Aging conference.

Alcor Now Accepts Donations Online

Given that the end of the year is approaching, and I just recently discussed my plans for a year-end charitable donation to the Methuselah Foundation over at Fight Aging!, I should note that Alcor now accepts donations online: "We now have the ability to accept charitable donations through our website. Alcor has a long, proud tradition of innovation and technical excellence in the field of cryonics. Without the charitable gifts from our members and supporters, the organization would be unable to prosper. A first draft budget has been completed for next year and the organization is likely to face a large deficit in 2009. Your gift will help sustain the general operations budget at the level necessary to continue in our quest for better cryopreservations. Your decision to donate is sincerely appreciated. Remember your donation is tax deductible."


Towards Tuning the Immune System

Researchers are making good progress towards control over immune cells, and future goals seems likely to be applicable to the restoration of some function to an age-damaged immune system. Researchers have identified "seven different receptors on T cells that can tamp down immune responses during a prolonged battle with an infectious pathogen or against developing cancer. Chronic over-stimulation of the immune system can lead to poor control of infections and cancer, so the results explain why it is that these key immune cells gradually become 'exhausted' and ineffective over time
. ... We are starting to see a picture emerging of a really tuneable array of inhibitory receptors expressed on T cells. That suggests it may be possible to not only dramatically enhance antiviral or antitumor T cell responses, but also to fine tune which response you want to enhance in order to reverse T cell exhaustion and continue fighting an infection or disease. This presents us with a great clinical opportunity. T cells have a lot of weapons at their disposal to control viral infection and most of them are disarmed when these cells become exhausted. It may be possible to selectively rearm T cells while generally reinvigorating them."


The Goal of New Neurons in an Old Brain

It used to be the common wisdom that adult brains never generated new neurons - that you had what you started with, and it was irreversibly downhill from there. Fortunately this turned out to be far from the case. The thinking now is that since mechanisms exist to generate new neurons, we should find out whether these mechanisms be enhanced and manipulated to regenerate at least some of the damage of aging - exactly the same model that drives stem cell researchers focused on other organs. But this is all some years behind other branches of regenerative medicine, and likely a much more challenging goal than repair of a heart or a liver. Researchers are still mapping out the basics with the new tools of modern biotechnology:

One of the most remarkable, and unexpected, discoveries in brain science over the past two decades was that, contrary to a century of neuroscience dogma, the brain can generate new neurons throughout adulthood. Not only can, but does, and prolifically: thousands of new neurons are created each day in several regions of the brain.


But it is not enough for such neurons merely to be formed. To play their part in memory storage, they must send out processes - dendrites to receive information, and axons to pass it along - to other brain regions, and become integrated into pre-existing neuronal circuitry. A new study by Sebastian Jessberger et al. shows that a protein called cdk5 plays a pivotal role in this integration.


Whatever the precise mechanism, the discovery of cdk5's role in guiding new neurons to their proper place improves the understanding of neurogenesis in the adult hippocampus, a process that is believed to be aberrant in cognitive aging, Alzheimer disease, and some forms of epilepsy and depression. In addition, it may suggest ways to improve prospects for neural transplantation for neurodegenerative diseases such as Parkinson disease.

The clinical benefits of experimental transplants have been inconsistent and largely disappointing to date, with most transplanted neurons unable to integrate into existing brain circuits. A better understanding of what neurons need to find their way and fit into their new surroundings may increase the chances of success for this treatment.

Progess continues, slow and steady.

Works in Mice, Not in Worms

The BBC provides a good example of the press running with the wrong conclusion due to insufficient knowledge of the field: researchers "genetically manipulated nematodes so that their bodies were able to 'mop up' surplus free radicals. This, in theory, should give them an advantage over normal nematodes in terms of ageing and lifespan. However, these worms lived just as long as the others, suggesting that 'oxidative stress' is less of a factor in the ageing of our cells and tissues as some have suggested." Except of course that a similar process performed in mice - genetic engineering to produce more natural antioxidants targeted to the mitochondria - does extend longevity. This may be another case of it being important as to exactly how you engineer extra antioxidant chemicals in the body, or it may be that the biochemistry of nematodes is unusual in not responding to more natural antioxidants. All in all, it's a little early to be declaring the death of oxidative damage as an important part of aging.


More On Exercise and the Aging Brain

It's well worth remembering that regular exercise brings benefits that no present medical technology can match-and at a fraction of the cost of medicines that do far less. EurekAlert! notes that researchers compared "brain scans of older adults who exercise to brain scans of those who do not. ... The researchers recruited 12 healthy adults, age 60 to 76. Six of the adults had participated in aerobic exercise for three or more hours per week over the last 10 years, and six exercised less than one hour per week. All of the volunteers underwent MRI to determine cerebral blood flow and MR angiography to depict blood vessels in the brain. ... researchers were able to make 3-D models of the blood vessels and examine them for shape and size. They then compared the blood vessel characteristics and how they related to blood flow in both the active and inactive groups. The results showed that the inactive group exhibited fewer small blood vessels in the brain, along with more unpredictable blood flow through the brain. ... The active adults had more small blood vessels and improved cerebral blood flow. These findings further point out the importance of regular exercise to healthy aging."