Belaboring the Point on Exercise and Visceral Body Fat

In the interests of informing those new to membership in the human race, I should note that excess visceral body fat is bad for your long term health. In addition, lack of exercise has many of the same end consequences. The trifecta of diet, exercise, and levels of fat combine to exert a great influence over the future trajectory of your life - including such items as your risk of diabetes, risk of dementia, and your life expectancy.

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.


Exercise reduce the rate at which some of the cellular and biomolecular damage of aging accumulates, either by slowing the ongoing addition of new damage, or by modifying the processes of repair. In a future of rapidly advancing biotechnology, even a single additional year of time to wait for new therapies is a big deal.

For the sake of piling it on, here's another study on fat, exercise, and insulin resistance - one of the precursors to type 2 diabetes, and an issue prevelant amongst older people.

Physical Inactivity and Obesity Underlie the Insulin Resistance of Aging:

Age-associated insulin resistance may underlie the higher prevalence of type 2 diabetes in older adults. We examined a corollary hypothesis that obesity and level of chronic physical inactivity are the true causes for this ostensible effect of aging on insulin resistance.


We compared insulin sensitivity in seven younger endurance-trained athletes (YA), 12 older athletes (OA), 11 younger normal weight (YN), 10 older normal weight (ON), 15 younger obese (YO) and 15 older obese (OO) subjects using a glucose clamp. The non-athletes were sedentary.


Insulin sensitivity was not different in YA vs. OA, in YN vs. ON or in YO vs. OO. Regardless of age, athletes were more insulin sensitive than normal weight sedentary subjects, who in turn were more insulin sensitive than obese subjects. Conclusions: Insulin resistance may not be characteristic of aging, but rather associated with obesity and physical inactivity.

A small sample size, I know, but it's representative of many other similar studies. Some of what we see as characteristic of aging these days is in fact characteristic of the effects of excess fat, too much food, and a lack of exercise. You can't turn back the clock just by taking better care of yourself, but you can choose to make a significant difference as to how fast you are damaging yourself - and thus your risk of suffering all of the common age-related conditions.

Revisiting Wine Consumption

A research group believes they have teased out the effects of wine consumption on life expectancy from all the confounding and related effects of diet and lifestyle. It'll take a few more such studies to convince me that this isn't just another artifact relating to inadvertent low-level calorie restriction, however. "Drinking up to half a glass of wine a day may boost life expectancy by five years ... The Dutch authors base their findings on a total of 1,373 randomly selected men whose cardiovascular health and life expectancy at age 50 were repeatedly monitored between 1960 and 2000. ... The researchers found that light long term alcohol consumption of all types - up to 20g a day - extended life by around two extra years compared with no alcohol at all. Extended life expectancy was slightly less for those who drank more than 20g. And men who drank only wine, and less than half a glass of it a day, lived around 2.5 years longer than those who drank beer and spirits, and almost five years longer than those who drank no alcohol at all. Drinking wine was strongly associated with a lower risk of dying from coronary heart disease, cerebrovascular disease, and death from all causes. These results held true, irrespective of socioeconomic status, dietary and other lifestyle habits, factors long thought to influence the association between wine drinking and better health."


Direct Cellular Reprogramming

Via EurekAlert!: "researchers describe how they are able to reprogram human adult skin cells into other cell types in order to decipher the elusive mechanisms underlying reprogramming. To demonstrate their point, they transformed human skin cells into mouse muscle cells and vice versa. This research shows that by understanding the regulation of cell specialization it may be possible to convert one cell type into another, eventually bypassing stem cells. ... Regenerative medicine provides hope of novel and powerful treatments for many diseases, but depends on the availability of cells with specific characteristics to replace those that are lost or dysfunctional. We show here that mature cells can be directly reprogrammed to generate those necessary cells, providing another way besides embryonic stem cells or induced pluripotent stem cells of overcoming this important bottleneck to restoring tissue function. ... Reprogramming mature cells will likely complement the use of embryonic stem cells in regenerating tissues. By elucidating the regulators of reprogramming [it] may be possible to generate replacement cells in cases where stem cells are not present or not appropriate."


Update on the Science Against Aging Initiative

I notice that the Science Against Aging initiative, brainchild of the Russian Science For Life Extension foundation, has a newly relaunched website. Sadly, it's Russian language only at the moment, which means most of we Western monolinguists are at the mercy of Google Translate or Yahoo! Babel Fish:

The purpose of the fund Science Against Aging:

- achieve the development and application of scientific methods for a substantial period of extension of healthy human life.
- Establish an integrated program of scientific study the mechanisms of aging;
- Obtain funding for this program;
- To develop scientific methods of intervention in the aging processes in order to slow down;
- Apply the results of scientific research for a substantial extension of healthy life.

The foundation recently announced their scientific advisory council. It includes some familiar faces, such as Aubrey de Grey of the SENS Foundation, the Gavrilovs behind the reliability theory of aging and longevity, and Vladimir Skulachev, whose work on mitochondrially targeted antioxidants that extend life in mice I've discussed here in the past.

Perusing the site via one of the automated translation engines mentioned above, you'll find a number of interesting articles, such as this one by the energetic longevity advocate Michael Batin. It's a very Russian view as to how the existence of aging leads to many of the ills we see in our societies; people give up because just at the point of reaching the apex of their powers they believe that nothing but decay lies ahead:

First of all, we must ponder, what prevents a person to change their lives for the better.

Why people do not get a new generation of modern professions, where the need for this? Why people do not protect their rights, do not realize their own interests? Why people do not make efforts to become happier? Because they do not have this power. Because people have no capacity. Because they are aging. For the same reason they are sick, are depressed and have little to solve that. Aging is a major obstacle for a man in his plans, wishes and dreams.

Besides, whatever happened in the society, the family with the man, aging methodically makes life worse and worse.

A Better View of Parkinson's Disease

EurekAlert! notes a synthesis of previous Parkinson's disease research into a complete understanding of what is taking place: "In a study that reveals the clearest picture to date of neuron death in Parkinson's disease, researchers [have] found that a trio of culprits acting in concert is responsible for killing the brain cells ... symptoms of Parkinson's - including uncontrollable tremors and difficulty in moving arms and legs - are blamed on the loss of neurons from the substantia nigra region of the brain. Researchers had previously suspected dopamine, alpha-synuclein and calcium channels were involved in killing the neurons, but could not pin the deaths on any single molecule. The new paper, along with previous studies, [shows] that it is the combination of all three factors that kills the neurons. The studies found that neurons die because calcium channels lead to an increase of dopamine inside the cell; excess dopamine then reacts with alpha-synuclein to form inactive complexes; and then the complexes gum up the cell's ability to dispose of toxic waste that builds up in the cell over time. The waste eventually kills the cell. ... It may be possible to save neurons and stop Parkinson's disease by interfering with just one of the three factors."


Reverse Engineering the Brain (PDF)

From the latest issue of Biomedical Computation Review, a very readable article on the state of research into how our brains work. From the longer term perspective of longevity, this is important: we'd like to be able to replace our neurons with something more durable further down the line. "For a century, neuroscientists have dissected, traced, eavesdropped on, and are now compiling a seemingly endless cast of players in the nervous system. As we keep gathering more and more molecular details, how do we know when we know enough? ... Some have decided it's time to just go ahead and create a brain in silico. And to a surprising extent, they've done it: Labs around the world are populated with autonomously functioning [so far non-human, proof of concept] brains based on what we know so far. These simulations match what happens at the cellular level in the brain when the nerve cells, or neurons, that make up the brain pump ions and produce electrochemical activity that propagates across the synapse from one neuron to another. ... We can simulate the neuronal dynamics beautifully so that you can't tell the difference between the model and real neurons."


Meanwhile, In China

You'll find an interesting interview over at h+ magazine with one of the researchers who has been performing first generation stem cell therapies for the past eight years in China. It provides some good insights into the comparative economics of the present situation: on the one hand, regions like the US that are research powerhouses but so heavily regulated that significant progress cannot be made on applications of that research; on the other hand regions like China where research is less well established but applications and development are more advanced.

It's a strange world we have come to inhabit, at least for those of us old enough to think it remarkable that China is in any aspect a bastion of freedom in comparison to the US - insofar as medical development and clinical application is concerned, in any case.

From the article:

From 2000 to 2001, China’s stem cell research was still poorly funded. James Thomson published his breakthrough work creating embryonic stem cell lines from human blastocysts in Science Magazine in 1998, which kicked off a race for funding in the West. After seeing the first successful Chinese case treated with stem cells at Zhengzhou University Hospital in 2001, I decided to get involved with the research. I was interested in taking laboratory bench work to the hospital bedside. I think that cell-based therapy has a lot of potential because most of the biological activities in our bodies occur at the cellular level. In 2004, after three years of clinical studies observing more than 100 cases, I decided to build a company to supply and work on safe adult stem cells.


As of February 2009, Beike has treated over 5,087 patients with cord blood stem cell injections for diseases like ataxia, autism, ALS, brain trauma, cerebral infarction, cerebral hemorrhage, cerebral palsy, diabetics, Guillain-Barre, encephalatropy, and spinal cord injury - many of these are considered incurable diseases.


We're a China-based stem cell company. Our major challenge is the U.S. FDA standard. For the time being, the U.S. and Europe hold the majority shares of the market because the cost for treatments is still too high for developing countries. We want to build our clinics and labs there.


The research environment in China is still behind. The communication between scholars is still very limited. However, we no longer have difficulty getting material support from overseas. Last year, we hosted China’s first ever symposium on advanced iPS (induced pluripotent stem cell) research as well as the first annual China Stem Cell Technological Forum. We hope to bring the Chinese closer to the international community.


After all these years of observation and practice, I consider adult stem cell-based therapy to be safe. I believe it will become one of the major players in medical industry because it overcomes the single molecule limitation (manipulating single molecules at the molecular level).


Beike did not go through the traditional path of a typical biotech company because it would have been too costly for us.

The work that has been taking place in China is closer to the way that things should get done if you'd like to see faster progress. Medicine is no different from any other field, in that the greatest benefit arises where people are free to work hard to bring new products to the marketplace, other people are free to compete for the customers with better offerings, and the customers themselves make informed choices as to where to spend their money. Anything that interferes with the simplicity of supply, demand, competition, and the care over money that comes from spending from your own purse will inevitably act as a spanner thrown into the wheel of progress.

I find it striking that after the collapse of socialism in Eastern Europe and the Soviet Union, virtually no effort was made to privatize health services. To be sure, there are now private health services in these countries, but the official systems of socialized medicine still exist. This fact is a testament to the reigning orthodoxy. The world seems to understand that it is a mistake to nationalize agriculture and factory production. No one advocates a Department of Software Development, even if there are far more interventions in this sector than there should be. And yet health care, all over the world, is assumed to be a normal function of government.

A Snapshot of Cell Reprogramming Research

From the Technology Review: "Treating embryonic cells from mice with a cocktail of proteins triggers production of new heart-muscle cells ... Working with mouse embryos about a week old, [researchers] discovered that a trio of proteins - including a pair of transcription factors and a protein that helps loosen tightly wound DNA - could direct certain embryonic cells to form cardiac-muscle cells, called cardiomyocytes. These cells not only produced proteins characteristic of early heart cells, but they eventually started to beat. ... Human trials of cell therapies for heart disease, which have mostly used stem cells derived from a patient's own blood, have yielded mixed results. It may be that transplanting cardiac myocytes rather than undifferentiated cells will prove more effective. ... we'd like to be able to make cardiac myocytes from any cell type. That would be the ideal therapy - to be able to turn those scar-tissue cells into cardiac myocytes and restore the function that's been lost ... The dream is to be able to take a skin cell or a cardiac fibroblast, any kind of cell a person has a lot to spare, and turn those into myocytes."


A Growing Interest in Heat Shock Proteins

A review paper from the community interested in metabolic manipulation to slow aging: "Heat-shock proteins (Hsps) are increasingly being implicated in aging phenotypes and control of life span across species. They are targets of the conserved heat-shock factor and insulin/IGF1-like signaling pathways that affect life span and aging phenotypes. Hsps are expressed in tissue-specific and disease-specific patterns during aging, and their level of expression and induction by stress correlates with and, in some instances, predicts life span. In model organisms, Hsps have been shown to increase life span and ameliorate aging-associated proteotoxicity. Finally, Hsps have emerged as key components in regulating aging-related cellular phenotypes, including cell senescence, apoptosis and cancer. The Hsps, therefore, provide a metric of individual stress and aging and are potential targets for interventions in aging and aging-related diseases." You might recall tha tthe cancer research community is also looking at how heat-shock proteins can be used to train the immune system to attack cancer cells.


A Different View of Where We'll All Be Around About 2030

A couple of days ago, I pondered the medical technologies of 2030 and the unpleasant spectre of aging too fast for the rate of development of rejuvenation medicine to catch up with. The synopsis is that we live in a strange fast-slow world; between here and 2030 is a single iteration for the weighed-down, regulated nigh unto death industry of medical development. But the biotechnology industry, like the computer industry, will have gone through many iterations and advanced enormously in the same period - the disconnect between what is possible thanks to new research and what is permitted by uncaring bureaucrats is huge now in the field of medicine, and will only get larger.

So it is that while 2030 is just a little way away for medicine, we can see smart people on the computing side of things predicting that 2030 is a good outside date for the Singularity - general artificial intelligence engineered one way or another. After that happens, you'll quickly get recursively self-improving general artificial intelligence, or so the argument goes. Personally, I think that it'll all happen more slowly than that for many of the same all too human reasons that medical development isn't as fast as we'd like, but you can't argue with the trends in raw computational power. At the present rate, improvements in hardware will allow us to simulate whole brains - create duplicate people - before researchers figure out all the details of how brains actually work to produce our minds.

There is something of a tendency in some circles to handwave "it becomes possible to solve meaningful problems rapidly" on the far side of a non-catastrophic Singularity. Which may be true after a few decades of we slowpoke, self-sabotaging humans sorting out how we interface with self-improving artificial intelligences. But to return to the point made in my last post, as things move much past 2030, those of us in middle age now have an increasingly poor outlook when it comes to deployment of working rejuvenation or longevity therapies. If significant progress hasn't come to market by 2030, our prospects start to look dire.

Sadly, I see no contradiction in a vision of a 2030, for example, in which a generation of artificial intelligences are being created the brute force way (scan and simulate a brain) to revolutionize and speed research, yet the medical technologies we are excited about today (stem cell organ regrowth, immune system reconstruction, repairing mitochondria, etc) are only just getting out into the field as broadly available medicine. That discrepency, if things happen that way, will be entirely due to relative levels of regulatory cost. If computer hardware was regulated the same way as medical technology, we'd still be stuck in a world of dedicated spreadsheet processors, room-sized mainframes, dial up BBS systems, and slightly more powerful systems restricted to research centers. Not to mention that all the progress in fundamental life science research enabled by bioinformatics in the past decades wouldn't exist.

A General Interest Calorie Restriction Article

From the Star-Telegram: "At 140 pounds and 6 feet tall, Fagg is bone thin. But his body mass index of 20 puts him within the optimal range for health. He might appear frail, but he is strong enough to do yoga and cardio workouts. If anyone doubts his fitness level, the 60-year-old Fagg is quick to challenge them to a hike from his home in Hurst to downtown Fort Worth. In 2007, he hiked down the north rim of the Grand Canyon and up the south rim, for a total of 65 miles, 13 of them straight up. 'My goal is to hike it again at 75,' Fagg said. He sees no reason why he won't be able to make it. Like many followers of the calorie restriction, or CR, lifestyle, Fagg hopes to live to be 100. But life extension is not the reason he eats so little. For Fagg and others, it's the health benefits that matter. ... Since the 1930s, researchers have documented the health benefits of calorie-restriction in animals, including a reduction in certain cancers. Although not a lot of research has been done on humans, two studies found that the probability of someone who practices CR coming down with diabetes was virtually nil."


More Reasons to Exercise

Via ScienceDaily: "moderate amounts of exercise alone can reduce the inflammation in visceral fat ... benefits of exercise were apparent, even without a change in diet. We saw improvements in insulin sensitivity, less fat in the liver, and less inflammation in belly fat ... Scientists now know that obesity is associated with a low-grade systemic inflammation. Obese people have higher levels of circulating inflammatory markers, such as C-reactive protein (CRP), which are produced and secreted by fat tissue. This inflammation then triggers the systemic diseases linked with metabolic syndrome, such as Type 2 diabetes and heart disease ... mice were assigned to either a sedentary group, an exercise group, a low-fat diet group, or a group that combined a low-fat diet with exercise ... The surprise was that the combination of diet and exercise didn't yield dramatically different and better results than diet or exercise alone." This suggests that the level of visceral fat is more important than other factors and whatever strategy you choose to get rid of it is going to provide some benefit. Which is not an excuse not to exercise or to overeat - a partial benefit is only a partial benefit.


Early Engineered Blood Vessels

Researchers are presently trialing a first generation of tissue engineered blood vessels, and as expected it's at least as good - and probably better - than the other artificial alternatives presently available:

They start by harvesting skin cells known as fibroblasts and growing these in a sheet. They then roll up the sheet and allow the cells to produce an interpenetrating mixture of structural support proteins, known as collagen and elastin.

The trouble with fibroblasts is that they can transform into smooth muscle cells that can eventually clog the vessel. So McAllister's team removed the fibroblasts, leaving behind just the protein scaffold. Then the researchers layered another sheet of fibroblasts on the outside of this scaffold, which is dense enough to prevent the cells from easily migrating to the inside of the engineered vessel. Finally, the team added a layer of the patient's own endothelial cells, which promote smooth blood flow, on the inside of the vessel.

Would the new vessels work? In the current study, McAllister's team implanted them into 10 kidney dialysis patients in Argentina and Poland, all of whom had suffered previous graft failures. Grafts in three patients failed in the first 3 months, a failure rate consistent with a high-risk population, the researchers report today in The Lancet. Two other patients didn't finish the study for reasons unrelated to the grafts. In the remaining five patients, the engineered grafts functioned normally to the study's conclusion, which was between 6 months and 20 months, depending on when the patients enrolled. The ongoing success of the engineered shunts bodes well, McAllister says, because close to half of all plastic shunts fail within 1 year of implantation.

The downside is that this really is a first generation technology - it's very expensive, due to the time taken to grow, and as presently implemented doesn't look like it will scale to tackle the really serious issues revolving around blood vessels in tissue engineering:

Unless you have a way of putting the blood vessels where they need to be, at every scale, or convincing blood vessels to grow according to plan, you simply can't engineer significantly sized pieces of tissue.

A method like the successful one above, wherein manufacturers essentially hand-roll each new section of blood vessel you need, won't scale to stocking new tissue with capillaries. But one step at a time.

An Interesting View of Calorie Restriction

Here is an interesting open access paper at PLoS ONE: "We generated microarray gene expression data from livers of male mice fed high calorie or [calorie restriction] CR diets, and we find that CR significantly changes the expression of over 3,000 genes, many between 10- and 50-fold. We compare our data to the GenAge database of known aging-related genes and to prior microarray expression data of genes expressed differently between male and female mice. CR generally feminizes gene expression and many of the most significantly changed individual genes are involved in aging, hormone signaling, and p53-associated regulation of the cell cycle and apoptosis. Among the genes showing the largest and most statistically significant CR-induced expression differences are Ddit4, a key regulator of the TOR pathway, and Nnmt, a regulator of lifespan linked to the sirtuin pathway. ... Our data show that CR induces widespread gene expression changes and acts through highly evolutionarily conserved pathways, from microorganisms to mammals, and that its life-extension effects might arise partly from a shift toward a gene expression profile more typical of females." So yet another theory to add to the many on the cause of longevity differences by gender.


Targeted Reprogramming of Cancer Cells

A good example of the sort of cellular hacking going on in the laboratory and early trials these days via EurekAlert!: researchers "have developed a nanoparticle - about one thousandth smaller than a printed period - that can travel through the blood stream. 'Decorated' with a tumor-targeting antibody, the nanoparticle is able to locate primary and hidden metastatic tumor cells and deliver its payload: a fully functioning copy of the P53 tumor suppressor gene. ... Normal cells have two copies of the functioning P53 gene. The protein produced by the P53 gene is activated to either coordinate the repair process in cells or induce cell suicide. ... In earlier work using animal models, [researchers] delivered functional p53 genes to tumor cells and tumor metastases in 16 different types of cancer, including prostate, pancreatic, melanoma, breast cancer and head and neck cancer. The presence of the replacement genes dramatically improved the efficacy of conventional cancer therapy. ... When the job of reinstating a normal P53 suppressor gene is done, the nanoparticle - essentially a little fat droplet wrapped around the gene - simply melts away, unlike non-biodegradable delivery systems. ... Clinical trials are now underway ... The trial already has enrolled six patients with various cancers and anticipates a total of 14."


Will The Biomedical Technologies of 2030 Grant Another 20 Years of Life?

Cards on the table: the wrong side of 40 looms for some of us. The present regulatory systems for medical development in the US and most other regions contributing meaningfully to progress don't look likely to become any less oppressive in the years ahead. It presently takes ten to twenty years to move a good research result out of trials and into the clinics, and that time frame is largely based on organizational activities and regulatory make-work that won't be speeded up by ongoing advances in biotechnology. Furthermore, the regulatory environment destroys or prevents many beneficial development programs by making them unprofitable.

This means that present glimmers of medical technologies capable of repairing specific forms of biochemical damage, such as work on mitochondrial repair, will most likely not be available for general use until people like me are hitting 60. They won't ever be available for healthy people "aging normally" inside US borders absent a revolution in the way the FDA operates. The same goes for organ replacement, other forms of growing any new tissue you like to order, rebooting the immune system, and so on.

Here is today's speculation: will these technologies of 2030 be good enough to grant an additional 20 years of life? How much certainty will there be by that time that these technologies will extend life significantly in humans? These are not questions that can be answered with any degree of certainty - you can only speculate.

People of my generation are most likely not going to get two shots at this. If the technology of 2030 isn't up to the task, then we don't plausibly get to wait around to 2050 and age 80. The trouble with being 80 is that (a) many people don't in fact make it that far, even allowing for a continuing upward trend in life expectancy, and (b) you may no longer be robust enough to have a good chance of surviving early rejuvenation therapies. The clock is ticking.

I have said in the past that, from a pure research timeline perspective, by 2040 we'll plausibly have all the technologies needed to repair and reverse aging. Unfortunately when we look beyond the laboratory, the field is strewn with roadblocks of legislation, slowing everything down. Even the time taken for new businesses to raise capital, try, fail, and try again is less than the delays imposed by the ball and chain of regulation.

Theory: It's All Down To Autophagy

As I've mentioned in the past, autophagy - the process by which cells destroy and replace damaged or old components - seems to be very important in the natural longevity you are granted by the operation of your metabolism. It's required for the longevity boost given by calorie restriction, for example. Some groups would go so far as to say that most or all longevity-inducing tweaks to metabolism operate through increased autophagy: "Autophagy is involved in cellular protein and organelle degradation, which is mediated by the lysosomal pathway. [Autophagy] has a key role in cellular housekeeping by removing damaged organelles. During aging, the efficiency of autophagic degradation declines and intracellular waste products accumulate. In Caenorhabditis elegans, there is clear evidence that lifespan is linked to the capacity to regulate autophagy. Recent studies have revealed that the same signaling factors regulate both aging and autophagocytosis, thus highlighting the role of autophagy in the regulation of aging and age-related degenerative diseases. Here, we examine in detail the interactions of the signaling network involving longevity factors SIRT1, mTOR, FoxO3, NF-kappaB and p53 in the regulation of autophagy. We discuss the possibility that these well-known stress resistance and longevity factors regulate the aging process via autophagy."


NPR On the Ongoing Biotech Revolution

Times are changing, and some very interesting and transformative technologies are emerging from the life sciences. Expect biotech to look increasingly like open source software development in years ahead: "at least three major technologies are shovel-ready: the programming of tissues, the ability to engineer cells, and robots. ... these discoveries mean that one can write out a life code, manipulate a cell, and execute a specific desired function. It means we can convert cells into programmable manufacturing entities. But this software builds its own hardware, allowing companies to begin using bacteria to produce chemicals, fuels, medicines, textiles, data storage, or any series of organic products. ... A second major tsunami is our increasing ability to grow complex organic structures, such as limbs, bladders, hearts, and tracheas. All complex organisms start out as undifferentiated, pluripotent cells, meaning these cells contain an entire genome and are able to produce all body parts. Mexico's dinosaur-like axolotl salamanders naturally regrow body parts, including sections of their hearts and brains as well as whole limbs. ... And soon, it may be possible to do this without a full body, just some cells. ... As innovators begin to read, reproduce, and program life, they will change almost every industry across the globe."


Immortality Institute Interview With Aubrey de Grey

As a part of their Sunday Evening Update series, the Immortality Institute folk recently interviewed biomedical gerontologist Aubrey de Grey. This comes after the recent launch of the SENS Foundation, spinning off the Strategies for Engineered Negligible Senescence (SENS) research efforts previously conducted under the auspices of the Methuselah Foundation.

From the discussion thread:

One of the most interesting things I learned is that Aubrey will not be involved with [the Methuselah Foundation] much at all, only with the SENS foundation. He confirmed that MFURI will become SFURI (SENS Foundation Undergraduate Research Initiative). He said the biggest advances he has seen in the last year or so have come from stem cell therapies.

He admitted to being surprised that the Theil donation did not spur other big donors to come forward. They are going to try to generate some revenue in the future through licensing of IP instead of exclusively through donations. SENS is going to partner with a lab in Germany quite soon, but he could not say which one as of yet (they still have to sign the paperwork).

I think we were all expecting greater things to result from the large donation made by entrepreneur turned venture capitalist Peter Thiel, in terms of further accelerating a sea change in opinion amongst philanthropists in any case. Of course, the research funded by that donation has produced progress, as Aubrey de Grey remarks in an open letter at the SENS Foundation site. As I noted a few months back, the matching portion of the Thiel donation expires at the end of this year - with much fundraising yet to go to hit the mark.

Ultimately, you find out how fast things can go by trying them out. Looking at matters in a broader perspective, the Methuselah Foundation and its donors have raised more than $10 million since 2005. Back in the 1990s, comparable organizations with comparable messages were struggling to raise $100,000 over a similar time frame. The tide for engineered longevity is rising, lifting all boats with it, just not as fast as we'd like.

The masses, and the wealthy philanthropists amongst them, largely continue to march towards aging and death, locked into the view that their lives must be like the lives of their parents and grandparents. The only way to turn things around is to keep walking against that flow, making noise, and persuading more people to do the sane thing and join us. It's never going to be as fast as we'd like it to be, but progress is being made.

Recent Stanford Conference on Longevity Science

A report here on the recent conference at the Stanford Center for Longevity, representative of the dominant "work to slow aging through metabolic manipulation" faction in the research community: "Recent, near-miraculous advances in our understanding of biological processes at the cellular and molecular level offer the possibility of extending individual lives by slowing the aging process itself. ... Not that environment doesn't play a key role in aging-associated disease. For instance, the gene cited by Brunet is involved in the insulin pathway. Brunet, whose laboratory is studying aspects of this pathway in mammals as well as in C. elegans, noted that restricting caloric intake by about one-quarter to one-third - which suppresses insulin levels - has a life-span-increasing effect on all other species in which it's been tried: worms, flies, mice, even monkeys. Experiments with humans are ongoing, but our life spans are so long that data are dribbling out slowly. However, an apparent diminution in aging-related conditions such as type-2 diabetes, stroke and cancer is being seen, she said."


On Humanin

Via EurekAlert!, a look at humanin and longevity associated with the insulin signaling system: "Dr. Nir Barzilai reports that a small infusion of [Humanin] HN is the most potent regulator of insulin metabolism that his research team has ever seen, significantly improving overall insulin sensitivity and sharply decreasing the glucose levels of diabetic rats. ...Dr. Barzilai is internationally known as a leading discoverer of longevity genes ... Last year, he reported that some of the oldest in this group have mutations in the gene for insulin-like growth factor 1 (IGF-1) receptor, genetic alterations that have been shown to prolong life span in worms and some mammals. In this [presentation], he reports that, while the production of HN generally decreases as people age, it decreases less in the centenarians and is the highest in their offspring. Studies are now underway [to] determine if the centenarians have a mutation in the HN gene in the mitochondria." Insulin metabolism is one of the major areas of focus for researchers aiming to understand how rates of aging are determined by the operation of our metabolic processes.


Just Successful Enough to Do Ourselves Harm

As a species we are presently succeeding ourselves into a harmful pit. We've succeeded in the goals of our ancestors (eat, feel good, evade pain, become wealthy) to the point at which we're breaking the evolved metabolic processes intended to deal with a short and brutish life of privation. We became fat and now surround ourselves with more food than we need, in other words - not a condition that our bodies respond well to, and so we suffer for it. The collection of symptoms suffered as a consequence of being fat, not exercising enough, and eating a lot is termed "metabolic syndrome." It's a step along the way to more serious failures of your organs and bodily systems, such as diabetes, that result from the damage being done by fat through the years.

Unfortunately, while we've succeeded enough to get into this hole, we've not yet succeeded enough to be able to dig our way out through medical science. Until that happens, indulgence will continue to have adverse consequences on your health and your longevity - lost years, lost money, sickness, and pain.

Here's an open access view of the processes that lead to the body's accelerated decay due to excess food, visceral fat, and the soft life of no exercise:

The nutritional milieu which modern humans have created for themselves is leading to rampant levels of obesity, type II diabetes (T2D) and insulin resistance. This is resulting in a reduction in life expectancy. The condition that precedes T2D, the ‘metabolic syndrome’, is currently defined as central obesity plus two factors: raised triglycerides (TGs), reduced HDL, hypertension and evidence of pathological insulin resistance


The metabolic syndrome is a continuum and may sit at the opposite end of the oxidative stress spectrum to the long-lived phenotype induced by calorie restriction. A common feature of these two phenotypes is the involvement of the insulin/insulin-like growth factor axis.


We believe that it is now possible to provide a basic hypothesis to explain insulin resistance and the metabolic syndrome by studying redox signalling. In short, insulin resistance is determined by the ability to resist oxidative stress (‘redox-thriftiness’), which is itself modulated by mitochondrial hormesis (‘preconditioning’) and thus, hormetic stimuli like physical activity and fasting. The development of the metabolic syndrome could then be defined by a "thrifty-inflammatory tipping point" - the point when insulin resistance goes from being thrifty (e.g. generally restricted to the musculature) to inflammatory (involving more tissues, such as adipose tissue).

We propose that temporal and tissue specific insulin resistance is a friend as long as you live within your hormetic zone, but it may become your enemy in a modern sedentary environment.


Ultimately, the term 'metabolic syndrome' is not truly descriptive of the condition now afflicting a large fraction of mankind. We propose a more appropriate term might be the 'Lifestyle-Induced Metabolic InflexibiliTy and accelerated AGEing’, or, ‘LIMIT-AGE’ syndrome. The ultimate conclusion from this may be that ‘thriftiness’ is only bad for us without hormetic stimuli; a situation that very rarely occurred in prehistoric times - until humans made their environment almost totally risk and hormetic stress free. It is likely that any level of hormesis is better than none: this may be critical in reintroducing ‘postive hormetic stressors’ into a modern lifestyle.

Mannoheptulos as Calorie Restriction Mimetic

The success of Sirtris at enriching its founders has given further impetus to the field of calorie restriction mimetic compounds. Scientists respond to the same incentives as the rest of us, after all. Here, Science News notes one of the latest lines of investigation. Researchers "have been mining avocados [for] MH (mannoheptulose)]. It's a fairly simple sugar with a 7-carbon backbone. When fed to mice in fairly concentrated doses (roughly 300 milligrams per kilogram of an animal's body weight), it improved insulin sensitivity and the clearance of glucose from the blood. Meaning it helped overcome diabetes-like impairments to blood-sugar control. MH supplementation also improved the ability of insulin, a hormone, to get cells throughout the body to do its bidding (and that's a good thing). MH revved up the burning of fats in muscle. That's the opposite of fat deposition and something that these scientists note 'would be an expected effect of a calorie restriction mimetic.' Treated mice also lived longer - some 30 percent longer than untreated animals. ... their food intake and weight matched that of untreated mice."


Learning From Cryonics History

An episode of NPR's This American Life looks at one unfortunate episode in early cryonics history: a failed provider who got in over his head, wherein the preserved bodies were lost. "It's the late 1960s, and in the new technology of cryonics, a California TV repairman named Bob sees an opportunity to help people cheat death. But freezing dead people so scientists can reanimate them in the future is a lot harder than it sounds. Harder still was admitting to the family members of people Bob had frozen that he'd screwed up. Badly." Caveat emptor should always be the motto - if you're interested in cryonics, be interested enough to learn about the cryonics providers that exist today and why they are unlike past failed efforts. Cryonics is a service that requires more than volunteer effort and you should expect to pay for it - an affordable amount if well planned, but nothing meaningful is free in this world. Like all services, you should look for a reputable provider who has been in the business for a while, has good references, and can point to pleased customers.


David Sinclair's Viewpoint

David Sinclair of Sirtris has penned an article for Seed Magazine, giving some insight into where he stands on engineered longevity.

During the Victorian era, children commonly died of illnesses like measles, mumps, and whooping cough; surely, no one would suggest today that we eliminate prenatal care, vaccines, or water purification in order to return to a more "natural" state. Now that we have the technology to eliminate the scourge of infant mortality, it would be immoral to not use it. In truth, we’re fighting aging and extending lifespan every time a doctor prescribes a statin drug or recommends a healthier diet to a patient. And the fact remains that science has not yet discovered an indisputable biological "expiration date" for a human life, nor is there good evidence that one exists.

In time, the idea of an inevitable, debilitating decline starting at age 50 will seem as horrifying and primitive as it does for us, in the age of potent antibiotic cocktails, to imagine a young person in the 19th century dying from an infection caused by a splinter. As a society, we should not accept a terrible period of suffering, dependence, sickness, and frailty if we don’t have to. There’s nothing more natural than marshalling the body’s own defenses to treat and heal itself, and that is precisely what longevity genes like SIRT1 do.

As I'm sure you're aware, I think that there are compelling arguments to say that chasing metabolic alterations as a path to any significant extension of life is a pipe dream. It will be enormously expensive and most likely produce therapies over the next couple of decades that slow aging to much the same degree as the simple practice of calorie restriction. Which does little for those people who are already old - such as we folk reading this now, getting older as we wait.

Meanwhile, there exist strategies that could produce technologies to reverse the damage of aging in the same period of time, at a similar or lower cost. This is, unfortunately, the minority view at present in the scientific community.

I have discussed these two paths before, and I consider the mostly obscure debate within the scientific community over research strategies for engineered longevity to be very important. The end result - meaning how long it will take to ramp up a research community eager to repair and reverse aging - will determine how long we all live. It is, sadly, still quite possible that the research community of this generation will continue to fixate on slowing aging the hard way, and we will miss out on rejuvenation technologies that will be developed in later decades to benefit our children or grandchildren.

But those technologies could be developed starting now. There's no barrier save for will and funding.

Growing Hair From Stem Cells

From the Daily Yomiuri, a short note on work aimed at tissue engineering new hair: a researcher "has succeeded in regenerating hair on mice using embryonic stem cells ... Yamaki extracted mesenchymal stem cells taken from the teeth of mice embryos and mixed them with mice embryonic stem cells, which form the basis of skin cells. The clumps resulting from the mix were then nurtured. It was later found that about 40 percent of the 48 clumps had one or two hairs growing from them. When protein, which quickens growth, is added, the hair growth rate increased to about 60 percent ... Hair growth was observed on all 12 mice that had the clumps implanted on their back muscles. Hair papilaries, which supply nourishment to the hair, also were found to have formed on the back muscle. ... If embryonic stem cells are combined with mesenchymal stem cells, which perform a number of other functions, a different organ can probably be created. The first thing I want to try to do is regenerate hair using human embryonic stem cells."


Regenerative Medicine For AMD

From the Times Online: "scientists have developed the world's first stem cell therapy to cure the most common cause of blindness. Surgeons predict it will become a routine, one-hour procedure that will be generally available in six or seven years' time. The treatment involves replacing a layer of degenerated cells with new ones created from embryonic stem cells. ... The treatment will tackle age-related macular degeneration (AMD), the most common cause of blindness. ... embryonic stem cells are transformed into replicas of the missing cells. They are then placed on an artificial membrane which is inserted in the back of the retina. ... Laboratory trials completed by the British team have demonstrated that stem cells can prevent blindness in rats with a similar disease to AMD. They have also successfully tested elements of the technology in pigs. ... the treatment would take 'less than an hour, so it really could be considered as an outpatient procedure. We are trying to get it out as a common therapy.' ... The clinical trial, due within two years, is expected to be the second in the world to use embryonic stem cells on humans. The first, on patients with spinal cord injuries, will start this year in America."


Plastinate Everyone

You might recall the recently voiced suggestion that it's something of an accident of history that the cryonics movement is the cryonics movement versus the plastination movement. Plastination is plausibly just as good a way of preserving the fine structure of the brain into a future where a patient can be restored to life as low-temperature storage.

Twenty years ago, Charles B. Olson published an article called "A Possible Cure for Death" in the journal Medical Hypotheses. In it, he favorably compares methods of chemical preservation to cryogenic preservation. Unfortunately, this article provoked no wide discussion or attempts at implementation. As the author notes on his website, other than requests for reprints, "nothing more came of it." And yet the arguments in it are still sound and just as persuasive today as they were then.

Not so long ago on the Cryonet list, a fellow asked: "How can we help those who cannot afford cryonics?" This is a valid question, given that the high level purpose of cryonics is to offer some alternative to oblivion for those who die before the advent of working rejuvenation medicine. While cryonics is very affordable if you plan ahead and take out a low-cost life insurance plan, there will always be those who get caught short through no fault of their own.

Here, plastination steps forward as a possible alternative that would cost little more than what is already spent on the disposal of remains. Plastinate the brain for the cost of an embalming, and cremate the rest. You're now set for a good number of decades in any very low-cost storage facility.

The way we do it is chemical preservation with the option to convert to cryopreservation. ... A hospital pathologist can remove the brain and submerge it in fixative. It would be shipped after 1 week in fixative. Permanent storage could be in fixative for the truly indigent. But a better option for those who could afford it would be to convert to cryopreservation. The cost might start at about $20,000, but could get down to about $12,000 after the first few due to economies of scale. The brain would remain in fixative until the full cryopreservation cost was paid for, and only then go into a dewar.

The economic advantages are considerable due to cutting out the need for a standby team to prepare a patient for cryopreservation - though as noted in the past, open questions remain as to how important it is to act quickly and whether and to what degree different types of preservation strategy affect the preservation of brain structures important to the mind's data.

But all of the above discussed options are better than no plan at all, a path that leads to oblivion and the grave. This is just another of the many ways in which the world we live in is a madhouse of waste, death, and destruction compared to other plausible worlds - such as the one in which people generally chose to have their brains plastinated and stored at death for the past few decades, allowing hundreds of millions of the deceased a shot at living again in the future. But in this world, they are all dead and gone, lost forever.

A View of Cryonics

From Singularity Hub, a piece on cryonics that you might not agree with all of, but is well worth the time to read: "Given the exponential rate of modern scientific innovation, cryonics suggests that new technologies may soon be available that can resurrect an individual considered 'dead' by today's standards. Because our personalities and memories have chemical foundations in the brain, they can hypothetically be preserved in the body, so long as neural tissue does not degenerate (as we'll see, that might be a logical jump). One way of preserving tissue is to store it at extremely low temperatures, effectively grinding your molecular chemistry to a halt. To put it bluntly, the cold keeps your body from rotting. But, as every high school student knows, your body is mostly water, which expands when frozen. This is where a process called vitrification enters the picture. Cryonics patients are preserved in vats of liquid nitrogen cooled to temperatures below -200°F. Because ice crystals can damage cells as they form, the water that fills our cells must be partially replaced before the body is cooled. Chemicals solutions called cryoprotectants are circulated through the patient's body, ultimately reaching a concentration greater than 50%. As the body is cooled, the cryoprotectants allow tissues to reach a glass-like solid state that is relatively free of ice crystals, thus preserving cellular integrity." You might also want to look at Alcor's FAQ for Scientists.


More Digging Into the Mechanisms of Calorie Restriction

Some interesting research into the roots of longevity gains through calorie restriction: "Working in yeast cells, the researchers have linked ribosomes, the protein-making factories in living cells, and Gcn4, a specialized protein that aids in the expression of genetic information, to the pathways related to dietary response and aging. ... Previous research has shown that the lifespan-extending properties of dietary restriction are mediated in part by reduced signaling through TOR, an enzyme involved in many vital operations in a cell. When an organism has less TOR signaling in response to dietary restriction, one side effect is that the organism also decreases the rate at which it makes new proteins, a process called translation. ... mutations to the ribosome, the cell's protein factory, sometimes led to increased life span. Ribosomes are made up of two parts -- the large and small subunits ... What we noticed right away was that the long-lived strains always had disruptive mutations in the large ribosomal subunit and never in the small subunit ... depletion of the ribosomes' large subunits was likely to be increasing life span by a mechanism related to dietary restriction - the TOR signaling pathway."


The Hypoxic Response Versus Cellular Aggregates

If you've been following along for the past couple of years, you'll recall that one important part of aging is the build-up of damaging biochemicals both within and between our cells. These by-products of metabolism eventually grow to a level at which they greatly interfere with the functioning of our cells, tissues, and organs - or even kill us.

What we'd really like to see developed over the next decade or two is an outgrowth of the targeted nanotechnology, immune therapies, and viral therapies presently in the laboratory aimed at these aggregates. Given that we make it to 30 years of age without too much harm resulting, getting the build-up cleaned out every decade should prevent it from contributing to aging in any way.

Of course that's much easier to say than accomplish, and there are many, many different forms of unwanted biochemical involved in this part of the aging process. Fortunately for us, I think that the parallel labor of listing and then figuring out how to safely break down many different biochemicals is a task well suited to the years ahead, in which biotechnology becomes very cheap, and many new hands join the workforce.

Meanwhile, a wide range of potential strategies for attacking, slowing, or preventing the build up of specific biochemicals are emerging. I noted a couple not so long ago. Here's another recent line of work.

Survival mode that protects cells when oxygen is low also slows aging:

A cell's protective reaction to a drop in oxygen is called the hypoxic response. Researchers at the University of Washington (UW) have found that nematode worms live longer if their genetic make-up permits their cells to turn on the hypoxic response under normal oxygen conditions.


"The research findings suggest that the hypoxic response promotes longevity and reduces the accumulation of toxic proteins by a mechanism that is distinct from both dietary restriction and insulin-like signaling. It appears to be an alternative pathway, "Kaeberlein said. "However, we don't know if future studies might reveal that all of these different genetic pathways converge somewhere down the line into a common mechanism for delaying the effects of age."


The key factor that controls the hypoxic response is called HIF. HIF is regulated by another protein called VHL-1 ... animals lacking VHL-1 were resistant to the toxic proteins known to cause Alzheimer's disease and Huntington's diseases, and that their cells accumulated less of an age-pigment called lipofuscin. Lipofuscin is thought to be one indicator of an animal's health during aging. According to Kaeberlein, "these observations may suggest that the hypoxic response not only increases life span, but also lengthens health span and protects against the molecular processes that lead to neurodegenerative diseases in people".


The authors note that the hypoxic response, including HIF and VHL-1, is very well conserved in organisms from nematodes to humans, raising the possibility that modulating HIF activity may be useful for treating some age-associated diseases, and perhaps even slowing aging, in people.

Which is interesting, but assume that it's going to be a decade before a good answer emerges as to how this all hangs together. Meanwhile, researchers could be done with figuring out a way to break down lipfuscin safely on that same time scale - progress is all a question of research priorities, and at the present time all too few resources are directed towards turning what is known about aging into therapies that will enhance healthy longevity.

Temperature and Lifespan

Body temperature is demonstrated to affect life span in lower animals, and now that researchers are digging into how this works, some of the same longevity mechanisms already discovered in other studies are seen to be involved. Via EurekAlert!: "It's true that [nematode] worms don't regulate their body temperature, but they do regulate their response to high temperature, slowing down processes that would otherwise go much faster. In fact, they even use steroid hormones to do this, just as we do to regulate our temperature ... this might have been a very early evolutionary link between cold- and warm-blooded animals ... the authors suggest that at high temperature, the worm's thermosensory neurons produce a signal that stimulates expression of the daf-9 gene, which produces a steroid hormone that extends lifespan. The researchers propose that this thermosensory system allows C. elegans to reduce the effect that warm temperature would otherwise have on the processes that affect aging, which is something that warm-blooded animals do by controlling the temperature itself. This system may allow the animal to maintain a more normal rate of aging even if the temperature rises ... Previous research also has linked the rate of aging in mammals with temperature. If mice are tricked into thinking that they are in a hot climate, they lower their body temperature and live longer."


An Autologous Stem Cell Trial in the US

After a good few years of trials in less oppressively regulated regions of the world, a small autologous stem cell therapy trial has started in the US. "For the first time in the United States, a stroke patient has been intravenously injected with his own bone marrow stem cells ... The Phase I safety trial [will] enroll nine more patients who have suffered a stroke and can be treated with the stem cell procedure within 24 to 72 hours of initial symptoms. ... Animal studies have shown that when you administer stem cells after stroke, the cells enhance the healing. We know that stem cells have some kind of guidance system and migrate to the area of injury. They're not making new brain cells but they may be enhancing the repair processes and reducing inflammatory damage ... This study is the critical first step in translating laboratory work with stem cells into benefit for patients. If effective, this treatment could be helpful to a huge segment of stroke patients to reduce their disability." Remember, if the FDA didn't exist, this type of therapy would already have been benefiting those patients who decided to take advantage of it. It is disingenuous to pretend that great and novel steps are being taken here - this work has already been proven in other parts of the world, and all that is happening now is make-work and obstruction on the part of govenment employees who care little about your health.


Following Up on Rebooted Immune Systems

A safe technology platform to allow destruction and recreation of our immune systems would offer a lot of promise for addressing issues that arise in the aging immune system.

One main reason your immune system fails with age appears to be that chronic infections by the likes of cytomegalovirus (CMV) cause too many of your immune cells to be - uselessly - specialized. ... researchers are looking into a possible way of clearing these infections from the body. ...

The flip side of clearing out CMV is to reboot your immune system. Clean it out and start afresh, absent the clutter of memory cells devoted uselessly to CMV that were crowding out the naive T cells needed to respond to new threats. There's more to the aging of the immune system than just this process of crowding, but it's a good start.

Trials are taking place in which specific diseases of the immune system are addressed by destruction and recreation - but it's not at present a procedure you'd enjoy all that much, having more in common with chemotherapy than medicine of the future. But hopefully we all recall that safe, painless elimination of specific cell types through nanotechnology targeting systems is on the way, and fairly advanced in the laboratory. That will make rebooting an immune system a much more practical prospect.

In any case, here is an update on one of the trials of immune system rebooting in recent years, in which the autoimmune disease of type 1 diabetes was effectively cured:

Patients who underwent a procedure to wipe out the immune system and reconstitute it with their own stem cells remained insulin injection-free for up to three to four years after the procedure ... The report extends research published in 2007 showing that the majority of 15 patients who underwent a blood stem-cell transplant were able to remain insulin-free for more than 18 months.

One component of aging is that we all suffer from increasingly deranged, broken, and misconfigured immune systems. On the one hand your immune system become hyper-sensitive and creates constant low-grade inflammation that causes all sorts of issues, and on the other hand it becomes ineffective at its primary functions - fighting pathogens, killing senscent cells, and eliminating cancer cells. It's on all the time, burning resources and causing damage, but not doing you any good.

I look forward to the years ahead in which we can have an old immune system cleared out and reset in an efficient and safe manner, using targeted cell killers and stem cell therapies.

Calorie Restriction, Metabolic Rate, and Longevity

One of the pieces of evidence that points to our mitochondria as a prime point of interest for engineered longevity is the correlation between maximum life span and resting metabolic rate (RMR) across species. In that light, this research on calorie restriction and metabolic rate is interesting even though it's an insect study: "Caloric restriction (CR) extends lifespan in most animals, but the mechanisms underlying this phenomenon are the subject of much debate. We investigated the association between longevity and resting metabolic rate (RMR) in Indian stick insects (Carausius morosus) [by] quantifying the response of RMR to diet history ... Over a range of body sizes, [RMR] decreased in response to CR, particularly when food was restricted during juvenile stages. With one exception, RMR of insects in different life-history stages matched current feeding level and was not substantially affected by intake history. Total lifespan was affected by intake, with insects that experienced CR early in development living longer than insects that were fed ad libitum. ... CR and decreased RMR were associated with slower progression through pre-reproductive life-history stages."


The Misrepair Accumulation Theory of Aging

Here is a twist on the "aging is biochemical damage" viewpoint that theorizes bad repairs to be the important form of damage: "It is now increasingly realized that the underlying mechanisms which govern aging (ageing) are a complex interplay of genetic regulation and damage accumulation. Aging as a result of accumulation of 'faults' on cellular and molecular levels, has been proposed in the damage (fault)-accumulation theory by Kirkwood. However, this theory fails to explain some aging phenotypes such as fibrosis and premature aging, since terms such as 'damage' and 'fault' are not specified. Therefore we introduce here a specification of the underlying mechanism of aging and arrive at a novel theory: aging of the body is a result of the accumulation of Misrepair of tissue. It emphasizes: a) it is Misrepair, not the original damage, that accumulates and leads to aging; and b) aging can occur at different levels, however aging of the body takes place at least on the tissue level, but not necessarily on cellular/molecular level. The novel concept of Misrepair introduced here unifies the understanding of the roles of environmental damage, repair, gene regulation, and multicellular structure in the aging process. The Misrepair-accumulation theory introduced in the present paper gives explanations for the aging phenotypes, premature aging, and the difference of longevity in different species, and is consistent with the point of view of physical theory of complex systems."


Hourglass IX At psique

The latest Hourglass blog carnival on the biology of aging and longevity science is over at psique, and closes with an interesting historical quote:

~These bodies which now we wear belong to the lower animals; our minds have already outgrown them; already we look upon them with contempt. A time will come when Science will transform them by means which we cannot conjecture, and which, even if explained to us, we could not now understand, just as the savage cannot understand electricity, magnetism, steam. Disease will be extirpated; the causes of decay will be removed; immortality will be invented~. -Winwood Reade, 1872, from his book The Martyrdom of Man

The difference between Reade's era and ours is that we have a fairly clear vision as to the means by which we will change our bodies for the better. We will develop biotechnological tools to repair the damage of aging that has been identified in past decades:

Many things go wrong with aging bodies, but only a few of them are primary changes in the structure of the body itself - that is, aging damage. Other changes (such as increases in inflammation and oxidative stress) are the secondary consequences of this primary change: either the direct results of those damaged components' inability to carry out their normal role in metabolism, or the body's adaptive or maladaptive attempts to compensate for those changes. Thus, by removing, repairing, replacing, or rendering harmless the damage, we restore the normal functioning of the body's cells and essential biomolecules, and the secondary changes are given the chance to return to their normal, youthful baseline.

Scientists have spent decades looking for such changes in aging bodies, this research has led to the conclusion that there are no more than seven major classes of such cellular and molecular damage ... We can be confident that this list is complete, first and foremost because of fact that scientists have not discovered any new kinds of aging damage in nearly a generation, despite the facts that research into aging has been slowly accelerating and that we have had ever-increasingly powerful tools with which to investigate the aging body.

If you look at the Strategies for Engineered Negligible Senescence (SENS) you'll see that present knowledge is detailed enough for researchers to get to work, assuming they can raise the funding. Indeed, a small amount of this work has been taking place in past years, and is bearing fruit - the chief obstacles to progress here are entirely a matter of will and resources, not knowledge. When a large number of people decide to support longevity science, the field will start to look a lot like the last decade of stem cell research. Until then, progress is painfully slow considering the costs of delay.

Update on Induced Pluripotency Research

It is impressive to see how rapidly researchers are moving forward with induced pluripotency. Here's another step forward via EurekAlert!: scientists have "used tiny molecules called microRNAs to help turn adult mouse cells back to their embryonic state. These reprogrammed cells are pluripotent, meaning that, like embryonic stem cells, they have the capacity to become any cell type in the body. The findings suggest that scientists will soon be able to replace retroviruses and even genes currently used in laboratory experiments to induce pluripotency in adult cells. This would make potential stem cell-based therapies safer by eliminating the risks posed to humans by these DNA-based methods, including alteration of the genome and risk of cancer. ... [MicroRNAs] are transient, non-coding molecules that do not incorporate into the genome, but promote self-replication and have the potential to induce pluripotency. They do their thing -- turn a somatic cell into an embryonic stem cell-like one -- and then they're gone ... The goal now is to ensure the safety of induced pluripotent stem cells and to differentiate them into cells that can be used to repair damaged tissue and treat disease."


More Thoughts on Cryonics

From Existence is Wonderful: "If you can manage to scrape away enough of the subcultural detritus and personality artifacts that have glommed onto cryonics over the years, what you're left with is: (a) an experiment in tissue preservation, (b) the idea that future technology may someday be able to repair injury and illness not addressable by today's medicine, and (c) a view of death as a process rather than a discrete event. None of these things seem to me particularly irrational or farfetched in and of themselves. Of course in reality you can't actually ignore the cultural connotations and fringe entanglements of something like cryonics. These things must be acknowledged and addressed if one wants to actually have a clear view of the subject, and that's part of what I am trying to do here. E.g., I think the notion of cryonics has been harmed by assertions that it's a means to (even potentially) 'buy immortality'. Immortality, after all, is incoherent - nobody knows how long they or anyone else is going to live, and it might end up being a pretty long time, but it sure as heck isn't going to be forever, any more than having a job gives you a shot at making Infinity Zillion Dollars."


More on CLK-1 and the Retrograde Response

You might recall that the gene CLK-1 can influence longevity in a range of species:

CLK-1 - or clock-1 - is a gene that affects lifespan, most likely through its influence on mitochondrial activity. It's the standard story, or at least appears to be: anything that can lower the rate at which mitochondria damage themselves will extend life in flies, mice, and so forth.

Here's more on CLK-1 in yeast and worms; an open access PLoS Genetics paper:

Mitochondrial respiration generates energy in the form of adenosine triphospate (ATP), a molecule that powers many cellular processes. When respiration is inhibited in C. elegans, rates of behavior and growth are slowed and, interestingly, lifespan is extended.


We find that inhibiting respiration increases the expression of genes predicted to protect and metabolically remodel the animal. This pattern of gene expression is reminiscent of the expression profile of long-lived respiration-defective yeast, suggesting ancient evolutionary conservation. Mutations in clk-1, which inhibit the synthesis of the respiratory-chain factor ubiquinone, produce gene expression, longevity, and behavioral phenotypes similar to those produced by inhibiting components of the respiratory chain.

We find that knocking down the activities of two similar genes - fsrt-1 and fstr-2- accelerates the behaviors and aging rates of clk-1 mutants ... Thus, fstr-1/2, which encode potential signaling proteins, appear to be part of a mechanism that actively slows rates of growth, behavior, and aging in response to altered ubiquinone synthesis. Unexpectedly, fsrt-1/2 are not required for the longevity and behavioral phenotypes produced by inhibiting the gene isp-1, which encodes a different component of the respiratory chain. Our findings suggest that different types of mitochondrial perturbations activate distinct pathways that converge on similar downstream processes to slow behavioral rates and extend lifespan.

Our mitochondria appear to be the crux of a great many evolved mechanisms of longevity, which continues to point them out as a good place place to start when trying to prevent or reverse the damage of aging.

On Preparing For the Future

From In Search of Enlightenment: "In the year 2048 the children from my grade 2 class will be the age of many of those in nursing homes today. Globally there will be 2 billion humans alive over the age of 60. And this will bring unprecedented levels of chronic disease (cancer, heart disease, stroke, [Alzheimer's disease], etc.). If there was something we could do to alter this possible future of unprecedented human suffering and disease from becoming a reality, shouldn't we try to avoid it? ... Instead of feeding the next generation of inquisitive thinkers useless platitudes about the importance of switching off lights to save the world we should encourage them to harness the great potential of [our present knowledge of biology to slow or reverse aging itself] ... Given the certainty and severity of the harm of aging you might expect that vast amounts of public funding are being invested in aging research. You might think that the brightest and most talented scientists who long to make the world a better place are being lured into the field. Unfortunately it is very hard to get people to rally behind aging research. This must change. A deceleration of the aging process might make nursing homes a thing of the past. And that would be an enormous achievement that all future generations of humans could enjoy."


SIRT1 and Cancer

This research suggests a way in which calorie restriction (which upregulates sirtuins) might be effective in resisting cancer: "The yeast and nematode equivalents of SIRT1 are fountains of youth that stretch lifespan. Whether SIRT1 slows aging in mammals isn't certain, but it's beneficial in other ways. The protein tunes up metabolism, reducing blood levels of glucose and insulin, and might forestall neurodegenerative illnesses such as Alzheimer's disease and ALS. Given its pro-life credentials, you might expect SIRT1 to inhibit cancer. And several studies suggest that it does. But other work indicates that the protein aids tumors. For example, SIRT1 chops off acetyl groups, which can inactivate the tumor suppressor p53. [Researchers] determined SIRT1's effect on the transcription factor c-Myc, whose expression surges in many breast, colon, and liver cancers. The two proteins are tangled in a regulatory loop, the team found. c-Myc latched onto SIRT1's promoter, spurring cells to manufacture more SIRT1. In turn, SIRT1 detached acetyl groups from c-Myc, hastening its breakdown. To test SIRT1's effects on tumor growth, the researchers implanted cancerous cells expressing c-Myc into nude mice that lack immune defenses. Boosting production of SIRT1 blocked tumor formation."


The Complexities of Cryopreservation

Preparing a newly dead patient for the long-term low-temperature storage offered by cryonics is a medical procedure - and as such just as potentially complicated as any other aspect of human medicine. A great deal of time and effort over past decades of the cryonics community has gone into developing the best-practice procedures presently used, but often overlooked by those who discuss cryonics.

A dense, informative post over at Depressed Metabolism examines this in some detail, including the present gaps in knowledge, resource constraints, and areas where improvement is desirable:

Is a patient who has suffered hours of warm ischemia better off simply being rapidly cooled and rendered into the solid state, as opposed to being subjected to 24, 48 or 72 hours of cold ischemia, followed by cryoprotective perfusion and freezing or vitrification? How do we even determine what the ultrastructural condition of a brain is following straight freezing? Freezing in the absence of fairly large amounts of colligative cryoprotectant agent(s) results in the collapse of tissue ultrastructure into dense channels of material, the structural condition of which it is currently not possible to determine by techniques such as transmission electron microscopy. Reaching conclusions based on the post-thaw ultrastructure (or lack thereof) of straight frozen tissue is complicated by the potentially myriad artifacts introduced during rewarming, thawing, fixation and embedding required to image tissue ultrastructure.

Given the extreme resource constraints that have historically been present in cryonics, and the lack of directly applicable mainstream medical research, the answer to the question of 'what to do' has been to apply reasoned extrapolation of high quality, peer-reviewed biomedical research to the care of the individual cryonics patient, and where possible, to conduct on-point in-house research to validate such armchair speculation.

Preserving the fine structure of the brain is vital to the endeavor of cryonics. While evidence exists that even simple freezing at liquid nitrogen temperatures might preserve enough for future revival through applied molecular nanotechnology, many open questions remain as to how important the quality of preservation is, and what methods of preservation best preserve the information stored in the brain. All other matters being equal, we'd expect a carefully vitrified brain to be easier to restore than a frozen brain, and we'd expect a brain preserved more rapidly after death to be easier to restore than one left for longer. But hard and fast evidence to back that up is somewhat lacking.

However you choose to educate yourself about cryonics, it should be clear that even if flawed, cryopreservation is the best post-death choice - if you like living, that is. Nothing else will yet give you a shot at being restored to live more productive, healthy years further down the line, and nothing else presently envisaged will do anything to help the hundreds of millions who will most likely die before the advent of effective rejuvenation medicine.

Steps Towards Reprogramming Cells For Regeneration

Researchers are working, step by step, towards the knowledge needed to reprogram cells to regenerate damage they presently let stand. Here is one small step forward: "A protein that the heart produces during its early development reactivates the embryonic coronary developmental program and initiates migration of heart cells and blood vessel growth after a heart attack ... The molecule, Thymosin beta-4 (TB4), is expressed by embryos during the heart's development and encourages migration of heart cells. ... Tremendous medical progress has been made to counter the damaging effects of heart attacks, but ordinarily, mammalian hearts are incapable of repairing themselves following damage. They are also limited in their ability to form new blood vessels. ... In this mouse study researchers found that TB4 initiates capillary tube formation of adult coronary endothelial cells in tissue culture. The molecule also encourages cardiac regeneration by inhibiting death in heart cells after an injury such as a heart attack and by stimulating new vessel growth. ... We observed that by injecting this protein systemically, there was increased cardiac function after a heart attack. We hope this protein can inhibit cell death that occurs during a heart attack in the short term, and that it may initiate new growth of coronary vessels by activating progenitor cells in the long term."


Stem Cells Versus Corneal Damage

From EurekAlert!: "Stem cells collected from human corneas restore transparency and don't trigger a rejection response when injected into eyes that are scarred and hazy ... The findings suggest that cell-based therapies might be an effective way to treat human corneal blindness and vision impairment due to the scarring that occurs after infection, trauma and other common eye problems ... corneal stem cells were able to remodel scar-like tissue back to normal. ... Our experiments indicate that after stem cell treatment, mouse eyes that initially had corneal defects looked no different than mouse eyes that had never been damaged ... The ability to grow millions of the cells in the lab could make it possible to create an off-the-shelf product, which would be especially useful in countries that have limited medical and surgical resources but a great burden of eye disease due to infections and trauma. ... The cornea and [its] stem cells themselves appear to be 'immune privileged,' meaning they don't trigger a significant immune response even when transplanted across species."


On The Launch of the SENS Foundation

As I'm sure you're aware, the Methuselah Foundation recently split in two, continuing separately as the Methuselah Foundation and SENS Foundation. The new Methuselah Foundation is focused on the Mprize for longevity science, while the SENS Foundation focuses on funding research and growth in the Strategies for Engineered Negligible Senescence, a research program aimed at greatly extending healthy human life. Both sides of the house continue to support one another's goals, and there's an overlap in volunteers, as you might expect.

As the Foundations take pains to point out, if you were donating to the Methuselah Foundation to fund SENS Research, your money will pass through to the SENS Foundation and continue to support that goal.

So, what are the roots of this change? I can't speak to the mindset of the co-founders of the original Methuselah Foundation, Dave Gobel and Aubrey de Grey, despite the volunteer work I perform here and there for the Methuselah Foundation, but I can offer my semi-outsider's opinion based on a few days of thinking about it. It runs something like this:

  • Back a few years, it seemed self-evident that the Mprize and SENS Research were synergistic programs for a single organization to operate, the growth of each boosting the other. Advocacy and encouragement for scientific research into extending healthy life on the one hand, and a specific research program aimed at doing just that on the other hand. That sounded sensible. It still sounds sensible.

  • As it turned out, it didn't work that way in practice, however. The people and strategies best employed on the two sides of the house were different and really didn't operate in synergy. Instead of an engine, you have something more like a gentle tug of war on resources and goals.

  • This is probably best illustrated at the present time by looking at the founders and board of the SENS Foundation versus who's who and the Mprize advisory board at the Methuselah Foundation. You'll see different circles of people with different backgrounds, career paths, and talents. Quite dissimilar.

So now we'll see two organizations heading in the directions they feel most comfortable taking for success. There are signs that the Methuselah Foundation is looking to tap new communities for its pro-longevity advocacy, for example, aiming to grow the healthy life extension community via a more populist approach than was employed in the past. I'm not sure how I feel about the first initiative, the My Bridge 4 Life program - it's too far from my target demographic in a number of ways for me to get a grasp on it - but the high level strategy seems worth trying.

The trick with the populist and indirect strategies, of course, is to avoid falling into the same sort of pit as ensnared American Academy for Anti-Aging Medicine (A4M) or the Life Extension Foundation. I can vouch for the fact that the principles of those organizations are greatly interested in seeing a world of working rejuvenation medicine come to pass - but they now spend most of their time in the operation of organizations that contribute little to that goal. You get things done by getting things done. If you're not working on A, you're not working on A, even if you're working on B that is related to A.

The future of the SENS Foundation looks much like the recent past of the pre-split Methuselah Foundation: conferences (such as the forthcoming SENS4), longevity research, fundraising, and as much advocacy within the scientific community as outside it.

So on the whole, I am optimistic. People unleashed to do as they want to do tend to get more done, and the split looks like a sensible choice. I look forward to seeing what the two Foundations come up with in the years ahead.

Common Sense, Health, and Longevity

The things that common sense tells us are good for long term health are in fact mostly good for long term health. Good diet and exercise will do more for you in the long term than any presently available therapy - which is all the more reason to get behind the wheel to push for the working medicines of rejuvenation that we know enough to create in the decades ahead. Here, Forbes looks at the basics: "Researchers at the University of Cambridge in England followed 20,000 middle-aged men and women in England for 11 years and found that nonsmokers with the healthiest eating and exercise habits at the outset had a 14-year-life-expectancy edge over the people with the worst habits. This followed a 2001 Loma Linda University finding that Seventh-Day Adventists who kept good habits lived to an average age of 88, versus 78 for those who behaved less well. ... Seventh-Day Adventists [have] a life expectancy four to seven years longer than that of average Americans, probably because their faith preaches a vegetarian diet and exercise. ... Researchers at the Pacific Health Research Institute in Hawaii who followed 5,820 Japanese American men for 40 years found those who avoided risk factors such as obesity, heavy drinking, smoking and high blood pressure in middle age had a 69% chance of living to be 85, versus just 22% for men with six or more risk factors."


Call For Submissions: Hourglass IX

Chris Patil is looking for your blog submissions for the next Hourglass blog carnival on aging science: "The ninth installation of Hourglass, a monthly blog carnival devoted to the best blogging about biology of aging, will appear at psique on Tuesday, April 14th. ... 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. Submissions should be emailed to [][at][gmail][dot][com]. ... By the way, if you'd like to volunteer to host, please email [Chris Patil] directly - basically the rest 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."


Excess Fat and Accelerated Cognitive Decline

Since today's Longevity Meme News was all about the ways in which excess fat tissue damages you over the years, I though I'd follow up with more of the same here. It's a correlation only, but like many of the others that tell us the same thing, it's sound science.

Being Overweight in Midlife Is Associated With Lower Cognitive Ability and Steeper Cognitive Decline in Late Life

BACKGROUND: Although an increasing body of evidence links being overweight in midlife with an increased risk for dementia in late life, no studies have examined the association between being overweight in midlife and cognitive ability in late life. Our aim was to examine the association between being overweight in midlife as measured by body mass index (BMI) and cognitive ability assessed over time.

METHODS: Participants in the Swedish Adoption/Twin Study Aging were derived from a population-based sample. The participants completed baseline surveys in 1963 or 1973 (mean age 41.6 years, range 25-63 years). The surveys included questions about height, weight, diseases, and lifestyle factors. Beginning in 1986, the same individuals were assessed on neuropsychological tests every 3 years (except in 1995) until 2002. During the study period, 781 individuals who were 50 years and older (60% women) had at least one complete neuropsychological assessment. A composite score of general cognitive ability was derived from the cognitive test battery for each measurement occasion.

RESULTS: Latent growth curve models adjusted for twinness showed that persons with higher midlife BMI scores had significantly lower general cognitive ability and significantly steeper longitudinal decline than their thinner counterparts. The association did not change substantially when persons who developed dementia during the study period were excluded from the analysis.

CONCLUSIONS: Higher midlife BMI scores precede lower general cognitive ability and steeper cognitive decline in both men and women. The association does not seem to be mediated by an increased risk for dementia.

Getting fat generally implies more eating and less exercise. In recent years, researchers have proposed a range of plausible biochemical mechanisms linking overeating, excess fat, and reduced exercise to a faster rate of progressive deterioration in the brain. The present weight of scientific evidence tells us that if you're presently overweight and would like a better chance of living a longer, healthier life, then you should adopt a healthier lifestyle and diet that results in a lower stable weight and less visceral fat tissue.

In the long term, as we get older, our remaining health and life span will increasingly be determined by advances in medical science rather than our own efforts in lifestyle and diet. But we have no assurance that the date upon which science can rescue us from the effects of aging will come soon enough to help. We would therefore would be wise to take all reasonable measures to (a) maximize our own personal longevity within the limits of today's knowledge and available technology, and (b) help make the future era of longevity therapies come about more rapidly.

CXCL5 and the Imflammation That Fat Tissue Generates

Researchers have been demonstrating over the past couple of years that excess fat tissue contributes to chronic inflammation, with the role of macrophage cells being particularly important. Here's more on that topic from EurekAlert!: "the inflammatory chemokine known as CXCL5 rises and falls with obesity and subsequent weight loss in humans. (Chemokines are structurally related signaling proteins that are secreted by cells.) ... Fat tissue known as white adipose tissue (WAT) is primarily involved in energy storage in the form of triglycerides and energy release in the form of free fatty acids, Fajas' team explained. However, WAT is more than a fat storage organ; it also secretes numerous other factors with roles in both health and disease. ... [CXCL5] is expressed at high levels in WAT, particularly in immune cells known as macrophages. Moreover, they report that CXCL5 is dramatically increased in the blood of people who are obese compared to those who are lean. Those CXCL5 levels drop when obese people lose weight and are also lower in obese individuals that continue to respond to insulin than in those who are insulin resistant. .... the [receptor for CXCL5] is active outside of muscle, in cells that line blood vessel walls and in the lung and intestine, for example. Therefore, increased CXCL5 circulating levels as observed in obesity could lead to other problems, including atherosclerosis and other inflammatory diseases."


How Overeating Leads to Insulin Resistance?

While some researchers are exploring the mechanisms by which calorie restriction brings health and longevity benefits, others are looking at how overeating harms us: "Obese people have been found to harbor proteins called branched-chain amino acids (BCAAs) at far higher levels than non-obese people. The suspicion has been that these amino acids, in combination with a high-fat diet, contribute to insulin resistance. ... In the case of the amino acids, we also are finding increased levels of their metabolic breakdown products, which suggests the whole system for handling the amino acid metabolic process has been overloaded. Our rat studies show that this overload causes changes at the cellular level that can lead to insulin resistance ... Insulin resistance occurred in animals with a diet high in the branched-chain amino acids, but only if they were ingested along with a high level of fat in the diet ... BCAAs comprise as much as 25 percent of amino acids in dietary protein, and are particularly enriched in diets high in animal (meat) proteins. ... I want to be clear that our animal data suggest that there is nothing wrong with obtaining protein from sources that are high in branched-chain amino acids, as long as you are not eating beyond what your energy needs are. If you add a lot of unneeded protein to a fatty diet, perhaps that's where you get into problems. The ancient Greeks were right: everything in moderation."


What Can Be Accomplished With Even Crude Control Over Immune Systems

Increasingly fine control over our immune systems will be very important to the future of longevity. The immune system is vital not just to our resistance to pathogens, but also to destruction of cancerous cells and destruction of senescent cells, amongst other duties. Both cancerous and senescent cells greatly harm us in their different ways.

One thing that has become apparent from watching researchers working on the immune system is that our immune systems are capable of far more than they presently accomplish. If intelligently dialed up or dialed back, directed towards specific targets, rebooted when performing poorly, and so forth, we could benefit greatly. We all have a horde of defenders in our bodies, but their leadership just isn't as good as it might be, and becomes ever more confused with each new battle.

The more threats you have encountered, the more cells become devoted to memory; eventually you don't have enough naive T cells left to mount any sort of effective defense.

A human-assisted human immune system could overcome all of these obstacles, and we've seen the first steps down this road already. One positive sign is that even incremental progress in immune system control can bring great benefits, meaning that step-by-step commercialization will likely support development all the way to a very sophisticated merging of machinery and cells a few decades from now.

Here is an example of a positive incremental step I noticed recently:

Professor Jonathan Sprent and Dr Kylie Webster from Sydney's Garvan Institute of Medical Research, in collaboration with colleagues, Dr Shane Grey and Stacey Walters, have successfully tested a method, in experimental mice, of adjusting the immune system for just long enough to receive a tissue transplant and accept it as 'self'. At no stage, during or after the procedure, is there any need for immunosuppressive drugs.


We took normal, healthy mice, injected them for three consecutive days with the complex, then transplanted insulin-producing cells on the fourth day," said Kylie. "By the time of transplant there were huge numbers of T regulatory cells in their systems, making graft-destroying T cells ineffective."

"The numbers of T regulatory cells dropped over time, and the immune systems returned to normal in about two weeks. By that time 80% of the mice had accepted the grafts of insulin producing cells as their own."

"This acceptance rate is very high for transplantation, with mice normally rejecting grafts within 2-3 weeks."

Where the Methuselah Foundation Goes From Here

An update from Methuselah Foundation CEO Dave Gobel: "The restructuring of Methuselah Foundation allows us to be more nimble as we grow, and enables us to incubate and launch a variety of programs. I'm writing you today to share with you our short, medium and long-term strategies that advance our core mission of ending age-related diseases through awareness, education, scientific research, and direct community outreach. ... As you know, it is has been a challenge to communicate our message to the mainstream public. It is our belief that providing instant real world updates to those with life threatening diseases, and their support networks, will introduce a significantly larger audience to our overall mission while providing a beneficial program for people in need. ... The core focus in our fight to end age related diseases is found in the MPrize, a breakthrough approach to giving cutting-edge science the resources needed to solve one of the largest humanitarian crises of our time. The MPrize springs from a simple truth: the greatest innovations in human history have always been fueled by three things... competition, imagination and the entrepreneurial spirit. Science is no different. ... We remain firmly committed to continuing support for groundbreaking rejuvenative research, taking further strides in our global mission to develop, promote, and provide widespread access to regenerative medicine solutions and therapies to end the disabilities and diseases of aging. We have many exciting new breakthrough rejuvenation projects in the works, which we will be announcing in the very near future."


SENS Foundation Launches

Strategies for Engineered Negligible Senescence (SENS) research will be conducted by the SENS Foundation going forward. This initiative is spun off from the Methuselah Foundation, which will renew its focus on the Mprize for longevity science and a number of other less research-focused endeavors. From biomedical gerontologist and SENS Foundation co-founder Aubrey de Grey: "I want to give you a feel for what we are achieving by summarising just two of the many recent elements of SENS-related scientific progress. One shining example is the discovery of enzymes that can destroy A2E, a by-product of the chemistry of sight, which is thought to be the primary cause of age-related macular degeneration (in turn, a major cause of blindness in the elderly). ... The other example, this time relating to mitochondrial mutations, [is] the breakthrough by Marisol Corral-Debrinski's Methuselah-funded group in Paris in cracking the problem of hydrophobicity of the proteins encoded by mitochondrial DNA. This obstacle, which had for over a decade completely stalled progress in the 20-year-old idea of making mitochondrial DNA redundant by duplicating it in the nucleus, is now largely solved, and there is great hope that this strand of SENS can be brought to complete fruition within only a few more years. I have no doubt that SENS Foundation is the right organization to take the next evolutionary steps in the engineering of comprehensive regenerative therapies. ... It promises to be a remarkable journey, and I look forward to your continued interest, support and collaboration as we increase our pace and set our sights ever closer to the horizon."


Large Scale Analysis of Gene Expression Changes in Aging

Over at Ouroboros, you'll find a look at what emerges from a very large comparative analysis of gene expression changes with aging. By finding the most important differences, and tracing back to the biological mechanisms associated with these genes, we should learn something about the validity of various theories of aging, and the importance of various potential strategies for slowing or reversing aging.

The core of the thing:

We performed a meta-analysis of age-related gene expression profiles using 27 datasets from mice, rats and humans. Our results reveal several common signatures of aging, including 56 genes consistently overexpressed with age, the most significant of which was APOD, and 17 genes underexpressed with age.

We characterized the biological processes associated with these signatures and found that age-related gene expression changes most notably involve an overexpression of inflammation and immune response genes and of genes associated with the lysosome. An underexpression of collagen genes and of genes associated with energy metabolism, particularly mitochondrial genes, as well as alterations in the expression of genes related to apoptosis, cell cycle and cellular senescence biomarkers, were also observed.

If you've been reading Fight Aging! for a while, you'll have seen most of these processes and systems mentioned in connection to the damage of aging. The failing immune system, the role of chronic inflammation, the biochemical junk cluttering the lysosome, mitochondrial DNA damage, senescent cells, and so forth.

As they point out at Ouroboros:

While this approach will likely fail to identify those genes that are age-regulated only in a single tissue, the advantage is that those genes that do come out of this analysis are likely to be the really interesting ones - components of a common aging program that operates in multiple tissues.

Building Tissue From Embryonic Stem Cells

A proof of concept for the use of pluripotent cells in tissue engineering from ScienceDaily: scientists "report on their research to optimize the potential of [human embryonic stem cells or hESC cells] to generate complex, functional multilayer tissues, such as the oral mucosa and skin, and to understand how tissue fabrication is controlled and directed. ... [Researchers] used tissue engineering principles to produce complex oral-lining tissues that mimic many features of their counterparts found in the oral cavity. Making these tissues was a two-step process. With a combination of chemical signals and specialized surfaces on which these cells attach, an hESC cell line [was] directed toward two divergent cell populations. The first population comprises the surface layer (epithelial cells) of complex tissues, while the other is found beneath these cells (mesenchymal cells). ... The populations were then grown at an air-liquid interface to mimic their growth environment in the oral cavity. Within two weeks, tissues developed that shared many features in common with normal tissues that were constructed with mature cells that are the 'gold standard' of normal tissue generation in our lab."


Stem Cells That Grow New Blood Vessels

Via EurekAlert!, we learn that a research group has "has identified how to use selected stem cells from bone marrow to grow new blood vessels to treat diseases such as peripheral artery disease. ... [Researchers] drew human bone marrow and simultaneously isolated three different types of stem cells that co-ordinate together to form new blood vessels. These are called pro-angiogenic stem cells. They were purified to remove any inflammatory or contaminated cells, and then injected into the circulation of mice which had one of their leg arteries ligated and removed. The researchers showed how these stem cells have a natural ability to hone in on the area of ischemia to induce blood vessel repair and improve blood flow ... We can select the right stem cells from the patient's own bone marrow and put them back in the area of ischemia to allow these cells to coordinate the formation of new blood vessels. These principles could be applied not only to ischemic limbs, but to aid in the formation of new blood vessels in ischemic tissue anywhere in the body, for example after a stroke or heart attack."


Why Does Calorie Restriction Improve Insulin Sensitivity?

We know that calorie restriction (CR) greatly improves insulin sensitivity - which seems to be one of the ways in which it increases life span - just as eating too much and getting fat tends to lead to insulin resistance and the diabetes that follows. Here, researchers are making slow inroads into understanding why CR does this: "Caloric restriction (CR) has been shown to retard aging processes, extend maximal life span, and consistently increase insulin action in experimental animals. The mechanism by which CR enhances insulin action, specifically in higher species, is not precisely known. We sought to examine insulin receptor signaling and transcriptional alterations in skeletal muscle of nonhuman primates subjected to caloric restriction over a 4 year period. ... CR increases insulin sensitivity on a whole body level and enhances insulin receptor signaling in this higher species. CR in cynomolgus monkeys may alter insulin signaling in vivo by modulating protein content of insulin receptor signaling proteins."


More Regeneration Than Thought

It's been a recurring theme in recent years that cell populations once thought to be static throughout much of life do in fact generate new cells at a slow rate or after injury. That such a process exists opens the door to efforts to speed it up as an alternative to other forms of regenerative medicine. For example, scientists have "shown the human body regenerates heart cells at a rate of about one percent a year, a discovery that could one day reduce the need for transplants. The study of 50 volunteers, using a dating method that detects traces of a carbon isotope left by Cold War nuclear bomb tests, raises the prospect of artificially stimulating the renewal process some day. ... Heart cells are unusual in that they stop dividing early in life. Doctors knew there were master cells called stem cells in the heart, but heart muscle usually simply forms scar tissue after damage and never fully regenerates. ... the rate at which the new cells are produced slows as we get older, with a young adult in their twenties renewing cells at a rate of about 1 percent a year, falling to half a percent a year by the age of 75. If you exchange cells at this rate it means that even if you live a very long life you will not have exchanged more than 50 percent of your cells. So at any given time your heart is a mosaic of cells you carry with you from birth and cells that that have been added later to replace cells that have been lost during life."


CPHPC and Amyloidosis

Centenarians get to be centenarians by surviving or not suffering the diseases that kill everyone else. So what kills centenarians? This isn't an academic question, as we'd like to engineer a future in which none of us suffer the major diseases of aging, and all of us make it past a century in good health. Understanding the processes that slay those who survive everything else the failing body can throw at us is just as essential to the future of longevity medicine as curing cancer and repairing mitochondria.

If forced to make an educated guess today, I'd have to say that the best evidence is for amyloidosis to be the killer of the oldest old - a buildup of metabolic byproducts that eventually clogs the body's systems to the point of failure. The Supercentenarian Research Foundation outlines some of the case for that conclusion:

Coles argues [that supercentenarians] 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.

Folk from the Biogerontology Research Foundation (formed "to support the application of our knowledge of the mechanisms of ageing to the relief of disability, suffering and disease in old age") were kind enough to direct my attention today to a recent update from the amyloidosis research community:

Prof Pepys’s persistence pays off

Amyloidosis is caused by the build up of abnormal "amyloid" proteins in body tissues. Prof Pepys has long believed that the key to understanding the disease is a related blood protein called SAP, which sticks to amyloid fibres and stops enzymes removing them.

The FT has covered his work several times. My predecessor David Fishlock described in 1990 Prof Pepys’s discovery of a way to image SAP and amyloid fibres. I wrote in 1995 and 2002 about progress in developing a drug called CPHPC, which aimed to clear the destructive amyloid deposits from patients by removing the protective SAP from their blood.

Prof Pepys was working then in collaboration with Roche. But the Swiss pharmaceutical giant eventually pulled out.

"While we had promising early results [with CPHPC] they were not enough to benefit patients with advanced disease," he says. "Something more dramatic is needed."

That something turns out to a combination of CPHPC with an antibody - a molecular guidance system designed to seek out amyloid deposits in vital organs.

Now Prof Pepys has reached an agreement with another big pharmaceutical group, UK-based GlaxoSmithKline, to collaborate on producing a treatment for amyloidosis based on the CPHPC-antibody combination.

Those of us interested in progress towards the tools needed to remove or repair changes in our tissues that accumulate with age should follow amyloidosis research with interest. Some fraction of the degenerations of aging is caused by just this sort of buildup of unwanted chemical aggregates. Strategies under development for dealing with specific aggregates may turn out be more broadly applicable to future engineered longevity therapies.

Convincing the Body to Clear its Own Biochemical Waste

A fraction of the damage of aging is caused by the build-up of biochemical waste within and between our cells. Some is common to all of us and a byproduct of the normal operation of metabolism, such as the amyloid implicated in Alzheimer's, which can be found in small amounts even in the young, or lipofuscin that increasingly harms our lysosomes. Other types of biochemical waste are peculiar to those unfortunate enought to suffer particular forms of genetic damage - such as the mutation that causes Huntington's disease.

It is instructive to watch early research and progress in treating diseases where the damage done depends upon a build up of unwanted proteins. Some of the lessons learned and new technologies deployed could be turned to address other types of biochemical, ones whose buildup contributes to the aging process. Here's an example of what I mean:

A new study has identified a potential strategy for removing the abnormal protein that causes Huntington's disease (HD) from brain cells, which could slow the progression of the devastating neurological disorder. [Research describe] how an alteration to the mutated form of the huntingtin protein appears to accelerate its breakdown and removal through normal cellular processes.


A key observation was that [the method used], while increasing the removal of mutant huntingtin, had little effect on the normal version of the protein. "One of the major challenges of research into neurodegenerative disorders like Huntington's, Alzheimer's and Parkinson's diseases - all of which involve accumulation of proteins within the brain - has been how to activate degradation machinery that only removes the disease-causing proteins and leaves normal proteins untouched."

As the ability of researchers to manipulate the elements of human biochemistry grows, we should expect to see ever more opportunties to harness and redirect existing cellular capabilities as a part of a new therapy.

Imminst TV

The TV section of the Immortality Institute site is central repository and chatroom for much of the video resulting from the work of volunteers there, running on ustream. "Our Executive Director, Mind, has compiled a list of the videos that he plays in there that are posted there. He has also compiled a list of some of the main guests and links to the interviews that he conducts for's main feature, the Sunday Evening Update show ... Sunday Evening Update is held most Sunday afternoons and provides news, views, and people from the world of life extension. Hosted by Immortality Institute Executive Director Mind (Justin Loew), past special guest speaker have included [Aubrey de Grey
and S. Jay Olshansky]. ... Our channel makes use of video and audio technology, as well as a traditional text chat interface. Come by to listen to and participate in the discussion, and type your questions for the guest speakers. During the rest of the week, stop by to watch rotating documentaries or our archived chats, and participate in various meetings held by active Immortality Institute members." It's a pretty active community of pro-longevity folk, so you should make a point of passing by to see if you fit in.


How Beta-Amyloid Kills Cells in Alzheimer's

A mechanism by which beta-amyloid buildup kills brain cells is proposed over at EurekAlert!: "attacks on the mitochondrial protein Drp1 by the free radical nitric oxide - which causes a chemical reaction called S-nitrosylation - mediates neurodegeneration associated with Alzheimer's disease. Prior to this study, the mechanism by which beta-amyloid protein caused synaptic damage to neurons in Alzheimer's disease was unknown. These findings suggest that preventing S-nitrosylation of Drp1 may reduce or even prevent neurodegeneration in Alzheimer's patients. ... found that beta-amyloid can generate nitric oxide that reacts with Drp1. By identifying Drp1 as the protein responsible for synaptic injury, we now have a new target for developing drugs that may slow or stop the progression of Alzheimer's." Mitochondria are the power plants of cells; all sorts of things start to go wrong when they are systematically damaged. While its true that we've seen mice packed to the gills with beta-amyloid and suffering no harm due to it, indicating that there might be something to blocking the way in which beta-amyloid damages cells, I'd prefer to see clearance or identification and removal of the root cause of the build-up of aggregates rather than a strategy of dealing with them after the fact.


All of What Was, Some of What Is, and None of What Will Be

The mind of humanity dwells somewhat in the now, a great deal in the recent past, and very little in the future. The greatest attention is focused on what is and what recently was - an outcome of our evolutionary history. You can imagine how a focus on learning to live in the world of the the recent past was a predictor for success under most circumstances for our more primitive ancestors.

These days, stand still to ruminate upon recent events and you're liable to have a building erected above you while you pause, and fifteen new technologies dropped into your lap to boot. The evolved biases stand, however: while a great many people claim to look foward with wisdom and sagacity, few do more than transpose the fundament and structure of last week ahead by seven days. We humans just don't put much effort into thinking about how the future will in fact be different from the past, and what that means for our actions and choices.

One manifestation of this bias is seen in the nature of the periodic articles about centenarians that are a staple of the popular press. Now that researchers can start to talk about biochemistry and genes in relation to longevity, these pieces are cropping up in the popular science press too. The underlying question is always "how did they do it, living to 100 like that?" More accurately, the question beneath that is "how can I do it too?"

The standard form of the answers to this question is always rooted in the recent past. If things never changed, if medical technology and culture remained static, how could I do as well as a centenarian? But of course all that stasis is implicit, hidden under the covers, as it is in so many other considerations of the future. The world of last week never ends in the inner mind of humanity, and we shall dwell in it forever.

Here's a short Scientific American piece in which S. Jay Olshansky says some sensible things about centenarian health and longevity as an example of the type.

SciAm: Is it possible that Dosova gave birth to a daughter when she was 54 years old? Olshansky: Believe it or not, that's exactly what you would think for someone who has had a very long life. In centenarians and supercentenarians - people over 110 - you see a higher level of fecundity much later in life. These women will still be having periods and producing eggs later than the average female. As long as the body believes it is reproductively active and keeps producing certain sex hormones, these seem to help protect the body against aging. As soon as menopause occurs, things begin to change in a woman's body very rapidly. If you look at records of centenarians, many of them in fact had children in their late 40s. So if Dosova did have a child at the age of 54, it would likely corroborate her story rather than detract from it.

Here, the claim of a 130 year old woman is fairly safe to throw out without iron-clad documentation. That she's a centenarian seems sound, but 130 stretches plausibility. The commentary on longevity is still sound, however.

But back to your future. In the world of last week, in which nothing really changes but your age, you won't make it to 100. That's a safe bet no matter how well you take care of your health. The only thing that will enable many of us to live in good health past a century of life is the advance of medical technology - in other words, new science and new therapies that don't exist in the here and now.

The speed with which medicine advances is predicated upon just how many of us support that advance. If you live your life in the land of last week, or the land of how your parents lived, or any of the other seductive places that your evolved nature causes you to be predisposed to enjoy, then I'm sorry to say that you're not helping. The coming decades could see some of the most transformative advances in medical technology yet, and it is possible to envisage with some precision the tools and therapies that could rejuvenate the old by repairing the damage of aging. This will only happen rapidly enough to help those of us reading this now if many more people get behind the wheel and push.

Recognize that the greatest determinant of your future health and longevity is medical science and technology that has yet to be developed, not whatever was a good health practice last week. Then figure out how you can help.

Speculating on Mitochondria and Accelerated Aging

Over at Ouroboros, some scientific speculation on the relationships between mitochondrial DNA (mtDNA) damage and aging that might - or might not - be illustrated by accelerated aging (or progeroid) conditions. Progeroid conditions are associated with failures of the repair processes for nuclear DNA, but how does the separate DNA in mitochondria figure in to this? "Repair mechanisms also exist for mitochondrial DNA, [but] do deficiencies in mtDNA repair play a similar role in aging? We've already seen that mitochondrial DNA damage accumulates with age. And calorie restriction, the gold standard of lifespan extension, prevents this increase in damage. ... The authors argue that the increased level of chromosomal breakage and the replicative pausing in the mutant mouse are responsible for the progeroid symptoms ... In their view, mitochondrial DNA replication is actually upregulated [so as to provide more energy] to compensate for the reduction in replication capacity. ... The phenotype of DNA repair mutants could be caused not by mutations themselves, but by the effort it takes to prevent DNA mutation from occurring past some threshold which would cause cellular catastrophe. ... Is it possible that the problem in progeroid models is not due to the DNA damage itself, but to [the energy-generation demands placed upon mitochondria in order] to prevent a catastrophic collapse of DNA integrity?"


Magnetic Cell Assembly

Researchers are presently working on a very diverse array of methodologies for tissue engineering, seeking the technology base of tomorrow that will enable cost-effective growth of replacement tissues and organs. Here is another in its early stages: "The power of magnetism may address a major problem facing bioengineers as they try to create new tissue - getting human cells to not only form structures, but to stimulate the growth of blood vessels to nourish that growth. ... magnetic particles suspended within a specialized solution act like molecular sheep dogs. In response to external magnetic fields, the shepherds nudge free-floating human cells to form chains which could potentially be integrated into approaches for creating human tissues and organs. ... The next step is to see if the spatial arrangement of these cells in three dimensions will promote vascular formation. A major hurdle in tissue engineering has been vascularization, and we hope that this technology may help to address the problem."