Redesigned and Spreading Out in Middle Age
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As you might have noticed, I've implemented a minor redesign here at Fight Aging! and over at the Longevity Meme in the past couple of days. It's a sort of spreading out in middle age: as the average size of monitors grows, an layout designed for 800x600 pixel screens begins to look cramped and low-rent. Now we're on a layout that has 1024x768 in mind, and, by the magic of adding a lot of empty space, the same old material suddenly looks much more up to date and sophisticated. Funny the way that works.

A couple of other odds and ends were tided up as I notice them, and I hope to achieve more of the same in the next few days. The search function here at Fight Aging! now uses Google rather than the increasingly hopeless in-built Movable Type search, for example, and is as a result much more useful. I've moved it up in the left navigation to a position that reflects its newly acquired utility.

So while my attention is focused on these and similar housekeeping matters, it's a good time for you, the audience, to point out things that might need updating or are otherwise not up to scratch. I'm hoping that nothing was outright broken by the update, but it's always possible I missed an item stuck away in the corners, or that appearances are suffering in one of the less common browsers. Let me know if that's the case.

Taming Microglia
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You might recall that microglia immune cells in the brain and nervous system are implicated in the damage of aging. Evolutionary adaptations beneficial in youth come back to bite you in later life, in this case via excessive release of inflammatory cytokines. Researchers are working on ways to deal with that, however: CHPG, an activator of a type of glutamate receptor, "shuts down activation of key immune cells in the brain known as microglia, which sense pathogens or damage in the spinal cord and brain. They helpfully foster the destruction of microbial invaders and clean up biological detritus that occurs after an injury, but researchers say they have a dark side as well ... Under certain conditions, like spinal cord injury and brain trauma, microglia [release] toxic chemicals that can kill healthy adjacent tissue, and this process can continue for months. ... The team had previously found that microglial cells express a certain receptor, the group I metabotropic glutamate receptor 5 (mGluR5), on their surface. Further work showed that if these receptors were specifically activated on microglia, these immune cells would not produce the neurotoxins that led to cell death near the site of injury. CHPG serves to selectively activate the receptor, reducing microglial toxicity."

Link: http://explore.georgetown.edu/news/?ID=41016%20&PageTemplateID=295

Bacterial Roots of Arthritis
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What triggers some immune systems to run amok, causing conditions like some types of arthritis? Here, researchers have a lead on one possible root cause: "a specific gene called NOD2 triggers arthritis or makes it worse when leftover remnants of bacteria cell walls, called muramyl dipeptide or MDP, are present. ... Despite recent advances in the treatment of arthritis, none target its cause. Our work with MDP and NOD2 is a step toward understanding the root cause of arthritis which one day may allow certain forms of arthritis to be prevented altogether. ...[Researchers] made this discovery through experiments using two groups of mice, one group was normal and the other had been genetically modified so that their NOD2 gene was deactivated (commonly referred to as 'knocked out'). Then they administered MDP to the joints of mice in each group, and unlike the normal group of mice, the mice with the deactivated NOD2 gene did not experience signs of arthritis. ... Now that we know that bacterial products can activate this NOD2 pathway and that this signal contributes to arthritis, the next step is to find treatments that either rid the body of this inflammatory signal or mask it. Either way, the net effect would be the same: people would be spared from a very crippling disease."

Link: http://www.eurekalert.org/pub_releases/2009-03/foas-bmo033109.php

Thinking About Cryonics
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I think it goes without saying that all minority interests suffer from credibility gaps. We humans are hardwired to be skeptical when we look in on something said to be good but not indulged by many people. It's a defense mechanism, most likely, but it does mean that when you do have a genuinely good, new idea, you'll know by the way you have to work hard to get anyone to listen.

Cryonics, the low temperature preservation of the fine cellular structure of the body and brain at the end of life, is a good idea. There's a non-zero chance you'll be repaired and revived in a future of wondrous technologies, with the chance to live on for a very long time in a fascinating era. That compares favorably with the other options open to the dying, but cryonics remains a fringe practice. It hasn't yet bootstrapped to the level of participation that prevents knee-jerk rejection from most people.

In this vein, a couple of recent posts from the community I'd like to draw to your attention:

A Few Cool Quandaries

I've recently found out just how "weird" and even "crackpottish" the idea of cryonics seems to Most People. I actually always saw it as one of the less weird things a person might conceivably find intriguing. But apparently that isn't the case.

The Daily Mail Tackles Cryonics

The Daily Mail, a UK tabloid legendary on the Internet for its dense celebrity reporting, has finally taken on the coolest topic of all - cryonics. Like many articles about freezing yourself solid to be revived in the future, this one is negative.

Or is it? The Mail is a media outlet renowned for its disdain for facts in an industry renowned for its disdain for facts, but here, possibly accidentally, it turned out an article that might actually give a net positive impression.

Looking at Stem Cell Research
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A broad, popular science look at stem cell research from the John Hopkins Magazine: "Stem cells have been regarded as the best - perhaps the last - hope for patients with certain diseases such as diabetes; if stem cells could be used inside the body to grow the pancreatic islet cells that produce insulin - cells that are ravaged by an immune response in diabetics - then, one day, injecting them into patients might reverse the disorder. The same might be true for Parkinson's disease, which afflicts 2 percent of people over age 65, and thousands of younger people. If stem cell therapies could be developed that would repair or replace damaged or dead dopamine neurons in the brain, sufferers would no longer lose control of their movements. Stem cell research affords scientists the chance to see if they can develop personalized 'drugs' that would work throughout the body, or to uncover the secrets behind the development of human tissues and the origins of disease. No other therapy or group of therapies comes close to its potential impact."

Link: http://www.jhu.edu/~jhumag/0409web/cells.html

Acetylation, NuA4, and Yeast Lifespan
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It's a little early to tell whether this will actually shed any light upon the metabolic processes of human longevity, even though Sir2 is involved, but it is interesting nonetheless: "making glucose is highly influenced by a large enzyme complex already known to fix damaged DNA, and which apparently affects yeast life span through a common chemical process - acetylation. ... when continuously acetylated, the so-called NuA4 enzyme complex causes yeast cells to live longer than they would under normal conditions. ... the constantly acetylated form of yeast cell can outlive the unaltered cell by 20 percent and that the constantly de-acetylated form had an 80 percent reduction in its lifespan compared to the unaltered cell. ... Because the NuA4 complex is highly conserved among species, what we've found in yeast translates to humans as well. What we've revealed about longevity in yeast perhaps someday can translate to human health. ... the team provided the first evidence that acetylation controls the activity of an enzyme called Pck1p, critical to sugar production in yeast and probably human cells. This enzyme is also controlled by the enzyme Sir2, which removes the acetyl group. Sir2 is heavily implicated in aging and a number of diseases by recent studies in mammals."

Link: http://www.sciencedaily.com/releases/2009/03/090324101801.htm

Dreams of Molecular Nanotechnology
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There's no law of physics that will prevent we clever humans - and our enhanced descendants - from eventually building technologies that can maintain and arrange every aspect of our bodies exactly as we'd like them to be. Technologies that can find every out of place molecule or damaged component and promptly fix it up. Aging will be a thing of the past in that era of molecular nanotechnology, whenever it comes to pass.

Systems that can identify, manage and place trillions of molecules accurately are not a pipe dream; after all, we are already surrounded by examples. You, for example, are just such a system, albeit somewhat slow at self-assembly to full size. There's nothing in the laws of physics that jumps out and says we can't do this. It's just a matter of time.

If you have the technology base to build a nanoforge to assemble a brick, then you also have the technology base capable of simultaneously assembling and controlling a hundred million medical nanorobots of arbitrary design and programming. Or an artifical lung better than the real thing, or replacements for immune cells that never get old or worn. You get the idea. A brick is just as complex as any portion of the human body if you have to build the thing molecule by molecule; more fault-tolerant, but just as complex.

Our cells are already very impressive examples of adaptive machinery. The machines our descendants will build with the knowledge gained from today's study of biology will be even more impressive yet. Cells, for all their intricacy, are far less efficient and organized than the laws of physics permit. One day, that inefficiency and disorganization will be eliminated by machinery intended to augment or replace our cells, and everyone will be the better for it.

If's good to look ahead up the ladder every now and again to remind yourself why you climb it. The future is golden, if we can sort out the issues on these bottom rungs to ensure we make it there. I notice that a presentation by Christine Peterson of the Foresight Institute transcribed at Future Current touches on some of what may come:

Another consequence of this in the long-term, and I think this will be true in your lifetime, is what would happen if we have atomic-scale control of our bodies. In the mid-term timeframe I was talking about nailing cancer. No more cancer cells, so that people do not die of cancer anymore. With this level of technology, you move on. What’s left? What kind of disease could a human being have that could not be addressed with this level of technology eventually? It’s hard to say.

I suppose a massive accident - you’re hit by a truck. That could be the end. But in terms of disease, where there is time, it’s not clear what kind of disease you could have that would not be treatable with this level of technology. Basically, you want to put the atoms of your body back in a healthy arrangement.

What about aging? Aging, as we know, is a very complex process. There are many things that are all going on at one time, but all of them are misarrangements of atoms. In principle, if you could figure out what a healthy pattern of atoms and molecules in the body is, you could then restore that pattern. The goal, of course, is that you not disrupt the structure of the brain, because that is where your memories and your personality are. I don’t mind if everything from [the neck] down is rebuilt - start from scratch, make it all perfect. But up here [the brain] we need to keep the patterns.

Ultimately, I think aging is addressable. When that happens is very hard to say.

Heat Shock Proteins and Cancer Immunotherapy
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One of the roles of heat shock proteins such as Hsp70 is to carry other proteins around a cell - for example, when they are damaged or misplaced and need to be broken down in a lysosome. This paper shows that if you hook out heat shock proteins from cancer cells, they come attached to all sorts of biochemicals that can be used to train the immune system to kill those cancer cells: "In the present investigation, we have demonstrated that immunization with tumor cell derived Hsp70 lead to an effective survival advantage in mice with minimal residual tumor cells from which Hsp70 is derived, by involvement of immune cell types in the rejection of tumors ... It has been observed that autologous Hsp70 induces specific anti-tumor immunity and effectively eradicates tumors in the host mice, thereby enhancing survival of tumor-bearing host. ... Furthermore, Hsp70 immunized mice did not show any systemic disorder. Therefore, it could be assumed as safe and might be clinically useful for vaccination against malignant human tumors."

Link: http://www.ncbi.nlm.nih.gov/pubmed/19309230

Improved Induced Pluripotency
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Researchers continue to move rapidly in advancing the state of the art in induced pluripotent stem cells: "A team of scientists has advanced stem cell research by finding a way to endow human skin cells with embryonic stem cell-like properties without inserting potentially problematic new genes into their DNA. ... This is not the first time that scientists have endowed differentiated cells like skin cells with the capacity to develop into any of the roughly 220 types of cells in the body, a process known as induced pluripotency. But it is the first time that they have done so without using viruses, which can insert potentially harmful genes into the cells' genetic material and trigger cancer. [The] new method imports the necessary genes on a small circle of DNA known as a plasmid. Over time, the plasmid disappears naturally from the cell population, avoiding the danger posed by using viruses. Scientists view pluripotent cells as invaluable to studies of normal and disease processes and to understanding the effects of certain drugs. In the future, doctors might be able to use such cells therapeutically to replace those affected by diseases such as Alzheimer's and Parkinson's or lost to traumatic injuries."

Link: http://www.eurekalert.org/pub_releases/2009-03/niog-nma032509.php

Help Build the Science of Aging Timeline
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Via Ouroboros, we learn of an interesting community project:

Paul House has started a project that should be of wide interest to Ouroboros readers: a Timeline of Discoveries in the Science of Aging. His goal is to facilitate the creation of a record of the major events in the history of (bio-)gerontology, and publish it in a visual interactive form that grows in response to user input. Clicking on an individual event along the timeline expands it into a full article.

...

The idea is for the site to be interactive in multiple ways - not only in the sense that the timeline is a clickable object that expands in response to user behavior, but also in the sense that user-generated content can be incorporated into the object itself. It’s like a visual wiki.

So if you can think of a major event in the history of our field that belongs on the chart, visit the Science of Aging timeline and make an entry.

It looks much like this once it's going:

This has a lot of potential to develop into a helpful educational tool for advocates, I think. A visual timeline is a very intuitive way to show people that there is momentum in the field, and that work is being accomplished. For better or worse, people are much more likely to get behind and help push a wheel that is already rolling - and so the easier it is to show that aging research is rolling along and producing results, the easier it will be to attract more supporters.

More on the Value of Exercise
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Level of exercise beginning in middle age and mortality rate are very well correlated, as shown by this study: "Despite the known hazards of physical inactivity, it continues to be a major health problem. Physical inactivity is associated with increased incidence rates of obesity, diabetes, cardiovascular diseases, osteoporosis, and cancer ... The absolute mortality rate was 27.1, 23.6, and 18.4 per 1000 person years in the groups with low, medium, and high physical activity, respectively. The relative rate reduction attributable to high physical activity was 32% for low and 22% for medium physical activity. ... Increased physical activity in middle age is eventually followed by a reduction in mortality to the same level as seen among men with constantly high physical activity. This reduction is comparable with that associated with smoking cessation." To restate that last point: lazing around and skipping over a little exercise every day costs you as much healthy life in the long run as smoking does.

Link: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2654773

Immunized Against Cancer?
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From ScienceDaily: "New research suggests that monoclonal antibody therapy of cancer can be improved to be much more powerful than it is today ... We believe that antibody therapy has the capacity to immunize people against cancer. Treatment modifications might be able to prolong, amplify, and shape a continuous immune response to cancer cells ... Scientists now believe that it will be possible to alter the antibodies so that they induce both kinds of human immunity - the innate immune response that is short-lasting and which directly kills tumor cells, and a long-lasting 'memory' response that comes from the adaptive immune response. ... We have long thought that monoclonal antibodies are capable of stimulating the innate immune system, but we now have evidence that the therapy can prime an adaptive response as well. Such responses would make the treatment much more powerful, capable of keeping cancer under control."

Link: http://www.sciencedaily.com/releases/2009/03/090320102128.htm

Autophagy and Neurodegeneration
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Autophagy, the process of recycling cellular components, is known to be important to the benefits of calorie restriction. This makes sense: more recycling of damaged components should mean they have less of a chance to cause additional damage due to their malfunctioning. Calorie restriction is known to slow onset of neurodegenerative conditions, and this also may have something to do with autophagy: "Protein aggregates or inclusion bodies are common hallmarks of age-related neurodegenerative disorders. ... Increasing evidence, [supports] the notion that in general aggregates confer toxicity and disturb neuronal function by hampering axonal transport, synaptic integrity, transcriptional regulation, and mitochondrial function. Thus, neuroscientists in search of effective treatments to slow neural loss during neurodegeneration have long been interested in finding new ways to clear inclusion bodies. Intriguingly, two studies [indicate] that autophagy may be a built-in defense mechanism to clear the nervous system of inclusion bodies. This new finding has implications for our understanding of aging and neurodegeneration and the development of new therapies."

Link: http://www.ncbi.nlm.nih.gov/pubmed/19305790

The Most Popular of Popular Media
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A theory on popular media: the more popular it is, the less the information it provides bears any semblance to accuracy, truth, or scientific fact. As the audience size grows - meaning that any given topic is going to be far outside the specialty knowledge of nearly all of the audience members - any urge to accuracy is completely subsumed by the need for do and say things that will keep that audience's fleeting attention. I think this principle is fairly well illustrated by Oprah and company's present examination of calorie restriction and some related topics in medical research in the context of enhanced human longevity.

There's a style to this sort of thing, in which the presenters construct a framework for their article or show that ostensibly bears some semblance to the underlying reality under discussion, but within which a majority of the "facts" provided are simply wrong, chosen for their ability to grasp attention rather than any scientific backing they may have.

Hence for a discussion of longevity, wild and unsupported claims are fair game. At the present time, the scientific consensus is that human practice of calorie restriction will not greatly enhance maximum longevity, but does greatly improve health and greatly reduce risk of age-related disease. That isn't as exciting, however, as earlier speculation on attaining 120 year or more life spans, so the more exciting "fact" is what gets aired:

Dr. Oz says calorie restriction is the number one way doctors say we can extend longevity. "The data that we have in rodents and some larger animals now indicate you can probably extend your life expectancy by up to 50 percent potentially from doing this," he says.

Freedom of speech bears just as much of an implied caveat emptor for the listener as any other freedom. Expect people to lie to you (by omission, laziness, or more direct motives) when it serves their own self-interest more than telling you the truth - which is the case for almost all popular media serving large audiences.

Old Cells
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The HHMI Bulletin looks at cellular senescence. There's a PDF version for those who don't want to click through six pages to read the whole thing: "cells might not sprout gray hair, get achy joints, or forget where they put their car keys, but they do age. ... researchers are just beginning to learn what happens to cells as they grow old, and they're making connections between those changes and cancer, deficiencies in wound healing, and other problems that increase in likelihood as a person ages. ... In a sense, cancer and senescence are opposite sides of the same coin. To remain robust, tissues rely on dividing cells for replenishment; yet, left unchecked, cell division leads to cancer. Thus, it might seem a Faustian bargain to guard against cancer now at the expense of decrepit tissues later. ... senescent cells produce an enzyme called beta galactosidase. When bathed in a particular sugar compound, cells with this enzyme turn blue, providing a way to spot senescent cells. Since then, researchers have used this method to show that tissues from people, as well as from animals such as rodents and monkeys, carried blue cells. And, 'the older you got the more blue cells you had.'"

Link: http://www.hhmi.org/bulletin/feb2009/features/old.html

Trending in the Right Direction
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Presently available medical technology is always crude when compared with what's presently taking shape in the laboratory. Take cancer therapies, for example: unpleasant and painful chemotherapy remains the state of the art in the field, but laboratories are turning out targeted therapies with next to no side-effects, or using the immune system to eliminate cancer.

This vast gap between lab and clinic is made particularly pronounced by the heavy burden of regulation that ensures commercial development of new therapies is expensive and slow, where it takes place at all. Yet even with this ball and chain, and even lacking the impressive technology still in trials, trends in results of therapy are still moving in the right direction. This is aptly illustrated by this data on cancer survival:

New data and analyses from a long-running study of cancer survival in Europe have shown that the number of people actually cured of cancer - rather than just surviving for at least five years after diagnosis - is rising steadily.

A special issue of the European Journal of Cancer [1] containing reports from the EUROCARE-4 Working Group, includes, for the first time, an estimate of the proportions of patients who are cured of their cancer in Europe and who, therefore, have a life expectancy equal to that of the rest of the population. The analysis divides patients into two groups - the proportion who may be considered cured of their disease and who are likely to die of something else, and those who will die of their cancer.

The study compared two periods - 1988-1990 and 1997-1999 - and found the proportion of patients estimated to be cured of lung, stomach and colorectal cancers increased from 6% to 8%, from 15% to 18% and from 42% to 49%, respectively.

...

"Geographic variation in the estimated proportion of patients diagnosed in 1988-1999 who were cured ranged from about 4% to 10% for lung cancer, from 9% to 27% for stomach cancer, from 25% to 49% for colon and rectum cancer, and from 55% to 73% for breast cancer."

There's a long way to go in terms of defeating cancer if you just project out that trend - but the work presently taking place in the laboratory goes far beyond trend continuation. The next generation of cancer therapies are completely new approaches and technologies that can be expected to greatly increase survival rates where they are deployed. This makes it all the more frustrating that we are saddled with a regulatory prison that prevents and discourages new medicine.

Regulatory bodies like the FDA have every incentive to stop the release of new medicine: the government employees involved suffer far more from bad press for an approved medical technology than they do from the largely unexamined consequences of heavy regulation. These consequences go far beyond the obvious and announced disapproval of specific medical technologies: the far greater cost lies in all the research, innovation and development that was never undertaken because regulatory burdens ensure there would be no profit for the developer. Personal gain for the regulator is thus to destroy the gains of people they will never meet, the exact opposite of what occurs in an open marketplace.
On Longevity Gene Networks
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Our genes of metabolism interact in a very complex and dynamic fashion, and some aspects of that interaction determine longevity. Efforts to pick apart this tangled web require equally complex tools of analysis: "The genome era and the advent of high-throughput technologies have brought about a huge increase in the amount of data available to biologists: each genome contains tens of thousands of genes, whose products can potentially interact with each other in an astronomical number of ways. This quantitative change has created a need for a qualitative change in the way we perform analyses: the human brain is not very good at understanding thousands of things at once, let alone millions or billions, so we must find new ways to extract comprehensible patterns from torrents of data. Many of the techniques being developed to analyze large biological networks fall under the umbrella of systems biology. Some of the newest tools have been used guide genetic perturbation studies in yeast, resulting in the discovery of novel lifespan control genes. What can such network analysis tell us about human aging?" The enormous complexity of metabolism-determined longevity is yet another argument for focusing on repair of already identified damage to reverse aging, rather than trying to manipulate this tangled system to slow aging.

Link: http://ouroboros.wordpress.com/2009/03/24/interactions-between-lifespan-control-genes-form-a-longevity-network/

What is Transhumanism?
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Via the Exception: "The doubling rate of medical knowledge is three years - that is, the next three years of medical research will yield as much knowledge as has been yielded in all of human history. The next three years will double our knowledge again, and again, and so on. This exponential growth in knowledge will rapidly enable us to eradicate disease and radically improve the human condition. Indeed, we will be able to look beyond curing the sick, towards a future in which we make ourselves more than healthy. We will be able to enhance our memory and our intellectual capacity. We will use technology to make ourselves faster, more efficient, and radically longer-lived. We will be able to augment our physical strength, stamina, and resistance to disease. We might enhance specific skills, such as visual acuity or musical talent. In the extreme, we will correct the molecular wear-and-tear that causes deterioration and death – reversing the aging process itself. Humans might even obtain entirely new capacities, such as infrared vision, or bat-like echolocation. The body of thought that deals with enhancement technologies is called transhumanism. In essence, transhumanists favor using technology to enhance mental and physical human capacities."

Link: http://exceptionmag.com/culture/society/000470/what-transhumanism?page=show

Ending Aging Translated into Russian
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A short Russian language blog entry provides we decadent Westerners with a picture of the cover of the translated version of Aubrey de Grey and Michael Rae's "Ending Aging".

Congratulations to those involved in the translation process: translation of a scientific work is never easy, especially when its focus is on research that is still cutting edge. Much of the crucial terminology in new fields is essentially made up from whole cloth or built of unusual compound words that draw on language roots and traditions of nomenclature that English and Russian may not have in common. In addition, precision of translation is important, as positions of understanding are built up over many succeeding steps - an incorrectly translated early stage can render whole pages of information nonsense.

Ending Aging is a dense, informative, and valuable book, as well as a call to action for an age in which we could, collectively, be doing far more to reverse the damage of aging than is presently taking place. The more people who have the chance to read Ending Aging, the better.

Bivalves in Aging Research
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You might recall that some species of clam live for as long as four centuries, and possibly longer. Others do not. Such differences between closely related species are an opportunity for researchers to uncover important mechanisms of longevity. From Ouroboros: "This invertebrate group includes species with the longest metazoan lifespan approaching 400 y, as well as species of swimming and sessile lifestyles that live just for 1 y. Bivalves from natural populations can be aged by shell growth bands formed at regular intervals of time. ... Extreme longevity of some bivalve models may help to analyze general metabolic strategies thought to be life prolonging, like the transient depression of metabolism, which forms part of natural behaviour in these species. ... One of the great advantages of bivalves is their variety: even though they're anatomically quite similar, they occupy a wide range of niches and consequently exhibit a large variation in aspects of their natural histories, including longevity. This makes clams and oysters excellent candidates for comparative biogerontology: studying organisms with basically identical body plans but wildly different lifespans allows us to focus more tightly on the features (molecular, cellular, systemic) that might explain the change in longevity. This theme is currently being developed - outside the mollusk community - into a large-scale project that will study dozens of species in four or five vertebrate clades."

Link: http://ouroboros.wordpress.com/2009/03/23/remain-clam-bivalves-as-models-for-aging-research/

Hyping Resveratrol
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I suspect that commercialization of resveratrol and other calorie restriction mimetics is going to reinforce an existing and undesirable view of longevity science - that it's all supplements and diet, that it's all slowing aging, that the "anti-aging" marketplace has legitimacy. This doesn't help generate support for serious attempts to repair the damage of aging and thus reverse aging - if the pill, supplement, and scam marketplace was going to help, we'd have seen some evidence of that already. But the contributions of the "anti-aging" marketplace (dietary supplements on one side and lies on the other) are largely distraction and disinformation: "The lure of eternal youth has produced a multibillion-dollar-a-year global marketplace full of potions and pills that, the manufacturers claim, can offer life-extending benefits. Amid the dizzying array, one substance is capturing prime time attention: resveratrol. Resveratrol advertisements - Reverse your biological clock! A miracle molecule! - are popping up everywhere, from the Internet to local health food stores. The stuff is even showing up in anti-wrinkle creams." Resveratrol doesn't even capture all the benefits of simply practicing calorie restriction, and slowing aging is a far worse outcome than reversing aging - the latter being a path that isn't any harder at this stage. Toiling to merely slow aging is the wrong, worse, and less helpful direction.

Link: http://www.boston.com/news/health/articles/2009/03/23/one_for_the_ages/?page=full

The First Rejuvenation Research Issue of 2009
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I'm sure you've all already noticed that Rejuvenation Research Vol 12 Number 1 is available online. I'm late as usual in pointing it out, but better late than never. I should draw your attention to one of the papers, "Unexpected Regeneration in Middle-Aged Mice", as the full PDF version is presently free for access in one of the journal publisher's occasional promotions.

Complete regeneration of damaged extremities, including both the epithelium and the underlying tissues, is thought to occur mainly in embryos, fetuses, and juvenile mammals, but only very rarely in adult mammals. Surprisingly, we found that common strains of mice are able to regenerate all of the tissues necessary to completely fill experimentally punched ear holes, but only if punched at middle age.

Although young postweaning mice regrew the epithelium without typical pre-scar granulation tissue, they showed only minimal regeneration of connective tissues. In contrast, mice punched at 5-11 months of age showed true amphibian-like blastema formation and regrowth of cartilage, fat, and dermis, with blood vessels, sebaceous glands, hair follicles, and, in black mice, melanocytes.

These data suggest that at least partial appendage regeneration may be more common in adult mammals than previously thought and call into question the common view that regenerative ability is lost with age. The data suggest that the age at which various inbred mouse strains become capable of epimorphic regeneration may be correlated with adult body weight.

Now this is interesting indeed. You'll recall the MRL mice that show unexpected regenerative powers, something that has been known for a few years now. What these researchers have shown is that several other species of lab-bred mice have similar unexpected regenerative capabilities. This leads me to expect that, in the years ahead, scientists will uncover a complex and interrelated network of controlling genes and biochemical processes that can be manipulated at several points to produce exceptional healing in mammals. That discovery process will look much like the ongoing work attending metabolic changes in calorie restriction - a lot of potential controlling genes, much confusion and contradiction in the early years, and progress to initial therapies on a timescale of 10 to 15 years.

On Terror Management Theory
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Thoughts from Ouroboros: "if an arbitrary belief serves to protect an individual from their fear of death, reminding them of their mortality will cause them to cling to and elaborate this belief. (The underlying edifice, terror management theory, deals with the way in which human minds navigate the double-bind of being simultaneously aware of our desire to preserve our lives and the technical impossibility of doing so.) The classical example of such a belief would be a religion promising an afterlife ... It also works just fine with a belief in which the individual, by dint of some combination of industry, sagacity and/or having been born in the right century, has a chance of not dying at all. A prediction: life extension advocates might tend to increase their estimation of the feasibility of significant longevity enhancement after being confronted by reminders of their own finite lifespans. (I know I feel a twinge even writing those words, so I suspect this prediction has some real teeth.)"

Link: http://ouroboros.wordpress.com/2009/03/18/love-death-and-terror-management-theory/

Living Scaffolds For Nerve Regeneration
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Via ScienceDaily: researchers "have engineered transplantable living nerve tissue that encourages and guides regeneration in an animal model. ... We have designed a cylinder that looks similar to the longitudinal arrangement of the nerve axon bundles before it was damaged. The long bundles of axons span two populations of neurons, and these neurons can have axons growing in two directions - toward each other and into the host tissue at each side. ... The constructs were transplanted to bridge an excised segment of the sciatic nerve in rats. Up to 16 weeks post-transplantation, the constructs still had their pre-transplant shape, with surviving transplanted neurons at the extremities of the constructs spanned by tracts of axons. Remarkably, the host axons appeared to use the transplanted axons as a living scaffold to regenerate across the injury. ... the constructs survived and integrated without the use of immunosuppressive drugs, challenging the conventional wisdom regarding immune tolerance in the peripheral nervous system."

Link: http://www.sciencedaily.com/releases/2009/03/090319160122.htm

Aubrey de Grey at TEDMED2009
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Biomedical gerontologist Aubrey de Grey will be presenting at TEDMED2009 in October. Registration is now open: "His research interests encompass the causes of all the accumulating and eventually pathogenic molecular and cellular side-effects of metabolism ('damage') that constitute mammalian aging and the design of interventions to repair and/or obviate that damage. He has developed a possibly comprehensive plan for such repair, termed Strategies for Engineered Negligible Senescence (SENS), which breaks the aging problem down into seven major classes of damage and identifies detailed approaches to addressing each one. A key aspect of SENS is that it can potentially extend healthy lifespan without limit, even though these repair processes will probably never be perfect, as the repair only needs to approach perfection rapidly enough to keep the overall level of damage below pathogenic levels. Dr. de Grey has termed this required rate of improvement of repair therapies 'longevity escape velocity.'" From the other side of the pro-longevity research community, David Sinclair of Sirtris is also presenting.

Link: http://www.tedmed.com/speakers#degrey

Towards a Cytomegalovirus Vaccine
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Cytomegalovirus (CMV) causes much of the decay of our immune system over the years by cluttering it up with uselessly specialized anti-CMV cells. Via EurekAlert!: "results of a trial involving 441 CMV-negative women give rise to optimism that a vaccine to prevent congenital CMV may be closer. Women who received the trial vaccine were 50 percent less likely to later become infected with CMV ... Aspects of CMV biology have caused skeptics to question whether it is possible to prevent infection through vaccination, explains ... The virus is well adapted to persist in an infected person and is readily passed from person to person through direct contact with numerous bodily fluids ... Healthy people typically experience no symptoms after being infected with CMV. There is a strong immune response to the initial infection, but this immunity cannot always prevent subsequent infections if a person re-encounters the virus. Finally, natural infection does not elicit a response sufficient to completely eliminate the virus. On the contrary, once a person is infected, the virus persists for life." A vaccine is a start, but it doesn't help those of us already damaged by exposure: some methodology must be developed to remove specialized immune cells and restore function rather than just prevent loss.

Link: http://www.eurekalert.org/pub_releases/2009-03/nioa-evs031609.php

Russian Media Coverage of Aubrey de Grey and SENS
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The Science for Life Extension foundation did a good job of marshalling up the Russian language media for Aubrey de Grey's recent trip to Moscow - I pointed out a good Russian media interview at the time. By way of their labors, and either Google or Yahoo!'s machine translation services (both of which produce fairly horrible results), a selection is provided herein. There's surprisingly little hype and mangling of the message beyond that produced by the translator automation.

The brave may want to dive right ahead into the audio and multimedia offerings:

And here are a range of print articles:

Aging: How to undo the verdict?

But what constitutes aging? The first group are those that occur in the body, starting from young age. The second are those that occur at the end of life. Defects and damage in the body accumulate and lead, eventually, to aging and death. To combat these processes now used two approaches. First - Geriatric, which offers a variety of means to hinder the processes that lead to aging. Second - Gerontology, examines why and how in the normal metabolism defects arise and how you can affect the metabolism. De Gray believes that both approaches are bad, and even the researchers involved in their study, does not believe that aging can be overcome in the near future.

The secret of eternal youth

Scientific lectures now rarely collect complete halls. But here both theme and persona of lecturer - everything straight-away cast a spell. Speech by British guest at the House of scientists gathered this full house.

In Moscow went scholar

Aubrey believes that the scientific and medical development [will be] improved faster than the accumulated damage in the body. This is the principle of [longevity escape velocity] escape from old age. As will become available first generation therapy, people get even more healthy 20-30 years old. During this time science and medicine will find new ways of strengthening and extension of health.

Scientist Aubrey de Grey

In fact, Aubrey is standing in the world scientific community. A doctoral thesis devoted to biology of aging. Defend it in Cambridge - one of the pillars of world science. And it does not promise instantaneous rejuvenation, asserting: fight with the old age - complex and long process. To be famous and created a Methuselah Foundation, which - funding for research to extend human life. Last year the fund has spent 2 million dollars worldwide. Now Aubry first came to Moscow - to seek allies.

Cellular technologies will bring to humanity a thousand years younger

Renowned gerontologist Aubrey de Gray is convinced that using cellular technology in the near future, life expectancy can be increased [by] 30 years

The first man, who live to 150 years, now may have 60

"I believe we can defeat aging in the near future. There is 50-percent chance that the man who was the first to live to 150 years old, is already live, and he is now 60 years old" - said De Gray on Saturday at a meeting with journalists in Moscow, organized by fund "Dynasty" and "Science for the extension of life."

Extravagant [Biogerontologist] Proposes the Methods of Retaining the Eternal Youth

Aubrey De Gray (Aubrey de Grey) - the world-famous British [biogerontologist] working in Cambridge, the chief editor of Rejuvenation Research, the only peer-reviewed academic journal devoted to effects on the aging process. His main research interests - the study of cellular and molecular damage in human aging, as well as the development of methods for the rejuvenation of the body based on the removal of lesions.

British gerontologist considers that life can be extended up to 1000 years

De Gray noted that most scientists agree that aging is not associated with [a] genetic program of self-destruction, supposedly rooted in the body, [but rather with] the accumulation of defects, damage, which then leads to disease and death.

Eternal youth is available in 30 years

"How do you feel about the participation of Russian research groups and organizations in your project?" - Asked Director Gray. "I have a lot of Russian colleagues in the UK and the U.S. - said the scientist. - We have not yet been funded gerontological research in Russia. But I see Russian scientists enormous scientific potential".

Death can be a bum beer

What such is old age? This is a breakdown in the organism as a result of the wear of some of its components. It means in order to avoid old age, it is necessary in time to change or to clean 'spare part'.

This week, staff met with the British [biogerontologist] Aubrey de Gray

Mr. de Gray, you are often accused of that, you're trying to "play God", doing research, which - extend [life]. How do you [respond to] these accusations?

- Deeply convinced that the reluctance to extend the life will be terrible crime against the "higher forces". After all, aging brings pain, suffering and infirmity, it kills people. All the major religions say that we are obliged to keep suffering to a minimum. If God wants us to live up to exactly 100 years old, he will find a way to realize their vision. The Holy Scripture does not indicate that we must not ease the [sufferings of] age.

Eternal youth is available in 30 years

"In the next 25-30 years will develop the first treatment, which would extend the healthy human life for 30 years", - promises to de Gray. However, a single treatment of old age will not be able to lead to a complete rejuvenation of the body. Soon, he again begins to accumulate damage, and possibly treat it will be increasingly difficult.

But these difficulties, according to de Gray, can be solved: "Progress in science is, and therapy will gradually improve".

The man who lives 1000 years has already been born

To prolong fleeting youth, to postpone inexorable old age, to conquer the diseases, which poison last year of the life of any person, these dreams disturb the imagination of people not of one hundred years. But the fantasy of scientists never stretched further 100-150 years of cheerful and healthy life.

Then came Aubrey De Gray and changed the course of ideas of people about the possibilities of science. Yes who is he, the agitator of scientific calmness?

I have omitted a bunch of others that are reprints in various different media outlets, but you get the idea. Engineered longevity through the application of science is an idea that the Russian media is receptive to, it seems.

A Few Cryonics Posts
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I've been meaning to point out a few posts on cryonics from elsewhere in the community, but it keeps slipping my mind. So here they are while I remember, starting with some areas ripe for improvement in the current practice of cryonics identified over at Depressed Metabolism:

Evidence Based Cryonics

There is an urgent need [for cryonics providers such as Alcor] to move from extrapolation based cryonics to evidence based cryonics. This will require a comprehensive research program aimed at creating realistic cryonics research models. It will also require vast improvements in the monitoring and evaluation of cryonics cases. The current debate should no longer be between advocates and opponents of standby and stabilization but about what stabilization procedures should be used by cryonics organizations given our current knowledge.

Microvasculature perfusion failure in cryonics

Under ideal circumstances cryonics patients are stabilized immediately after pronouncement of legal death by restoring blood flow to the brain, lowering temperature, and administering medications. In most cryonics cases, however, there is a delay between pronouncement of legal death and start of cryonics procedures. In some cases there are no stabilization interventions at all. Provided that these periods of warm and cold ischemia are not too long, such patients can still be perfused with a vitrification agent. But how thorough cryoprotectant perfusion (and thus vitrification) in these cases can be remains an unresolved issue.

The cryonics industry is still small, which means that despite the sterling efforts of those involved on the research and development side, little work has been done in the grand scheme of things, in comparison to the technology involved in any larger industry. Cryonics is still a good sight better than the alternative, but we shouldn't overlook the spacious room for improvement.

On that note, I see that Robin Hanson is offering to debate anyone for an hour on the topic of cryonics, and provides another of his examinations as to just how rational it is to be signed up for cryosuspension:

More precisely, if folks are reasonably smart about when to try to revive you, your total revival chance is something like a sum across all future times of such calculations, each one given no destructive failed prior attempt.

If you make 50K$/yr now, and value life-years at twice your income, and discount future years at 2% from the moment you are revived for a long life, but only discount that future life based on the chance it will happen, times a factor of 1/2 because you only half identify with this future creature, then the present value of a 5% chance of revival is $125,000, which is about the most expensive cryonics price now.

So cryonics might be an economically sound choice - based on the way in which people tend to value predictions about the future, and under Hanson's model - even when that prediction is for a low chance of success. This has similarities to the structure of Pascal's Wager, though I'm sure someone will be by to tell me why that's an inaccurate comparison.

Validating Animal Studies of Aging
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Most work on aging and longevity research involves the study of comparatively short-lived animals. It is important that scientists demonstrate this research to be relevant to human aging, however: "Studies of longevity in model organisms such as baker's yeast, roundworm, and fruit fly have clearly demonstrated that a diverse array of genetic mutations can result in increased life span. In fact, large-scale genetic screens have identified hundreds of genes that when mutated, knocked down, or deleted will significantly enhance longevity in these organisms. Despite great progress in understanding genetic and genomic determinants of life span in model organisms, the general relevance of invertebrate longevity genes to human aging and longevity has yet to be fully established. In this study, we show that human homologs of invertebrate longevity genes change in their expression levels during aging in human tissue. We also show that human genes encoding proteins that interact with human longevity homolog proteins are also changed in expression during human aging. These observations taken together indicate that the broad patterns underlying genetic control of life span in invertebrates is highly relevant to human aging and longevity."

Link: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2657003

Alzheimer's as Diabetes of the Brain
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The lifestyle risk factors for Alzheimer's disease look a lot like those for diabetes - in other words get fat and don't exercise and your brain will suffer. Some researchers propose that Alzheimer's is a form of diabetes: "Insulin is the hormone that allows cells, including some brain cells, to take up energy in the form of glucose. Proper insulin function in the brain appears necessary to the formation and maintenance of memories. And, crucially, a lack of insulin or insulin resistance is connected both to amyloid protein regulation and to the modification of tau proteins, which can cause tangles. In other words, insulin seems to hold up a conceptual umbrella under which the amyloid and the tangle camps might finally meet. ... Type 2 diabetes is also a risk factor for Alzheimer's and cognitive decline. In 2005, researchers at Brown showed that by knocking out insulin production and causing brain insulin resistance in rats, they could create a model of Alzheimer's, complete with plaques and abnormal accumulations of tau. ... Scientists have also described links between abnormal insulin and other hallmarks of Alzheimer's, such as oxidative damage and inflammation."

Link: http://www.slate.com/id/2213755/

Evaluating the Life Lost to Fat
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A topic I revisit here and at the Longevity Meme with depressing frequency is the damage done to health and longevity through holding on to excess body fat. There's a lot of denial on this topic, but it's hardly rocket science: the weight of scientific evidence clearly shows that extra fat increases the risk of all sorts of age-related conditions that will cut years from your life. Not to mention the years in which you're made more miserable than you would have otherwise been due to suffering those conditions.

Not all of the mechanisms by which fat tissue hurts us are fully understood, but enhanced levels of chronic inflammation seems to be one of them. Correlation with lack of exercise is no doubt another, given the large difference regular exercise can make to your healthy longevity over the years. We already know that rising levels of chronic inflammation are important in shaping the deterioration of the aging body, and it looks like extra fat tissue creates that issue earlier and in greater force than would otherwise be the case.

I noticed a popular press article today on one of the recent studies that links fat to a shorter, less healthy life:

The studies used Body Mass Index (BMI), a measurement that divides a person's weight in kilograms by their height squared in meters to determine obesity. Researchers found that death rates were lowest in people who had a BMI of 23 to 24, on the high side of the normal range. Health officials generally define overweight people as those with a BMI from 25 to 29, and obese people as those with a BMI above 30.

...

Peto and colleagues found that people who were moderately fat, with a BMI from 30 to 35, lost about three years of life. People who were morbidly fat - those with a BMI above 40 - lost about 10 years off their expected lifespan, similar to the effect of lifelong smoking.

Moderately obese people were 50 percent more likely to die prematurely than normal-weight people ... obese people were also two thirds more likely to die of a heart attack or stroke, and up to four times more likely to die of diabetes, kidney or liver problems. They were one sixth more likely to die of cancer.

This is in the same ballpark as other studies and reviews I've seen in past years. If you want a better chance of living longer, don't get fat - it's pretty much common sense.

A Mainstream Media Piece on Calorie Restriction
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The quality of these sorts of articles is slowly improving, though there are still the normal errors and biases lurking in the background. From the National Post: "As early as the 1930s, it was shown that calorie reduction could double the lifespan of rats. What's more, a 1988 study noted that mice on a calorie-restricted diet had a more youthful appearance, a higher activity level and a delay in age-related diseases, compared with those on an unrestricted feeding schedule. The first studies on the effects of caloric reduction on humans were done in the 1940s, when it was observed that Scandinavians, living on a diet in which their calories were restricted by 20% because of the hardships of the Second World War, showed a decrease in cardiovascular disease. More recently, investigations have shown that a reduction in body weight decreases the risk of Type 2 diabetes, hypertension, cardiovascular disease, dementia, and cancers of the breast, prostate and colon. Other researchers examined a group who had been on a calorie-restricted diet for six years and found they had improved blood fat profiles, lower fasting glucose and insulin levels, lower body fat and a reduced level of C-reactive protein, a measure of inflammation. Further work has shown a neurological benefit for a calorie-restricted diet. One study involving mice demonstrated that intermittent fasting helped to decrease the effects of degenerative brain disease."

Link: http://www.nationalpost.com/life/health/story.html?id=1395296

Telomere Length and the Sister Study
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Some more evidence that shortened telomere length correlates with conditions and risk factors that are known to be bad for your long term health: "One of the studies published this week found that women who were obese for a long time had reduced telomere length. The researchers looked at the relationship between various measures of current and past body size and telomere length in 647 women enrolled in the Sister Study. They found that women who had an overweight or obese body mass index (BMI) before or during their 30s, and maintained that status since those years, had shorter telomeres than those who became overweight or obese after their 30s. ... This suggests that duration of obesity may be more important than weight change per se, although other measures of overweight and obesity were also important. Our results support the hypothesis that obesity accelerates the aging process. ... women who reported above-average stress had somewhat shorter telomeres, but the difference in telomere length was most striking when we looked at the relationship between perceived stress and telomere length among women with the highest levels of stress hormones. Among women with both higher perceived stress and elevated levels of the stress hormone epinephrine, the difference in telomere length was equivalent to or greater than the effects of being obese, smoking or 10 years of aging."

Link: http://www.eurekalert.org/pub_releases/2009-03/nioe-fss031609.php

Aubrey de Grey's BIL Presentation
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Over at Future Current, you'll find a transcript of Aubrey de Grey's presentation at the BIL unconference. He goes into detail as to some of the research presently supported by the Methuselah Foundation, that funding made possible by generous donations from the pro-longevity community over the past few years. Such as:

A fantastic, originally Serbian immunologist called Janko Nikolich-Zubich, who is a prominent gerontologist and works in Tucson at the University of Arizona, has become very interested in the possibility of being more ambitious about repairing and rejuvenating the immune system than anyone has previously been. There are two major things that go wrong with the immune system during aging and they fall into two of seven categories that I always talk about. People have been exploring these things in isolation in a somewhat halfhearted sort of way for quite some time, but no one has had the balls to do them together.

I have managed to persuade Janko to do this. He is basically applying a combination therapy to mice whose immune systems are going downhill because of aging and seeing whether the immune systems can be really rejuvenated so that the mice are better at resisting infection, getting back to where they were in early adulthood. It is a reasonably long project, as is more or less any project involving the aging of mice, but it is already underway. It is being funded by the Methuselah Foundation and we are extremely happy about it.

If you look at Nikolich-Zubich's research brief, you'll see:

Diagnosis of the most critical, primary defects in innate and adaptive immunity of the old age is being followed by studies to repair or modulate those defects by immune intervention as well as by tailored, rational vaccine design. ...

The main virus targets of these studies are herpesviruses (HSV and CMV) and flaviviruses (chiefly the West Nile virus - WNV).

...

Another fascinating problem is the interaction of the immune system with life-long chronic and persisting pathogens from the herpesvirus family, and the impact of this interaction upon the aging immune system. These studies should pave way for the immune reconstitution and vaccine engineering experiments that will ameliorate and treat the undesirable consequences of immune senescence.

Cytomegalovirus (CMV) is the most interesting item here, because it seems to be a major culprit in degrading the immune system with age. While it doesn't cause much immediate harm, over time its presence causes more and more of the immune system's resources to be (uselessly) dedicated to fighting it, leaving little left for more critical tasks. You can look back in the Fight Aging! archives for more on that - there's a healthy body of investigative research publications on cytomegalovirus and its effects on the immune system over time.

Austad's Expectations
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Via the Tyler Morning Telegraph: "At least one person alive right now may live to be at least 150 years old. That's according to Dr. Steven Austad ... It seems a little far out but within a little more than 100 years in the United States, through medical research and the advances that have taken place, we have doubled life expectancy in the United States. If it doubles again we will hit that 150 year-old mark ... Your ancestry only accounts for a small amount. It turns out if you look into it, the length of time that you live is only about 25 percent affected by your genetics. How you live your life can have an enormous impact ... reasons some opposed the notion of developing drugs to delay aging are: fear that it will only preserve maladies but won't improve the quality of life; the naturalistic argument, in which people are lead by beliefs that we are not meant to tamper with the stages of life; the drug would only be available to select people; and shortages in resources including jobs and food due to a larger, older population. ... We've already made a decision as a society that things that benefit some people as long as it does not harm other people are OK. We're not going to stop all medical advances until we can make those advances to everyone. I think the history of medicine shows that new advances do tend to spread out and it may take a while ... or most of human history, humans' lifespan has increased. ... So why stop now?"

Link: http://www.tylerpaper.com/apps/pbcs.dll/article?AID=/20090314/NEWS09/903130335

An Interview With Aubrey de Grey
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An interview with biomedical gerontologist Aubrey de Grey at (Ciencia) x (Libre): "I meet Aubrey de Grey after his lecture at the CosmoCaixa Barcelona Museum. He’s had an intense day: several press, radio and television interviews in the morning, followed by a two hours lecture in front of a demanding public. ... de Grey is quite clear: aging is not inscribed in our genes, is the result of the accumulation of damage not repaired and that just ends up being fatal. Evolutionary biology says he is right: our genes allow us to live long enough to reproduce successfully, and after that [we] matter little at the 'eyes' of the selfish gene. If we repaired these damages in time [could] we not live a thousand years? ... most biogerontologists don't study ageing in order to figure out how to fix it: they study it as a phenomenon to be understood, rather in the same way that seismologist study earthquakes. You know [they] understand that earthquakes are sometimes quite bad for you, but they don't aspire to actually stopping them from happening. And most biogerontologists are the same, so that's why I call myself a biomedical gerontologist. I am not trying to use therapies that already exist, but I'm trying to develop new therapies that will actually do something about ageing."

Link: http://cienciaxlibre.wordpress.com/2009/03/15/interview-with-aubrey-de-grey/

The Chattering Classes on the Longevity Dividend
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Here are a couple of recent posts on the prospects for longevity engineering from the political blogger set, so focused firmly on what it means for policy - as for everything that gets discussed in that sphere. Very dreary after the first five minutes or so, but what do you expect? The more interesting artifacts are, I think, the comments to the second post, and that's where we see what that sort of circle really thinks about longevity research and the future.

The Longevity Dividend

The original justification for retirement was that by the time people reached a certain age, they were worn out and used up and deserved a few years of dignified leisure in their decline. But that idea is already changing as lives extend, and medical developments on the horizon suggest that it might change a lot more. Could we save our troubled pension systems by developing ways to keep people healthy, and working, much longer

...

But even much more modest progress--extending healthy middle age from 60 to, say, 80 - would permit significant shifts in retirement ages and allow for a longevity dividend that could go a long way toward preventing the looming pension meltdown.

Work Longer, Be Happier?

It wouldn’t be politically easy, of course, to shift grant money away from diseases toward more basic research to slow aging. Nor would it would be easy to raise the retirement age. But Mr. Reynolds argues that that most people - i.e., most voters - would be willing to work longer in exchange for better health. “Seems like there’s an opportunity here for a politician who’s willing to get ahead of the curve,” he says. What do you think? Would you take that bargain? And what kind of research would best benefit from this sort of shift?

I seem to recall bemoaning the culture of entitlement that underlies so much of public discourse. Where on earth does one get the idea that life and health without hard work is possible? It should go without saying that if you're alive and in good health, then you're going to be working one way or another - there's no such thing as a free lunch, and that roof over your head doesn't pay for itself. Enjoying your work and making the best of life is up to you, and in theory you should be getting pretty good at that task after a few decades of practice.

The Earnest Search For Longevity Mechanisms
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The work of Genescient provides good insight into what the search for longevity genes - and biological mechanisms of metabolism connected to aging - looks like these days. As more automation is applied to the search, the pace of discovery is picking up: "Using genetically selected long lived Drosophila and the latest genetic tools, Genescient has identified over 100 gene networks that are altered in long lived strains of Drosophila melanogaster and that are also linked to longevity and age-related diseases in humans ... We then make maps of networks pointing to the genes appearing in our proprietary list and their relationships. This elucidates possible human therapeutics to treat chronic diseases of aging and improve function. Once found, we then quickly test these compounds in Drosophila for their effects on median lifespan, background mortality, and the rate of aging at different doses. ... Because the selected Drosophila genetic pathways are also linked to conserved age-related disease genes in humans, direct therapeutic effects on human health can be expected. In our first attempts at selection using this screening procedure, we have already initially tested 13 compounds on normal flies. We found 12 that extend significantly the normal Drosophila lifespan, reduce background mortality rates, or slow the rate of aging."

Link: http://genescient.com/documents/science_primer.html

Healthy Life Extension At Convergence08
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From Future Current, a transcript of a panel on healthy life extension at Convergence08. Here, Aubrey de Grey points out that there are "an enormous number of millions of dollars already being applied to Alzheimer's research specifically over the developed world, added to all the other diseases of aging. The difficulty with that approach to combating these things is that by the time these diseases have gotten far enough along to actually be called diseases, things are getting pretty far out of hand and [intractable] ... The real reason why what I call 'the geriatrics approach' to combating aging is intractable is simply because it is not applying the really rather reliable principle of 'prevention is better than cure.' Essentially the targets for these interventions are consequences of stuff that is going on throughout life and progressively accumulates to result in various types of molecular and cellular damage that are side effects of our normal metabolism. As people get older, those side effects continue to accumulate. If you are attacking the side effects of those consequences, namely those particular diseases, then your job is just going to be getting harder and harder as time goes by. This geriatrics approach is therefore going to be a short-term approach, and a losing battle."

Link: http://www.acceleratingfuture.com/people-blog/2009/longevity-convergence/

The Open Access Journal AGING
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By way of Ouroboros we learn of a new open access journal on aging science, titled AGING. I'm always pleased to see the spread of open access science in the areas I'm interested in: it heralds faster research as barriers to the spread and analysis of knowledge are lowered.

AGING publishes high-impact research papers of general interest and biological significance in all fields of aging research including but not limited to cellular senescence, DNA damage and repair, organismal aging, age-related diseases, genetic control of aging from yeast to mammals, regulation of longevity, evolution of aging, anti-aging strategies and drug development and especially the role of signal transduction pathways in aging and potential approaches to modulate these signaling pathways to extend lifespan.

In the first issue, there are a couple of items of interest, amongst them a review paper on chromatin modifications and aging. This is a topic that has cropped up before, and is an aspect of epigenetics in aging:

Strictly speaking, 'epigenetics' refers to chromatin and DNA modifications that are heritable through cell division, but do not involve changes in the underlying DNA sequence ... Chromatin structure is not fixed. Instead, chromatin is dynamic and is subject to extensive developmental and age-associated remodeling. In some cases, this remodeling appears to counter the aging and age-associated diseases, such as cancer, and extend organismal lifespan. However, stochastic non-deterministic changes in chromatin structure might, over time, also contribute to the break down of nuclear, cell and tissue function, and consequently aging and age-associated diseases.

It's all still somewhat up in the air as to what is causing what with respect to chromatin changes, and this biochemistry is very complex. But take a look at the paper and see what you think.

Chromatin Modifications: The driving force of Senescence and Aging?

It has been well recognized that, as the mammalian cell ages, its chromatin structure evolves, both at a global level and at specific loci. While these observations are mostly correlative, recent technical developments allowing loss-of-function experiments and genome-wide approaches have permitted the identification of a causal relationship between specific changes in chromatin structure and the aging phenotype. Here we review the evidence pointing to the modulation of chromatin structure as a potential driving force of cellular aging in mammals.

...

if chromatin modifiers can directly contribute to the aging phenotype, what is the molecular circuitry leading to the modulation of their activities during the aging process, and may it be altered as a therapeutic means?

Decoys Versus RAGE
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I've mentioned the role of RAGE, the receptor for advanced glycation end-products (AGEs), in aging before. As AGEs build up, RAGE is ever more triggered, causing cells to act inappropriately. Cell receptors could be considered as keyboards or buttons - hit them with the right sort of molecules and you're instructing the cell to take action. This sort of errant instruction of cells is particularly important in age-related conditions where AGE levels are very elevated, such as diabetes, but is a damaging consequence of age-related increase in AGE levels for all of us. RAGE is "involved in a wide spectrum of diseases, including diabetes mellitus, atherothrombosis, chronic renal failure, rheumatoid arthritis, neurodegeneration, cancer and aging. Circulating soluble forms of RAGE (sRAGE) [may] counteract RAGE-mediated pathogenesis by acting as a decoy. Several studies suggest that decreased levels of sRAGE [may] be useful as a biomarker of [RAGE hyperactivity] and inadequate endogenous protective response." Past work supports this sort of intervention: "administration of the ligand-binding decoy of RAGE, soluble or sRAGE, suppresses early initiation and progression of atherosclerosis in diabetic mice."

Link: http://www.ncbi.nlm.nih.gov/pubmed/19275604

A Look Back at Deathism
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Michael Anissimov here looks back at deathism past: "One of the more memorable life extension debates I've been to was a summer 2007 meeting of the Bay Area Future Salon where Aubrey de Grey went up against William Hurlbut, who used to work under Leon Kass on Bush's Religious Right-dominated President's Council on Bioethics. Unlike Kass, who is laughed at and rejected by mainstream bioethics for his nutty, highly quotable opinions (much to the disappointment of Wesley J. Smith), Hurlbut is somewhat more sane-sounding. He is intellectual and often presents his ideas using reasonable rather than bombastic uber-conservative language. ... Read up on the debate between Aubrey and Hurlbut at Future Current. Hurlbut was being so sincere and honest that I almost felt sorry for him trying to argue his points in a room full of transhumanists. But then again, he wants us all to die at a predetermined age, so you can’t have too much pity. If I may be allowed to suggest a motto for Hurlbut's philosophy: 'Be a man. Die.'"

Link: http://www.acceleratingfuture.com/michael/blog/2009/03/hurlburt-on-the-unmanliness-of-life-extension/

Ouroboros at ETech
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Chris Patil of Ouroboros was at ETech to give a presentation:

To describe, in an accessible manner, recent progress and ongoing current work in understanding the basic biology of aging, including research currently being performed in his own lab group as well as subjects of interest in the broader field of biogerontology. From there, he will proceed to several ambitious, collaborative, interdisciplinary ventures currently getting underway. These include a new project, recently initiated by himself and others, that will compare dozens of animal species and ask questions about how natural selection has "tuned" longevity over the course of evolution - with the ultimate goal of achieving a greater understanding of the mechanisms limiting human longevity.

To defend the idea of intervening in the process of human aging, from the standpoint of quality of life, individual rights, and overall benefit to society. In the process, he will answer some of the major objections to extending human longevity, and also discuss the real social challenges resulting from various possible life extension technologies.

Though apparently it's not a great crowd for life science research and biotechnology. In one of his blog posts on ETech, he muses on the concept of "segmental longevity therapies", which I find intriguing:

I’m using the term in the sense of “segmental” progerias, conditions in which an organism expresses some but not all component of accelerated aging. What if the first longevity therapies are much better at dealing with one aspect of the aging process than others? For example, imagine a therapy that kept brains completely intact (no Alzheimer's) but was lousy at maintaining the musculature - or even more problematically, vice versa. Obviously we’re not going to design therapies to ignore specific systems, but on the other hand, we’re not in tight control over what sorts of technologies are going to emerge (or come into wide use) first. The first longevity therapies may well be segmental, whether or not they 'ought' to be. What are the ramifications of that?

This doesn't seem unlikely on the face of it. For example, consider the outcome if the first meaningful therapy out of the gate is the repair of mitochondrial damage, and nothing else gets off the ground for a decade following that. Repairing mitochondria seems plausibly likely to help everything except cancer. Equally, if effective repair of age-damaged immune systems is first to market, that helps suppress cancer and the consequences of sensencent cells, amongst all the other jobs of the immune system, but doesn't do much for things like muscle loss, cardiovascular disease, Alzheimer's, and so forth.

The ramifications that spring to mind are that (a) these therapies will be reduced in effectiveness of extending life by other limiting conditions, (b) we'll want researchers to work in parallel on all the modes of age-related damage such that those limits are all pushed out at the same time.

Calorie Restriction Versus Cancer
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Via Newswise, a look at the mechanisms behind the interaction of calorie restriction and tumor growth: "The connection between food consumption and tumor growth is not new. In the early 20th Century, scientists first noted the correlation between a restricted diet and decreased tumor size and incidence. However, some cancers' growth rate was unaffected by a decrease in food consumption. The reason for this difference remained unclear. ... researchers have [now] pinpointed a cellular pathway that determines whether cancerous tumors respond to dietary restriction during their development. Studying human cancer cell lines in mice, researchers have found that when this pathway, known as PI3K, is activated permanently via mutation, tumors grow and proliferate independent of food consumption. However, when the PI3K pathway operates normally, dietary restriction (defined as a 60% reduction in normal intake), results in smaller tumors. ... We already know that the United States has an epidemic of obesity and that obesity is probably the biggest contributor to cancer in the U.S., even more so than smoking. Does this research have anything to do with that correlation between obesity and cancer, that if we make animals really obese, that this pathway is also involved in determining their sensitivity to cancer? Answering that question is the next step."

Link: http://www.newswise.com/articles/view/549948/

Guided Tissue Self-Assembly
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From the MIT Technology Review: "Cells coated with sticky bits of DNA can self-assemble into functional three-dimensional microstructures. ... Unlike top-down methods, in which scientists build cell structures on scaffolds, the new technique allows tissue engineers to dictate the precise geometric interactions of individual cells. ... So far these microstructures are rudimentary - far from the structural sophistication of a whole organ. But by tweaking the ratio of cell types, the density of DNA on the cells' surfaces, and the complexity of the DNA sequences, [researchers] hope to build larger and more intricate assemblies. ... even if this technique turns out not to scale up well [it] could in principle provide structural building blocks for use in other emerging bottom-up approaches, such as layer-by-layer tissue printing or laser manipulation. ... It has a lot of potential, and it may provide therapies in the future, but other challenges need to be overcome to make a clinically viable product."

Link: http://www.technologyreview.com/printer_friendly_article.aspx?id=22274

An Interesting Perspective on Neurodegeneration
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This open access paper outlines an interesting perspective on the origins of the many common forms of age-related neurodegeneration, such as Alzheimer's disease:

The present article examines several lines of converging evidence suggesting that the slow and insidious brain changes that accumulate over the lifespan, resulting in both natural cognitive aging and Alzheimer's disease (AD), represent a metabolism reduction program. A number of such adaptive programs are known to accompany aging and are thought to have decreased energy requirements for ancestral hunter-gatherers in their 30s, 40s and 50s. Foraging ability in modern hunter-gatherers declines rapidly, more than a decade before the average terminal age of 55 years. Given this, the human brain would have been a tremendous metabolic liability that must have been advantageously tempered by the early cellular and molecular changes of AD which begin to accumulate in all humans during early adulthood. Before the recent lengthening of life span, individuals in the ancestral environment died well before this metabolism reduction program resulted in clinical AD, thus there was never any selective pressure to keep adaptive changes from progressing to a maladaptive extent.

I can't say I'm completely sold on the high level conclusion, which seems to depend on relatively unsupported assumptions about the dominant selective pressures acting during specific decades of primitive hunter-gatherer life. Some thought-provoking points are made along the way, however, so I encourage you to read the whole thing.

All humans begin to develop the neurological markers of AD during their early 20s and continue to do so throughout life, most towards clinically irrelevant degrees. But why would these markers present in everyone? How could natural selection have allowed them to become so invasive and ubiquitous if they did not hold some sort of evolutionary significance?
Engineering a Capillary Network
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Creating networks of tiny blood vessels is a major hurdle in tissue engineering. Fortunately, many groups are working away on a variety of strategies to address this issue. From Chemical Science: "Candy floss (also known as cotton candy) has been used by US scientists to create a web of microscopic tubes to mimic the capillary network that carries blood to human tissue. [Researchers] mimicked the capillary network structure by sticking two sugar rods to a candy floss ball. They poured a molten polymer over the candy floss, left it to solidify, then dissolved the sugar, leaving a complex network of channels connecting two larger inlet and outlet channels. They then injected fluorescently labelled blood into the system and followed its progress using a video fluorescence microscope. They found that the blood flowed through as it would in a real system. [This] method addresses a limitation in tissue engineering: how to make an artificial vascular system for the new tissue. Since blood can only diffuse a few hundred micrometres from a capillary, organs need these networks to deliver oxygen and nutrients to every cell. His technique is cheaper and less time consuming than existing methods for making the networks, such as layer-by-layer 2D structure stacking or 3D printing, where templates for growing cells are built up."

Link: http://www.rsc.org/Publishing/ChemScience/Volume/2009/04/Making_capillaries_candy_floss.asp

Regrowing Stroke-Damaged Brain Tissue
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From ScienceDaily: "scientists reveal how they have replaced stroke-damaged brain tissue in rats. ... by inserting tiny scaffolding with stem cells attached, it is possible to fill a hole left by stroke damage with brand new brain tissue within 7 days ... Previous experiments where stem cells have been injected into the void left by stroke damage have had some success in improving outcomes in rats. The problem is that in the damaged area there is no structural support for the stem cells and so they tend to migrate into the surrounding healthy tissues rather than filling up the hole left by the stroke. ... Using individual particles of a biodegradable polymer called PLGA that have been loaded with neural stem cells, the team of scientists have filled stroke cavities with stem cells on a ready-made support structure. ... This works really well because the stem cell-loaded PLGA particles can be injected through a very fine needle and then adopt the precise shape of the cavity. In this process the cells fill the cavity and can make connections with other cells, which helps to establish the tissue ... We would expect to see a much better improvement in the outcome after a stroke if we can fully replace the lost brain tissue, and that is what we have been able to do with our technique."

Link: http://www.sciencedaily.com/releases/2009/03/090308222732.htm

The Present Bottom Line on Calorie Restriction
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I noticed a recent review paper that does a good job of summing up the present consensus on the practice of calorie restriction - eating fewer calories while still obtaining all the necessary micronutrients - in humans:

There are currently no interventions or gene manipulations that can prevent, stop or reverse the aging process. However, there are a number of interventions that can slow down aging and prolong maximal lifespan up to 60% in experimental animals. Long-term calorie restriction without malnutrition and reduced function mutations in the insulin/IGF-1 signaling pathway are the most robust interventions known to increase maximal lifespan and healthspan in rodents.

Although it is currently not known if long-term calorie restriction with adequate nutrition extends maximal lifespan in humans, we do know that long-term calorie restriction without malnutrition results in some of the same metabolic and hormonal adaptations related to longevity in calorie restriction rodents. Moreover, calorie restriction with adequate nutrition protects against obesity, type 2 diabetes, hypertension and atherosclerosis, which are leading causes of morbidity, disability and mortality.

...

More studies are needed to elucidate the molecular mechanisms underlying the beneficial effects of calorie restriction in humans and to characterize new markers of aging/longevity that can assist clinicians in predicting mortality and morbidity of the general population.

It should be clear by now that even absent significant longevity benefits in humans, there are many very good reasons to be practicing calorie restriction - such as a much better chance to avoid the common conditions that cut people short in later life. Every additional year of healthy life you can engineer for yourself is an extra year you can wait for longevity science to advance to produce methods of repair for the damage of aging. At the present pace of basic research, enabled by biotechnology that continues to improve at a breakneck rate, a few years is a significant length of time.

Towards an End to Metastasis
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If we could shut down metastasis, cancer would be a far less dangerous proposition, open to a broader range of less harmful therapies: "Cancer metastasis, where the cancer spreads from its original location, is known to be responsible for 90% of cancer-related deaths. ... scientists have found that an enzyme called LOX is crucial in promoting metastasis ... Drugs to block this enzyme's action could keep cancer at bay ... The researchers studied breast cancer in mice, but are confident that their findings will apply to humans with other cancer types too. LOX (lysyl oxidase) works by sending out signals to prepare a new area of the body for the cancer to set up a camp. Without this preparation process the new environment would be too hostile for the cancer to grow. ... it was the first time one key enzyme has been identified as responsible for effectively allowing the cancer to spread. ... the next stage will be to find out if the LOX protein can be switched off to stop cancer spreading."

Link: http://news.bbc.co.uk/2/hi/health/7813072.stm

The Gavrilovs on Aging and Evolution
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Some of the basics on aging and evolution are covered again in this Psychology Today article: "How does it happen that, after having accomplished the miraculous success that led us from a single cell at conception through birth and then to sexual maturity and productive adulthood ... the developmental program formed by biological evolution fails even to maintain the accomplishments of its own work? ... humans need to have a life expectancy of only twenty-five to ensure continuance of the species. We are well equipped to reproduce as teens, and a life expectancy of twenty-five left us with enough young-elders to pass on the full amount of culture needed to survive and evolve on the African plain to our current biological form. Not only old age, but middle-age appears to be totally irrelevant to survival. ... The mutation accumulation theory embodies the idea that [a] mutant gene that kills children will not be passed on to the next generation, but a negative gene - e.g., Alzheimer's disease - will be neutral to natural selection. Over time, these genes [will] survive and accumulate in the human population. Related to mutation accumulation is the antagonistic pleiotropy theory, which is the idea that some genes that have a survival value for reproduction carry within themselves negative effects as we age. Pleiotropic genes have more than one effect--in aging, antagonistic effects."

Link: http://blogs.psychologytoday.com/print/3712

More Scientist Bloggers Sought By Ouroboros
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The eminently respectable group blog Ouroboros, focused on the biology of aging and related aging research, is looking for more scientist bloggers to swell their ranks:

Do you want to write for Ouroboros? The three main criteria are as follows:
  • Be a working scientist in a field relevant to the biology of aging.
  • Have strong English writing skills, and a perfectionist streak about your prose.
  • Be willing and able to commit to writing a ~500-word post based on a recent journal article about the biology of aging, around once every two weeks.

Writers tend to converge on subjects that interest them, so it would be nice if you had a sense of what sort of pieces you’d like to cover. Our current contributors are working on calorie restriction, transcriptomics and systems biology, telomeres, and mitochondria - but that leaves a lot of ground un-covered.

Writing about science for an open audience is an excellent opportunity for young researchers in this field to broaden their pool of connections and hone their writing skills while at it. If you know of anyone who might fit the criteria and be interested, send them over.

Faking Calorie Restriction
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Via the Times of India, which somewhat misses the point by focusing on sugar rather than food in general: "over-consumption of sugar is directly linked to ageing. The researchers, however, say that it's not sugar itself that is important in this process, but rather the ability of cells to sense its presence, that affects the lifespan of a person. ... the study found that if they removed the gene for a glucose sensor from yeast cells, they lived just as long as those living on a glucose-restricted diet. This implies that the fate of these cells doesn't depend on what they eat, but on what they think they're eating, according to the researchers. ... It was found that the lifespan of yeast cells increased when glucose was decreased from their diet. ... They then asked whether the increase in lifespan was due to cells decreasing their ability to produce energy or to the decrease in signal to the cells by the glucose sensor. The scientists found that cells unable to consume glucose as energy source are still sensitive to the pro-aging effects of glucose. On the other hand, obliterating the sensor that measures the levels of glucose significantly increased lifespan." It will be interesting to see whether this is also true - and/or useful - in mammalian cells, and perhaps the basis of a different approach for calorie restriction mimetics.

Link: http://timesofindia.indiatimes.com/Lifestyle/articleshow/4233765.cms

Aspiring to Longevity
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A somewhat rambling and superficial look at aspirations to longevity, scientific and poetic, from the Vancouver Sun: "Now, say some longevity experts, [greatly extended healthy life] may be within reach of scientists working in air-conditioned labs to unravel the genetic code, map the hidden processes of the immune system, explore nanotechnologies that could make possible repairs to body structures too tiny to see and to develop ways to grow or construct and then safely install new or synthetic body parts. We don't blink at new hip joints, transplanted heart valves or minuscule plastic lenses that unfold inside the eye like flowers following cataract surgery, longevity advocates argue, so what's surprising about the looming possibility of even more extensive and complex replacements? ... We are now beginning to talk about curing old age. It really does look as though there is no fixed, non-changeable upper limit to life span. ... replacing damaged organs to greatly extend the human lifespan by substituting young and healthy for old and failing is no longer science fiction. ... if trends in increasing life expectancy are sustained or accelerated by medical breakthroughs, then it certainly seems plausible to speculate that somebody alive today might indeed still be living in 2159."

Link: http://www.vancouversun.com/Life/story/1360075/story.html

Replacing a Damaged Stem Cell Population
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You might recall that a combination of chemotherapy and introduction of new immune system stem cells has been used to successfully "reboot" a damaged immune system in a number of different early trials, thereby curing an autoimmune disease. Judging from this research I noticed today, the strategy seems to work for damaged muscle stem cell populations as well:

An experimental procedure that dramatically strengthens stem cells' ability to regenerate damaged tissue could offer new hope to sufferers of muscle-wasting diseases such as myopathy and muscular dystrophy, according to researchers from the University of New South Wales (UNSW). The world-first procedure has been successfully used to regrow muscles in a mouse model, but it could be applied to all tissue-based illnesses in humans such as in the liver, pancreas or brain, the researchers say.

The research team, which is based at UNSW and formerly from Sydney's Westmead Children's Hospital, adapted a technique currently being trialled in bone marrow transplantation. Adult stem cells are given a gene that makes them resistant to chemotherapy, which is used to clean out damaged cells and allow the new stem cells to take hold.

...

"The beauty of this technique is that chemotherapy makes space for stem cells coming into muscle and also gives the stem cells an advantage over the locals. It's the first strategy that gives the good guys the edge in the battle to cure sick tissues,"

...

"In muscle, most stem cells die in the first hour or are present in such low numbers that they are not much help," Professor Gunning said. "Until now, the new healthy cells had no advantage over the existing damaged tissue and were getting out-competed.

Destroy the old and replace with the new: this approach to regeneration is in its infancy, but it holds a great deal of promise for dealing with the damage of aging in stem cell populations. All development is focused on specific diseases at the moment - a situation forced upon us by regulatory bodies who deny approval for therapies for aging - but the technology platforms produced can then be applied to age-related damage in a more enlightened time or place.

The chemotherapy is the ugly part of the equation for the moment, a deeply unpleasant procedure that no right-minded person would ever undertake without good cause. Fortunately, the development of methods for killing specific cell populations with few or no side effects is also advancing rapidly. One can evisage a future not so many decades away in which our stem cell populations are routinely destroyed and replaced every thirty years or so to eliminate accumulated damage that reduces their effectiveness.

The Path to Synthetic Organs
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Yet another path towards replacement - or even additional, completely novel - organs is examined at EurekAlert!: researchers "have assembled different types of genetically engineered cells into synthetic microtissues that can perform functions such as secreting and responding to hormones, promising more complex biological capabilities than a single cell alone could produce. ... This is like another level of hierarchical complexity for synthetic biology. People used to think of the cell as the fundamental unit. But the truth is that there are collections of cells that can do things that no individual cell could ever be programmed to do. We are trying to achieve the properties of organs now, though not yet organisms. ... While the synthetic tissues today comprise only a handful of cells, they could eventually be scaled up to make artificial organs that could help scientists understand the interactions among cells in the body and might some day substitute for human organs. ... In principal, we might be able to build a stem cell niche from scratch using our techniques, and then study those very well defined structures in controlled environments."

Link: http://www.eurekalert.org/pub_releases/2009-03/uoc--aci030409.php

Dopamine Neurons From iPS Cells
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Via EurekAlert!: "researchers have developed a novel method to remove potential cancer-causing genes during the reprogramming of skin cells from Parkinson's disease patients into an embryonic-stem-cell-like state. Scientists then used the resulting induced pluripotent stem (iPS) cells to derive dopamine-producing neurons, the cell type that degenerates in Parkinson's disease patients. This marks the first time researchers have generated human iPS cells that have maintained their embryonic stem-cell-like properties after the removal of reprogramming genes. ... Until this point, it was not completely clear that when you take out the reprogramming genes from human cells, the reprogrammed cells would actually maintain the iPS state and be self-perpetuating ... Because [dopamine neurons] reside in the patients' brains, researchers cannot easily access them to investigate how the disease progresses at the cellular level, what kills the cells, or what might prevent cellular damage. Therefore, the ability to create patient-specific iPS cells, derive the dopamine-producing cells, and study those patient-specific cells in the lab could be a great advantage for Parkinson's disease researchers."

Link: http://www.eurekalert.org/pub_releases/2009-03/wifb-bpp030309.php

Instructing the Immune System
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The immune system - even an age-damaged, failing immune system - is a powerful tool. The challenge is that we don't really know how to effectively use it; vaccines, for example, are a very crude method of instruction. All this will change in the next decade or two as the biotechnology revolution rolls on, and here is an example of the sort of thing we can look forward to: "while vaccines prepare antibodies to identify an attacker, they often don't give specific instructions on exactly how to bring it down. Some antibodies may successfully hit a pathogen's weak spot, while others may miss the mark entirely. That's part of the reason why it normally takes several weeks or months for some vaccines to build up an effective immune response. Now [researchers] have developed preprogrammed chemicals that bind to antibodies and tell them how to recognize part of a pathogen, known as its epitope. In experiments, the team found that such chemicals prompted a therapeutic immune response that inhibited the growth of two types of tumors in mice. ... It's appealing as an approach. It's a way to get instant immunization as opposed to waiting for kinetics to develop T cell responses." Clinics of the not-so-distant future may well be places where our immune system is enhanced to accurately protect us from cancer, senescent cells, and a far greater range of pathogens than is presently the case.

Link: http://www.technologyreview.com/printer_friendly_article.aspx?id=22243

Telomeres and Autoimmune Disease
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An interesting correlation to add to the others involving telomerase:

In rheumatoid arthritis, T cells are chronically over-stimulated, invading the tissue of the joints and causing painful inflammation. This derangement can be seen as a result of the loss of the immune system's ability to discriminate friend from foe

...


"What we see in rheumatoid arthritis is an aged and more restricted T cell repertoire," she says. "This biases the immune system toward autoimmunity."

...

They found the answer in telomerase, the enzyme that renews telomeres and is necessary to prevent loss of genetic information after repeated cell division.

...

T cells are some of the very few cells in adults that can turn on telomerase when stimulated, probably because they have to divide many times and stay alive for decades. Weyand and Fujii found that T cells from patients with rheumatoid arthritis make 40 percent less telomerase enzyme when stimulated.

The researchers suggest that restoring telomerase to T cells could possibly help reset the immune system and halt rheumatoid arthritis, but I think that remains as a conjecture to be proven. Is there a slippery slope of declining telomerase for some people, ending up with immune systems that fall into disfunction at earlier ages? Or does some other aspect of this particular autoimmune disease cause the drop in telomerase production? Identifying the cart and the horse here isn't straightforward.

Telomerase is tied in to more than just telomeres: it seems to influence mitochondrial function as well. Variations in telomerase activity and telomere length are clearly associated with aging and specific age-related conditions, but it's far from clear how it all links together, and all of the interesting new research results I'm aware of from the past couple of years have served to complicate the picture.

The Importance of the Stem Cell Environment
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Research indicates that a future path for stem cell therapies might involve manipulating the cells' immediate environment in ways that reprogram those cells in specific, controllable ways: "We found that adult human mammary stem and progenitor cells exhibit impressive plasticity in response to hundreds of unique combinatorial microenvironments. Our results further suggest that rational modulation of the microenvironmental milieu can impose specific differentiation phenotypes on normal stem or progenitor cells, and perhaps even [restore cancerous cells to normal behavior]. All of this points to the rational manipulation of adult stem and progenitor cells as a promising pathway for beneficial therapies ... Working with unique microenvironment microarrays (MEArrays) [we] can use combinations of proteins from a select tissue to create multiple microenvironments on a single chip about two square centimeters in area ... These results are exciting because they indicate that we can test a large number of effectors and determine which ones to use to direct the fate of adult stem and progenitor cells. This give hope that one day - sooner rather than later - the information could be used for therapy."

Link: http://www.sciencedaily.com/releases/2009/02/090227093558.htm

SIRT1 Sits at the Center of a Web
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In a complex, evolved system like our cells, everything connects to everything else. Evolution is adept at generating systems with a lot of reuse, feedback loops, and the same component performing multiple simultaneous jobs. It does make it very challenging for researchers to determine what is going on in our metabolism, however. Isolating a gene and the protein it produces because it is important to a cellular process you are interested in barely gets your foot into the door - then must follow years of tracing relationships to other genes, proteins, mechanisms, and so forth.

Over recent years it has become clear that the gene SIRT1 is important to the health and longevity benefits of calorie restriction. It has also become clear that SIRT1 is very well connected inside the cell, being involved in any number of aspects of our metabolism. So while, for example, one group has good evidence that SIRT1 works by promoting repair processes involving heat shock proteins, we also see that is important to the regulation of autophagy, another process well-linked with health and longevity benefits.

SIRT1: Regulation of longevity via autophagy

Recent studies have emphasized the importance of SIRT1, a mammalian homolog of Sir2 longevity factor, in the regulation of metabolism, cellular survival, and organismal lifespan. The signaling network interacting with SIRT1 continues to expand as does the number of functions known to be regulated by SIRT1.

Autophagy is also an emerging field in longevity studies. [Autophagy] is a housekeeping mechanism cleaning cells from aberrant and dysfunctional molecules and organelles. The extension of lifespan has been linked to the efficient maintenance of autophagic degradation, a process which declines during aging. Interestingly, recent observations have demonstrated that SIRT1 regulates the formation of autophagic vacuoles, either directly or indirectly through a downstream signaling network.

...

The interactions of SIRT1 [can] also regulate both the autophagic degradation and lifespan extension emphasizing the key role of autophagy in the regulation of lifespan.

Interesting, altering SIRT1 on its own, such as through the use of calorie restriction mimetic drugs, doesn't appear to gain anywhere near the entire benefit of calorie restriction. So other mechanisms are at work in addition to those uncovered through exploring SIRT1's connections.

Another Media Article on Intermittent Fasting
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The health benefits of intermittent fasting - practiced as a form of calorie restriction - seem to be the flavor of the week. Here's an article from the Independent: "a mounting body of evidence is hinting strongly at the therapeutic value of intermittent fasting - of taking the occasionally day - weekly or monthly, perhaps - off food altogether. Much of that evidence comes from [a] 'quite large body of results' from animal studies. Mattson explains that in laboratory tests, rats and mice on fasting diets tend to live longer, develop fewer cancers and show reduced cognitive decline in ageing compared with animals with continuous access to food. A few recent human studies seem to back up the view that intermittent fasting, and calorie restriction more generally, are fertile areas for healthcare research. ... Studies on animals suggest this is a protective response. At a cellular level, the dearth of food prompts a mild stress reaction. ... We've seen this with brain cells and also liver and heart cells. Mild stress prompts an increase in production of stress-resistant proteins ... Thanks to almost universally encouraging results from animal studies, several are already under way or in the pipeline. It's not inconceivable that in the next few years doctors will be recommending intermittent fasting in the same breath as five-a-day and regular exercise."

Link: http://www.independent.co.uk/life-style/health-and-wellbeing/features/the-nofood-diet-1635808.html

Sidestepping the Blood Vessel Issue
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A major challenge in tissue engineering lies in generating the intricate network of blood vessels necessary for any mass of tissue. Researchers are making progress on strategies to deal with that issue, however: "Efforts to use tissue engineering to generate whole organs have largely failed primarily due to the lack of available blood vessels. Now we've essentially hijacked an existing structure to overcome this problem ... The researchers capitalized on a portion of the circulatory system shared by animals and humans called microcirculatory beds ... This is an incredible opportunity to bulk-deliver cells that don't just die. Conceivably, we could use this technique at least to supply the synthetic function of an organ by stimulating the cells to form insulin-producing pancreas cells or albumin-producing liver cells. ... The researchers concede, however, that much remains to be done before the technique could be used to generate whole organs. Indeed, [other] methods might be developed that could be more effective. But for now, they've overcome a major hurdle in tissue engineering. ... Eventually science will find a way to fabricate an organ in all its complexity. But in the short term we need to find more options for patients who are dying while waiting for transplants."

Link: http://www.sciencedaily.com/releases/2009/02/090226110657.htm

Shunning Advances Through the Instinct to Equality
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It is not uncommon to see people suggest that efforts to extend healthy life should not take place while there is great suffering and poverty in the world. These is something deeply hardwired into the way our brains work that leads to an instinctive rejection of disparity in wealth - or at least a rejection of that guy over there having more wealth. As this bioethicist puts it:

When I talk to people about my interests in [engineering greater healthy longevity through science] are a number of reservations and concerns they have. Let me briefly identify, and address, two of them: (1) many feel that talk of retarding human aging sounds like mere science fiction; and (2) many express the viewpoint that it is distasteful to worry about decelerating aging when there is so much poverty and disease in the world.

But the instinct that leads to rejecting longevity engineering is a patchy one that leads us falsely. You don't see many of these people giving up their comfortable lifestyle because it is better than poverty. You also don't see many of them decrying the progress of the past century that has led to better medicine - all accomplished while there was much poverty and disease in the world. They accept the beneficial progress that has taken place while at the same time recoiling from more beneficial progress accomplished under the same circumstances.

This is an issue rather than a depressing curiousity because widespread support is needed if engineered longevity is to make progress at a rapid pace. That same bioethicist believes this is a matter for persuasion and education:

One might wonder why, given all the pressing issues facing women in the world today, that they ought to add aging and longevity science to the list of things to address. "Is it really a priority?" one might ask. "Is it a priority in a world with disease and poverty?"

This is a fair question. And the answer is "YES!". Why? Because most disease in the world today is caused by aging. Now you won't find data from the World Health Organization that states that explicitly. But what you will find are the data concerning the proximate (rather that evolutionary) causes of morbidity and mortality. But behind the proximate causes of most human deaths (like cancer and heart disease) are the biological processes of aging. In other words, it is not a coincidence that most people who suffer disease and death today are over age 60. The vulnerabilities of late life reflect the tradeoff that natural selection has made between the fitness of a parent and reproduction. Natural selection favors a strategy in which organisms invest fewer resources in the maintenance of somatic cells and tissues that are necessary for indefinite survival of the individual (source).

The enormous and unprecedented disease burden the world will experience this century makes vivid the human toll of this tradeoff. Take the year 2005, the latest year that one can easily find the stats from the World Health Organization. Approximately 55 million people died in 2005. Of that number, 35 million died of chronic disease. That number is twice the number of deaths due to infectious diseases (including HIV/AIDS, tuberculosis and malaria), maternal and perinatal conditions, and nutritional deficiencies. That is a staggering figure. Furthermore, between the years 2005-2015 WHO estimates that 220 million people will die from chronic disease, most of them (144 million deaths) in lower middle income countries like China and India. The diseases associated with aging are not, contrary to popular perception, only a problem for people living in the developed world. Indeed, being vulnerable to disability and frailty is a much greater disadvantage if one lives in a poor society with no decent health care or pension, as the link between income and "ability to work" is much more direct. So the chronic diseases associated with aging are a problem for all societies, not only the richest countries in the world.

Which is nicely done, presenting facts to change minds without attempting the much harder task of addressing the underlying prejudice against unequal progress. I'd prefer to live in a world in which it was realistically possible to bring entire populations to a greater understanding of economics, such that only a few people instinctively seek to block progress in the name of equality, but I don't believe that this is such a world.

Threads Made of Stem Cells
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The infrastructure technologies required for the application of rapid prototyping to tissue engineering - "printing out" entire organs to order - continue to advance: "A new trick invented by a team of [scientists] has greatly improved the chances for creating artificial tissue - they can weave threads made of stem cells into almost any shape. Ultimately this could lead to artificial transplants, with the resulting synthetic tissue able to adapt to many different purposes. ... Stem cell research is centered around two things--[controlling cellular differentiation] and determining how to structure networks of the cells to create large-scale artificial tissue. There are a number of techniques for doing this, including ink-jet-like printing, but the new method can create 'printed' line-based structures of embryonic stem cells for the very first time. And interestingly it's a technique borrowed from the paint industry: electrospraying. Instead of directing a fluid through a nozzle simply using the force from compressed gas, electrospraying charges the fluid and accelerates it between the nozzle electrode and a distant 'target' electrode--among other things, this allows for fine control of the spraying process."

Link: http://www.fastcompany.com/blog/kit-eaton/technomix/new-stem-cell-trick-could-lead-print-out-organs

The Tartan on Aubrey de Grey
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An article from the Carnegie Mellon student newspaper on biomedical gerontologist Aubrey de Grey: "People like to characterize me as an immortalist. What I'm interested in doing is helping people from getting sick. ... Life extension research is a controversial topic - partly because the National Institutes of Health (NIH) does not classify aging as a disease. ... Metabolism is not understood well enough to be improved upon, and so it is not possible to prevent damage from occurring. The disease, resulting from large concentrations of damage, can only be reined in for a while - some time can be bought - before other problems stemming from the still-present damage become apparent. Given that it is difficult either to prevent the damage from occurring or to control the effects of damage, de Grey offers a third strategy: limit the damage. As long as damage is kept below a certain threshold, he claims, we can indefinitely postpone the corresponding disease, a process that de Grey calls 'the engineering approach.' ... These [prospective] treatments are what de Grey collectively refers to as SENS, which he opines may lead to 'robust human rejuvenation,' the total circumvention of the aging process. The Methuselah Foundation, of which he is a co-founder, offers a cash prize to the research team that extends the life of the common laboratory mouse."

Link: http://thetartan.org/2009/3/2/scitech/aubrey