Thoughts and a couple of charts at BoingBoing, bringing a few of the ideas of engineered longevity a little closer to the masses. Every little bit of advocacy helps in the long run:

Charts: 1

The bad news is that despite all our advances in medicine, sanitation, and other relevant factors, the chart still tapers off around age 100. Average lifespan has increased, but maximum lifespan has not changed significantly.

One reason may be that research to prolong maximum lifespan receives minuscule funding, especially compared with popular endeavors such as cancer research. Many people seem to feel that extending maximum lifespan would be "wrong" (even at a time of rapidly declining birth rates in many nations) or "unnatural" (even though our average life expectancy used to be around 40, and has improved through totally unnatural means such as antibiotics).

As you may infer from the quotation marks, I disagree. Of course, I realize that these are controversial issues.

One of the most effective special-interest groups seeking funding for longevity research is www.methuselahfoundation.org.

Charts: 2

We can feel happy that people today are surviving more tenaciously than anyone expected half a century ago. How will our current prediction turn out fifty years from now? Presumably the answer depends on our priorities. If lives are worth saving, perhaps it will make sense to fund more research into the aging process.

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Over at Ouroboros, a look at the enhancement debate and how it impacts advocacy for engineered longevity:

I suspect that the structure of arguments about cognitive enhancement will mirror those of future debates regarding lifespan extension.

Both fields involve treatments that promise to improve or increase a parameter of human performance - one that varies to some extent within the natural population, but that seems fixed for a given individual. In both cases, human beings are 'fine' without the intervention - that is, we live comfortably (and, for the most part, happily) knowing that there is nothing much we can do to make ourselves smarter, and looking forward to our allotted threescore years and ten.

Beginning from the premise that what isn’t broken ought not be fixed, or that the 'natural order' of things ought not be meddled with, critics of both cognitive enhancement and lifespan extension may argue that neither sort of intervention in Normal Human Lives(tm) is warranted.

Pro-death advocates like Leon Kass have already argued extensively for forcing people to age, suffer, and die on just this sort of "natural order" argument. Which they apply selectively, of course, by not arguing that we should go back to living in caves, catching food with our teeth, and abandoning all that we have made.

To my mind, that there are any people at all who argue against future human enhancement through technology (while eagerly availing themselves of present human enhancement through technology) implies that this has much more to do with fear of change than anything else.

Some people would rather embrace any present horror than even the most positive change. This is not one of the better traits we humans seem to have hardwired in our evolutionary heritage.

A great many people grow up with what they know - having things far better than their parents, despite the efforts of past luddites who strived to block advancements - and then spend the rest of their lives fighting against visionaries who are trying to make things even better.

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It is strange, but the argument for greater support of longevity science as a way to avoid staggering ongoing rates of disability and death doesn't carry a great deal of weight with most people.

Let's look at the dimensions of the human holocaust that we call "natural death."

The death toll in the Year 2001 was worst in India. Almost 9 million casualties. The bodies were piled nearly as high in China. The United States fell in third, with 2.4 million fatalities. 21 nations lost over half a million lives, each. These 21 countries represented all cultures, races, creeds, and continents. The human death toll in the Year 2001 from all 227 nations on Earth was nearly 55 million people, of which about 52 million were not directly caused by human action, that is, not accidents, or suicides, or war. They were "natural" deaths.

If this argument worked, we'd be done already. But people will accept any terrible situation if it's all they have ever known. Sad but true. On that note, I notice that bioethicist Colin Farrelley is hitting on the argument by megadeaths in a couple of recent posts:

Whether it be the "Black Plague", small pox, malaria, cancer or heart disease, human populations are susceptible to a diverse array of chronic and infectious diseases that threaten both the lives of individuals and the prosperity of nations. And so it is imperative that we think rationally about how we can best respond to these diverse threats to our health and survival. We need accurate data concerning the probable risks of disease facing the world's populations this century and an open mind about the potential strategies for dealing with these threats.

The greatest threat facing the world's existing 6.7+ billion population are the chronic diseases associated with aging. In the year 2005, approximately 55 million people died. 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 combined. 35 million deaths a year dwarf the estimated deaths caused by climate change - approximately 150 000 deaths.

...

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.

One last point to make to illustrate the magnitude of the problem of chronic disease. It is estimated that between the mid-14th century and mid-17th century, the "Black Death" plague killed approximately 25 million people. This means that the current deaths caused by chronic disease in just one year outnumber the deaths caused by 3 centuries of the "Black Death" plague. This clearly illustrates why the imperative to combat chronic disease is one of the greatest imperatives ever facing humanity. And since aging is the major cause of these afflictions, one of the greatest moral imperatives facing humanity today is to tackle aging itself so that we can avoid the unprecedented rise in chronic disease that is expected to befall the world's populations this century.

All true: yet how to proceed armed with these obvious facts to which people are willfully oblivious?

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As a followup to de Wolf's post on the self-sabotaging misconceptions that lead people away from successfully arranging cryopreservation upon death, you'll find an unfortunate and cautionary tale over at Depressed Metabolism. Even with the best of intentions and good preparation, life - and especially the actions of other people who think they know best - can still sabotage your efforts to take advantage of cryonics and thereby ensure a chance at future restoration:

I have been informed that Marcelon (Marce) Johnson died on 01/21/2009, was cremated, and not cryopreserved.

I understand this information may come as a surprise and as a disturbing shock to many people, especially those who loved and knew Marce, as I did. I thus feel an obligation to explain how this happened and to provide some closure to this story for the many people who helped, or tried to help, avert this catastrophe.

While Marce was alive I was unable to share the full story of what was happening. Now that she is dead and gone I believe it important and the responsible thing to do to relate the story as best I know it.

Read the whole thing, learn from it, and amend your own plans as appropriate.

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One should always read the science press with a skeptical eye: scientists are just like the rest of us in that they sometimes get things wrong and often don't know everything of interest in a field. That latter point is especially true as most fields of research in the life sciences have expanded far beyond the awareness capacity of a single busy professional. So it's very helpful to have some background knowledge yourself, to help sort out the relevant from the potentially flawed.

Take this recent work on calorie restriction for example, which is announced as a potential proof that calorie restriction is not going to be useful in healthy humans:

"Our study questions the paradigm that caloric restriction is universally beneficial," Sohal said. "Contrary to what is widely believed, caloric restriction does not extend (the) life span of all strains of mice."

By measuring the animals' metabolic rate, Sohal and his colleagues came to a deceptively simple conclusion: Caloric restriction is only useful when, as in the case of the obese mice, an animal eats more than it can burn off.

"Your energy expenditure and your energy intake should be in balance," Sohal said. "It's as simple as that. And how do you know that? By gain or loss of weight.

"The whole thing is very commonsensical."

For humans of normal weight, Sohal strongly cautions against caloric restriction. In a 2003 study, he and Forster found that caloric restriction begun in older mice - both in DBA and leaner C57 individuals - actually shortened life span.

Given the very large number of studies showing strong positive effects on health and longevity in individuals of normal weight through calorie restriction, one should immediately be cautious in looking at this sort of claim in a single paper. Over at the Immortality Institute, calorie restriction expert Michael Rae dives in to take it apart in more detail:

These guys have really made some extremely unreasonable leaps of reasoning.

First, yes, it's true that DBA/2 mice are resistant to the effects of CR on lifespan -- that's been shown repeatedly, since at least the early 80s, and not just by Sohal; and (per this study) yes, they apparently have some aesthetically happy genetic perk, that allows them to eat ad libitum without gaining any weight, while other mice gain weight as one would expect.

But so what? First, as Anthony noted, while they have demonstrated these two facts, they haven't done anything to prove that this resistance to weight gain in response to an AL diet is what *causes* their resistance to the age-retarding effects of CR in this strain.

Second, as Matt notes, these are sickly mice

...

in [their prior referenced 2003] study, they violated almost every rule of adult-onset CR in the book: they administered CR as shock therapy instead of stepwise to allow for gradual adaptation, and they didn't boost the %protein in the diet to ensure that they got the full rodent 'RDA' of the AL mice. Weindruch and Walford's big 1982 breakthru', showing that you COULD actually make CR work in adults, was based precisely on not making those mistakes - and it's been repeated numerous times since.

...

the current study doesn't come anywhere close to proving what Sohal is evidently asserting about it.

For those of us without this level of background knowledge, the weight of science test is the best way to go: only start to pay serious attention to a claim when it has a cluster of papers backing it. One paper standing in opposition to dozens or hundreds of others is either wrong or the first sign of a change of viewpoint - for an observer outside the scientific community there's no harm done in dismissing it in either case. If change is underway, there will be more papers and studies to support the new viewpoint in due course.

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Back in full flow for 2009, you'll find a brace of posts on aging research from the past few days over at Ouroboros.

Telomere length and psychological stress:

it should come as no surprise to learn that chronic psychological stress has been associated with accelerated telomere shortening in circulating white blood cells. The problem arises in trying to provide a biological mechanism that links this form of stress to increased telomere loss.

Links between accelerated aging and extended longevity:

I’m sitting in an auditorium listening to a seminar by Laura Niedernhoefer from U. Pittsburgh. She’s telling us that Ercc1-/- mice, which are deficient in nucleotide excision repair, show transcriptional changes that mirror those found in old wildtype or unusually long-lived mutant animals. Her data is strongly reminiscent of recent findings that progeroid DNA repair mutants exhibit transcriptional similarities to aging calorie-restricted and dwarf animals.

Old cells and organ transplants:

Because senescent cells accumulate with age, senescence has been considered a biomarker of aging - that is to say, a measurable feature of a tissue that would allow us to calculate its "biological" or "physiological" age without necessarily knowing the chronological age of the donor. This makes abundant sense: tissues with more senescent cells would have lower proliferative capacity and higher levels of deleterious secreted factors; given two samples of the same chronological age, one could argue that the one containing more senescent cells was "older" in some meaningful way. This idea is central to a recent paper demonstrating that senescence correlates negatively with the efficacy of a transplanted tissue.

More on old cells and transplants:

Another group, working in a mouse model, has shown that older donor tissues express higher levels of the senescence marker p16, which is negatively correlated with proliferative capacity. But the old material doesn’t just start from behind, but also gets worse more rapidly: p16 levels rise dramatically in old grafts following transplantation, much faster than in young grafts, indicating that older cells are more sensitive to the stresses of undergoing transplantation and that they respond to this stress by undergoing senescence.

All organs equal before oxidative damage:

What causes organ failure during aging? Is it stochastic, with individual organ systems deteriorating and failing more or less independently - or is it more like a chain of dominoes, with a primary organ failure in one tissue putting pressure on other tissues and accelerating their decline?

Mitochondrial uncoupling protein extends lifespan:

The most surprising result is that [mutants lacking uncoupling protein] have shorter lives, implying that mitochondrial uncoupling is a key mechanism for controlling oxidative stress throughout the lifespan.

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A study on correlations between air quality and life expectancy is doing the rounds in a science press at the moment. The bottom line from their statistical analysis:

average life expectancy in 51 U.S. cities increased nearly three years over recent decades, and approximately five months of that increase came thanks to cleaner air.

Which doesn't seem unreasonable on the face of it: there's plenty of supporting evidence for the general thesis that air quality and longevity have some correlation. My caveat would be that any single study showing an effect of less than a year on human longevity should be taken with a grain of salt. Firstly that's certainly small enough to be either an artifact or due to some other, related correlation, and secondly it doesn't much matter in the grand scheme of things.

You can probably push your life expectancy a decade or more in either direction - 20 times as long as the variation in the paper - just by changing what you eat and the level of exercise in your life. Beyond that, progress in medical science has the potential to increase your healthy life span by a far greater number of years.

We don't have all the time in the world to make our future better, healthier, and longer. It's best to focus on what will have the greatest impact: everything else is a distraction.

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Alcor does a good job at their website clearing up the major myths and answering questions about cryonics, the practice of low-temperature, ice-free storage of the body and brain after clinical death. After you die, the structure of your brain remains intact - if stored, plausible future technology could one day restore you to life. The important thing, the core of what is you, is the data represented by the preserved structure of your brain.

But if you want to benefit from cryonics, you have a little work to do. Like most forms of insurance, it has to be set up in advance and preparations kept up to date if you want to benefit. Over at cryonics blog Depressed Metabolism, Aschwin de Wolf looks at some of the self-sabotaging assumptions that get in the way:

Unfortunately, advances in the science of cryopreservation will not automatically translate into better patient care. Other factors, such as the delay between time of "death" and start of procedures, and the protocols, equipment and personnel of the responding cryonics organizations, matter as well. For example, if a cryonics standby team is not able to get to a patient before 24 hours after cardiac arrest, pumps him full of air during remote blood washout, and ships him back to the cryonics organization at subzero temperatures, that patient will not benefit from advances in human cryopreservation such as rapid induction of hypothermia, neuroprotection and vitrification.

...

Both critics and supporters have made specific probability estimates about how likely cryonics is to work. In its worst form such probability assessments convey nothing more than putting a number on overall feelings of pessimism or optimism.

...

At the time a person really needs cryonics, he may no longer be able to communicate those desires, lack funding to make arrangements, or encounter hostile relatives. A more subtle variant concerns the person who expects that aging will be solved before cryonics will be necessary. This person may or may not be right, but such optimism may not make him more immune to accidents than other people. This mindset is often observed among young "transhumanists" and practicing life extensionists.

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Avoid chronic inflammation like the plague:

Chronic inflammation is a pathological condition characterized by continued active inflammation response and tissue destruction. ... chronic inflammation can be a major cause of cancers and express aging processes.

Moreover, many studies suggest that chronic inflammation could have a serious role in wide variety of age-related diseases including diabetes, cardiovascular and autoimmune diseases. The inflammatory process induces oxidative stress and reduces cellular antioxidant capacity. Overproduced free radicals react with cell membrane fatty acids and proteins impairing their function permanently. In addition, free radicals can lead to mutation and DNA damage that can be a predisposing factor for cancer and age-related disorders.

As I've noted in the past, the best short term way of evading chronic inflammation, and thereby increasing your chances to living more healthy years, is to avoid carrying excess visceral fat. But that only gets you so far: eventually even the healthiest immune system in the healthiest body starts to fall into a permanent condition of chronic inflammation called inflammaging. Evolution didn't produce a system that can be used for as long as we modern humans would like:

Inflammation is necessary to cope with damaging agents and is crucial for survival, particularly to cope with acute inflammation during our reproductive years. But chronic exposure to a variety of antigens, especially to some viruses such as cytomegalovirus, for a period much longer than that predicted by evolution, induces a chronic low-grade inflammatory status that contributes to age-associated morbidity and mortality. This condition carries the proposed name "inflammaging". Centenarians are unique in that, despite high levels of pro-inflammatory markers, they also exhibit anti-inflammatory markers that may delay disease onset. The key to successful aging and longevity is to decrease chronic inflammation without compromising an acute response when exposed to pathogens.

So when I say "avoid chronic inflammation" I'm not really talking about sane lifestyle choices, although that's very necessary as well. I really mean "do what you can to help advance medical research into repairing our aged immune systems." As time goes by, you'll find that the greatest determinant of your health and longevity is medical technology that can repair the damage of aging. While we're healthy and active, we should do what we can to advance that medical research; it'll pay off later.

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My attention was drawn today to an article I missed from the latest FUTURIST magazine, the author painting Silicon Valley as the hub for modern transhumanism, including advocates for engineered longevity. Insofar as transhumanism has a geographic hub, I'd say Silicon Valley is as good a guess at it as any:

Aubrey de Grey, an English biologist with a doctorate from Cambridge University, is head of the Methuselah Foundation and one of the world's foremost antiaging champions. With high-profile partners like Arizona State University's new Biodesign Institute, the Methuselah Foundation is trying to reverse degenerative cell damage. Little in the way of usable research has been produced, but the unabashed ambition of his work (and his creeping mainstream acceptance) has made de Grey something of a guru to the transhumanists of Silicon Valley. He visits the Bay Area every couple of months, often speaking at the offices of Yahoo and Google.

On an unseasonably warm winter's day, de Grey was at Brickhouse, the product-innovation division that Salim Ismail runs for Yahoo. De Grey had come to promote his new book, Ending Aging. Wiry and fidgety, de Grey spoke in a distinct English accent, avoiding eye contact. A rust-colored beard hung nearly to his waist, and his hair was pulled back in a long ponytail. De Grey set up a projector and screen as 50 employees gathered around during lunch break and started munching on catered gourmet sandwiches.

The lights came down, and de Grey began a talk titled "Prospects for Extending Healthy Life--A Lot." While the audience idly chewed away, de Grey told them, "I think that many people in this room have a good chance of living to one thousand." That got the Yahoo workers' attention. Several in the audience put down their focaccia and took out notepads. De Grey launched into a sermon about the inhumane effects of aging.

It's a neutral piece, as you might be able to tell - the author is clearly one of those who remain to be convinced that change is afoot, healthy longevity is good, and the biotechnology revolution will take us all to far places. The movement for engineered longevity is, however, a movement, and it's steadily growing. That growth means an increase in advocacy, fundraising, funded research, and other metrics of success.

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Amongst plenty of other evidence, I think that the effectiveness of the targeted mitochondrial antioxidant SkQ1 demonstrates handily that the reactive oxygen species generated by your mitochondria are killing you slowly. The damage they cause is a significant portion of aging itself, and targeting mitochondria has become a matter of great interesting to a variety of research groups. The more varied the scientists producing technologies aimed at mitochondria, to more rapidly we are likely to see a good result rapidly. Competition and diversity are real signs of progress soon to come.

I noticed today that the radiology and cancer research community might also have cause to develop means of delivering drugs to mitochondria to alter the output of reactive oxygen species:

Adverse effects of ionizing radiation are mediated through reactive oxygen and nitrogen species. Mitochondria are the principal source of these species in the cell and play an important role in irradiation-induced apoptosis. The use of free radical scavengers and nitric oxide synthase inhibitors has proven to protect normal tissues and, in some cases, to sensitize tumor tissues to radiation damage. Dual molecules that combine radical-scavenging and NOS-inhibitory functions may be particularly effective. Drugging strategies that target mitochondria can enhance the effectiveness of such agents, in comparison to systemic administration, and circumvent side effects.

Which is a good thing. The more the merrier. Still, throwing antioxidants at our mitochondria can only slow down the process of damage. A much better approach is to repair mitochondria that become damaged due to the reactive oxygen species they emit, or change our cells such that the most common forms of mitochondrial damage no longer matter. Both of these are very plausible lines of research, and advances along this road have been demonstrated in the laboratory in recent years:

• Slightly Insider Info: Mitochondrial Protofection Works
• SENS 2 Report: Moving Mitochondria

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I pointed out the LifeStar Project website yesterday at the Longevity Meme. This is the brand under which the Millard Foundation will invest in advancing the development of practical, working longevity medicine. The Foundation is a wealthy family concern under the control of a few people with a demonstrated interest in longevity science, and with the resources to get things done.

In short, this is another of the beneficial signs we advocates have been hoping would emerge sooner rather than later. A philanthropic organization drawing upon existing fair-sized resources and possessed of the will to use them in advancing the cause of human longevity through the most direct methods possible. From their website:

therapies are rapidly being developed, in labs all over the world, which, in combination, will be able to actually prevent age-related diseases and loss of functionality. The governments of the world are unprepared to answer this challenge, but potentially could be.

What is needed - and does not yet exist - is a concerted, focused, competent, and fully-funded effort to catalyze the coalescing of this work into the complete set of therapies and protocols that will prevent the occurence of these diseases.

The LifeStar World Health Initiative has been created to respond to this need. With the right approach, we believe this result can be produced within the next 10-15 years.

The Millard Foundation principals, and by extension the LifeStar Project, differ from other large Foundations interested in aging and longevity - such as the Glenn Foundation and the Ellison Foundation - by virtue of their strong support for the "repair the damage" viewpoint that informs the Strategies for Engineered Negligible Senescence. Aging is exactly the results of an accumulation of biochemical damage acquired over time: we should be trying to directly repair that damage, not just slow down its accumulation by tinkering with genes and metabolism.

The resources backing the "repair the damage" viewpoint are growing steadily year by year in a variety of different ways. The successful fundraising of the Methuselah Foundation is one visible form of that growth, and convincing folk like the Millard family to direct their resources to this grand project is another. I'm sure we'll be hearing much more from the LifeStar Foundation in the years ahead.

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The Glenn Foundation continues to expand its funding for mainstream aging research, largely aimed at slowing down aging through metabolic and genetic manipulation. Via the Gerontology Research Group website, we learn:

Breaking news was announced at the very start of the [Processes of Aging Conference at the Salk Institute] by Marc Collins that The Paul Glenn Foundation will fund the Salk Institute for aging studies at the rate of $1 million per year for the next five years, along with the prior MIT and Harvard Glenn Centers.

As noted, that's three research centers now being funded by Paul Glenn. The prior two:

Paul F. Glenn Laboratories at Harvard

The Paul F. Glenn Laboratories are dedicated to finding the molecular causes of aging so we can understand the mechanisms of normal aging and develop interventions to delay its onset and progression, thereby extending the healthful years of human life.

Glenn Laboratories for the Science of Aging

Why do living things age? What genes influence longevity? Is it possible to extend youthfulness by means of genetic manipulation? Our research analyzes these tantalizing questions and others in molecular detail.

I hope that the years ahead see more visionary funding sources, such as the Millard Foundation, depart the "slowing aging" mindset and start to more seriously fund the very plausible research aimed at repairing the damage of aging, thus reversing aging itself. Now that more philanthropists are becoming involved in supporting aging research, I think that this is a good goal to aim for: convincing philanthropists that the presently minor voice in the aging research community is in fact the best path ahead.

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Oxidative damage to cells and important molecules is generally considered an important root cause of aging, though there's certainly a great deal of ongoing debate in the scientific community over exactly how and why this is the case. I noticed an open access review paper today that makes an effort to tie inconsistencies in the observed behavior of antioxidants - sometimes demonstrated to prolong healthy life and otherwise improve matters, and more often shown to do very little - with the presence of iron. The main foundation for this theory is that:

in some circumstances (especially the presence of poorly liganded iron) molecules that are nominally antioxidants can actually act as pro-oxidants. The reduction of redox stress thus requires suitable levels of both antioxidants and effective iron chelators.

An iron chelator is a substance that can bind iron and remove it from ongoing reactions with other molecules - such as the way iron turns mild oxidants into very damaging oxidants.

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular 'reactive oxygen species' (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation.

Also of interest: iron has been implicated in a different area of aging biochemistry, the buildup of chemical junk called lipofuscin in lysosomes within our cells that prevents the normal processes of cellular recycling and generally makes a mess of things. For example, when cells can't deal with iron correctly, lipofuscin becomes an even bigger problem:

Further experiments confirmed that when TRPML1 is defective, iron becomes trapped in the lysosome. One result of the buildup is formation of a brownish waste material, lipofuscin, known as the "aging pigment." In skin cells, lipofuscin is the culprit responsible for the dreaded liver spots that appear with increasing age, but in nerve, muscle and other cells, its accumulation has more serious consequences.

Precisely targeted chelation - aimed at the lysosomes though gene engineering or other sophisticated strategies, which won't happen using anything you can buy in the store - has been proposed as a way to deal with lipofuscin accumulation. This is analogous to the way in which antioxidants precisely targeted to the mitochondria, oxidative damage central in your cells, have a good track record of extending healthy life in experiments with mice and lesser animals.

So back to the original paper I mentioned, which concludes:

Overall we argue, by synthesising a widely dispersed literature, that the role of poorly liganded iron has been rather underappreciated in the past, and that in combination with peroxide and superoxide its activity underpins the behaviour of a great many physiological processes that degrade over time.

Which may be the case. I'm still sold on the idea that where you target antioxidants in the cell is the dominant explanation for experimental observations to date, however. Targeted to the mitochondria, we see a balance of experiments showing extended healthy life. Targeted elsewhere, the balance of experiments show no significant effect. When we consider that the cell is a highly specialized grouping of components, each serving a very different purpose, this sort of result makes a lot of sense.

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Humanity+, formerly the World Transhumanist Association, is positioning itself these days as an unthreatening organization with a middle-of-the-road position on futurism, interested in human growth and welfare. In this era, that means a lot of consideration given to policy, government, control, and the teeming environmentalist masses who are terrified of science and believe the world is ending. The latest iteration of the transhumanist declaration contains a wealth of that sort of thing lurking between the lines. Far more, in fact, than actual thoughts on progress!

This is a way forward, consciously chosen. I like the name change, but I can't say I think the rest of it is a good path ahead - I'm more in favor of suitably outrageous extremes, freedom, and getting things done directly - but the nascent Humanity+ strategy is an appealing choice for many.

Humanity+ is presently electing a new board with voting taking place from today through Thursday:

Humanity+ (WTA) Board members set policy goals and oversee their implementation, contributing with their experience and expertise to the WTA's work. We’ve got a very full agenda for the coming year, setting up our new website, revising the Transhumanist Declaration, fundraising, building our network of chapters and student groups, and publishing our new H+ magazine.

...

Voting will be conducted Monday January 12th to Thursday January 15th, 2009.

...

You can become a voting member here:

http://transhumanism.org/index.php/WTA/joinnow/

The varied candidates have posted their statements online at the Humanity+ site; you might recognize some of the names from the pro-longevity community.

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Time flies: it doesn't seem as though more than two years have passed since entrepreneur turned fund manager Peter Thiel made a $3 million matching pledge to the Methuselah Foundation. Every two dollars of a donation to Strategies for Engineered Negligible Senescence (SENS) research aimed at repairing the damage of aging and reversing its effects draws an additional dollar from this matching fund.

Over that time, $1.3 million have been drawn from the fund, boosting the $2.6 million raised for research. That leaves another $1.7 million to go - and a little under 12 months until this matching pledge expires. Three years seems an eternity when it's ahead of you, but when you're done you wonder where it went so quickly.

Thanks to solid fundraising over the years of its existence, the Methuselah Foundation has made a real impact on the course of longevity research. First by influencing the debate within the aging community, engaging the public, and helping to change a stagnant research culture in which no-one could talk about engineering additional longevity without risking their funding. Secondly, through funding SENS research aimed at repairing the known biochemical damage that causes aging and age-related disease. Thirdly, and this is a project for the long term, building a community of younger researchers, the gerontologists of tomorrow, who are very interested in the fastest possible path to reversing aging.

If you want something done, it's not enough to agitate for it, and its not enough to have the money. You also need a community of workers. Over a timespan of, say, twenty years, I think we'll see many growing bootstrap efforts like the Methuselah Foundation that merge advocacy, fundraising, and cultivation of a research community. This is how a field of research moves from the ideas of a few people to become a self-sustaining culture that gets the job done.

These are still early days in the grand scheme of things, but that's no reason to let things go at their own pace. Here is a great opportunity to help move things along: push a few dollars in the direction of SENS research and help polish off Peter Thiel's matching fund this year.

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Continuing investigation into the mechanisms of regeneration is producing a steady stream of minor improvements and practical learnings. For example, the potential for scar-free regeneration of damaged skin by mimicking aspects of the process of embryonic development:

Scarring in the skin after trauma, surgery, burn or sports injury is a major medical problem, often resulting in adverse aesthetics, loss of function, restriction of tissue movement and/or growth and adverse psychological effects. Current treatments are empirical and unpredictable, and there are no prescription drugs for the prevention or treatment of dermal scarring.

We have investigated the cellular and molecular differences between scar-free healing in embryonic wounds and scar-forming healing in adult wounds. We have identified Transforming Growth Factor beta 3 (TGFbeta3) as a key regulator of the scar-free phenotype in embryonic healing. Exogenous addition of TGFbeta3 to cutaneous wounds in pre-clinical (adult) in vivo models reduces early extracellular matrix deposition and these molecules are deposited with a markedly improved architecture in the neodermis, resembling that of normal skin. This improvement of structural organisation in the healing wound is self-propagating and leads to a reduction of subsequent scarring.

TGFbeta3 has completed safety studies and entered human clinical trials. Data from these studies have demonstrated that TGFbeta3 (Juvista) in humans is safe and well tolerated. Acute, local administration of TGFbeta3 (Juvista) significantly reduces dermal scarring in a dose responsive manner resulting in the regeneration of a skin structure that is permanently improved.

Manipulation of skin healing today, and one would hope far more impressive manipulations of internal organ regeneration tomorrow. Small steps on a long road. One potential future for the field of regenerative medicine sees very little in the way of stem cell therapies as we current understand them: instead of transplants, our existing cells are controlled by precise signals, manipulated into working the way we want them to.

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The latest edition of Rejuvenation Research has been up and I've been forgetting to mention the fact. One paper in particular caught my eye, and I think you'll find it interesting.

Engineered Repeated Electromagnetic Field Shock Therapy for Cellular Senescence and Age-Related Diseases:

A new consensus of gerontologists proposes that delay of biological senescence is the most potent public health measure for preventing chronic disease in late life. At the most fundamental level, cellular aging is characterized by a decline in repair and homeostatic systems. Thus, interventions that protect or rejuvenate these cellular systems hold significant promise for preventing or delaying the onset of age-related diseases.

The most likely candidates for delaying senescence are the longevity-linked transcription factors DAF16 and HSF1. If one were to engineer negligible senescence, a key target would be the heat shock protein axis regulated by HSF1. This pathway is the preferred pathway to prevent protein damage or aggregation, whereas DAF-16/FOXO is a backup pathway activated during stress. Reduced HSF1 activity appears to accelerate tissue aging and shortens life span. Conversely, over-expression of HSF1 increases life span and decreases amyloid toxicity in animal models.

This paper describes enhancement of the HSR/HSF1 pathway engineered by repeated electromagnetic field shock (REMFS). In a recent study, we demonstrated that REMFS therapy upregulates the HSR/HSF1 pathway, delays cellular senescence in young cells, and transiently reverses it in senescent cells, thus altering cellular mortality. The technology of applying certain beneficial EMF energy to the human body to stimulate the natural stress response and activate the repair and maintenance systems is a new strategy for engineered negligible senescence. We discuss the exciting clinical implications of REMFS therapy in human aging and disease.

A different approach indeed, leaving aside the standard objections to merely slowing aging by manipulating pathways versus reversing aging by repairing damage. I can see that electromagnetic fields could be thought of as broadly similar to drugs: a tool that can be used to interfere in a particular biochemical reaction while trying to avoid interfering in others. Any such body of work is far behind the drug industry of course, largely due to the past history of technology and available tools, I would imagine. Yet the established radiology and MRI technology base could be starting point for a future branch of medicine that employs careful and extremely precise manipulation of electromagnetic fields. This is not implausible.

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CLK-1 - or clock-1 - is a gene that affects lifespan, most likely through its influence on mitochondrial activity. It's the standard story, or at least appears to be: anything that can lower the rate at which mitochondria damage themselves will extend life in flies, mice, and so forth. I noticed a piece today on a drug candidate for neurodegenerative diseases that researchers now think works through manipulation of CLK-1:

Recent animal studies have shown that clioquinol - an 80-year old drug once used to treat diarrhea and other gastrointestinal disorders - can reverse the progression of Alzheimer's, Parkinson's and Huntington's diseases. Scientists, however, had a variety of theories to attempt to explain how a single compound could have such similar effects on three unrelated neurodegenerative disorders.

...

"Clioquinol is a very powerful inhibitor of clock-1," explained Hekimi, McGill's Strathcona Chair of Zoology and Robert Archibald & Catherine Louise Campbell Chair in Developmental Biology. "Because clock-1 affects longevity in invertebrates and mice, and because we're talking about three age-dependent neurodegenerative diseases, we hypothesize that clioquinol affects them by slowing down the rate of aging."

...

Hekimi is optimistic but cautious when asked whether clioquinol could eventually become an anti-aging treatment.

"The drug affects a gene which when inhibited can slow down aging," he said. "The implication is that we can change the rate of aging. This might be why clioquinol is able to work on this diversity of diseases that are all age-dependent."

However, he admits to being concerned about how people may interpret his results.

"The danger is that you can buy a kilogram of this compound at a chemical wholesaler, but we don't want people to start experimenting on themselves. Clioquinol can be a very toxic substance if abused, and far more research is required."

Wait and see is a smart strategy in medicine so long as you have the time for that choice. This is a mechanism for affecting mitochondria that I haven't seen mentioned much in the past, and so a big dive into the unknown. Even if progress is made in manipulating it, I imagine we won't hear much on the development side for some years. Those of you interested in keeping your mitochondria in better shape would most likely be better off exercising and eating less in any case - even the current batch of potential mitochondria-affecting drugs don't do as well as calorie restriction and exercise combined.

Needless to say, the real solution to all this is not to dig up drugs that slow things down, but rather to develop processes that repair or replace damaged mitochondria and thus reverse this aspect of aging. Based on what has been taking place in laboratories over the past few years, this doesn't look to be any harder, and should be a lot more effective.

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Robert Freitas, the nanotechnologist and longevity science advocate, has an article in the current Life Extension Magazine, also available online:

Nanotechnology is the engineering of molecularly precise structures and, ultimately, molecular machines. The prefix 'nano-' refers to the scale of these constructions. A nanometer is one-billionth of a meter, the width of about five carbon atoms nestled side by side. Nanomedicine is the application of nanotechnology to medicine. The ultimate tool of nanomedicine is the medical nanorobot - a robot the size of a bacterium, composed of molecule-size parts somewhat resembling macroscale gears, bearings, and ratchets. Medical nanorobotics holds the greatest promise for curing disease and extending health span. With diligent effort, the first fruits of medical nanorobotics could begin to appear in clinical treatment as early as the 2020s.

...

Right now, medical nanorobots are just theory. To actually build them, we need to create a new technology called molecular manufacturing. Molecular manufacturing is the production of complex atomically precise structures using positionally controlled fabrication and assembly of nanoparts inside a nanofactory.

...

But now it’s time to put our theories to the test. After working closely for three years with Philip Moriarty, one of the leading scanning probe microscopists in the UK, our international colleague is now undertaking direct experiments to build and validate several of our proposed mechanosynthesis tooltips in his laboratory. We are also preparing a research program proposal of our own to solicit additional funding from various US public or private sources to support further mechanosynthesis-related experimental and theory work on a greatly accelerated schedule. We expect these efforts will ultimately lead to the design and manufacture of medical nanorobots for life extension, possibly during the 2020s.

But read the whole article: make machines small enough, and they could interface with our cells to repair damage, replace worn structures, or even replace the function of cells entirely. More effective oxygen-carrying blood cell machines, for example, or hyper-efficient immune cell machines. Cells are just complicated small devices, and we humans are becoming very good at making complicated small devices - it's just a matter of time until we can build better machinery than than the evolved biological devices presently powering our bodies.

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Scientists are a cautious lot, and funding is available for careful studies that replace sound assumptions with even more sound established facts. Now that calorie restriction (or dietary restriction, DR) research is attracting so much funding at the development end of R&D, you'll see more studies aimed at firming up the foundations. Take this open access paper for example:

One of the promising advances towards the goal of uncovering the mechanisms by which DR extends life was the discovery that the effect is evolutionarily conserved. However, even with the use of short-lived model organisms for relatively rapid lifespan experiments, the mechanisms remain elusive. This is likely to be largely due to the complexity of physiology involved in determining length of life, but may be also in part due to technical issues in experimental design hampering a clear path of progress.

The ease with which complexity can be introduced into these studies can be illustrated by the large effects on fly lifespan caused by very small changes in nutrition. For example, substituting one source of the dietary yeast Saccharomyces cerevisiae, with another from a different supplier in an otherwise identical diet can have large effects on fly lifespan. Similarly, lifespan differences have been reported due to the use of different bacterial strains as food for Caenorhabditis elegans or by interchanging casein and soy peptone as the source of dietary protein for rodents. In fact, a recent article has proposed that DR itself may have arisen as a by-product of laboratory life as animals are unintentionally subjected to selective breeding in the presence of an artificially rich nutritional environment. Clearly, these issues need to be addressed if we are to uncover the molecular mechanisms of DR.

As might be expected from the weight of existing evidence for calorie restriction to extend healthy longevity, increasing the rigor of the experiments didn't prevent the beneficial effects:

In this study, we have examined the effect of laboratory stock maintenance, genotype differences and microbial infection on the ability of dietary restriction (DR) to extend life in the fruit fly Drosophila melanogaster. None of these factors block the DR effect.

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This year's Edge annual question is:

What game-changing scientific ideas and developments do you expect to live to see?

With that lead-in, it's perhaps not surprising to see a range of thoughts on engineered longevity in amongst a range of less relevant but still interesting responses:

Gregory Benford:

Live to 150: I expect to see this happen, because I'll be living longer. Maybe even to 150, about 30 more years than any human is known to have lived. I expect this because I've worked on it, seen the consequences of genomics when applied to the complex problem of our aging.

Emanuel Derman:

The biggest game-changer looming in your future, if not mine, is Life Prolongation. It works for mice and worms, and surely one of these days it'll work for the rest of us.

David Eagleman:

While medicine will advance in the next half century, we are not on a crash-course for achieving immortality by curing all disease. Bodies simply wear down with use. We are on a crash-course, however, with technologies that let us store unthinkable amounts of data and run gargantuan simulations. Therefore, well before we understand how brains work, we will find ourselves able to digitally copy the brain's structure and able to download the conscious mind into a computer.

Bart Kosko:

Society will change when the poor and middle class have easy access to cryonic suspension of their cognitive remains - even if the future technology involved ultimately fails.

Today we almost always either bury dead brains or burn them. Both disposal techniques result in irreversible loss of personhood information because both techniques either slowly or quickly destroy all the brain tissue that houses a person's unique neural-net circuitry. The result is a neural information apocalypse and all the denial and superstition that every culture has evolved to cope with it.

Corey S. Powell:

I have little doubt that progress in fighting disease and patching up our genetic weaknesses will make it possible for people to routinely reach the full human lifespan of about 120. Going far beyond that will require halting or reversing the core aging process, which involves not just genetic triggers but also oxidation and simple wear-and-tear. Engineering someone to have gills is probably a much easier proposition. Still, if we can hit 200 I see no reason why the same techniques couldn't allow people to live to 1,000 or more. Odds: 60 percent.

I can't say as I think any of these folk are exactly on the ball, even Benford, who clearly subscribes to the mainstream view of genetic and metabolic reprogramming to slow aging rather than the damage repair view of the Strategies for Engineered Negligible Senescence. It is promising to see engineered longevity as a prominent topic, but it still looks like a lot of fumbling around in the dark is taking place. That shows that more work is needed on the part of advocates to direct interest and potential support onto the best paths forward.

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