"Is There a Maximum Human Life Span?" and "Longevity for the Long Term"

The maximum human life span will be whatever we make it to be over the decades ahead - the advance of biotechnology will see to that. But even here and now, the question "is there a maximum human life span?" doesn't exactly have a straightforward answer. Here speaking on the topic at a recent Humanity+ conference is L. Stephen Coles of the Gerontology Research Group:

At the same event, Gregory Benford (scientist, science fiction author, and board member of Genescient) discussed his view of the future of engineered longevity:

You'll find links to more video presentations from the conference over at the Humanity+ website.

The Prospects for Kidney Stem Cell Therapies

From the Harvard Gazette: "It has long been a given that adult humans - and mammals in general - lack the capacity to grow new nephrons, the kidney's delicate blood filtering tubules, which has meant that dialysis, and ultimately kidney transplantation, is the only option for the more than 450,000 Americans who have kidney failure. But a new study [may] turn that paradigm on its head, and someday lead to a new treatment for those suffering from kidney disease. ... [researchers have] identified adult kidney stem cells in the zebrafish that can generate new nephrons. These cells can be transplanted from one fish to another fish, whereby they grow into functional nephrons in the transplanted recipient. [This] provides a proof of principle that adult kidney stem cells exist in nature and that treating renal disease with a stem cell-type therapy is theoretically possible. ... Investigators have been searching for the adult renal stem cell in mice and humans for some time, but so far the results have been controversial. ... There is a general belief that while there are kidney stem cells in mammals, including humans, they generate nephrons and then disappear during fetal development or soon after birth. ... The mystery is why these particular cells aren't retained in the adult kidney, where they could be called upon to make new nephrons."

Link: http://news.harvard.edu/gazette/story/2011/01/adult-kidney-stem-cells-found-in-fish/

Skin Cells Directly Converted to Beating Heart Cells

From ScienceDaily: "scientists have converted adult skin cells directly into beating heart cells efficiently without having to first go through the laborious process of generating embryonic-like stem cells. The powerful general technology platform could lead to new treatments for a range of diseases and injuries involving cell loss or damage, such as heart disease, Parkinson's, and Alzheimer's disease. ... this work represents a new paradigm in stem cell reprogramming. We hope it helps overcome major safety and other technical hurdles currently associated with some types of stem cell therapies. ... scientists have been trying to develop ways to 'reprogram' adult human cells back to a more embryonic-like, or pluripotent, state, from which they are able to divide and then change into any of the body's cell types. ... Although the technology to generate these cells, dubbed induced pluripotent stem (iPS) cells, represents a major advance, there are some hurdles to overcome before it can be adapted to therapies. ... [researchers] decided to try to tweak the process by completely bypassing the iPS stage and going directly from one type of mature cell (a skin cell) to another (a heart cell). ... the protocol is fundamentally different from what has been done by other scientists in the past [and] giving the cells a different kind of signal could turn them into brain cells or pancreatic cells."

Link: http://www.sciencedaily.com/releases/2011/01/110130213901.htm

Uncertainty Over Life Expectancy Becoming a Mainstream Concept

Following on in the theme of last week's post on the spreading ideas of longevity science, I think it's fair to say that uncertainty in projected life expectancy is now a fairly mainstream concept. Vast sums of money - the massive industries of pensions, life insurance, and so forth - rest upon reasonably accurate actuarial projections of life span and mortality rate.

Long term projections of life span continue to trend upward as the actuaries revise their opinions on biotechnology - but I believe they still fail to account for potential revolutionary advances in medicine that lie ahead. The level of uncertainty at least is fairly well grasped now within the actuarial industry, but for various political reasons it is only slowly seeping into official projections.

Unfortunately for these industries, and for governments whose politicians have made promises of future entitlements based upon old projections of life span, the advance of biotechnology is making the future exceedingly uncertain. Uncertain in a good way, of course - more life for us. If there are people and institutions out there whose livelihoods depend upon betting against increasing longevity ... well, the sooner they find a different business to be in, the better off they'll be.

I recently noticed a BusinessWeek article that touches on this and related issues:

As the 79-million-strong Baby Boom generation starts hitting age 65, demographers and medical researchers are increasingly at odds over how long they'll live. It's a question with major implications on a national level, for how much Social Security and Medicare will cost future generations of Americans. On a personal level, life expectancy complicates plans for saving and spending: Live too long and risk running out of money; die young and you can't take it with you.

...

One obvious way to finance a longer retirement is to save more, either by spending less or working longer. If maximum life spans extend to 100 years or even past 110, longer careers will be easier for older Americans and might even be psychologically beneficial, says Steven Austad, a professor at the University of Texas Barshop Institute for Longevity and Aging Studies in San Antonio. "The retirement age of 65 makes no sense whatsoever anymore," Austad says.

Retirement is one of many things that will be changing. I think that the idea of uncertainty in future life span due to advancing biotechnology may be a good path for many new faces to find their way to the healthy life extension community. It is a way past the unspoken assumption that so many people have: that their lives will look the much same as those of their parents and grandparents in scope. Further, it doesn't take much investigation for an interested person to move past the very conservative viewpoint of uncertainty in life expectancy being a matter of a few years added here and few years lost there, and find scientists who talk of adding decades to life in the first half of this century. Even those scientists are moderates compared to folk at the SENS Foundation and similar visionaries - and the first step to finding out that all this exists is to step beyond the first, naive assumptions most people have about the future of human life span.

Prohibitin and Calorie Restriction

More sophisticated studies of the biological changes produced - quite quickly - by calorie restriction continue to yield new information: "Caloric restriction (CR) is well known to expand lifespan in a variety of species and to retard many age-related diseases. The effects of relatively mild CR on the proteome profile in relation to lifespan have not yet been reported, despite the more extensive studies of the stricter CR conditions. Thus, the present study was conducted to elucidate the protein profiles in rat livers after mild CR for a relatively short time. Young growing rats were fed CR diets (10% and 30% CR) for 1 month. ... The most remarkable protein among the differentially expressed proteins was found to be prohibitin, the abundance of which was increased by 30% CR. Prohibitin is a ubiquitously expressed protein shown to suppress cell proliferation and to be related to longevity. The increase in prohibitin was observed both in 10% and 30% CR by Western blot analysis. Furthermore, induction of AMP-activated kinase (AMPK) protein, related to the actions of prohibitin in promoting longevity, was observed. The increased prohibitin level in response to subtle CR suggests that this increase may be one of the early events leading to the expansion of lifespan in response to CR."

Link: http://www.ncbi.nlm.nih.gov/pubmed/21256116

Nanoparticles Spur Wound Healing

An example of one of the ways in which the natural process of healing can be adjusted, or rescued when it fails: "investigators have developed a novel system for delivery of growth factors to chronic wounds such as pressure sores and diabetic foot ulcers. ... the team [reports] fabricating nanospheres containing keratinocyte growth factor (KGF), a protein known to play an important role in wound healing, fused with elastin-like peptides. When suspended in a fibrin gel, these nanoparticles improved the healing of deep skin wounds in diabetic mice. ... It is quite amazing how just one dose of the fusion protein was enough to induce significant tissue regeneration in two weeks. Previous reports have suggested that KGF can help heal chronic wounds. But in most studies the growth factor was applied to the surface of the wound, limiting its availability to deeper tissues and requiring repeat applications to produce any clinical benefit. Using large quantities of growth factor would make this therapy extremely expensive. Our work circumvents these limitations by more efficiently delivering KFG throughout the wound to stimulate tissue regeneration. ... The authors describe developing a fusion protein from recombinant KGF and elastin-like-peptides, which are major constituents of skin and other connective tissues. Laboratory experiments showed that the fusion protein retained the wound-healing properties of both elastin and KGF and that it rapidly and efficiently self-assembled into nanoparticles in response to a simple increase in temperature. When applied to deep skin wounds in genetically diabetic mice, the nanoparticles accelerated healing by stimulating the formation of both surface epithelial tissue and thick fibrous connective tissue."

Link: http://www.eurekalert.org/pub_releases/2011-01/mgh-gna012611.php

NOVA on Longevity Science

An edition of the PBS popular science series NOVA that aired today looks at a little of present day longevity science:

This provocative episode of NOVA scienceNOW examines whether we can slow down the aging process, looks at the latest on human hibernation, and checks in with bioengineers and a computer scientist inventing ways to keep us "going forever." Neil deGrasse Tyson also takes a lighthearted look at whether the tricks that have kept a 1966 Volvo running for 2.7 million miles can also help the human body go the extra mile.

You can watch it online, and one of the embedded section of the show is provided below. This isn't earthshaking stuff, and should all be familiar old news to readers here, but I'm all for seeing more high quality productions that aim to introduce the public to the fundamental ideas of applied aging and longevity research:

As was pointed out to me in a private email, there is a refreshing lack of negativity in the program - it's a generally positive outlook on the science that is presented. That may be a sign of progress.

Enhancing Memory With Insulin-Like Growth Factor

From ScienceDaily: "A naturally occurring growth factor significantly boosted retention and prevented forgetting of a fear memory when injected into rats' memory circuitry during time-limited windows when memories become fragile and changeable. ... To our knowledge, this is the first demonstration of potent memory enhancement via a naturally occurring factor that readily passes through the blood-brain barrier - and thus may hold promise for treatment development ... The staying power of a memory depends on the synthesis of new proteins and structural changes in the connections between brain cells. These memory-strengthening changes occur within time-limited windows right after learning, when memories undergo consolidation, and also right after a memory is retrieved, a process called reconsolidation. Hints from other studies led the researchers to suspect that IGF-II plays a role in these processes within the brain's memory center, the hippocampus, where it is relatively highly concentrated. The little-known growth factor is part of the brain's machinery for tissue repair and regeneration; it is important during development and declines with age. ... learning boosted the expression of naturally occurring IGF-II in the hippocampus. So the researchers injected synthetic IGF-II directly into the hippocampus during windows of consolidation or reconsolidation, when memories are malleable. Remarkably, the rats' memory markedly improved - with the effects lasting at least a few weeks. An examination of the animals' brains revealed that IGF-II had strengthened the cellular connections and mechanisms underlying long-term memory - a process called long-term potentiation."

Link: http://www.sciencedaily.com/releases/2011/01/110126131534.htm

The 2nd Annual Young Cryonicists Gathering

The cryonics community last year held an outreach event for younger members - a part of the necessary structure of cryonics as a process is a continuing community to maintain the preserved bodies and brains of those who preceded them. This year the event will be held in May: "This cryonics focus group seminar hosted by Bill Faloon and Carin Idun will be held on Thursday, May 19 and Friday, May 20, 2011, in Fort Lauderdale, Florida. Invitations were mailed to CI and Alcor members ages 13-29. The purpose of the young cryonicists' seminars is to develop a continuing social network of like-minded individuals who otherwise might not have the opportunity to meet in person. This gathering is open to young cryonicists from all cryonics organizations. Registered participants will also enjoy the opportunity to attend the Suspended Animation conference. You must be registered in advance to attend." As I noted last year, "this sort of event sounds like something worth making an institution in the community. Cryonics has a long way to go to become mainstream, but every step is a step closer. So many, many lives will be lost between now and the advent of working rejuvenation medicine - and the methodology presently exists to save those lives though cryonics. Most people are not aware of it or interested in it, however, and cryonics provision needs to be scaled up to handle the masses. Scaling is a trivial problem compared to convincing people that a viable workaround to death exists; as soon as there is desire for a product, there will be competition and development."

Link: http://www.alcor.org/blog/?p=1529

Investigating the Quality Control of Mitochondria

Mitochondria are the power plants of your cells, and are very important in degenerative aging. Differences in mitochondrial structure correlate strongly with differences in species life span, and there is every reason to believe that accumulated damage to mitochondria plays a large part in the destruction of health and vigor that comes with age.

We know that mechanisms like autophagy exist within a cell to recycle damaged mitochondria: these mechanisms are just not effective enough to prevent the forms of damage that contribute to aging. But do mitochondria repair themselves? The distant ancestors of mitochondria were free-living bacteria, so it might not be unreasonable to expect them to be at least partly capable of self-repair. If natural mechanisms of mitochondrial repair can be identified, then potentially better repair and rejuvenation biotechnologies could arise from that knowledge. Clearly whatever mechanisms exist are not good enough to keep us from degenerating, but we clever humans should be able to greatly improve upon the basic model.

The research community is not lacking in means to deal with mitochondrial damage, of course - there are at least four or five potential paths ahead, such as replacing mitochondrial DNA throughout the body or moving the most important mitochondrial genes into the cell nucleus. But the more the merrier: twenty lines of research are far more likely to produce a meaningful result sooner and more effectively than five.

I looked at mechanisms of repair in mitochondria a few years back, a post largely focused on DNA repair. For today we'll look at a different aspect of repair, the removal of damaged molecules that degrade the effectiveness of cellular machinery. I'm going to direct your attention to a pair of papers that propose that mitochondria maintain an internal mechanism of quality control that is separate from - but very similar to and influenced by - the housekeeping processes of the cell itself.

Possible Existence of Lysosome-Like Organella within Mitochondria and Its Role in Mitochondrial Quality Control:

The accumulation of unhealthy mitochondria results in mitochondrial dysfunction, which has been implicated in aging, cancer, and a variety of degenerative diseases. However, the mechanism by which mitochondrial quality is regulated remains unclear. Here, we show that Mieap, a novel p53-inducible protein, induces intramitochondrial lysosome-like organella that plays a critical role in mitochondrial quality control.

Mieap, a p53-Inducible Protein, Controls Mitochondrial Quality by Repairing or Eliminating Unhealthy Mitochondria

Maintenance of healthy mitochondria prevents aging, cancer, and a variety of degenerative diseases that are due to the result of defective mitochondrial quality control (MQC). Recently, we discovered a novel mechanism for MQC, in which Mieap induces intramitochondrial lysosome-like organella that plays a critical role in the elimination of oxidized mitochondrial proteins ... However, a large part of the mechanisms for MQC remains unknown. Here, we report additional mechanisms for Mieap-regulated MQC.

The really fascinating thing here, for those of you following along at home, is the involvement of p53, a protein cog in the cellular machinery that seems to have its thumb firmly stuck into every pie when it comes to aging, cancer, and all related topics. At least one method of extending healthy and maximum life span in mice involves alterations to p53, and no doubt more will follow.

The Big Think Series on Longevity

SIngularity Hub likes the Big Think series on longevity: "Thinking about living forever? You've got a lot of reading to do...or maybe you can just watch a few videos. The science surrounding longevity is a hive of interweaving studies and counterstudies that can leave the average reader confused. Singularity Hub will always give you a look at the best life-extension technologies as they emerge, but what if you need the very basics? In that case, BigThink's series "Living Longer, Better - and Maybe Forever" is a fun place to start. With videos from Aubrey de Grey, Ray Kurzweil, Leonard Guarente, and many others the series gives its audience a first look at some of the technologies and possibilities for the future of human life. ... If you have to begin with one expert to introduce you to longevity, it should probably be Aubrey de Grey. The rather-famous scientist has made a career of studying how human-life could be extended well beyond the means of today. Passionate, thoughtful, and sporting an unforgettable beard, de Grey's talks about longevity are typically as insightful as they are memorable. ... Part of what makes the BigThink 'Living Longer, Better - And Maybe Forever' series a good place to start is that the videos selected are a small sample of the much longer footage collected. Aubrey de Grey, for instance, has more than a half hour of interview videos available on BigThink divided into sections for easy browsing. If any of the speakers in the series interest you, you can be almost certain that there is more video of their thoughts for you to explore."

Link: http://singularityhub.com/2011/01/24/bigthinks-series-on-longevity-a-fun-place-to-start-video/

SENS Foundation FAQ Posted

The SENS Foundation has posted a FAQ on their work to defeat degenerative aging: "Can anything really be done about age-related degeneration and disease? Isn't getting sicker as we get older just a fact of life? It is informative to think about similar questions which might have been asked at different points over the past century. Can we really do anything about wound infections? After the invention of antibiotics the answer was a resounding, 'Yes'. When will the next outbreak of smallpox occur? After the WHO's program of eradication the answer became, 'Never'. Cholera, and John Snow's work on its epidemiology; polio, and the Salk vaccine... the list goes on. All these advances in medicine changed the answers to questions, and showed that a 'fact of life' is often just a problem waiting for a solution. So it is with the sickness of older age. It has not yet been addressed effectively, but that does not mean that it cannot be addressed. It simply means that we have to find new ways to tackle the problem, and the most promising of these is rejuvenation biotechnology. ... Wouldn't it be easier to find ways to slow down age-related degeneration than to reverse it? First, let's be clear on what 'reversing age-related degeneration' means, in rejuvenation biotechnology. We are not trying to reverse the process which causes degeneration: that process is highly complicated and not well understood. Rather, we are working to repair the result of that process, sidestepping our ignorance of the process itself. We believe that this side of the problem of age-related degeneration can be solved more rapidly and effectively. The human body, by its nature, is a very complex system, built from finely-regulated, metabolic subsystems. Tinkering with one aspect inevitably ripples in unexpected ways through the entire system, and in ways which we can rarely predict with any great confidence. This entails a high risk of negative side-effects occurring when any one of them is modified. Reversing age-related degeneration - in the damage repair sense - avoids the complex pathways of metabolism, and has the potential to be simpler and more effective than methods which only slow it down."

Link: http://sens.org/sens-research/faq

Crunching the Numbers on a Longevity Study

Some people have better genes than others, at least when it comes to living a longer, healthier life. They are perhaps more resistant to some forms of biological damage, perhaps have better repair mechanisms, perhaps can respond more effectively at a cellular level to good diet and lifestyle choices. The reasons why natural longevity has an inherited component are largely unknown and will be a subject for research for the next few decades - indeed, I expect the first generation of meaningful rejuvenation therapies to arrive in advance of a full understanding of the natural differences in human longevity. That full understanding simply isn't necessary for researchers to make progress in repairing and reversing the known biochemical differences between an old person and a young person.

One noteworthy study of human longevity is the Long Life Family Study - the link there goes to a secure site with a self-signed certificate, so your browser will require you to click through a warning message in order to view it.

The goal of the Long Life Family Study (LLFS) is to answer an important question: Why do some people and their families live very long lives? LLFS is a unique international project that is studying families who have several members reaching a very old age. Families from the United States and Denmark will help us learn why some people live until a very old age and why some families maintain their health far longer than the average family.

A recent open access paper crunches some the numbers from the Long Life Family Study and presents graphs and tables that illustrate the degree to which long-lived folk have better measures of health throughout their old age when compared with the rest of us. It is an interesting read on a number of levels, not least as an introduction to how these studies work under the hood, and what the researchers are looking at.

This paper compares the prevalence of disease as well as physical and cognitive functioning in LLFS probands and offspring to two community based cohorts that were not selected for longevity. These comparison cohorts include the Cardiovascular Health Study (CHS), the [Framingham Heart Study (FHS)] original and FHS offspring cohorts.

...

Probands and offspring of the LLFS cohort were less likely to have diabetes, chronic pulmonary disease and peripheral artery disease than the CHS and FHS cohort members. Measures of physical function and cardiovascular risk factors were more optimal in LLFS compared to the other groups. High density lipids were higher and triglycerides were lower in LLFS probands and offspring. This is consistent with previous reports of the children of centenarians having better lipid profiles than controls. These findings suggest that the strategy of recruiting families with a history of longevity yielded rates of healthy aging not unlike that seen when recruiting offspring of centenarians.

One of the goals of the mainstream aging research establishment is to try and replicate the factors that lead to the upper end of natural human longevity: adding a decade or so to healthy life through genetic manipulation and drugs aimed at altering metabolism. As a goal considered in isolation this is laudable - but in the broader context of what is possible, this is a slow, poor way forward in comparison to damage repair strategies.

Progress in Progeria Research

The accelerated aging condition progeria so far appears to be an extreme example of one type of cellular damage that usually only provides a very modest contribution to degenerative aging. Here is news of recent research: "Hutchinson-Gilford Progeria Syndrome, also known as progeria, is caused by a mutation in the gene encoding for the protein lamin A, an important component of the membrane surrounding a cell's nucleus. The mutation results in a truncated form of lamin A called progerin, which in turn causes misshapen cell nuclei and DNA damage. ... [researchers] have produced the world's first human cell model of progeria, a disease resulting in severe premature ageing in one in four to eight million children worldwide. This model has allowed them to make new discoveries concerning the mechanism by which progeria works. ... the team used a novel technique of deriving induced pluripotent stem (iPS) cells from cells of human progeria patients. This human progeria model allows the group to trace and analyse the distinctive characteristics of progeria as it progresses in human cells. ... The researchers used their iPS cells to identify two types of cells - mesenchymal stem cells (MSCs) and vascular smooth muscle cells (VSMCs) - that were particularly adversely affected by progeria. This means that a young patient with progeria would typically have fewer MSCs and VSMCs than other children. MSCs were found to be very sensitive to a low oxygen environment and their losses could delay renewal of the various tissues they gave rise to, thus exacerbating the patient's symptoms of ageing. The same effect on VSMCs could explain why their number was reduced in the patient's heart vessels. ... This new study provides further evidence for the role of lamin processing in connective tissue function, as well as insights into the normal ageing process. We hope to soon find new routes of intervention to treat this incurable disease. Such interventions may be of use in treating atherosclerosis in general, a condition afflicting many millions of individuals."

Link: http://www.sciencedaily.com/releases/2011/01/110124102948.htm

Supercooling Applied to Cryopreservation

Of possible long-term relevance to cryonics: "A technology used to freeze sushi is solving a dilemma for organ storage. By borrowing tech used to preserve high-end food delicacies, a Hiroshima University research group proved it possible to safely freeze whole teeth and their delicate attaching tissues. As long as the freezer stays cold, the folks at Hiroshima U. think your teeth could be stored for 40 years, no problem. But the sushi-storage system isn't a one trick pony: internal organs could be next thanks to the magic of supercooling. In typical cryo-storage, fast freezing of organs requires poisonous levels of anti-freeze, and let's face it, no one wants a poisoned kidney transplanted into their body. But slower freezing causes cell popping ice crystals to form. So, what do you do to prevent ice crystals during slow freezing? Use magnets. ABI is the Japanese company producing the freezer system. ABI's 'Cells Alive System' (CAS) vibrates water with magnetic fields, preventing freezing, even at supercool temperatures of -10 degrees Celsius (According to the Patent.) When the field is turned off, the water in the food instantly freezes. No time for ice growth. ... A very tricky part of tooth preservation is keeping tooth ligaments alive, or even some of the ligament cells. Implanting ligaments is important. We have ligaments attached to teeth because the force of chewing could grind our chompers out of our jaws. When the research team tried slow freezing a whole fresh tooth without the CAS magnetic fields, the ligaments didn't survive and were severely damaged. However, a CAS magnetically vibrated tooth's ligaments survived. CAS frozen ligament cells grew as well as those from a fresh tooth, and showed only minor damage."

Link: http://singularityhub.com/2011/01/23/food-freezing-technology-preserves-human-teeth-organs-next/

Genescient on Genescient

As a companion piece to my opinions on Genescient from a year and a half ago, you might look at a recent h+ Magazine article in which one of the company VPs provides an overview of their present work:

In this article, I describe our efforts at Genescient LLC in Irvine, CA to develop strategies to delay aging and age-related disease. Genescient's primary business focus is on the development of pharmaceuticals for age-related diseases, but in conjunction with its spinoff firm Life Code LLC, it has provided testing services for the development of nutraceuticals based on its unique genomics platform. Our findings can be summarized as follows:

  • Aging is linked to altered expression in more than a hundred genes;

  • We employed artificial intelligence algorithms combined with animal longevity assays to screen for wide-spectrum herbal extracts that extend lifespan;

  • We succeeded in doubling [fruit fly] lifespan using a novel class of nutrigenomic supplements that modulate genes involved in both aging and age-related disease.
  • It's an interesting piece. My take on Genescient remains much the same: their work is a very efficient next generation approach to what is a comparatively ineffective course of action in regards to aging. In this it epitomizes the mainstream of aging and longevity research - the development of ever more sophisticated methodologies aimed at slowing down the aging process through manipulation of metabolism. Sadly, however, any foreseeable method of slowing aging will be of little use to people who are already old ... and none of us are getting any younger as we wait on progress in research and development.

    Genescient generates a raft of genetic and other information that will be useful throughout the life science field - including aging research - regardless of the outcome of their other work. The company will also make the founders a large pot of money if there's any justice in the world, given that they are effectively a next generation Sirtris. But none of this changes the fact that, from the perspective of progress towards extending human life, all that investment would be far better spent on SENS.

    I say that because what we want to see are the biotechnologies of rejuvenation, not mere slowing of aging. Given that aging is an accumulation of biological damage, it seems clear that the future of human longevity will be overwhelmingly determined by methods of biological repair, not by methods of modestly slowing down the pace of damage. Any working repair methodology will produce a degree of rejuvenation, and it can be used over and again as the damage slowly returns - unlike a change in metabolism, which has a limited benefit and cannot turn back the clock.

    If the longevity research community continues to spend the present majority of its time on ways to slow aging, then we're all going to age to death with very few additional years to show for that research investment. It's that simple.

    Thoughts on the Non-Issue of Overpopulation

    A post from the author of the Finnish language book Evolving Humanity: "The replenishment rate required to keep a population stable is about 2.1 children per woman. The average fertility rate in a lot of industrialized countries is well below this - for instance, 1.58 in Canada, 1.42 in Germany, 1.32 in Italy, 1.20 in Japan and 1.04 in Hong Kong. The EU average is 1.51. Yes, in a lot of poor countries the figures are considerably higher - Niger tops the chart with 7.68 children per woman - but even then the overall world population growth is projected to start declining around 2050 or so. To give a sense of proportion: suppose that tomorrow, we developed literal immortality and made it instantly available for everyone, so that the death rate would drop to zero in a day, with no adjustment to the birth rate. Even if this completely unrealistic scenario were to take place, the overall US population growth would still only be about half of what it was during the height of the 1950s baby boom! Even in such a completely, utterly unrealistic scenario, it would still take around 53 years for the US population to double - assuming no compensating drop in birth rates in that whole time. We've adapted to increasing lifespans before. Between 1950 and 1990, the percentage of population over 65 almost doubled in Sweden, going from 10.3 to 18.1. (In the United Kingdom it went up from 10.7 to 15.2, in the US from 8.1 to 12.6, and in the more-developed countries overall it went from 7.6 to 12.1.) The beauty of economics is that like all resource consumption, having children is a self-regulating mechanism: if a growing population really does exert a heavy strain on resources, then it will become more expensive to have children, and people will have less of them. ... I see no reason to presume that radical life extension and indefinite youths would pose us any problems that we couldn't handle, at least not on the overpopulation front." You might also look at the demographic models mentioned in the Fight Aging! archives.

    Link: http://xuenay.livejournal.com/337695.html

    The Potential to Block Metastasis

    Blocking metastasis would be a big step towards the defeat of cancer, and a number of different approaches show promise. Here, researchers "have discovered a rogue gene which - if blocked by the right drugs - could stop cancer in its tracks. ... the discovery is a breakthrough in our understanding of how cancer spreads. It is hoped the research will lead to new drugs that halt the critical late stage of the disease when cancer cells spread to other parts of the body. The culprit gene - known as WWP2 - is an enzymic bonding agent found inside cancer cells. It attacks and breaks down a natural inhibitor in the body which normally prevents cancer cells spreading. .... by blocking WWP2, levels of the natural inhibitor are boosted and the cancer cells remain dormant. If a drug was developed that deactivated WWP2, conventional therapies and surgery could be used on primary tumours, with no risk of the disease taking hold elsewhere. ... the discovery could lead to the development of a new generation of drugs within the next decade that could be used to stop the aggressive spread of most forms of the disease, including breast, brain, colon and skin cancer. ... The late-stages of cancer involve a process known as metastasis - a critical phase in the progression of the disease that cannot currently be treated or prevented. The challenge now is to identify a potent drug that will get inside cancer cells and destroy the activity of the rogue gene. This is a difficult but not impossible task, made easier by the deeper understanding of the biological processes revealed in this study."

    Link: http://www.eurekalert.org/pub_releases/2011-01/uoea-brg011911.php

    Fifty Years From Now, You're Either Dead or Dying - So Do Something About It

    Much of the more active end of the present transhumanist community is very concerned with existential risk on a grand scale: the Singularity Institute, the Lifeboat Foundation, the Center for Responsible Nanotechnology, and so forth. It doesn't hurt to have some people thinking about the end of the world - it seems like a good plan, given the balance of risk and odds as we presently understand it. A tiny risk, gargantuan consequences, a lot of people in the world, and just a few thinking meaningfully about how it might all fall into the pit. A sort of inverse Pascal's Wager, if you like.

    As a fraction of the community of folk focused seriously on advancing technology and pushing out the horizons of what is considered possible - as opposed to those who are short-sighted or merely along for the ride - I think that the existential analysts are somewhat overweighted, however. There are too many people finding reasons to say "hold up a moment here" and too few with the pedal floored to the metal.

    I'm of the opinion that "hold up a moment here" is a poison of this age. It's in the air, a toxin that seems right at home in the cultural background mix of NIMBY, death by precautionary principle, environmentalist Malthusianism, bioethicists whose funding depends on finding roadblocks, and comfortable, wrong-headed assumptions that next year will look just like last year. Vast numbers of people are trapped in the illusionary moment, fighting every change in an age of change - and there are so many of them that some little part of their attitudes inevitably seeps into every part of the grand multi-threaded conversation that is our culture. Even those parts that are ostensibly focused on achieving progress.

    The precautionary principle is a distillation of inaction forced by excessive caution. More extreme expressions of the precautionary principle have been seized upon and promoted by all sorts of opponents of progress because they represent a halt to all progress: no advance is ever risk-free. Demanding - and attempting to enforce - risk free progress is one and the same with halting the engine of science and technology. Many foolish people want just this, sadly, and would condemn every living person to suffer and die from degenerative aging to achieve their ends.

    Sadly, the popularity of extreme expressions of the precautionary principle obscure the high costs of adhering to even moderate versions. If you attach a ball and chain to those working on medical progress, medical progress will be slow. How can anyone advocate slowing down progress in the face of 100,000 deaths each and every day? Yet this seems to be the mainstream position; those who do not contribute to getting the work done have largely fallen down the rabbit hole of doing nothing but throwing roadblocks in the path ahead. Great job, you all - I hope you manage to live with yourselves if scientists create working anti-aging medicine within our lifetime despite your efforts. If science is held back well enough ... well, then we all age, suffer and die. Well done. Applause. A pity you won't be there to receive the gratitude of the masses - who won't be there either.

    While this all takes place, hovering over us all is the grand sword: that in fifty years, barring a big fat revolution in the entire ethos and strategic direction of the life science community, we're all dead or dying. There's your existential risk. A very large "certainly dead, all of us, unless we do something" existential risk. Not a small or unknowable or yet to be quantified risk, but a certainty ... unless we act to develop rejuvenation biotechnology.

    So we can floor the pedal, or we can talk about why it's a terrible idea to floor the pedal without doing all sorts of other things first. I know which approach I think will dig us out of the hole we're in - and it's not the one that involves moving ahead slowly.

    The Russian Press on KrioRus

    Here is a short popular Russian press article on KrioRus, the Russian cryonics provider: "It's freezing outside for everyone - but a select few are hoping that the ice holds the key to eternal life. A cryonics firm on Moscow's outskirts has already consigned 15 Russians to the deep freeze in the hope of being reanimated in the future as medical science advances to extend the lives they have completed. Booking a place in the future doesn't have the sci-fi good looks one might hope for, with the company operating in a mundane industrial block. 'It's true, we aren't very glamourous here,' Valeria Praid, the [cryonics] firm's general director, member of the Russian Council of the Transhuman Movement, and futurologist told [the media]. ... Sceptics may point out that frozen people are dead people and so freezing bodies that can no longer sustain life is a futile exercise, but the issue is apparently more complex, and there are different kinds of scientifically recognised death: Clinical death - when the body stops functioning as a whole, but while many cells and organs continue to operate and their structures have not yet started deteriorating. Biological death - the partial destruction of the body's structures. Information-theoretic death - the destruction of the human brain (or any other cognitive structure) and the information within it to such an extent that recovery of the original person is ostensibly impossible. Cryonics, or biostasis, allows corpses somewhere between biological death and information-theoretic death to be preserved, presumably with hopes of revival." More public attention for the endeavor of cryonics is always a good thing.

    Link: http://themoscownews.com/society/20110121/188353056.html

    Growing Human Liver Tissue

    Via EurekAlert!: "A new study reports on the success of growing human liver cells on resorbable scaffolds made from material similar to surgical sutures. Researchers suggest that this liver tissue could be used in place of donor organs during liver transplantation or during the bridge period until a suitable donor is available for patients with acute liver failure. ... liver cells have excellent regenerative potential making liver cell transplantation a viable therapeutic approach for patients with metabolic defects or fulminant hepatic failure as the native liver is preserved while liver dysfunction may resolve as regeneration occurs. ... Currently isolated liver cells are used for liver cell transplantation, but these cells suffer during cell isolation and cryopreservation, which is one reason there is limited success with this type of transplant procedure. ... In applying their tissue engineering approach, [the] researchers were able to successfully create new liver tissue providing a potential solution to the obstacles challenging liver cell transplantation. ... The team isolated liver cells from 12 human liver specimens with a viability of 82%. After a two-day culture period, liver cells formed tightly packed cellular aggregates, called spheroids, and took on a liver-like appearance. Human liver cells were distributed across a three-dimensional porous structure of the polymer scaffolding. From day two to four, the average number of spheroids more than doubled from 18 to 41 per visual field. ... Our experimental model represents a promising technique to culture human liver cells and prepare them for transplantation on a biodegradable polymer scaffold into the peritoneal cavity. Further studies are underway to confirm our results and may ultimately offer viable clinical options for liver cell transplantation in the future."

    Link: http://www.eurekalert.org/pub_releases/2011-01/w-sgh012011.php

    The Ideas of Longevity Science are Spreading

    When it's working, advocacy for longevity science funding and progress towards rejuvenation biotechnology is a steady process of growth; an accumulation of articles, conversions, acts of persuasion, and new advocates. It continues year after year, and perhaps it is sometimes hard to tell whether we're better placed in 2011 than we were in 2010, but we can certainly look further back to see clear and meaningful progress over the past five or ten years in public awareness of longevity science, media attention, and support for bold action in the scientific community science. Turning a formerly fringe idea into a mainstream vision for the future - persuading the world, in other words - doesn't happen overnight, sad to say. But it does happen, and it is well underway for the goal of greatly extended healthy longevity.

    I noticed one small sign of the spread of ideas today: a paper in the Cambridge Journal of Healthcare Ethics written by a professor in the field, which opens this way:

    Picture this. You are having your regular medical checkup, when, all of a sudden, the physician turns to you and says: "Oh, did I remember to mention that you can now live forever?" You look at the doctor enquiringly and she goes on: "Well, it's not actual immortality, you know, but they've invented this treatment - I don't have the full details - that stops aging, getting physically older. It might not be for everyone, but you seem to be a suitable candidate. You could still die of accidents and illness, of course, but they've calculated that with care and any luck you should live to be a thousand, as opposed to the hundred or so that you would now have. And in a millennium, techniques will advance further, so there could be more in store for you after that."

    You might look back into the Fight Aging archives for the origin of that thousand year life span figure. In essence it's based on accident rates; sooner or later that piano will fall on you, assuming you fail to alter your life in ways that greatly reduce risk over the long term.

    Pianos or not, our lives are too short, ramping down into dysfunction, frailty, and disease just as we become good at this business of living. But in this age of rapidly advancing biotechnology we have the opportunity to do something about this problem: we don't have to suffer the unmodified human condition, as our ancestors did. The scenario painted above by the quoted bioethicist will never happen quite as written, but with the right levels of funding we are no more than a few decades from therapies that can in fact significantly reverse and repair the degenerations of aging. They will not be perfect, these first generation medical technologies, but they will give us additional decades, and science will not be standing still while we enjoy those extra years of healthy life. Twenty years is an eternity in biotechnology: whole new fields will emerge and radical new leaps forward will be made, all the better to further repair the damage of aging and give us yet more years to enjoy being alive. This is actuarial escape velocity, a future in which the scientific community can add healthy years to our lives faster than we are aging our way towards frailty and the grave.

    The funding needed to start in earnest upon this grand project is presently absent, sadly. The steps required to gain that funding are all a matter of advocacy: persuasion, the growth of the community of people who are aware of the possibilities offered by longevity science, more articles and papers discussing how to use biotechnology to shape the future of our lives. So we should be pleased to see concepts like the thousand year life span and actuarial escape velocity making their way out into the broader community. Of such small steps is progress made.

    Revisiting the Gender Longevity Gap Once More

    There are a great many theories as to why the well-known gap between male and female longevity exists. Here, researchers look at differences in lifestyle choices and pin the blame on smoking and drinking: "Since the late 1990s there has been evidence that women now outlive men in all countries of the world. Historical records show that in Sweden, Denmark, Italy, The Netherlands, England and Wales, the life expectancy of women has exceeded that of men since the mid to late 18th century, and there has been speculation about the causes of gender differences since that time. Different explanations have been postulated for this gender gap, including biological factors. However, there is considerable variability, and sometimes rapid change, in the magnitude of the female mortality advantage over time and in different countries, a variability that poses challenges for simple biological explanations for the gender gap. Earlier research suggested that health behaviours, and particularly men's higher prevalence of smoking, were a major cause of gender differences in the US. Here, we use contemporary mortality data for 30 European countries to examine the extent to which men's higher mortality can be explained by smoking-related and alcohol-related deaths. ... Smoking-related deaths accounted for around 40% to 60% of the gender gap, while alcohol-related mortality typically accounted for around 20% of the gender gap. The range in the contribution of smoking-related deaths reflects gender differences in the uptake of smoking by gender in earlier decades."

    Link: http://tobaccocontrol.bmj.com/content/early/2010/12/20/tc.2010.037929.full

    Parkinson's as a Contagion in Brain Cells

    It has been known for a while that alpha-synuclein is important in Parkinson's disease, and here is insight into how the condition might spread within the brain once it gets started: "damaged alpha-synuclein proteins [can] spread in a 'prion-like' manner, an infection model previously described for diseases such as BSE (mad cow disease). ... This is a significant step forward in our understanding of the potential role of cell-to-cell transfer of alpha-synuclein in Parkinson's disease pathogenesis and we are very excited about the findings ... A previous observation that aggregated alpha-synuclein protein gradually appears in healthy young neurons transplanted to the brains of Parkinson's patients initially gave rise to the group's hypothesis of cell-to-cell protein transfer. The theory has now been tested in several cell culture experiments. ... We have now shown that alpha-synuclein not only can transfer from one cell to another, but also that the transferred protein can seed aggregation of alpha-synuclein in recipient cells as well. This could be an important mechanism for the spread of the pathology. ,... Transplant trials in mice [strengthened] the theory of cell-to-cell transfer ... Six months after Parkinson's disease model mice were transplanted with healthy dopamine neurons, we found that the new brain cells contained human alpha-synuclein, indicating cell-to-cell transfer from the host brain to the transplants."

    Link: http://www.eurekalert.org/pub_releases/2011-01/lu-upi011911.php

    A World Without Sleep

    Removing the human need to sleep will undoubtedly happen at some point in the decades ahead of us. The potential economic benefits are vast, and so as soon as it becomes remotely plausible we will see tremendous investment in realizing whatever biotechnology ultimately makes it feasible. You might look at the present large and ongoing investment into developing sleep suppressant drugs that are free from significant side effects as a small foretaste of what is to come.

    A life without sleep would be a life effectively made 30% longer. There's a thought for the day - not all methods that might be experienced as life extension involve your body being alive for more calendar years. For example, one of the advantages of the very long term goal of incrementally replacing brain cells with nanomachinery is that it opens up the possibility of increasing your "clock speed": of thinking faster and experiencing more time per second than a present day human could. By that point, of course, we would hope that much of the challenge of aging has long been solved.

    Over at Depressed Metabolism, you'll find a different angle on sleep: used as an argument to show one of the ways in which knee-jerk reactions to cryonics are illogical.

    Imagine that human culture has never experienced sleep, but suddenly must experience it to survive. Would they be apprehensive about experiencing it for the first time? Of course!

    Just picture... this total suspension of consciousness, experienced for the very first time in human history. The notion would totally blow our minds. It would be completely shocking. We might even make up stories about dying and being replaced by an identical clone being, or trying to console ourselves that at least we will have a successor on the following day to carry out our desires.

    Contrary to popular belief, there is no particular reason to assume that humans who "survive" events like freezing or vitrification would be any different from humans that "survive" sleep or anesthesia. The definition of consciousness we care about is the lifelong continuity of experiences created by memories.

    Our memories are encoded in the fine structure and connections of our brains, and for so long as that structure is preserved then we continue to exist as a person - whether or not our brains are currently in operation. The essence of cryonics is to preserve that structure after the point at which our bodies and modern medicine are no longer up to the task. The molecular nanotechnologies and biotechnologies of the future will be capable of restoring a preserved brain to active life: it's just a matter of organization and waiting, which in and of itself is no small challenge, but not an insurmountable one either.

    A Discussion on the Future of Nanoscience

    The development of nanotechnology has great relevance to the future of healthy longevity; at its simplest, aging is a matter of atoms and molecules being out of place. As our ability to control the building blocks of matter improves, so too will medicine improve in leaps and bounds. Here is an interesting discussion from Nanowerk - experts in the field looking ahead to what is to come: " One of the beautiful things about biology is that biology functions at many different length scales, and all of those length scales are working together to make the being functional. So if you think about down to the molecular scale, to DNA and coding and genetic information, to protein that the genetic information codes, to tissues that it builds up to functional levels - you know, human beings walking around - it's pretty fascinating to think about how all that works together. But it is all basically encoded in these molecules within cells. ... I think the impact of nanoscience in medicine is going to grow dramatically over the next 10 to 20 years, especially in the field of regenerative medicine. Another thing that I am hopeful about is that we will be able to hijack the brilliant mechanisms of biology to construct for us functional non-biological nanosystems. ... one area that's absolutely ripe for incredible advances is the life sciences and medicine, where aggregations of individual nanodevices to create nanosystems will allow us to embrace, rather than run away from, the complexity of biological systems and will give us the tools, I believe, to understand and engineer biological circuitry, which as the root of systems biology and ultimately, I think, will give a technological foundation for personalized medicine. ... I believe that the broad umbrella of nanoscience is rapidly dissolving the traditional barriers between [disciplines], and maybe wiring them a bit together with the idea that now people are thinking about atoms and materials as arbitrary forms, not in the historical sense. Physicists are now using biological systems, and biologists are exploiting solid state devices and microfluidic devices within a myriad of research efforts. People are thinking much more broadly than in the past [and] I think it's the discoveries in science that are driving this direction. When I look at the students who are entering the university system, they're highly motivated by the idea of breaking down the normal barriers and focusing on the new scientific opportunities that emerge."

    Link: http://www.nanowerk.com/news/newsid=19676.php

    Making Human Cells More Resistant to Damage

    Are there practical, safe, comparatively simple ways to make human cells more resistant to damage, and thereby reduce the effects of aging and disease? Perhaps, and here is an example of this sort of research: researchers "have discovered a molecule that can make brain cells resistant to programmed cell death or apoptosis. ... This molecule, a tiny strand of nucleotides called microRNA-29 or miR-29, has already been shown to be in short supply in certain neurodegenerative illnesses such as Alzheimer's disease and Huntington's disease. Thus, the discovery could herald a new treatment to prompt brain cells to survive in the wake of neurodegeneration or acute injury like stroke. ... There is the real possibility that this molecule could be used to block the cascade of events known as apoptosis that eventually causes brain cells to break down and die. ... The researchers looked at a number of steps in apoptosis and found that miR-29 acts at a key point in the initiation of apoptosis by interacting with a group of genes called the BH3-only family. Interestingly, the microRNA appears to interact with not just one but as many as five members of that family, circumventing a redundancy that existed to allow cell death to continue even if one of them had been blocked." This is somewhat a damage resistance strategy - it doesn't block damage, but it stops a cell from destroying itself in response to damage. This may allow certain classes of cell to continue functioning usefully under some forms of attack (such as the neurodegenerative conditions mentioned above), but as a general strategy it has flaws - cells usually destroy themselves for good reason. Having malfunctioning cells stick around rather than remove themselves is not a good thing in most tissues.

    Link: http://www.sciencedaily.com/releases/2011/01/110118122740.htm

    Humanity+ Board Elections Open

    Humanity+ is a long-standing transhumanist advocacy organization, formed in support of improving the human condition through applied science: extended healthy longevity, engineering the mind, the advent of strong AI, the elimination of disease and suffering, and so forth. In its present guise, I think the organization is better addressing its mission in comparison to past years when it was branded as the World Transhumanist Association. The board of directors is very different nowadays and perhaps more energetic; certainly more appropriate to the way in which Humanity+ presently organizes itself.

    Humanity+ is an international nonprofit membership organization which advocates the ethical use of technology to expand human capacities. We support the development of and access to new technologies that enable everyone to enjoy better minds, better bodies and better lives. In other words, we want people to be better than well. ... Approximately 6000 people belong to Humanity+ from more than 100 countries, from Afghanistan to Brazil to Egypt to The Philippines. Supporting and sustaining members elect the Board, and participate in Humanity+ leadership and decision-making. Humanity+ members also participate in more than two dozen chapters around the world.

    A great deal of the advocacy process is a matter of slowly raising the water level of awareness and understanding - bootstrapping the size of the community and the breadth of information associated with it. Over the years advocates and supporters produce discussions, articles, and hold events: these form a diffuse and ever growing cloud of information. The larger the cloud, the easier it is for people to encounter your ideas, and the more receptive they will be when they dive in to find a great deal of material ready and waiting for them. In this respect, I think that Humanity+ and h+ Magazine are performing good work these days - increasing the size of the cloud, looking more professional while doing so, and maintaining a profile appropriate to a distributed non-profit whose leaders and activists are scattered across the world.

    I see that the latest Humanity+ board elections are open as of today, and run for the next couple of weeks. If you're a member, don't forget to vote. If you aren't a member and agree with the positions advocated by Humanity+, then sign up so you can vote on the next board election.

    A final thought for today, from the Transhumanist FAQ:

    Success in the transhumanist endeavor is not an all-or-nothing matter. There is no "it" that everything hinges on. Instead, there are many incremental processes at play, which may work better or worse, faster or more slowly. Even if we can't cure all diseases, we will cure many. Even if we don't get immortality, we can have healthier lives. Even if we can't freeze whole bodies and revive them, we can learn how to store organs for transplantation. Even if we don't solve world hunger, we can feed a lot of people. With many potentially transforming technologies already available and others in the pipeline, it is clear that there will be a large scope for human augmentation. The more powerful transhuman technologies, such as machine-phase nanotechnology and superintelligence, can be reached through several independent paths. Should we find one path to be blocked, we can try another one. The multiplicity of routes adds to the probability that our journey will not come to a premature halt.

    Hypoxia and Stem Cells

    We know that the cellular response to hypoxia appears to be involved in calorie restriction, possibly because it spurs greater housekeeping efforts - researchers can modulate or replicate some of the effects of calorie restriction by tinkering with hypoxia inducible factor 1 (HIF). Here is a different role for that family of proteins: "Adult stem cells must persist throughout life to ensure continuous replenishment of dead or damaged cells in various tissues of the body. While numerous studies have already begun to identify some of the factors and mechanisms that regulate long term function and survival of stem cells, there is still much to learn in this regard. A growing body of evidence suggests that various types of stem cells exist in a hypoxic microenvironment, which may be conducive to stem cell longevity. We have recently shown that the oxygen dependent transcription factor hypoxia inducible factor 1alpha (Hif1α) is essential for maintenance of functional levels of telomerase in murine embryonic stem cells (mES). Importantly, long-term proliferation of mES cells with reduced Hif1α levels led to telomere shortening and ultimately cell senescence. Studies by others over the past 10 years has also indicated that hypoxia and Hif expression are essential for self-renewal and are involved in the regulation of proliferation for some types of stem cells."

    Link: http://www.ncbi.nlm.nih.gov/pubmed/21239881

    A Look at the Nanotechnology of Targeted Cancer Therapies

    From Nanowerk: "Chemotherapeutics generally show a delicate balance between maintaining a high enough dose to kill cancer cells while avoiding a dose so high that it causes severe toxic effects. One of the many promises of nanomedicine is a class of nanoscale drug delivery vehicles that can pinpoint cancer cells and deliver their tumor-killing payload right into cancer cells with high efficiency and no side effects. As an example of how scientists are approaching this goal, [we] have provided a first report on in vivo cancer therapy with mesoporous hollow silica nanomaterials. Based on this novel silica nanorattle structure, the Chinese research team further extended their work to fabricate 'all-in-one' multifunctional gold nanoshells on silica nanorattles (GSNs) which combine remote-controlled photothermal therapy with chemotherapy - resulting in a 'magic bullet' to kill cancer cells. The results indicate that a combination of hyperthermia and chemotherapeutic agents is an encouraging approach to optimizing cancer therapy for the synergistic effects are greater than the two individual treatments alone. ... GSNs are a promising building block with many biomedical applications, such as biological imaging, thermal ablative cancer therapy and immunoassays. Due to the specific silica nanorattle core, GSNs are also promising as a versatile and multifunctional drug delivery platform for their high-payload delivery of various drugs into their targets."

    Link: http://www.nanowerk.com/spotlight/spotid=19721.php

    An Interesting Theory on Cancer and the Immune System

    The next decade will see the introduction of a wide range of comparatively sophisticated methods of manipulating the human immune system: tuning its reaction to specific biochemicals, altering the processes of inflammation, and training it attack and destroy unwanted cells or waste byproducts of metabolism. This will be good news for those people unfortunate to suffer autoimmune diseases, amongst others: the immune system touches on every important aspect of our biology in some way, shape, or form, and the decline of the immune system with age is an important component of the frailty that accompanies degenerative aging.

    Bearing that in mind, I noticed an interesting open access paper the other day that advances an almost hormetic theory of cancer development. To the author's way of thinking, while the immune system does indeed attack and destroy cancer - and this is one of its primary tasks - cancers nonetheless thrive under sustained but weak immune attacks. Thus a damaged immune system may be doing more harm than good in this respect.

    Cancer immunotherapy by immunosuppression

    We have previously suggested, based largely upon mouse studies, that incipient cancers are probably stimulated to grow by a stimulatory immune reaction. We think the evidence suggests that a new expanded hypothesis is tenable: any tumor that continues to grow is probably being continuously immunologically stimulated by a low level of immunity. We will also discuss the therapeutic implications of this new hypothesis. Almost the entire literature seems currently to be predicated upon the assumption that the immune response is "surveying" and inhibiting cancer, if indeed it does anything. Our new hypothesis admits the persisting possibility of a cure by sufficiently raising the level of the immune reaction via immunizations of various types, but recognizes that this has not yet met with unmitigated success and that there may be an alternative.

    Read the rest of the paper for the arguments that lead to this position - that suppressing the immune system is worth trying as a cancer therapy. As a theory it makes some sense at my level of understanding of the various processes involved, but this is all off at the other end of the pool of ideas from the mainstream of cancer and immunological research. The focus there is on enhancing and training the immune system to destroy cancer, an approach that is achieving very promising results in the laboratory and early trials - which is not even to talk about the granulocyte therapy that I think is the present grail of the field.

    You might recall that people were enthused a few years back over the work of researcher Zheng Cui, who showed that (a) one breed of lab mice shug off cancer because their immune cells are different in ways that enable them to kill cancer dead, (b) transplanting those immune cells into more vulnerable mice also kills cancer dead, and (c) this same state of affairs exists in humans. Somewhere, someone has an immune system that can kill your cancer. If you could find them and undergo a transplant of leukocyte or granulocyte immune cells, the evidence to date suggests that this would be a very effective therapy.

    If nothing else, the paper I quote above is a good example of the fact that no field of science is monolithic - and that there are always a good few plausible ideas that run contrary to current mainstream thinking. Perhaps these researchers are on to something, perhaps not; further investigation will show one way or another.

    A Master Switch for Inflammation?

    Chronic low level inflammation is an important contributing process to aging - and many age-related conditions have an inflammatory component to their mechanisms. Present means of managing inflammation are very crude, and fail to benefit many patients, but more sophisticated methodologies are on the horizon: "Scientists have identified a protein that acts as a 'master switch' in certain white blood cells, determining whether they promote or inhibit inflammation. ... Inflammatory responses are an important defence that the body uses against harmful stimuli such as infections or tissue damage, but in many conditions, excessive inflammation can itself harm the body. In rheumatoid arthritis, the joints become swollen and painful, but the reasons why this happens are not well understood. Cells of the immune system called macrophages can either stimulate inflammation or suppress it by releasing chemical signals that alter the behaviour of other cells. The new study [has] shown that a protein called IRF5 acts as a molecular switch that controls whether macrophages promote or inhibit inflammation. The results suggest that blocking the production of IRF5 in macrophages might be an effective way of treating a wide range of autoimmune diseases, such as rheumatoid arthritis, inflammatory bowel disease, lupus, and multiple sclerosis. In addition, boosting IRF5 levels might help to treat people whose immune systems are compromised."

    Link: http://www.eurekalert.org/pub_releases/2011-01/icl-sft011411.php

    Early Nanotechnology Versus Cancer, an Overview

    This open access review paper surveys current uses of nanotechnology in the research and development of cancer therapies: "Nanooncology, the application of nanobiotechnology to the management of cancer, is currently the most important chapter of nanomedicine. Nanobiotechnology has refined and extended the limits of molecular diagnosis of cancer, for example, through the use of gold nanoparticles and quantum dots. Nanobiotechnology has also improved the discovery of cancer biomarkers, one such example being the sensitive detection of multiple protein biomarkers by nanobiosensors. Magnetic nanoparticles can capture circulating tumor cells in the bloodstream followed by rapid photoacoustic detection. Nanoparticles enable targeted drug delivery in cancer that increases efficacy and decreases adverse effects through reducing the dosage of anticancer drugs administered. Nanoparticulate anticancer drugs can cross some of the biological barriers and achieve therapeutic concentrations in tumor and spare the surrounding normal tissues from toxic effects. Nanoparticle constructs facilitate the delivery of various forms of energy for noninvasive thermal destruction of surgically inaccessible malignant tumors. Nanoparticle-based optical imaging of tumors as well as contrast agents to enhance detection of tumors by magnetic resonance imaging can be combined with delivery of therapeutic agents for cancer. Monoclonal antibody nanoparticle complexes are under investigation for diagnosis as well as targeted delivery of cancer therapy. Nanoparticle-based chemotherapeutic agents are already on the market, and several are in clinical trials. Personalization of cancer therapies is based on a better understanding of the disease at the molecular level, which is facilitated by nanobiotechnology. Nanobiotechnology will facilitate the combination of diagnostics with therapeutics, which is an important feature of a personalized medicine approach to cancer."

    Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3018446/

    Immune System Rejuvenation Achieved Through Targeted Cell Destruction

    Our innate and adaptive immune systems vigorously assault bacteria, viruses, fungi, and other trespassers that can cause us harm, but their efforts decline with age. A poorly functioning immune system is an important component of age-related frailty - a time in life when you can no longer shrug off even the common illnesses that bothered you little when you were young. Diseases that young people barely notice can kill the elderly, and the failing immune system can be blamed for much of this.

    Progressive immune failure is unusual in that it is just as much an issue of configuration as it is of the accumulating biochemical and cellular damage that affects all bodily systems in aging. The body is limited in the number of immune cells it supports, and if the current crop of cells have become largely useless - because they are too busy chasing the memories of a lifetime of pathogens to adapt to new threats - then you have a largely useless immune system. Your body still has the theoretical capacity to mount a better immune defense, but not with the immune cells it has. Unfortunately, that unhelpful population of cells blocks the creation of new, fresh immune cells by virtue of the fact that it exists at all: it's using up the available space to no good end, but your body has not evolved to recognize the need to remove them.

    I should add that this is a very high level and simplistic explanation; a little more can be found back in the Fight Aging! archives:

    Our immune systems do a great job for most of our life spans, and even past our peak reproductive life spans - but that's all that evolutionary pressure will ensure. After that, you're on your own. The price of an evolved system that does amazingly well right out of the gate in a newborn is an evolved system that serves the old very poorly.

    All is not gloom, however, and we can look ahead to very near-future biotechnologies that will address this issue and go some way towards restoring good immune function to the old. Scientists are in the midst of developing a new generation of technologies that can very precisely kill specific cell types - the cancer research community has been demonstrating targeted cell killing methods in the laboratory for some years now. These cell killing technologies are perfect for use in attempts to restore an age-damaged immune system to a more youthful state by culling the unwanted cells:

    Now in theory, an old immune system that is top-heavy in memory T cells could be at least partially restored (remember that there are other issues and degenerations beyond the one I discuss here) by destroying all the unwanted memory cells. In recent years researchers have destroyed and then used stem cells to recreate the entire immune system in human trial patients, and have done this to essentially remove misconfigured immune cells that were the source of an autoimmune disorder. If that can be done, then it should certainly to be possible to take one of the new generation of targeted cell destruction technologies developed in the cancer researcher community and use to it destroy only a specific population of T cells.

    I've been talking about this for a few years now, so I'm always pleased to see signs of progress in efforts to reverse declining immune response by selective destruction of immune cells. Here is an example of one early stage effort that demonstrates a benefit resulting from this approach: the researchers removed the existing population of immune cells, which caused the natural generation of a better-equipped replacement population of cells, and a consequently better immune system. That replacement process cannot happen without some intervention to remove the cells in the first place:

    Aging is associated with a decline in [the creation of B-cells] in the bone marrow and accumulation of long-lived B-cells in the periphery. These changes decrease the body's ability to mount protective antibody responses. We show here that age-related changes in the B lineage are mediated by the accumulating long-lived B cells.

    Thus, depletion of B-cells in old mice was followed by expansion of [populations of progenitor cells that create B-cells and] a revival of [lymphopoiesis, or the creation of B-cells] in the bone marrow, and generation of a rejuvenated peripheral compartment that enhanced the animal's immune responsiveness to antigenic stimulation.

    Collectively, our results suggest that immunosenescence in the B-lineage is not irreversible, and that depletion of the long-lived B cells in old mice rejuvenates the B-lineage and enhances immune competence.

    As a first step, this looks promising. We can look forward to seeing much more of this sort of approach tested and trialed in the next few years.

    An Interview With Max More, New CEO of Alcor

    From KurzweilAI.net, a friendly interview with Max More, who was recently hired as CEO of cryonics provider Alcor: "I spent the last 10 or 11 years learning about business processes and culture, and have run some nonprofits before, but I'm looking forward to tackling the challenges. Fortunately, I'm far from alone in this responsibility. In addition to Alcor's highly experienced board of directors, my first week on the job demonstrated the dedication, skill, and helpfulness of Alcor's staff. While it takes a while to get up to speed on all the operational details of an organization like Alcor, I'm looking forward to working with the board to develop a renewed and refined strategic plan that will help us realize Alcor's huge potential to help far more people have a chance at renewed life in the future. ... My goal is really to maintain the traditions of Alcor, to protect its patients, but also to stimulate new growth, to improve the way everything functions, and to change the whole public perception to a much more positive view. Alcor is the most technologically advanced cryonics organization. We are on a path to continue improving our capabilities while doing our utmost to protect and preserve our existing cryopreserved members. ... the most important thing to me is making sure the organization is stable and will not get knocked out by financial or legal attacks or other issues. One of my top priorities is to make sure that we're stable for the long-term by either increasing income or reducing costs. ... Another priority is to restart growth. When I signed up as an Alcor member [for cryopreservation] in 1986 I was the 67th member. Since then, Alcor has grown to about 930 right now, and the number of cryopreserved people has gone from six to 102. At the Extropy Institute Extro conferences, if asked who were members, out of few hundred people, a majority would put up their hands, showing off their bracelets. Today, you don't get the same response - the recent growth has really slowed down. It seems ridiculous to me that in a world population of close to 7 billion, we only have 1000+ members signed up. I think we can do much better, starting with the most promising groups, such as transhumanists."

    Link: http://www.kurzweilai.net/alcor-update-from-max-more-new-ceo

    An Argument for Continuing Vaccination Throughout Life

    This paper suggests that modest benefits to life expectancy - and certainly to immune system health - could be made by establishing vaccine programs that continue throughout life, not just in childhood as is presently the case: "Infectious diseases remain a significant cause of [morbidity and mortality] in adults aged over 60 years, and many of these diseases are vaccine-preventable (VPDs). There is a pressing need to promote a lifelong vaccine schedule to increase vaccination against VPDs during the different stages of life. We outline the impact of vaccines on the burden of common infectious diseases and consider the negative clinical impact of VPDs in the unvaccinated population. We further illustrate that vaccine uptake is associated with a reduction in the burden of VPDs at any age of life, due to herd immunity. Disability-free and healthy aging is closely linked to childhood health and medical conditions in young adulthood. The midlife vaccine gap drastically impacts health in later life, especially in unvaccinated and older populations. These arguments underline the need for a preventive lifelong health perspective from childhood through old age."

    Link: http://dx.doi.org/10.1089/rej.2010.1078

    Aubrey de Grey in GQ Magazine

    An article on the work and vision of biomedical gerontologist and longevity science advocate Aubrey de Grey was published last year in the May 2010 issue of GQ. Unfortunately, the GQ folk decided not to get around to reprinting the article online - which is irritating, to say the least. Why go to the trouble of producing something in the first place if you are just going to throw it away, never to be seen by the thousands who might read it in the years ahead?

    Fortunately, a kind fellow at Reddit recently posted scans of the article to Flickr, and here it is: "Life Begins at 140." Jump on in and read the piece before these vanish from the Flickr servers.

    (If the links above no longer work, you might try the copies stashed over at Next Big Future). Some quotes:

    De Grey likes to compare the future of treating aging to the time line of human-powered flight. For millennia, man dreamed of flying. Nothing happened. Five hundred years ago, Leonardo da Vinci presented detailed drawings of flying machines. Nothing happened. Then, in a mad rush, we catapulted from the Wright brothers to Lindbergh to the Concorde to the space shuttle.

    Fewer than sixty years have passed since Watson and Crick - modern medicine's Orville and Wilber - proposed the structure of DNA. Only seven years have passed since the Human Genome Project mapped our genetic sequence. Gene therapy wasn't even theorized until the 1960s. In the past few years, it's been used in major medical breakthroughs: It was used to cure squirrel monkeys of color blindness, and recently doctors in Paris used it to slow a fatal brain disease called X-linked adrenoleukodystrophy in young boys. What comes next, de Grey predicts, is a series of extraordinary medical progressions, each a further order of magnitude more sophisticated than anything available today.

    ...

    It's easy to poke fun at Aubrey de Grey and his quixotic ideas, but a couple of weeks in his presence made it obvious to me that he's entirely serious about his quest. I don't think he's full of shit in the least. I have no idea if a single one of his seven steps will work, but I'm grateful for his crazy devotion. He says he never takes a day off, because he's acutely aware that every day he's delayed means another 100,000 humans will die. He's not getting rich and isn't driven by his own self-presevation. Rather he's practically killing himself, it sometime seems, so that rest of us may have a chance to live. I, for one, deeply wish for his success. The truth is, I'd like to be young again. I'd like to be young for a thousand years.

    And even if de Grey isn't correct, there may be significant ancillary benefit to his ideas. So maybe we won't live to be a thousand, but perhaps de Grey and his team will make a few smaller breakthroughs and we'll get to 150. or perhaps his efforts will help cure Alzheimer's disease. Or diabetes. Or cancer. If his insights help us live only five extra years, or just one year - or, hell, one month - isn't that worth the three bucks he asks from every many, woman, and child in the United States? Maybe tossing a billion at de Grey isn't a waste at all. Maybe, once you think about it, it's an absolute bargain.

    A billion dollars will, in de Grey's estimation, buy us a 50% chance of being able to rejuvenate aged mice - return them to a youthful state by repairing the known forms of cellular and biochemical damage that cause degenerative aging. This would involve something like $150 million spent over ten years on each of the strands of SENS, the Strategies for Engineered Negligible Senescence: that money would be used to establish research centers, recruit scientific teams, and get the work done.

    Some of these areas of research are closer to fruition than others. For example, the moving of vulnerable mitochondrial genes into the nucleus to protect them from damage: this has already been demonstrated for a couple of the thirteen genes than must be moved. Several research groups performing this work already exist - they would be happy to ramp up their efforts and expand if funded aggressively. Other areas, like the WILT approach to eliminating cancer, will need a great deal more toil and discovery to reach the stage of a satisfactory biotechnology and therapy.

    A failure here means that it will take longer than ten years and more funding to achieve meaningful results. But I think that for most of the threads of SENS the estimate of $150 million and 10 years isn't unreasonable for a crash course of scientific development spread across several labs - and nor is it unreasonable to expect real results at the end of that time.

    Folk like you and I can help here and now by supporting the SENS Foundation - give money, or persuade other people to the same. It's the most important line of scientific research that exists today, the one that will make the largest difference to your future - and the future of everyone you know.

    A Look at the Barshop Institute for Longevity and Aging Studies

    Local San Antonio media take a look at the work of the Barshop Institute for Longevity and Aging Studies: "Naked mole rats aren't much to look at. In fact, you might think the pink, wrinkly, squinty rodents are downright ugly. However, some researchers at the University of Texas Health Science Center at San Antonio feel otherwise ('I think they are incredibly cute,' says Zimbabwe-born scientist Rochelle Buffenstein as she tenderly picks up one of thousands squeaking and scurrying through a maze of tubes and plastic tubs). But it's not for their outward appearance that scientists are studying the rodents. Buffenstein and others look beyond the translucent skin and healthy tusks ('They've been called saber tooth sausages and worse,' she says) and see, if not the secret to eternal youth, a chance to cobble a few more decades onto our average 78-year lifespan. That would explain why the Barshop Institute for Longevity and Aging Studies at the UTHSC-SA maintains the world's largest colony of the naked rats. While not much larger than mice, which live around two years, these creatures keep active and healthy for as long as 30 years. And they have an amazing ability to fight cancer and toxins. This is just one of many areas of anti-aging research that's underway at the San Antonio research center. There's hope that scientists here will find a trigger or series of triggers in the human genetic code that could one day extend the 'youthspan' of people - giving people an extra 20 years, 40 years, maybe even longer, to be young and healthy. To be flip about it: researchers are hunting for the Fountain of Youth. And they're closing in. Discoveries are coming in at such a pace that Gen Xers may find themselves saddled with the Baby Boomers for longer than they had planned."

    Link: http://sacurrent.com/news/story.asp?id=71922

    Synthetic Blood Cell Prototypes Demonstrated

    More progress towards entirely artificial blood: "A team of scientists has created particles that closely mirror some of the key properties of red blood cells, potentially helping pave the way for the development of synthetic blood. ... researchers used technology known as PRINT (Particle Replication in Non-wetting Templates) to produce very soft hydrogel particles that mimic the size, shape and flexibility of red blood cells, allowing the particles to circulate in the body for extended periods of time. Tests of the particles' ability to perform functions such as transporting oxygen or carrying therapeutic drugs have not been conducted, and they do not remain in the cardiovascular system as long as real red blood cells. However, the researchers believe the findings - especially regarding flexibility - are significant because red blood cells naturally deform in order to pass through microscopic pores in organs and narrow blood vessels. Over their 120-day lifespan, real cells gradually become stiffer and eventually are filtered out of circulation when they can no longer deform enough to pass through pores in the spleen. To date, attempts to create effective red blood cell mimics have been limited because the particles tend to be quickly filtered out of circulation due to their inflexibility."

    Link: http://uncnews.unc.edu/content/view/4200/74/

    And they will look at you and ask "but what's a root canal?"

    If you are in your twenties, it's fair to expect that your children will never undergo any dental procedure that was in common use throughout your life to date. Your grandchildren won't even know what a root canal surgery or filling is unless you tell them. Regenerative medicine and tissue engineering will transform the field of dentistry profoundly over the next two decades, and what little of the old that's left after that will be mopped up by biotechnologies that destroy the ability of harmful bacteria to thrive in your mouth. There will be no cavities or periodontitis, and where accidents cause damage, the teeth, bone, gum tissue, and related structures such as the ligaments that attach teeth to the jaw will be replaced anew with tissue grown from the patient's own cells.

    Here's a position paper that is a good example of the sort of vision presently held by dental researchers:

    Root canal therapy has been the predominant approach in endodontic treatment, wherein the entire pulp is cleaned out and replaced with a gutta-percha filling. However, living pulp is critical for the maintenance of tooth homeostasis and essential for tooth longevity. An ideal form of therapy, therefore, might consist of regenerative approaches in which diseased/necrotic pulp tissues are removed and replaced with regenerated pulp tissues to revitalize the teeth.

    Dental pulp regeneration presents one of the most challenging issues in regenerative dentistry due to the poor intrinsic ability of pulp tissues for self-healing and regrowth. With the advent of modern tissue engineering and the discovery of dental stem cells, biological therapies have paved the way to utilize stem cells, delivered or internally recruited, to generate dental pulp tissues, where growth factors and a series of dentine extracellular matrix molecules are key mediators that regulate the complex cascade of regeneration events to be faithfully fulfilled.

    Moving away from the current state of the art artificial replacements for teeth and parts of your teeth is just a starting point, however. You might look back into the Fight Aging! articles for more on the technology-in-waiting that will transform dentistry - regrowing every part of the tooth and jaw tissues, and eliminating a large part of the mechanisms that cause damage in the first place:

    Dentistry is one of the fields of medicine in which the near future is especially rosy, and progress towards the envisaged biotechnologies is rapid.

    Progress in Growing Capillaries

    From EurekAlert!: researchers "have broken one of the major roadblocks on the path to growing transplantable tissue in the lab: They've found a way to grow the blood vessels and capillaries needed to keep tissues alive. ... The inability to grow blood-vessel networks - or vasculature - in lab-grown tissues is the leading problem in regenerative medicine today. If you don't have blood supply, you cannot make a tissue structure that is thicker than a couple hundred microns. ... As its base material, a team of researchers [chose] polyethylene glycol (PEG), a nontoxic plastic that's widely used in medical devices and food. ... the scientists modified the PEG to mimic the body's extracellular matrix - the network of proteins and polysaccharides that make up a substantial portion of most tissues. [They then] combined the modified PEG with two kinds of cells - both of which are needed for blood-vessel formation. Using light that locks the PEG polymer strands into a solid gel, they created soft hydrogels that contained living cells and growth factors. After that, they filmed the hydrogels for 72 hours. By tagging each type of cell with a different colored fluorescent marker, the team was able to watch as the cells gradually formed capillaries throughout the soft, plastic gel. To test these new vascular networks, the team implanted the hydrogels into the corneas of mice, where no natural vasculature exists. After injecting a dye into the mice's bloodstream, the researchers confirmed normal blood flow in the newly grown capillaries. Another key advance [involved] the creation of a new technique called "two-photon lithography," an ultrasensitive way of using light to create intricate three-dimensional patterns within the soft PEG hydrogels. ... the patterning technique allows the engineers to exert a fine level of control over where cells move and grow. In follow-up experiments [the] team plan to use the technique to grow blood vessels in predetermined patterns."

    Link: http://www.eurekalert.org/pub_releases/2011-01/ru-bbb011111.php

    Suspended Animation Conference, May 2011

    Via Depressed Metabolism, I see that cryonics technology company Suspended Animation is hosting a conference later this year: the company "will sponsor the conference, 'Suspended Animation - The Company and The Goal,' which will be held in Fort Lauderdale in May, 2011. The conference will feature speakers on the latest strategies and advances toward perfecting reversible human suspended animation. During the conference, SA will also host tours and demonstrations at its facility in Boynton Beach. ... Suspended Animation's 2011 conference has been designed to meet your needs. It will provide you with a comprehensive picture of the world of cryonics. It will reveal the scientific foundations of cryonics, the latest advances in cryopreservation research, and the scientific basis for thinking that revival from cryopreservation is a realistic possibility. It will give your desire for survival a jolt of reality that will make you realize that, while the path ahead is difficult, you can help to make it easier. .... [Greg Fahy will present] major new findings from Phase I of a revolutionary longterm project to achieve reversible whole-body solid state suspended animation in humans. This project, conducted at 21st Century Medicine, is the only whole body vitrification research being conducted in mammals and was funded entirely by a $5.6 million dollar grant from the Life Extension Foundation. Cryobiologist Greg Fahy will discuss how well whole animals can be cryopreserved right now, the possibility of using a single advanced vitrification solution to cryopreserve entire animals and, eventually, humans, and a unique, newly-invented technology to produce large, cryopreserved tissue slices for scanning and transmission electron microscopy."

    Link: http://www.depressedmetabolism.com/2011/01/10/suspended-animation-conference-2011/

    A Little Technical Background on Fight Aging!

    Not so long ago, Fight Aging! was subject to a seemingly random distributed denial of service (DDOS) attack - which may have been no more than the flailing of a badly configured spam bot network, but it still managed to knock the site offline. One of the ways in which less ethical folk can make money online is by building up networks of compromised machines, a mix of vulnerable servers found and taken over, coupled with personal computers that fall victim to malign websites and browser vulnerabilities. These networks can be rented out to spammers and used to execute commands to write comments, register at forums to make spam posts, and send email - spam remains a profitable industry, sadly, which is why we see so much of it.

    Fight Aging! is built upon Movable Type, a popular blogging software platform. Since this is a popular platform, it is targeted by most spammers and spam-enabling toolkits; they largely focus on leaving spam comments. Fight Aging! is not a well trafficked blog, as I outlined yesterday, but it does touch on topics that are associated with high value keywords in the world of search engine advertising. This means that there are plenty of people and software programs out there who want to insert links into Fight Aging! pages - such as in the comments to a post - that point to their site. By doing so, they gain authority in some search engines, but also gain a few additional visitors. Given that it costs next to nothing for the spammers to try to submit comments, they don't spend too much time thinking about whether it's worth it or not for any individual site - they'll just spam everyone they can find who might be remotely relevant to whatever moneymaking scheme lies at the base of it all.

    The bottom line is that I see a lot of hits to the comment posting pages of Fight Aging! as a matter of course. The DDOS event was a very large step up from business as usual, coupled with what amounted to a download of the entire site - possibly to identify higher value pages to try to spam with comments. But who knows; one of the realities of managing a site is that it is rarely worth the cost to try to find out exactly why this sort of thing happened, provided that it stops.

    At the time, I was hosting Fight Aging! on a shared server at getNetworks, who I should note have provided unfailingly good service for very little money since this site launched back in 2004. The support folk there did the sensible thing and blocked access to Fight Aging! to protect the other paying customers on the same server. The upside of a shared server web hosting arrangement is that it is cheap. The downside is that you have comparatively little control over the configuration of server and its software. The DDOS attack was a final prompt urging me to up and move Fight Aging! to a new home, one that gave me enough control to add armor against problems of this nature and tinker the hosting environment to be more to my liking.

    Today, Fight Aging! runs on a small EBS boot instance in Amazon EC2 running Fedora Core 14. Web pages are served by Apache 2, Perl 5, and PHP 5, and data is stored in MySQL 5.

    But what on earth does that all mean? Stick around, and find out. EC2 is the Amazon Elastic Compute Cloud, a service that allows people to register accounts and launch and manage a fleet of virtual servers (or "instances"). When I log in to one of my virtual servers, it appears to me just like a physical server, but it is in fact drawing on the resources from any number of physical machines, and where the physical processing actually happens may vary from moment to moment. This is cloud computing, where the "servers" we customers interact with are abstractions.

    On EC2, server uptime, bandwidth, and storage space are metered like water. If I use more, I pay more. Virtual server instances come in various sizes; "small" in this case means the equivalent of a single processor machine with 1.7G of RAM - though the comparison is slightly fuzzy, given that this is only an abstraction of a machine. It works out to be considerably cheaper than renting a physical server, and I gain some useful tools, such as the ability to clone the entire Fight Aging! server whenever I want and spin up a backup or test version in a matter of minutes should I want to tinker.

    Most virtual server instances on EC2 do not persist their hard drive data when they are shut down - they were launched from a server disk image, will do their work, and no-one really cares about the additional data they collect while running. For those of us who need something that behaves more like a real server, where data is kept around even if the server restarts, there is the Elastic Block Store (EBS) option. Clearly I care about ongoing storage of data for Fight Aging! - posts, comments, logs, and so on - and so the Fight Aging! instance uses EBS.

    The instance runs Fedora Core 14, which is an open source Linux operating system variant. It, like most modern Linuxes, gives me the freedom to install more or less anything a server would need using simple commands. Gone are the days in which you had to fight your machine tooth and nail to install anything; package management software has come a long way, and installing new software is as simple as typing "yum install [name of package here]" and pressing enter a couple of times.

    This is a LAMP system - Linux, Apache, MySQL, and PHP and/or Perl. The vast majority of web servers use at least one of these open source, freely available technologies:

    • MySQL is the database, in which all of the data on posts, categories, comments, and the like is stored in ways that make it efficient to arrange, query, and rearrange.
    • Apache is the web server, the software that handles the process of responding to your browser and handing out the files packed with data that the browser forms into web pages.
    • PHP is a programming language that is most often used to write dynamic web applications and web pages. Fight Aging! has little of the dynamic in its pages - at least in the grand scheme of things - but it is there. So the pages most often accessed by visitors, such as this one, are written in PHP.
    • Perl is also a programming language that sees much of its use in web applications.

    In essence, and somewhat dumbed down, the Movable Type blogging software is a set of web pages written in the Perl language that allow me to use a web browser to manage the process of creating a whole set of other web pages written in PHP - like the page you're reading now. I enter the information needed to create these PHP pages - the text and template information like the header and footer - and then Movable Type code churns along to write out PHP files that Apache and PHP can turn into web pages when you request them.

    The process by which a webserver reads a PHP or Perl file, processes its instructions, accesses the database, and marshals the end result of all that activity into a stream of data to feed to your browser is not instant. It can, however be made considerably faster than the default situation on a shared server allows for. That in turn improves the server's robustness when faced with a sudden influx of visitors or a DDOS attack.

    On the Fight Aging! server I employ layers of caching provided by the MySQL query cache, Memcached, the Alternative PHP Cache, and FastCGI. The basic idea behind caching is that if you need the same result more than once, a web page for example, why take all the effort to built it from scratch multiple times? The same goes for the result of asking the database for a particular piece of data, any array of data you build in code, and even the machine-level instructions that hand-written code compiles into when it is prepared for execution. Do it once, and save the result for the next time you need it. The four items I list above are all open source, freely available technologies that considerably speed up the operation of the Fight Aging! web server through caching - by saving it from performing the same expensive tasks over and over again.

    Despite that, I have to say that the administrative interface of Movable Type 4.35 is still horribly slow. You folk get to see the blindingly fast front end of the site, and I'm stuck with the bloat that SixApart have coded into their later versions. Before I made the move to EC2, I was still using Movable Type 3.3 - an old version, but solid and I had customized it over the years to remove a number of the issues it had. Movable Type gets the job done, but I have been consistently disappointed with each new version: every upgrade has proved slower and more bloated than the last, while adding very little that was of benefit to my needs. Unfortunately, complaining about blogging software is much like complaining about political parties - they are all variations on terrible, and you either learn to live with it or move to an island (which in this analogy would be writing your own blogging software, a process that has a whole host of its own drawbacks).

    There is more to managing a web site than the web server, however - there is also the minor matter of email. In a shared hosting environment, this is managed for you by the host, but there is no such provision in EC2; you have to roll up your sleeves and manage it yourself. Thus next door to the Fight Aging! web server instance in my EC2 account there stands a small Ubuntu Linux mail server instance. Having spent some time assembling the thing, I'll say this about building mail servers: it's very much like piling up an abstract sculpture made of balanced, loaded weapons that you don't fully understand, all the while hoping that the instruction manuals are up to date and accurate. The nature of the email ecosystem makes mail servers far more complex and consequential than web servers.

    If you fail to correctly configure your web server, the worst that can happen is that it doesn't work at all, or hands out copies of your unprocessed code to any visitor who happens by. By way of comparison, the worst that can happen if you incorrectly configure a mail server is that spammers will descend upon you, turn it into a spam proxy, and lead to your domain becoming blacklisted in ways that are very hard to remove. Also, your server will reveal a range of personal information about you and anyone else who uses it, will lose random emails and leave no record that it did so, and will tell you that it delivered emails that it in fact didn't deliver. Additionally, many domains will reject your email outright or flag you as a spam source based on nothing more than the way in which your mail server responds to requests. I could go on - there's more, but you get the point.

    Email is hard. So I was cautious and built the Fight Aging! mail server from a great set of instructions - which I should add still required me to come back and spend some days configuring yet more information into the system once I had the basics sorted out. For example, I use Sender Policy Framework to try to ensure that no-one can forge emails from @fightaging.org addresses, and just getting that to work correctly required testing across several days of operation.

    Internally, a mail server is a collaboration between numerous pieces of distinct software that hand pieces of mail off to one another: the local delivery mechanism, the outbound delivery mechanism, the virus checker, the spam checker, the greylister, and so forth. Each of these is written by an entirely different group, often years apart in time, and so has completely different modes of configuration and operation. The pipes that pass mail and other information between these pieces of software are complex and infinitely configurable - and have to be done exactly right, or else. The "or else" here is usually of the "and now I discard this random piece of important mail without telling you" variety.

    It was a challenge, but fortunately I now have a functional, defensively configured mail server, fingers crossed.

    Beyond the modest cost of using the EC2 platform, all of the high-powered, complex software I've mentioned in this post is free - open source and gratis. The results of countless programmer-years of work can be downloaded and worked with in a matter of seconds, with no outlay other than my time. We live in a fascinating age.

    The Thousand Year Life Span

    An updated piece on Aubrey de Grey and the Strategies for Engineered Negligible Senescence from the BBC: "Nearly one in five people living in the UK will survive to see their 100th birthday, according to the government. But a Cambridgeshire academic who specialises in the ageing process says that effective medical care could make it possible to live much longer. Dr Aubrey de Grey said: 'I think the first person to live to 1,000 might be 60 already.' ... Dr de Grey is the chief scientific officer of the SENS Foundation (Strategies for Engineered Negligible Senescence) which carries out research into the prevention and cure of ageing. He agreed that the [government] figures were a reasonable projection but added that this was not a new idea. 'Longevity has been increasing by a couple of years each decade for more than 50 years now, due to the success we have had in keeping people from getting the diseases of old age, and in keeping them in better condition throughout their whole lives.' ... We will not be simply keeping people alive in a frail, sick state. We will be actually keeping them in a youthful state so that they have a low probability of dying each year. ... The medicines that I think are going to come along in the next 20 or 30 years are ones that not only slow down the ageing process and keep us from getting quite so sick, quite so young, but also reverse the ageing process. In other words, conduct periodic repair and maintenance at the molecular and cellular level, so that even if we have already accumulated some of the damaging effects of ageing we can be periodically fixed up - like any simple man-made machine. Once we get medicine like that, we should be in a very powerful position to keep people in a genuinely youthful state - not just looking young, but feeling young and functioning young - for as long as we like."

    Link: http://news.bbc.co.uk/local/cambridgeshire/hi/people_and_places/newsid_9330000/9330487.stm

    Resilience and Longevity in Humans

    Here is a recent study of psychological resilience in centenarians: "Resilience, a psychological construct, has been defined differently in extant literatures. In this paper, we adopt the simplified and straightforward definition [that] resilience connotes the ability to adapt positively to adversity. Previous studies have demonstrated that resilience is generally positively correlated with cognitive function, physical health and self-reported health among the elderly, as well as with self-rated successful aging in developed countries. ... We aim to investigate whether centenarians are significantly more resilient than younger elders and whether resilience significantly contributes to exceptional longevity. ... We use a unique dataset from the Chinese Longitudinal Healthy Longevity Survey with the largest sample to date of centenarians, nonagenarians, octogenarians, and a compatible group of young old aged 65-79. ... Logistic regressions based on the cross-sectional sample show that after controlling for various confounders, including physical health and cognitive status, centenarians are significantly more resilient than any other old-age group. Logistic regression analyses based on the longitudinal data show that nonagenarians aged 94-98 with better resilience have a 43.1% higher likelihood of becoming a centenarian compared to nonagenarians with lower resilience. ... Resilience significantly contributes to longevity at all ages, and it becomes even more profound at very advanced ages. These findings indicate that policies and programs to promote resilience would have long-term and positive effects on the well-being and longevity for senior citizens and their families." There is of course a question of causation here: if you are more healthy throughout life, which people who become centenarians generally are, won't that make you better able to deal with the various other slings and arrows that come your way?

    Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3004383/

    Audience Data for Fight Aging!

    As you may know, the Longevity Meme website will be retiring in the near future after ten years online - most of the site contents have already moved over to Fight Aging!, with the newsletter being the final and largest transfer still in progress. In the course of moving over content, I've been spending more time on technical work and looking over logs and analytics than is usually the case. So I thought I'd share some of the data on readership and the site setup this week.

    As should be clear from what follows here, Fight Aging! is a modest advocacy concern, with a lesser reach than people seem to assume. Where there is influence, that influence stems from who is reading the site and the newsletter, not how many people there are in the direct audience:

    • The human-readable side of the Fight Aging! site averages around 600 distinct visits a day, or ~17,000 visits over a month. Interestingly, that didn't change much when pages moved over from the Longevity Meme - nearly everyone who visited the Longevity Meme was already visiting Fight Aging!
    • 60% of visitors are US-based, and 25% hail from the English-language trifecta of the UK, Canada, and Australia.
    • I don't keep track of the level of traffic to the RSS feeds, as that really tells you nothing about the number of people who read them - once that content is let free to make its way out into the world, it's next to impossible to track where it might end up and who is looking at it.
    • That said, there are a dozen or so subscribers to the Kindle Edition of Fight Aging! - there's one way to measure an RSS readership.

    • Per Technorati, Fight Aging! is in the top 100 science blogs by influence - though I'm not sure that many people pay attention to Technorati's ratings these days, or that they are in any way meaningful.
    • Fight Aging! hosts 7,626 entries: 5060 news items, 380 newsletters, and 2186 blog posts of varying sorts - the results of the better part of a decade of daily posting. Visitors have left 3,137 comments over the years. If you keep writing fast enough and long enough, you will eventually accidentally produce some quality posts. Interestingly, you will also forget that you wrote them: I'm continually surprised by what I stumble over while searching Fight Aging! for a specific reference. A great deal of the good stuff isn't linked from that sidebar on the left there.
    • The Longevity Meme Newsletter - soon to become the Fight Aging! Newsletter - has just under 3000 subscribers. Defunct addresses are removed as they fail, but as is always the case in such matters, your guess is as a good as mine as to what a count of subscribers actually translates to in terms of readership. After all, newsletters can be ignored or forwarded on, and are also available online as web pages and RSS feeds.

    It is interesting to look at what the free website audience analysis projects have to say about Fight Aging!, if only for the fact that they are amusingly inaccurate for any site with a low level of traffic. For example, see Alexa's data:

    Fightaging.org has a three-month global Alexa traffic rank of 470,610. While it is ranked #154,484 in the US, where about 67% of its visitors are located, it is also popular in Ukraine, where it is ranked #52,772, and it is relatively popular among users in the city of Raleigh-Durham (where it is ranked #13,167).

    The Ukraine and Raleigh-Durham? Color me skeptical in both cases - but this is what happens with small sample sizes, given the methods used by these services to establish their data sets. There's much more than that snippet at Alexa to read, of course, and you may find the other information to be of value.

    In terms of what I know that visitors to Fight Aging! are looking at, obtained from Google Analytics and local server logs, here's the list of most popular pages:

    Page% Views
    Home Page18.9
    Calorie Restriction Explained2.99
    Primary Aging Versus Secondary Aging2.15
    Twelve Longevity Enhancement Methods Demonstrated in Mice1.69
    Stem Cells, Regenerative Medicine, and Tissue Engineering1.56
    More On TA Sciences, TA-651.40
    An Introduction to Healthy Life Extension and Engineered Longevity1.06
    Overpopulation: Not a Problem Now, and Never Will Be1.04
    AGE Breakers Beyond Alagebrium0.97
    Is Nuclear DNA Damage a Cause of Aging?0.93

    When it comes to Google searches delivering visitors to the door, this is what it looks like over the past 60 days:

    KeywordVisitsKeywordVisits
    primary aging449site:fightaging.org melatonin137
    fight aging410aging is a disease131
    what is wealth320fight aging130
    calorie restriction279caloric restriction129
    popular media231secondary aging109
    ta-65 scam192ta-65109
    aubrey de grey diet152what is protandim?108

    All of these have bounce rates of 95% and higher - i.e. they came, they saw, they quickly left. This is one of the reasons why paying for search traffic or paying to optimize search traffic are not viable paths in advocacy, at least not without a very well crafted and considered approach that surrounds the effort. I look on this sort of data as an alert to tell me where I've accidentally placed highly in Google's search results and no more - one has to wonder how I am managing to place on the first page of results for "popular media," for example.

    So there you have it, a brief overview of where Fight Aging! stands in the grand scheme of things. I you find it helpful, good.

    Summarizing the Use of Medical Nanorobotics in the Repair of Aging

    VIa Accelerating Future, I see that the nanorobotics chapter from the Future of Aging is available online: "Robert Freitas' book chapter for The Future of Aging compilation is now online. It looks very interesting. Freitas always produces fantastic work, that's one of the reasons Kurzweil constantly cites him. ... I talked to Freitas about this work, and he said, 'It's a major piece of work - a current update and the most comprehensive summary so far of the many potential applications of advanced diamondoid medical nanorobotics to conventional and anti-aging medicine.' ... Theoretical designs for diamondoid nanomachinery such as bearings, gears, motors, pumps, sensors, manipulators and even molecular computers already exist. Technologies required for the molecularly precise fabrication of diamondoid mechanical components and medical nanorobots, along with feasible strategies for the mass production of these devices, are the focus of active current research. This chapter describes a comprehensive solution to human morbidity and aging which will be attained when mankind has established control over all critical molecular events in the human body through the use of medical nanorobotics. Medical nanorobots can provide targeted treatments to individual organs, tissues, cells and even intracellular components, and can intervene in biological processes at the molecular level under direct supervision of the physician. Programmable micron-scale robotic devices will make possible comprehensive cures for human disease, the reversal of physical trauma, and individual cell repair."

    Link: http://www.acceleratingfuture.com/michael/blog/2011/01/comprehensive-nanorobotic-control-of-human-morbidity-and-aging/

    Analyzing a Single Mitochondrion

    Cells contain many swarming mitochondria - constantly reproducing by division and being culled by recycling mechanisms. These are the cell's power plants, the evolved remnants of symbiotic bacteria that contain their own DNA and toil to turn food chemicals into ATP. Mitochondrial DNA damage is important in aging, but it progresses in ways that are challenging to examine due to the nature of the mitochondrial life cycle. Here, researchers demonstrate a new application of technology that - even though focused on mitochondrial disease - will enable far more detailed research into mitochondrial damage and aging: "The trouble is that it's very difficult to extract single mitochondria from an individual cell. For years, the best technique has been to break open a group of cells and collect the mitochondria from all of them in a kind of soup. As you might guess, it's hard to determine which mitochondria came from what cells - yet that's what we need to know. ... The research team [has] potentially solved this problem by realizing that several devices and techniques can be used together to extract a single mitochondrion from a cell that possesses a genetic mutation. They employed a method previously used to extract single chromosomes from isolated rice cells where a laser pulse makes an incision in a cell's outer membrane. Another laser is used as a 'tweezer' to isolate a mitochondrion, which then can be extracted by a tiny pipette whose tip is less than a micrometer wide. ... This approach allowed the team to place a single mitochondrion into a small test tube, where they could explore the mitochondrion's genetic makeup by conventional means."

    Link: http://www.sciencedaily.com/releases/2011/01/110106145303.htm

    Biological Chains of Causation, With a Pause for Drug Development at Each Link

    Much of modern medical research is a matter of following chains of causation in our biology. Studies first uncover correlations between a particular protein and a medical condition, and then later work attempts to unpick the chain of signals and causative events in search of a first cause: protein A is behaving differently in disease Y because protein B is apparently doing something odd as well, and it can be shown that changing B directly changes A. It's already known that protein B interacts with protein C, and protein C leads to a well studied network of proteins, so some people start to look there as well for causative effects. There is a certain amount of searching for the keys under the lamp that takes place - established groups with their domain knowledge are always going to follow up when a new relationship touches on their area. Meanwhile, other researchers dive into the unknown darkness to find new relationships between the millions of distinct cogs and wheels of human biology.

    It's a fearsomely complex business, and progress is very incremental. Each defensible new discovery in a chain of proteins and signaling mechanisms presents a point of opportunity at which some team somewhere will set up drug development. They are seeking a way to manipulate that link in the chain - that protein - to hopefully affect the disease process in a beneficial way, and perhaps do a little better than the drugs based on previously discovered links.

    Here is an example of this sort of research, an investigation into the biochemistry of Parkinson's disease. Parkinson's is a neurodegenerative condition which might be considered a runaway example of one narrow mechanism of cell loss and damage - a process that takes place in all of our brains proceeds much faster in Parkinson's patients, leading to far greater loss of function. As to why this is the case ... well, scientists are still in search of that definitive answer.

    After analyzing cells and post-mortem brain tissue from animals and humans, researchers noted that oxidative stress - a known culprit in neuron death - activated a protein called tyrosine kinase c-Abl in the nigra-striatum area of the brain. Neurons in this part of the brain are particularly vulnerable to Parkinson's injury.

    Activation of this protein led to changes in another protein called parkin, which is known to be mutated in hereditary Parkinson's. The altered parkin lacked the capacity to break down other proteins, leading to harmful clumps of unprocessed protein in the neuron. The scientists believe this accumulation leads to progressive neuron death, resulting in Parkinson's symptoms that worsen over time.

    ...

    "When we blocked tyrosine kinase c-Abl activation, parkin function was preserved and neurons were spared," Dr. Imam said. "We believe these studies provide sound rationale for moving forward with a preclinical trial of tyrosine kinase c-Abl inhibitors, with the goal of developing a potent therapeutic drug for slowing the progression of Parkinson's."

    If preclinical trials in animal models of Parkinson's disease yield positive results, the next step would be clinical trials in human patients, Dr. Imam said.

    The accumulation of unwanted molecular waste in and around cells is a common theme in aging - and many diseases of aging involve an accelerated build up of one or more forms of damaging molecule. Without developing fundamentally new technologies to clear out these waste molecules on a regular basis, however, the most likely best that can be done through manipulation of our metabolism is to slow down the fall into a disease state. This is why greater support for bioremediation as a broad technology platform would be a good thing:

    Bioremediation is the process of using plants and microorganisms (or aspects of their biochemistry) to restore a damaged or polluted environment. Medical bioremediation applies this same philosophy to the aging body - many aspects of aging can be thought of as having roots in damage and pollution at the level of our cells and cellular machinery.

    ...

    The most promising approach is to enable cells to break the junk down so that they don't fill up after all. This can be accomplished by equipping the lysosome with new enzymes that can degrade the relevant material. The natural place to seek such enzymes is in soil bacteria and fungi, as these aggregates, despite not being degraded in mammals, do not accumulate in soil in which animal carcasses are decaying, nor in graveyards where humans are decaying. This suggests that the micro-organisms present in soil have enzymes capable of breaking these aggregates down, and work now being carried on at Arizona State University, has already confirmed this analysis.

    Mitochondria, Hormesis, and Lifespan

    While we're on the subject of mitochondrial processes leading to signals that change life span: "An unequivocal demonstration that mitochondria are important for lifespan comes from studies with the nematode Caenorhabditis elegans. Mutations in mitochondrial proteins such as ISP-1 and NUO-6, which function directly in mitochondrial electron transport, lead to a dramatic increase in the lifespan of this organism. One theory proposes that toxicity of mitochondrial reactive oxygen species (ROS) is the cause of aging and predicts that the generation of the ROS superoxide should be low in these mutants. Here we have measured superoxide generation in these mutants and found that it is in fact elevated, rather than reduced. Furthermore, we found that this elevation is necessary and sufficient for longevity, as it is abolished by antioxidants and induced by mild treatment with oxidants. This suggests that superoxide can act as a signal triggering cellular changes that attenuate the effects of aging. This idea suggests a new model for the well-documented correlation between ROS and the aged phenotype. We propose that a gradual increase of molecular damage during aging triggers a concurrent, gradually intensifying, protective superoxide response."

    Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2998438/

    Research in Mitochondrial Signals and Extended Lifespan

    This is interesting research: scientists "used the roundworm Ceanorhabditis elegans to show that perturbing mitochondrial function in subsets of worm cells sent global signals governing longevity of the entire organism. ... In this study we show how signals sent from distressed mitochondria are communicated to distant tissues to promote survival and enhance longevity ... The identity of the signal sent from mitochondrially-distressed cells - a hypothetical factor Dillin calls a 'mitokine' - remains unknown. Nonetheless, he speculates that mitokines could one day be lobbed as messengers from healthy to unhealthy tissues to treat degenerative conditions. ... Imagine if we could perturb mitochondria in the liver, and make them send a mitokine to degenerating neurons. Instead of trying to get a drug into the brain, we could exploit the body's ability to send out a natural rescue signal. ... many investigators, Dillin included, have observed puzzling relationships between mitochondria, energy generation and longevity-interactions that suggest that living long does not necessarily require prospering at the subcellular level. ... As a postdoctoral fellow I did a screen looking for worm genes that increased longevity. Many genes were related to mitochondrial function. If you disabled them, worms lived longer, although their respiration or metabolism was reduced. We wondered whether this is why animals lived longer. ... To determine how cells respond to the pro-longevity cue, the group monitored a cellular emergency plan called the Unfolded Protein Response (UPR). Cells mount it when proteins accumulate excessively and begin to unravel - or 'misfold' - which is toxic to cells. To avert cell death, the UPR mobilizes a team of helpers who, like sales clerks at a Gap sweater table, refold accumulating misfolded proteins piling up inside a cell. When Dillin and colleagues fed worms reagents blocking the UPR, they found that disruption of [mitochondrial activity] in neurons or intestine no longer had a lifespan-enhancing effect. This dramatic finding illustrates that initiating refolding of proteins, in this case in response to faraway mitochondrial stress, is in fact the very activity that enhances longevity." You might compare this to the benefits of autophagy, another housekeeping and repair activity that takes place inside cells.

    Link: http://www.eurekalert.org/pub_releases/2011-01/si-wli010311.php

    The Perils Hidden in Success

    Advancing medical technology has brought tremendous and accelerating benefits to health and longevity over the past century. The staggering increases in wealth that support this advance introduce more subtle forms of risk to health and wellbeing, however - disease and ill health that is more a matter of what we do to ourselves than what is done to us by various pathogens. Type 2 diabetes, for example, is a lifestyle condition that is essentially caused by eating too much over a long enough period of time. Adopt the right lifestyle and you are very unlikely to suffer its effects. Yet so very many people have type 2 diabetes - and as the population of various regions of the world move from being poor to being wealthy, they suffer ever more from these sorts of medical conditions, even as their lifespans increase.

    It is clearly the case that failing to be more successful and wealthy than your ancestors is worse than having the opportunity to eat yourself into an expensive and debilitating degenerative condition - but why sabotage the benefits that you do have? Most of us should know better, but the siren call of low-cost calories and luxurious laziness is very effective. Still, it is a choice. We have willpower and the free will with which to use it. You can blame your genes and circumstances if you like, but that's just as much a choice as it is to surmount those challenges to stay lean and healthy.

    Here's a readable open access paper that covers some of the high points on this topic:

    Most of the human population in the western world has access to unlimited calories and leads an increasingly sedentary lifestyle.

    ...

    Ancient man was a hunter-gatherer, often travelling long distances to find food, avoid threats and seek shelter. In contrast many modern western societies have transformed their surroundings in order to minimise (or even eliminate) environmental threats and stresses that our ancestors were exposed to, including food and water shortages, predation, infections, extremes of temperature and the need to carry out regular physical activity. Moreover, the modern western environment now contains almost unlimited supplies of foods containing high level of saturated fats, salt and refined sugars. This also appears to be coupled with a reduction in the consumption of plant products including fruits, nuts and vegetables. The result of this obesogenic environment is a burgeoning rise in lifestyle-induced diseases that are generally associated with energy imbalance, abnormal fat deposition and inflammation. The links between obesity, the metabolic syndrome, diabetes, vascular disease and even cancer, and a sedentary lifestyle, are now all too clear.

    In this regard, our ability to succeed has outstripped our ability to manage the consequences of our success - a common theme in the history of human development. Success is far better than failure, of course, but success while sidestepping any potential downsides is even better yet. This is perfectly possible for most of us as individuals: we can enjoy the benefits of this technologically advanced society we find ourselves in, so far removed from our near ancestors that it's hard to even visualize the level of pain and privation they suffered on a constant basis. We just have to choose to devote willpower and time to a sane diet and moderate exercise. It's that simple.

    Why Isn't More Being Done Now to Help the Aged?

    Researcher Tom Kirkwood here argues that lack of progress in aging and longevity science is only one manifestation of our communal lack of interest in providing tools to enable a better life for the old and the frail: "Although there are many who think that ageing begins at 40, 50 or 60, we are learning that the underpinning mechanisms of ageing play out throughout the life course. Appreciating the life course nature of ageing helps surmount the objection sometimes raised against research on ageing, namely, that we should set a lower priority on research for old people who have had their 'innings' already. Indeed, if we can deliver a world that gives greater health to older people, it will be our children and grandchildren who will benefit the most. We age, not because our genes programme our death but because our bodies accumulate a growing burden of faults in their cells, tissue and organs. ... Often, a relatively simple modification of the environment can remove what was previously an insuperable obstacle, an obvious example being, for a wheelchair user, the provision of a ramp and a door wide enough to take a wheelchair. For a person with arthritis of the hand, use of a conventional mobile phone may be impossible, so such a person is disabled with respect to making telephone calls while on the move. However, simple technological solutions exist, at least in principle, for this problem. Technology, properly developed and applied, will liberate large numbers of older people from entirely unnecessary social isolation and enforced dependency. The result, even if the technology solutions were funded entirely by the state resources, would be savings in the provision of high- dependency support services that would easily repay the necessary investments. However, there is no need to see the future provision of technology solutions as requiring state support. The market opportunities for companies are enormous already and growing every year. It is hard to escape the impression that what is holding these developments back is nothing less than a pervasive lack of imagination, propelled perhaps by equally pervasive ageism. It is here that there is a role for us all in fighting for the necessary change in attitude and effective commitment to fresh action."

    Link: http://www.publicservice.co.uk/feature_story.asp?id=15472

    Humanity+ Conference in London

    From h+ Magazine: "People who are new to Humanity+ and to transhumanist thought in general might well be under the impression that the H+ movement is primarily an American beast. Optimism with regard to the future seems to be part of the American psyche, so I was surprised when I learned that H+ began its existence as the World Transhumanist Association, founded in the UK by philosophers David Pearce and Nick Bostrom in 1998. Ten years later, the organisation was renamed to Humanity Plus, and the first UK conference for H+ was held in London in April 2010. The first H+ conference of 2011 will also be held in London on January 29th, building upon the success of last year's meeting, and promises to be a fascinating exchange of ideas. ... [Amongst the topics] is the popular transhumanist topic of life extension. Dr Marios Kyriazis will be talking about how the convergence of different areas of science may allow dramatic life extension, and will briefly discuss some of the implications to our society. Following from Marios' talk, Dr Aubrey de Grey will give a presentation on some of the latest developments in the field of life extension, explaining that if we are able to extend our lives by more than one year per year of progress, we can achieve a longevity escape velocity and potentially live for a very long time indeed."

    Link: http://www.hplusmagazine.com/editors-blog/humanity-london-january-29th-theories-and-possibilities-future-humanity

    The Road to Biological Joint Replacement

    Running in parallel to the tissue engineering goal of growing replacement inner organs such as hearts and livers you will find research aimed at building new biological joints. Joint replacement could be far safer, more effective, and long-lasting if biological parts were used instead of the present state of the art artificial materials. In the long run the pendulum will swing back to favor the artificial, but for now biology is the wave of the future. For example, there is this recent news:

    Biological Joints Could Replace Artificial Joints Soon

    Artificial joint replacements can drastically change a patient's quality of life. Painful, arthritic knees, shoulders and hips can be replaced with state-of-the-art metal or ceramic implants, eliminating pain and giving a person a new lease on life. But, what if, instead of metal and plastic, doctors were able to take a patient's cells and grow an entirely new joint, replacing the old one with a fully functional biological joint? A team of University of Missouri and Columbia University researchers have found a way to create these biological joints in animals, and they believe biological joint replacements for humans aren't far away.

    ...

    The scaffold was implanted in rabbits with a surgical technique currently used for shoulder replacement in humans. The surgery removes the entire humeral head, or the ball part of the ball-and-socket shoulder joints. The scaffolds are infused with a growth factor, which encourages the host's own cells, including stem cells, to become cartilage and bone cells. The advantage to this technique is that it avoids the need to harvest and implant cells, which requires multiple surgeries. ... The study found that the rabbits given the infused scaffolds resumed weight-bearing and functional use of their limbs faster and more consistently than those without. Four months later, cartilage had formed in the scaffolds creating a new, functional cartilage surface for the humeral head.

    This is an encouraging demonstration, and one more in a long line of the same. The cartilage engineers have been advancing the state of their art steadily over the past few years, as a look back in the Fight Aging! archives shows. This is exactly the sort of thing that I like to see - consistent material progress towards the components of a general repair kit for human beings. It is a sign of health for this part of the field, and we can hope that in the years ahead the other needed areas of medical development will come to show the same or better levels of progress.

    Stem Cells and Baldness

    It is revealing that stem cell research into therapies for baldness attracts far more public and media attention than stem cell therapies for heart conditions - human nature and human priorities are not what they might be. That aside, progress is occurring here just as in other areas of regenerative medicine: "Common baldness could have its roots in a newly identified stem cell defect, a finding that could potentially lead to new hair-loss treatments down the road ... Researchers say they discovered that a cellular malfunction short-circuits the process by which hair follicle stem cells turn into hair-producing progenitor cells. That defect, rather than any loss of stem cells themselves, sparks the onset of androgenic alopecia, the medical term for a type of genetic hair loss that affects both men and women ... In men, this hair loss is commonly known as male pattern baldness, marked by the familiar receding hairline and thinning hair on top of the head - a condition that sometimes leads to complete baldness. In women, female-pattern hair loss causes the hair to get thinner all over but rarely leads to baldness. ... Previously we thought the stem cells were gone, and if that was the case it would be very difficult. But because they are present it should be possible to treat ... A complex series of analyses revealed that bald and haired tissue contain equivalent amounts of preserved stem cells, which give rise to progenitor cells. Bald tissue, however, did not contain the normal amount of progenitor cells, suggesting a malfunction in the normal behavior of hair follicle stem cells. ... The follicles that make hair don't go away completely, but they become miniaturized, to the point where the hair they normally make to replace hair when it naturally falls out becomes microscopic and therefore invisible."

    Link:http://www.businessweek.com/lifestyle/content/healthday/648236.html

    There Are Many Good Biomarkers for Age-Related Frailty

    Good measures of frailty in age, and good correlations with mortality rate, have been comparatively easy for the medical establishment to discover and verify - take grip strength, for example. Here is another: "In an analysis of nine studies involving more than 34,000 people age 65 and older, faster walking speeds were associated with living longer: Predicted years of remaining life for each age and both sexes increased as gait-speed increased, with the most significant gains after age 75. In addition, researchers found that predicting survival based on gait speed was as accurate as predictions based on age, sex, chronic conditions, smoking history, blood pressure, body mass index and hospitalization. ... Walking is a reliable tool to measure well-being [because] it requires body support, timing and power, and places demands on the brain, spinal cord, muscles and joints, heart and lungs. Slowing down is associated with getting older. By age 80, gait speed is approximately 10% to 20% slower than in young adults. ... In the study, gait speed was calculated using distance in meters and seconds. All subjects were instructed to walk at their usual pace and from a standing start. Average rate of speed was 3 feet per second (about 2 miles an hour). During the 14-year course of the study, there were 17,528 deaths. Those who walked slower than 2 feet per second (about 1.36 miles an hour) had an increased risk of dying. Those who walked 3.3 feet per second (about 2.25 miles per hour) or faster survived longer than would be expected by age or sex alone." Eliminating the slow spiral down into frailty and physical incapacity is one of the noble goals of longevity science.

    Link: http://www.usatoday.com/yourlife/health/2011-01-05-walking05_ST_N.htm

    Support Real Progress in Life Extension

    When it comes to a motto and a goal in life, you could do far worse than "support real progress in life extension." I may be biased on this topic, of course:

    As we start the new year, it is helpful to draw attention to the sobering fact that no credible human rejuvenation therapies are available today, and it is doubtful that such therapies will see the light of day in the short term.

    ...

    There is a broad consensus in the life extension community that more resources need to be allocated to combating aging as such, as opposed to increasingly futile efforts to extend life by treating aging-associated diseases. Unfortunately, the objective to launch a serious rejuvenation research program has limited mass appeal so far. As a consequence, we will have to get involved ourselves. Hopefully we can shift the focus from extensive hypothetical discussion about the consequences of human enhancement technologies to supporting and engaging in real experimental research to make these technologies facts of life.

    We are all of us dying slowly, cut down by the progressive biological mechanisms of degenerative aging that bring frailty and disease. What can we do about this? I offer some suggestions here at Fight Aging!, which essentially boil down to specific recommendations for the following:

    • Help to fund ongoing meaningful research in rejuvenation biotechnology.
    • Persuade increasing numbers of other people to do the same.
    • Work on improving your ability to do well with the first two items above.

    As the biotechnology revolution continues, a further option becomes open: to do some of the work ourselves, as amateur life scientists and technicians. Just as many smart people learned to write code and build sophisticated software applications once computers became cheap, so too will many smart people participate in biotechnology research and development:

    This coming sea change in the life sciences is something to look forward to and prepare for - there are a great many important tasks in longevity science that might progress effectively in distributed communities outside the established research institutions. That list of tasks will only grow larger as the cost of required tools and knowledge falls ever faster.

    On Stem Cell Aging

    Stem cells work to maintain your tissues, but their ability to carry out their job diminishes with age, causing a corresponding decline in tissue function. An understanding of why stem cell decline occurs is important in determining what to do about the problem. For example, if the problem is damage in the stem cells themselves, then replacement is a very viable option. If, however, the issue is caused by broader damage in supporting cell populations that leads important signaling processes and stem cell niches to run awry, a completely different strategy is needed. Researchers do not yet have a full understanding as to the mechanisms by which stem cells decline with age, but they are working on it: "Stem cell aging is a novel concept that developed together with the advances of stem cell biology, especially the sophisticated prospectively isolation and characterization of multipotent somatic tissue stem cells. Although being immortal in principle, stem cells can also undergo aging processes and potentially contribute to organismal aging. The impact of an age-dependent decline of stem cell function weighs differently in organs with high or low rates of cell turnover. Nonetheless, most of the organ systems undergo age-dependent loss of homeostasis and functionality, and emerging evidence showed that this has to do with the aging of resident stem cells in the organ systems. The mechanisms of stem cell aging and its real contribution to human aging remain to be defined. Many antitumor mechanisms protect potential malignant transformation of stem cell by inducing apoptosis or senescence but simultaneously provoke stem cell aging."

    Link: http://www.ncbi.nlm.nih.gov/pubmed/21181890

    DNA Damage, Cancer, and Aging

    A short open access paper: "Defects in the DNA damage response often lead to an increased susceptibility to cancer, and so the DDR presents an interesting set of novel therapeutic targets. The maintenance of genomic integrity by the DDR has also been found to be involved in the process of organismal ageing. While the removal of cells containing damaged DNA can be beneficial in the prevention of cancer, it may contribute to both normal and pathological ageing. ... Given the frequency at which DNA lesions occur (approximately 10^4 per cell per day), a complex system of damage detection and repair is required in order to preserve the integrity of the genome. This system is termed the DNA damage response (DDR), and encompasses: the recognition of DNA damage; the transduction of signals through appropriate pathways; and the activation of cellular responses ranging from DNA repair and chromatin remodeling to the activation of cell death if the damage is irreparable. ... The maintenance of the DDR is essential for faithful replication of the genome, and so is critical for cellular survival. The loss of certain DDR components can lead to an increased susceptibility to cancer due to the ensuing genomic instability and the subsequent mutation to genes required for cellular replication and division. The DDR is also involved in the induction of senescence and apoptosis when the damage cannot be repaired. While this can prolong longevity during early stages of life due to the suppression of tumorigenesis, it may become detrimental in ageing due to the loss of stem and progenitor cells for renewal. This is a phenomenon referred to as antagonistic pleiotropy, and it highlights the importance of carefully balanced cell signaling cascades and regulatory systems in the maintenance of survival. Further studies of the roles of DDR-associated proteins, along with the discovery of new ones, will therefore not only enhance our understanding of cancer and mechanisms to treat it, but will also enhance our understanding of the ageing process. This may uncover ways to treat premature ageing or other age-related pathologies, such as the decline of the immune system in the elderly."

    Link: http://www.impactaging.com/papers/v2/n12/full/100248.html

    The Simulation Argument: Maybe You're Already Either Immortal, Doomed, or Dead

    The Simulation Argument as advanced by Nick Bostrom suggests that we should give more thought as to whether we are simulated beings, running in a computer of some description. In essence, our present trajectory in technology suggests that there is nothing to prevent our descendants from running very detailed simulations of their past, including simulations of people - they will, after all, have access to staggering amounts of processing power, entire solar systems worth of matter converted into high grade nanoscale computing devices. Running a simulation of what is to them early civilized history would be a trivial expenditure given their vast resources, so they will probably do this many, many, many times. Therefore any random pick of what appears to be a human living in the natural universe is actually much more likely to be a simulated human living in a simulated environment:

    This paper argues that at least one of the following propositions is true: (1) the human species is very likely to go extinct before reaching a "posthuman" stage; (2) any posthuman civilization is extremely unlikely to run a significant number of simulations of their evolutionary history (or variations thereof); (3) we are almost certainly living in a computer simulation. It follows that the belief that there is a significant chance that we will one day become posthumans who run ancestor-simulations is false, unless we are currently living in a simulation.

    This is a modernized and somewhat gloomy brain in a jar scenario: more plausible, given its greater attachment to what we know about technology, and heavier on the existential angst. Either there is no golden future of humanity, or we're most likely participating in it already, but from inside the laboratory and cut off from that reality. Ghosts in the machine.

    I've written on the topic of lazy immortality in the past, and the beliefs that attend it:

    Wouldn't it be nice to wake up and find that we were all immortal? That would save a whole lot of work, uncertainty, and existential angst - and we humans are nothing if not motivated to do less work. The best of us toil endlessly in search of saving a few minutes here and a few minutes there. So it happens that there exist a range of metaphysical lines of thought - outside the bounds of theology - that suggest we humans are immortal. We should cast a suspicious eye upon any line of philosophy that would be extraordinarily convenient if true, human nature being what it is.

    ...

    If you buy in to, say, the Many Worlds Interpretation of quantum mechanics (which a great many people in the field do) and you are fine with identifying your self as a specific pattern, no matter if there are discontinuities in the existence of that pattern, then you might argue that you are immortal.

    If you ascribe a high level of probability to the belief that you are a simulated being, then you find yourself in an interesting position vis a vis your immortality or lack thereof - very similar to the position of theologians and believers, in fact. You may indeed be immortal in the pattern sense if those who run the simulation are ethical in ways that include not destroying sentient life if it could be saved without disrupting the experiment. Equally, depending on the nature of the computing hardware, you may be better thought of as less an individual and more a flitting sequence of briefly instantiated patterns, each having no relation at all to the last, running on different small pieces of a gargantuan machine. You are dead, briefly alive, dead again - over and again, millions of times a second. You are not alive and continuous in any way that I would recognize; no one small instantiation exists for long enough to even experience the coherent illusion that it is alive.

    Or perhaps the plug will be pulled at some random time in the future and the simulation shut down, its data discarded. Or perhaps just your pattern won't be saved when your course in the simulation is run. Or perhaps the whole simulation was only started five minutes ago, our time, and so you are somewhat less old than you think you are. There are deeper rabbit holes to explore, but you might give pause to think that religious folk have it easier in one way at least: they've already been gifted with a rich history of theological argumentation and nonsense, and thus have no real need to work hard to make up any more of it.

    The bottom line is that being a simulated being in someone else's simulation is pretty ugly from an existential point of view. In the real world, there's the possibility to bootstrap into the million year life span though advancing technology; not a giant possibility for any of us in middle age today, but it's not zero either. The members of a simulated world society could do all the right things and reach the same end goal - but they'd still be stuck in the simulation and at the mercy of its creators, so wouldn't have won anything approaching the same victory.

    For all concepts of lazy immortality or variants on the brain in a jar, I think that the best course is to proceed as though what we see is what we get - assume we are in the real world, in these imperfect bodies, faced with real versions of these real challenges of aging and death. To do otherwise is to relinquish our potential, to lie back and relax whilst we are quite literally fighting for our lives:

    Once upon a time, the planet was tyrannized by a giant dragon. The dragon stood taller than the largest cathedral, and it was covered with thick black scales. Its red eyes glowed with hate, and from its terrible jaws flowed an incessant stream of evil-smelling yellowish-green slime. It demanded from humankind a blood-curdling tribute: to satisfy its enormous appetite, ten thousand men and women had to be delivered every evening at the onset of dark to the foot of the mountain where the dragon-tyrant lived. Sometimes the dragon would devour these unfortunate souls upon arrival; sometimes again it would lock them up in the mountain where they would wither away for months or years before eventually being consumed.

    Which is from the Fable of the Dragon-Tyrant, a mythologized view of the relationship between humanity and aging - also by Nick Bostrom. You should read it if you haven't already.

    Lessons on Regrowth

    From the Boston Globe: "The dream of regenerative medicine is that it will one day be possible to replace flawed tissues - to create a new spinal cord, repair a defective heart, or regrow a limb. But as scientists make steady progress toward that tantalizing goal, some are studying a range of simple organisms, from tadpoles to salamanders to flatworms, that can already rebuild complete limbs or tails. In his laboratory at Tufts University, biology professor Michael Levin is investigating an often-overlooked mechanism that may play a key role in triggering this regenerative capacity in such critters: electrical signals. When people think of electricity in the body, they usually think of brain and nerve cells, or muscles. But Levin and other scientists study the bioelectrical signals that exist in all cells, and the role those play in allowing organisms to generate precise, functional replacements for body parts. ... Levin has altered the electrical signaling in cells and observed dramatic effects: A tadpole can regenerate a completely normal tail after it has lost that ability. ... Levin and colleagues triggered that regeneration using drugs that affected the bioelectrical signaling in tadpoles. The drug increased the transport of sodium into cells, triggering the tadpoles to regrow perfectly formed tails, which include a complex mixture of tissues including spinal cord, muscle, and skin. Levin's hope is that electrical signals might be a master switch that allows the organism to boot up its regenerative program, rather than requiring scientists to build a new organ or appendage cell by cell."

    Link: http://www.boston.com/business/healthcare/articles/2011/01/03/lessons_on_regrowth_on_a_small_scale/

    Why Longevity-Enhancing Genes are Not Selected by Evolution

    Longevity may or may not be advantageous from an evolutionary point of view - it depends on the circumstances, which is why we see a wide variety of life spans in nature. Many species can be genetically altered in minor ways to live for longer in good health. One possible reason why these longevity-enhancing mutations don't occur in nature is that they may diminish an organism's reproductive vigor while young: "Reduced fecundity has been associated with some alleles that enhance longevity in invertebrate and mammalian models. This observation has been suggested to support the antagonistic pleiotropy theory of aging, which predicts that alleles of some genes promoting fitness early in life have detrimental effects later in life that limit survival. In only a few cases, however, has the relative fitness of long-lived mutants been quantified through direct competition with the wild type genotype. Here we report the first comprehensive analysis of longevity/fitness trade-offs by measuring the relative fitness of 49 long-lived yeast variants in a direct competition assay with wild type cells. We find that 32 (65%) of these variants show a significant defect in fitness in this competition assay. In 26 (81%) of these cases, this reduction in fitness can be partially accounted for by reduced maximal growth rate during early life, usually resulting from a G0/G1-specific cell cycle defect. A majority of the less fit longevity-enhancing variants are associated with reduced mRNA translation. These findings are therefore consistent with the idea that enhanced longevity often comes with a fitness cost and suggest that this cost is often associated with variation in a subset of longevity factors, such as those regulating mRNA translation, growth, and reproduction."

    Link: http://www.ncbi.nlm.nih.gov/pubmed/21191185