Fight Aging!

Apparently, 'tis the season for folks to come out and bemoan the terrible, horrible increase in healthy life span we'll see in the years ahead. The latest example can be found at the Atlantic, entitled "The Coming Death Shortage." The mind boggles - well, mine does in any case. I've always have a hard time understand how one can argue in favor of suffering, disease, decrepitude and death.

Like many articles, this one gives priority to serious misunderstandings related to economics, the root cause of expensive medicine (regulation, nothing else), and changes in cost and effectiveness of medicine over time. Not to mention a deep fear of change - a fear so deep that hundreds of millions of deaths are seen as better than any large shift in society or habit. Wow.

Every argument in this piece could have been made in opposition to research aimed at extending healthy life spans back in 1900. The world does not seem to have ended due to the increases in life expectancy since then. It has certainly changed a great deal - and I challenge anyone to suggest that folks are worse off now. Works like this Atlantic piece could - and should - be written off as ludicrous piffle if only folks like the author were not so serious in their efforts to prevent medical research into healthy life extension from moving forward.

UPDATE: Conveniently enough, you can find the full article text posted at the transhumantech Yahoo! group.

You'll find a real classic of anti-longevity sentiment at the Washington Dispatch. Living longer, healthier lives, how terrible some people think it would be! Despite years of advocacy and education, many basic errors in thinking about healthy life extension (and society and economics in general for that matter) remain widespread, especially amongst the wonks concerned with social security. This one in particular doesn't seem to understand that longer lives mean longer, healthier lives - and more years of work and savings. The underlying sentiment that it is better for people to suffer and die than to change a broken system is distressingly common. Change happens - in this case, wonderful change leading to longer lives and healthier people. Be prepared for the future and you'll do just fine.

Link: http://www.washingtondispatch.com/article_10773.shtml

The BBC has more on recent research into metabolism, healthy life extension and the hormone thyroxine. While the potential of an improved metabolism to lead to a somewhat extended healthy life span is demonstrated by calorie restriction, tinkering with thyroxine on an ad hoc basis - as for any hormone - seems to be a potentially dangerous proposition. "We know thyroxine affects your metabolic rate. The key is getting the right dose. ... Having an over-active thyroid gland puts you at a three-fold risk of potentially fatal heart disorders and a three to four-fold risk of osteoporosis. An over-active thyroid causes considerable morbidity in the ageing population. ... he warned people who had even a slightly higher level of thyroxine were at risk of ill health."

Link: http://news.bbc.co.uk/1/hi/health/4396495.stm

The Indian Express surveys the better known longevity research currently taking place around the world: genetic engineering, calorie restriction mimetics and various means of preventing damage caused by free radicals produced by our metabolism. What all these strands of research have in common is that they are most likely not the best way forward to a cure for aging. While this research may lead to a few decades of extended healthy life span by slowing age-related degeneration, it do not go anywhere near as far as is thought to be possible. Biogerontologist Aubrey de Grey argues, for example, that it is at least as easy to reverse aging as it is to simply slow it.

Link: http://www.indianexpress.com/full_story.php?content_id=67428

Nature reports that scientists have brought osteoarthritis, an all too common age-related condition, to a halt in mice: "The researchers investigated a family of enzymes, called aggrecanases, that are thought to contribute to osteoarthritis by chewing up a vital component of cartilage that makes it tough and elastic. The teams showed that mice genetically engineered to lack a working form of one such enzyme, ADAMTS5, seem impervious to arthritis. ... Various enzymes come and go and all turn out to be dead ends. But now we might be on to something. ... The researchers are particularly hopeful because the mice lacking the working enzyme showed no signs of problems elsewhere in their bodies."

Link: http://www.nature.com/news/2005/050328/full/050328-6.html

You'll find a patch of good commentary over at Anti-Aging Medicine & Science under the title "Perhaps, most people just don't realize that there is an alternative to the quasi-random fate that nature doles out."

Most people want to live for only a few decades. If you don't believe me take a poll of your friends and neighbors, you may be surprised at what they say.

Myself, I'm 56 years old and I have not yet experienced a fraction of the things I would like to experience in my lifetime; a trip to the Orient, SCUBA diving, hiking down to the Colorado River in Grand Canyon National Park, a week at Caesar's Palace, to samba at Carnival and viewing Earth from outer space. Naturally, money/time is my limiting factor. But what if I could live a longer healthy life? What would be the possibilities?

We make the future through our actions, as I am fond of pointing out. That future can include working anti-aging medicine that will greatly extend our healthy life spans - if we act to make it so. There are ways for anyone, no matter what their background and resources, to help make the future a better place. Donate to the Mprize for anti-aging research; visit the Longevity Meme Take Action! section; find out how you can help biogerontologist Aubrey de Grey make faster progress in his SENS initiative; start a blog like this one; talk to your friends about healthy life extension. No-one has to sit back and hope that the future of medicine will turn out well - we can all pitch in and help.

Betterhumans notes more progress in the discovery and manipulation of pluripotent adult stem cells. "Stem cells from hair follicles can develop into neurons, muscle and more, suggesting that hair is a potent and accessible source of cells for regenerating tissues." Judging from progress to date, I would expect to see more reserves of potentially very useful stem cells found in the adult body - research into regenerative medicine should benefit accordingly. Therapies most likely to be accelerated by this and similar lines of research are those aiming to replace comparatively small populations of damaged cells in the body - good examples of the type are cures for age-related diabetes or Parkinson's.

Link: http://www.betterhumans.com/News/news.aspx?articleID=2005-03-28-3

Have you ever had one of those discussions wherein, after you have carefully made your points, the other side responds in such a way as to demonstrate that they were not even listening? Welcome to the world of advocacy for longevity and real anti-aging research, where you can hear the same tired, erroneous, debunked objections today as you could two decades ago. Witness a recent article on Aubrey de Grey's work that starts out well but abruptly falls off the precipice:

The first and most obvious drawback to the indefinite postponement of death is the spectre of catastrophic overpopulation. De Grey has an answer.

He suggests that in the future people should be given a choice - either live forever young yourself, or have children.

How simple and convenient. And how likely do you think people are to accept that?

What, in fact, would be the point of living interminably without children?

It sounds like a charter for the supremely selfish.

The achievement of endless life doesn't seem to me the pinnacle of human progress De Grey believes, but merely its end.

De Grey suggests that people who expect to live for centuries would take better care of the world. Perhaps. But who exactly will these people be?

You can pretty much guarantee that the anti-aging therapies will be available only to those who can afford it - which means wealthy Westerners, predominantly Americans.

Do we really want these people to inherit the Earth?

And what of the rest of humanity? What are they to make of it all?

Will it mean the end of war, famine, poverty - or will it make these things worse?

The perceived prize for the winners would be that much greater and the loss so much more that conflict would surely be bitter.

How would you feel about knowing you'll live long enough to see the next Ice Age, the next major meteor strike on the planet, the next world war?

How can De Grey and his fellow fantasists be sure all their work won't simply be swept away by a pandemic of as-yet unknown disease?

And on this Good Friday, is it fair to question whether lengthening our stay in this world is simply postponing our arrival in the next? There will be those who think so.

Most writers settle for three objections or so, with Malthusian concerns about population as a favorite (debunked by many, many authors including Max More) - not so here; this ambitious soul has reeled off a real litany of errors and pessimism. The error most worthy of being addressed in this post - all have been tackled many times before by far better writers than I - is a profound but sadly commonplace misunderstanding of economic realities. Economics means change; prices move, wealth changes hands. The poor are not always poor, high prices are not always high. All new technologies - medical technologies included - are only available to the comparatively wealthy at the outset. High prices relect the need to recoup the cost of initial development and research. Costs and prices drop rapidly with the passing of time and increasing adoption, however. Reliability and effectiveness increase at the same time. To paraphrase a poster from Slashdot, "that the wealthy act as guinea pigs for new medical treatments and fund the continuing improvement and wider availability of such treatments should appeal to your class warefare soul."

I'll leave up to you folks to address the other points in the comments, should you feel so inclined. I'm more interested in the larger question of successful education and advocacy; all of these objections to healthy life extension have been debunked, addressed, talked out and analysed again and again over the past decades (and even prior to that). Why do they keep cropping up as knee-jerk reactionism to any mention of healthy life extension research when a few minutes of research would uncover the history of discussion on these points? How can we as advocates do a better job of making people aware of the good counter-arguments?

Suggestions taken.

You'll find a good essay on the history, practice and science of cryonics over at Kuro5hin. "Together, function and structure allow for life. Cryonics does not preserve all biological functions - vital functions like brain activity and heart-beat are over when modern medicine pronounces a person dead. But cryonics does preserve structure, and this is what makes it so important as a life-saving procedure. It may seem fanciful that death can be stopped as a result of cryonics, but the practice has scientific support." Cryonics is an experiment with an uncertain chance of success - but it is the best option open for the unfortunate millions who will die from age-related degeneration before real anti-aging medicine can be developed and deployed.

Link: http://www.kuro5hin.org/story/2005/3/22/13539/6192

KeralaNext.com provides a good summary of recent research into Hutchinson-Gilford Progeria Syndrome, a condition of greatly accelerated aging. The genetic cause was recently identified - this offers hope for a cure in the years ahead, as well as increased understanding of the normal aging process. "Low levels of HDL, or the 'good' cholesterol, play a role in the development of heart disease in children with progeria. ... Dr. Smoot said that the next step in research will be to understand the relationship between the lamin A protein and HDL cholesterol levels. Such research, she said, could have 'huge implications for everybody. Aging and heart disease are the two most significant issues for most people in Western society, so anything we learn along the way might provide clues for the general population.'"

Link: http://www.keralanext.com/news/indexread.asp?id=165525

The Financial Times is running an alternately insightful and obtuse article on increasing longevity and what that means for personal finance and over-regulated pension or social security schemes. As is all too common in this sort of article, increased longevity is presented as a bad thing due to the changes it will bring. Living healthily for longer, how terrible the bean counters think it would be! This is an excellent example of the way in which systems come to be given more weight and priority than the people they are supposed to serve. The lesson here is to plan your future under the assumption that the idiots in charge do not have your best interests in mind and are not going to be around to pick up the pieces.

Link: http://news.ft.com/cms/s/2833a776-9f7f-11d9-b355-00000e2511c8.html

In the latest Longevity Meme newsletter, I take a look at currently funded medical research likely to have a notable effect on healthy life span, the divide between prevention and cure, and why a better approach is needed.

The bottom line is that most of us reading this newsletter today are not going to greatly benefit from the "one cure at a time" approach to medicine. We won't suffer the horrible effects of Alzheimer's, nor will we die from heart disease. Cancer will most likely be a controllable, chronic condition 20 years from now. Yet we won't be living much longer overall as a result of those advances - they do not address the underlying cause of aging and age-related death.

A real sea change must come about in the way in which aging is addressed by the research community, not to mention the level of funding put into longevity research. We are very close - a matter of decades - from being able to greatly increase the healthy human life span; by decades initially, and far more subsequently. You can find more details on how this could happen at Aubrey de Grey's Strategies for Negligible Engineered Senescence (SENS) website.

Everything else aside, the funding must be there. That $1 billion per year for directly longevity research has to happen. Making it happen is up to all of us - we make the future through our actions and expressing our wishes to those who direct investments. So stand up today and do something for the future of medical research and healthy longevity!

You can sign up to receive the newsletter via e-mail over at the Longevity Meme website.

A large number of newsworthy events are taking place in the world of stem cell research and legislation at the moment, but I thought it worth drawing attention to the Wired Rave Award for medicine given to Robert Lanza of Advanced Cell Technology:

In his interview with Wired Magazine, Dr. Lanza commented, "There are 3,000 Americans dying every day from diseases I believe could be treated using stem cell technology." He also cited advice from some of his mentors, including Jonas Salk, B.F. Skinner, and Christiaan Barnard. That advice was to "Make a difference."

William Caldwell, Chief Executive Officer of ACT Holdings, Inc. said, "It is gratifying to see the technology community recognizing the importance of regenerative medicine and the scientists working in the field."

Michael D. West, Chairman, President, and Chief Scientific Officer of Advanced Cell Technology, Inc. commented, "I am very happy for Dr. Lanza's continued recognition in the field of stem cell research. Dr. Lanza has long been and will continue to be an important leader and contributor to our scientific team at Advanced Cell Technology."

If ever there was a model for people laboring determinedly in the face of opposition to make a young company and its medical breakthroughs a success, the Advanced Cell Technology team would be it. All this story needs now is a happy ending that involves renewed venture funding, more advances in stem cell technologies, and the widespread deployment of new stem cell therapies for age-related conditions.

The latest poll from the Coalition for the Advancement of Medical Research shows strong support for embryonic stem cell research and therapeutic cloning - especially once the goals, such as curing common age-related conditions, are explained. "59% strongly or somewhat favored [this] research, and only 33% opposed or strongly opposed it. But after a brief description of the research was read, the percentage in favor increased to 68% compared to only 28% opposed. A question regarding the use of [therapeutic cloning] found that 60% strongly or somewhat favored the research, and only 35% somewhat or strongly opposed it. However, after a more detailed description [was read], the more respondents favored the research, 72% compared with only 23% opposed."

Link: http://www.camradvocacy.org/fastaction/news.asp?id=1326

Funded longevity research today is largely based on determining ways to "fine-tune" our metabolic processes - calorie restriction mimetics such as those sought by Sirtris are a good example. The Scotsman looks at another methodology: "We found making the metabolism in cells less efficient meant more oxygen was consumed and fewer free radicals were produced. In effect, a pharmaceutical target would pump up the metabolic rate to reduce the free radical production. Because free radicals also play a role in causing cancer and other diseases, reducing the number produced can not only increase the length of time someone lives, but increase their healthy lifespan." This sort of work is not expected to bring more than ten or twenty extra healthy years, however - going beyond this requires better technology.

Link: http://news.scotsman.com/scitech.cfm?id=325642005

(From Haaretz). Scientists are looking to the rejuvenation of aging stem cells in the body: "The big revolution will come when stem cells can be used to stop the aging process. Five years ago, when scientists were talking about 'stopping the biological clock,' it sounded like science fiction. ... scientists took an old mouse and a young mouse and joined their blood systems. They found that the exposure caused the stem cells of the elderly mouse to be renewed ... The search for substances that will cause our stem cells to be rejuvenated could be one of the big revolutions of our times." There are many caveats associated with this line of research - we have no idea whether or not rejuvenating stem cells would have a large effect on the aging process, for example - but it certainly shouldn't be dismissed.

Link: http://www.haaretz.com/hasen/spages/556718.html

The Times is running a very sane article on the hype surrounding growth hormones in the "anti-aging" marketplace. "Taking hormones to hold back the years is based on a myth. And, for people who have no medical need for hormone supplementation, swallowing the dream could hold fatal risks. ... Extensive work from Scandinavia has shown that injecting the hormone does not restore muscle mass or fitness to the elderly." Unlike calorie restriction, there simply isn't an overwhelming weight of science and knowledge backing the use of hormones - and most of the widely available (and useless) products are sold by the shady, disreputable end of the "anti-aging" industry. Buyer beware.

Link: http://www.timesonline.co.uk/printFriendly/0,,1-100-1540797-100,00.html

As a reminder, registration is still open for TransVision 2005, the yearly conference of the World Transhumanist Association to be held in late July in Caracas, Venezuela:

Dear Transhumanist friend,

You can still register for TransVision 2005 (www.TransHumanismO.org/tv05) to take advantage of this great opportunity to talk, meet and share with many Transhumanists from around the world. If you are also interested in presenting at TV05, you can still send us your presentation proposal and your updated picture to: jose_cordeiro@yahoo.com. So far, we have confirmed participants from 21 countries from the Americas (North, Central and South), Asia, Africa and Europe. TV05 will thus be the greatest gathering of international Transhumanists so far in history.

Coming to Venezuela is a lifetime opportunity. The country is beautiful and the people are incredibly friendly (and beautiful too, we have the largest number of official Miss Universes in the world, not per capita, but in total numbers, and the same with Mister Universes:-)

Venezuela has extraordinary natural beauties like the Caribbean beaches for scuba diving, snorkeling or just swimming (see www.venezuelatuya.com). Venezuela also has the highest cable car in the world (up to 15,000 feet high), the highest waterfall in the world (Angel Falls in Canaima, Gran Sabana, with close to 3,000 feet high in the Orinoquia-Amazonia) and the longest cave in the world (Cueva del Guacharo, which was visited several times by French scientist Jacques Cousteau).

You can get a roundtrip airplane ticket from anywhere in North America to Caracas for less than $500, and from Europe for less than $700. From North America, you can probably get the best deals if you book separately first from your city to Miami and then from Miami to Caracas (Miami-Caracas can be as little as $200 roundtrip in advance, for example, check www.travelocity.com with flexible dates). From Europe, there are usually cheap direct flights via Frankfurt, Lisbon, Madrid, Paris and Rome, but you need to book now, since July is high season for travel and the inexpensive tickets go fast.

Most TV05 participants will be staying in a fantastic four star hotel, built by Nelson Rockefeller himself, for as little as $55 single or $30 double rooms, per night, if we book for you here in advance (otherwise it might be over $100 per night). The "Hotel Avila" (www.hotelavila.com.ve) is considered the "Grand Dame" of hotels in Caracas and it is listed as Fodor's Choice in Venezuela. No one can beat that, with free breakfast, swimming pool, gym and everything else expected from such hotels in a marvelous tropical setting.

The TV05 Caracas Organizing Committee is here to help you with any questions and/or doubts so that we will have a very successful TV05: the first international Transhumanist conference in the developing world.

Transhumanistically yours,

Josi Cordeiro, M.S. (jose_cordeiro@yahoo.com)
Conference Chair (www.cordeiro.org)

James Hughes, Ph.D.
International Organizing Committee (www.TransHumanism.org)

Santiago Ochoa, M.S.
Venezuelan Organizing Committee (www.TransHumanismO.org)

The conventional wisdom on the future of tissue engineering is echoed in the People's Daily Online: "Part of human tissues such as bone, muscle, blood vessel, or even nerve can be 'batch-produced' in another 10 or 15 years said Doctor Cui Zhanfeng ... Cui said that despite of some explorations there would be many [technically] difficult problems before realizing batch production of human tissues. For example the sources of stem cells, the material for support, bioreactor, how to enlarge tissues in industrialized production as well as any rejections caused by implanting. They are involved in many areas of engineering, medical science and materials."

Link: http://english.people.com.cn/200503/23/eng20050323_177955.html

EurekAlert reports that a new study on the use of adult stem cells to repair heart damage is underway in the US. "Previous research in animals showed that when adult stem cells were injected directly into the heart muscle, heart function was restored to its original condition within two months. [Last November] the Hopkins team showed, again in animal studies, that more than 75 percent of dead scar tissue disappeared after therapy, which produced mostly healthy, normal-looking heart tissue and left only a small trace of the heart attack. The Phase I study is being conducted at Hopkins, with support from Baltimore-based Osiris Therapeutics, which developed the stem cell product. The study will involve 48 adults who have had their first heart attack within 10 days of enrollment in the trial."

Link: http://www.eurekalert.org/pub_releases/2005-03/jhmi-hbh032505.php

The news that the US house will actually be voting on legislation to loosen restrictions on Federal embryonic stem cell research funding has some commentators puzzled:

Why would House leaders be ready to allow a vote on the question of expanding funding for embryonic stem cell research? This can only mean embarrassment for Bush, and surely they know that. I wouldn't be surprised to hear of the Senate holding such a vote, but the House leadership is generally far more reliably partisan.....

Ronald Bailey has his own theories on the move:

Republican know-nothings are apparently beginning to feel the heat from voters about stem cell research. The troglodytic Republican leadership has apparently agreed to allow a vote on the Stem Cell Research Enhancement Act of 2005, according to the Washington Post. Basically, the act would allow federal funding of stem cell lines derived from leftover embryos donated by couples who have stopped their infertility treatments.

Why have our solons at last chosen to allow such a vote? Because they want to get re-elected. They've finally awakened to the fact that polls consistently show a majority of Americans favoring human embryonic stem cell research. The Post reports that a new poll finds that two-thirds of the public supports stem cell research.

As a follow on to my remarks on the ambitious nature of Ray Kurzweil's timescales for longevity research, it would seem to be a useful exercise to ask just how long it takes to ramp up funding for specific medical research. How long after the first advocacy organizations get underway does it take to direct $500 million or $1 billion per year into a narrow field of medical research?

We can look at a number of historical initiatives over the past four decades in an attempt to find out; cancer, AIDS and Alzheimer's are the most obvious. While digging up private investment figures is a real undertaking, one can at least get an idea as to boundary points and timescales involved by looking at public funding. Based on a casual examination of the recent past, it would seem that a good ten to twenty years is required to generate large public research programs; private research is sometimes ahead, sometimes behind in its own funding while this is going on.

While it is gratifying to see the success of regenerative medicine as a viable field of research - especially given the understanding of cellular biochemistry and genetics that will be generated in the course of deploying stem cell therapies for age-related conditions - it is not going to do anywhere near as much for healthy longevity as a directed program of research into understanding and curing the aging process. The question would be whether we can muster a surge of advocacy for serious anti-aging research akin to that of AIDS groups, or whether we face the slower ramp up of cancer or Alzheimer's research - tens of millions of lives hang in the balance with each passing year. We cannot afford to waste time.

From Express India, an update on progress in trials and research in that country. "The premier medical institute in the country is all set to prove to the world the efficacy of its stem cell therapy conducted over the last 18 months on heart patients ... In our study we used this therapy on 33 patients and all of them are showing positive results. ... Researchers at AIIMS have also conducted some pilot studies for use of stem cells in diabetics and now plan to inject these cells directly into pancreatic arteries of these patients." Indian scientists are optimistic about the future: "For future research, we are looking at all areas - diabetes, muscular dystrophy, cerebral palsy, other neurological disorders and Parkinson's disease. The residual damage after stroke too can be minimised by injecting stem cells."

Link: http://www.expressindia.com/fullstory.php?newsid=43720

Science Daily reports on the continuing realization that moving into the third dimension makes a big difference to stem cell research: "In conventional cell cultures, cells usually grow as flat deposits bathed in growth medium. ... Specific genes, proteins and hormones normally produced by healthy cells are often absent in two-dimensional colonies. ... Researchers here have used a new microscopic, three-dimensional scaffolding to coax mouse stem cells to transform themselves into fat cells, and then to function identically to how fat cells naturally do in the body. ... This discovery offers hope of a new approach to growing fat tissue for use in breast reconstruction surgery and other clinical needs, and may even be important for curing [age-related] diabetes."

Link: http://www.sciencedaily.com/releases/2005/03/050323123719.htm

Despite being obscured by the nonsense put out by the "anti-aging" marketplace, serious research into how our skin ages is taking place - just as for aging in other important organs. You may recall that we mentioned work on lost elasticity in skin last year, for example. A New Scientist article provides some details on continuing research into how and why our skin ages: "Wrinkles and the leathery feel of old skin are thought to result from changes in the dermis, the deepest layer of skin. This becomes fibrous, making the skin less elastic ... changes may also be taking place in the epithelial cells above the dermis." We can hope that this won't immediately be trivialized by the quick buck contingent at Revlon et al, as this sort of work has important implications for treating a wide range of serious age-related disorders.

Link: http://www.newscientist.com/article.ns?id=dn7173

The Immortality Institute has launched an essay contest: winning essays will be considered for inclusion in the next Institute book. The topic for consideration is oblivion: "In Lamont's The Illusion of Immortality the term immortality refers to existence of a soul in an afterlife. The illusion to which Lamont refers is that there likely does not exist an immortal soul. ... the term immortality as used by scientists today mainly refers to agelessness of an entity or organism. The Immortality Institute prefers to use the term physical immortality as to mean the 'concept of existing for a potentially infinite or indeterminate length of time.' How does one come to terms with the seemingly inescapable problem of oblivion after ones own death? In the 70 years since Lomont first published his work, why has so little been written about the problem of oblivion after death? Can science prove or disprove oblivion after death?"

Link: http://www.imminst.org/contest/

Ray Kurzweil is getting his messages on healthy life extension and the accelerating rate of scientific progress, as expressed in his recent book, down to a fine art. Have a look at the talking points in this interview:

Information technology is affecting almost every field. We're now understanding biology as information processing; we're learning to understand the processes underlying these biological pathways. Whereas drug discovery used to be literally that, discovering drugs, which is to say finding something that happened to work. Now we're entering an area where we actually understand the exact sequence of biological events. We can intervene very precisely by blocking one key enzyme, one key step.

...

Our mortality is something that should be in our hands; it's something I want in my hands. Science and technology are accelerating. I believe we'll demonstrate a mouse that doesn't age within approximately a decade. And within a decade of that we'll translate that into human therapies.

...

We can talk poetically about how aging is natural, but the reality is if you visit an old-age home you see people who've lost their loved ones and have lost their faculties. It's really a tragic situation and it's not something I desire. I want to keep my faculties.

I think that his timelines are overly aggressive, but only because high levels of funding for the relevant branches of aging and anti-aging research have yet to be attained. The prediction of an ageless mouse in ten years, for example: that is based on Aubrey de Grey's timeline, which in turn is based on a fully funded program starting now. Needless to say, that funding does not yet exist; obtaining it is going to the be the work of years, maybe a decade. There is also still the matter of the business cycle, regulation and human interactions on the way from science to commercial product, all of which are still occurring at a comparatively slow rate.

Still, Kurzweil is getting important ideas out there (far more effectively than I am, I might add) and helping to educate the public of the possibilities offered by research into the aging process. This is a great help in efforts to obtain funding for efforts like the proposed SENS program over the long term.

Two critical reviews at Betterhumans today: Bruce J. Klein of the Immortality Institute reviews Aging, Death and the Quest for Immortality by C. Ben Mitchell. In return, Mitchell reviews the Immortality Institute's The Scientific Conquest of Death. Sparks fly (politely), as might be expected when two essentially opposing viewpoints meet. On the one hand we have scientific rationalism and the quest for physical immortality through better medicine and other forms of advanced technology. On the other hand, we have religion and the acceptance of spiritualism, faith - and aging and death as inevitable.

You will have to excuse my bias in this sort of debate; the very mildest criticism I can think to make of pro-death religious views is that they smack of surrender in the face of a hard problem. Those of us reading this today have been dealt a raw hand, destined to age, suffer progressive degeneration and die. Yet our situation is far better than that of our ancestors - we are in a position to do something about the aging process and death through age-related disease. Do we sit back and invent justifications for a terrible, horrible state of affairs just because it'll take work, imagination and fire to make a better world? Of course not.

(From Science Daily). The vast sums of money invested in Alzheimer's research are paying off as capabilities and tools improve. "Researchers at UC Irvine have identified a trigger at the molecular level that marks the onset of memory decline ... The trigger is a protein called "beta amyloid" that accumulates within neurons ... Although several researchers have studied the association between beta amyloid and memory, the UCI research team is the first to identify that early beta amyloid accumulation within neurons is the trigger for the onset of memory decline in Alzheimer's." As understanding of biochemical processes increase, so too do the chances of near-term therapies or even a cure. Preventing and repairing neurodegenerative conditions is especially important to the future of healthy life extension.

Link: http://www.sciencedaily.com/releases/2005/03/050309130709.htm

A rather wonkish piece from Chemical & Engineering News looks at likely prospects for the future of public funding of stem cell research in the US. As is true of most such articles, private funding - the majority of medical research funding over the long term - is not discussed. "The genesis of this complex picture is a federal policy that only allows federal funding of research on [human embryonic stem cell] lines derived before Aug. 9, 2001. Of the initial 78 lines covered by this policy, only 22 lines are currently viable. This number is a sharp contrast to the more than 150 lines that have been derived since the policy was announced and are prohibited from study with federal funds." In fact, none of those 22 lines are viable for research - all are contaminated.

Link: http://pubs.acs.org/cen/news/83/i12/8312stemcells.html

It's time for another look at the damage done to good science by errant politicians, administrators and managers. State funding or not, things would go so much faster if they would all just stand aside; private funding stands idle while politicians and anti-research groups bicker and try to halt medical progress. More importantly, millions continue to suffer and die as cures are delayed.

Stem cell research is, like cancer research, very important in its own right. Looking ahead, however, both fields require a level of understanding of our cellular biochemistry that will prove essential to later attempts to cure aging. Work done now on cancer and stem cells forms the foundation on which serious anti-aging medicine can be built.

Washington House Endorse Stem Cell Research:

The state would permit stem cell research, including the controversial use of embryonic stem cells, and prohibit human cloning under the measure that passed on a 59-36 vote and now heads to the Senate, where a similar bill is awaiting action.

"We have taken a very important step forward for all the people in this state who are hoping for cures, for all the children with diabetes, for all the parents with Parkinson's and Alzheimer's," said Rep. Shay Schual-Berke, D-Normandy Park, the bill sponsor. "It would be immoral and unethical to not take advantage for the living."

Illinois Referendum More Likely:

Last year, the Illinois Senate narrowly defeated a bill that would have provided public funds for this research.

In response, Comptroller Hynes proposed taking this issue to the voters. He is seeking approval for a binding referendum to be placed on the 2006 general election ballot.

Hynes' referendum would create the Illinois Regenerative Medicine Institute. If approved, the state would issue $1 billion in bonds to pay for stem cell research over the next decade. Bonds would be funded by a 6 percent tax on cosmetic surgery procedures such as facelifts and liposuction.

Harvard Provost Approves Embryonic Research:

In an attempt to find treatments for diseases like juvenile diabetes and Parkinson's disease, University Provost Steven E. Hyman has approved plans for controversial research that would clone human cells to create embryonic stem cells.

The research - which was proposed by co-director of the Harvard Stem Cell Institute (HSCI) and Cabot Professor of the Natural Sciences Douglas A. Melton and Harvard biologist Kevin C. Eggan - was quietly approved by Hyman in January.

The approval was not made public until yesterday, when it was reported by The Boston Globe.

A Roundup of Other States:

At a fever pitch in Missouri and just beginning to simmer in Kansas, the battle about the propriety of stem cell research is being waged in state legislatures throughout the country.

Twenty states are considering proposals that would in some way restrict making cloned cells available for research, according to the Biotechnology Industry Organization.

Who is Allowing Stem Cell Research?:

William Hoffman of the University of Minnesota has compiled a map of the countries with the most flexible and permissive policies on embryonic stem cell research. ... In the US, California is singled out because of its Proposition 71 that provides a state constitutional right to pursue stem cell research. It's important to note that permissive stem cell research policies do not necessarily imply scientific leadership; the US, after all, has more genome sequencing centers than any other nation.

While all of this is going on, the threat of Federal legislation to ban this promising research is still present. Various other groups are attempting to block state funding through CIRM in California. It's certainly not too late to write to your elected representatives and tell them to stop blocking progress towards cures for age-related conditions.

Progress is slowly being made in controlling stem cell differentiation in both embryonic and adult stem cells. This is key to the reliable use of stem cells in regenerative therapies for age-related and other conditions. The Australian reports on recently published work: "Our experiments have shown adult stem cells isolated from the olfactory mucosa have the ability to develop into many different cell types if they are given the right chemical or cellular environment ... New nerve cells, glial cells, liver cells, heart cells, muscle cells -- all were grown in a dish from stem cells from the human nose." A methodology for obtaining and differentiating multipotent, easily extracted adult stem cells would certainly speed up many lines of research.

Link: http://www.theaustralian.news.com.au/common/story_page/0,5744,12616654%5E28737,00.html

One of the most recent grants provided by the Ellison Medical Foundation went to biologist Alexander Varshavsky "to conduct a systematic investigation of the genetics and biochemistry of aging. ... Every cell contains within it a molecular machine to eventually destroy its own proteins, he notes ... Detailed understanding of these protein-destruction pathways will have a profound impact on the practice of medicine, because all kinds of things that go wrong with us, from cancer and infectious diseases, to neurodegenerative syndromes and even normal aging, have a lot to do with either inherent imperfections of the ubiquitin system, or with an overt damage to it in a specific disease ... His aim is to discover the molecular circuits that contribute to normal aging, and also to see whether some of the alterations that he plans to introduce could slow down the aging process."

Link: http://pr.caltech.edu/media/Press_Releases/PR12663.html

As noted by the Press-Telegram, groups opposed to embryonic stem cell research are starting legislative efforts to halt or impede the California Institute for Regenerative Medicine. "Two state senators with opposite views on stem cell research forged an odd political alliance Wednesday when they introduced a proposed constitutional amendment to 'reform' the new $3 billion California Institute for Regenerative Medicine, which is already facing two lawsuits seeking to put it out of business." Here, "reform" means "pull the rug out from underneath." I would find it easier to respect the positions of those who oppose research into curing age-related conditions if they were open and honest about their motivations.

Link: http://www.presstelegram.com/Stories/0,1413,204~21474~2766214,00.html

Discover has an interview with scientist Paul Berg: "There are things that really trigger a strong sense of injustice in me, and frankly, the bills pending in Congress to ban cloning for stem cell research were one ... By its nature, science is an uncertain business, and predicting outcomes and results with certainty is foolhardy. I believe that the availability of embryonic stem cells provides a new and powerful approach to understanding the genetic and cellular basis of disease and for that reason is likely to lead to new knowledge and better treatments for those who are afflicted with those burdens. I'm convinced, however, that we are far less likely to find cures or new therapies without research on stem cells. ... I'm an experimentalist, and the only way I can tell you if it's going to work is to let me try it. But if you're going to prevent me from trying it, we'll never know."

Link: http://www.discover.com/issues/apr-05/departments/discover-dialogue/

I thought I would draw your attention to a pair of long, excellent posts from two other healthy life extension blogs. Firstly, Jay Fox writes on accelerating change and the implications for longevity science:

"The intuitive view is that the pace [of technology] will continue at the current rate," despite the fact that "a serious assessment of the history of technology shows that technological change is exponential."

...

The take-home message here is not that technology is incapable of increasing lifespan beyond the treatment of a few diseases, but that there is a whole frontier of biomedical research which has the capacity to greatly extend lifespan.

Meanwhile, Kevin Perrott points out the "a peculiar new-found reluctance on the part of a few of Aubrey de Grey's colleagues to provide opinion on his theories" over at Health Extension:

There was a time not too long ago when much more vociferous denounciation was available.

Declining to comment because they don't want to endorse his work however is a bit thin I think. Perhaps they just might as well say that they have not read his work enough to formulate an opinion for if they had, surely these highly trained individuals would be able to logically refute his theories based on their vast knowledge?

...

Well, I for one would like to hear a little more commenting and some proper debate. I have been following reasonably closely how the biogerontology community responds to de Grey's theories and have yet to encounter any well thought out and researched position which can justify saying that what he proposes is not possible. Quite the reverse, we are faced everyday with much that indicates that his proposals are likely.

I think that "no comment" is a promising sign - it shows that those scientists most closely connected to aging research are starting to take Aubrey de Grey's work more seriously. In other words, realizing that they cannot just dismiss it out of hand when they cannot muster a proper debate or appropriate level of familiarity with the Strategies for Engineered Negligible Senescence (SENS) proposals. The next step, as SENS gains more support and influence, is for these scientists to become familiar with this work, participate in scientific debate on the details and merits, conduct research, and thereby make progress in the fight to cure aging.

Randall Parker of FuturePundit does his normal good job of following on recent research into fasting and calorie restriction. "Another approach that may eventualy obviate the need for fasting is a class of drugs called calorie restriction mimetics. The idea behind calorie restriction mimetics (which are the subject of active research in a number of labs) is that they'll fool your metabolism into thinking you haven't eaten. Then your cells would throw themselves into the same state they go into when they are not getting as much calories. Appetite suppressants would remain useful for anyone who is overweight. But the benefit of fasting would be delivered by a separate calorie restriction mimetic drug."

Link: http://www.futurepundit.com/archives/002670.html

The signs of the Alcor publicity and outreach drive are spreading, as illustrated by an article at the National Geographic News site. It goes into some detail with regard to the science and practice of cryonics - a big improvement over other mentions in the media in past years - including a discussion of vitrification. "A few years ago, cryobiologists discovered a new preservation process, called vitrification, which virtually eliminates ice-crystal formation. Rather than freezing the tissue, vitrification suspends it in a highly viscous glassy state. In this mode, molecules remain in a disordered state, as in a fluid, rather than forming a crystalline structure." As the article notes, there is still a way to go in terms of growing the industry and improving the technology, however.

Link: http://news.nationalgeographic.com/news/2005/03/0318_050318_cryonics.html

Entropy crops up here and there in debates over the feasibility of developing working anti-aging medicine. For example, see Preston Estep's comments, which sum up the "entropy is bad for the prospects of healthy life extension" position:

In plain English, the loss of order and information essential for biological function. The general concept of biological entropy encompasses several dynamic phenomena ... It is difficult to imagine how the information-rich order that is established during embryogenesis and development can be restored or replicated.

This sort of argument is considered to be an unhelpful, wrong or irrelevant by - so far as I can see - most scientists in the field. Steve Harris put forward a very useful analogy on the Gerontology Research Group e-mail list just the other day:

I mean "entropy" as a law of physics has to do with aging in the same way that "gravity" has to do with the cause of airline crashes. It's a necessary but not sufficient condition. And even more than that, you wouldn't expect the FAA report in any given crash to spend much time discussing gravity, in trying to figure out the factors that are the cause of an airline crash. Similarly, in that sense, I think that discussion of entropy in discussions of aging, is wasting time.

In talking about the "causes" of aging, I presume we mean the differential and explanatory causes of aging. In that sense, invoking "entropy" is no more explanatory than "gravity" as a cause of airline disasters.

In terms of where I stand, I think it's fairly self-evident that if we can learn to repair an aging car, we can learn to repair an aging human. Yes, it's many, many times more difficult - but but both cars and humans are machines composed of many working parts. As such, the best thing we can do (as opposed to say, discussing entropy or gravity) is to accelerate research into understanding and fixing age-related damage to our health.

As noted in a brief Daily Telegraph spot on telomerase, cancer and aging, the 2nd International Conference on Healthy Aging and Longevity is underway in Brisbane. The speaker list looks just as interesting as last year for those of us in the healthy life extension community - many familiar and respected names and topics. Presentations include "The Molecular Basis of Life-Span Becomes Clearer," "Caloric Restriction Mimetics: The Next Phase" and "Drug Therapy Versus Calorie Restriction to Delay Age-Related Disease Onset and Prolong Life." Good stuff, and kudos to the organizers for putting up the necessary funding and effort to develop this successful conference series.

Link: http://dailytelegraph.news.com.au/story.jsp?sectionid=1274&storyid=2829662

As something of a followup to yesterday's post on Leon Kass et al, I though I'd point out an article from Wired on the topic. It gives a little more detail on the latest round of efforts to suppress medical research likely to produce therapies and cures for age-related degenerative conditions - not to mention the related infighting.

On Thursday, Sen. Sam Brownback (R-Kansas) reintroduced a bill to ban human cloning that has failed to pass twice since 2001. The bill would ban both reproductive cloning, which would lead to a baby, and therapeutic cloning of the type researchers believe could lead to treatments for human diseases.

But a new group has entered the debate. Led by Leon Kass, chair of the President's Council on Bioethics, and Eric Cohen, editor in chief of The New Atlantis, a conservative journal on technology and society, the group says Brownback's strategy is flawed.

Brownback's bill "appears unlikely to succeed in the next Congress as well," the group wrote in a document listing its goals. The American Journal of Bioethics blog published text from the document.

Titled "Bioethics for the Second Term: Legislative Recommendations," the group's plan says in part: "Meanwhile, South Koreans successfully cloned human embryos; British HFEA authorizes human cloning-for-research; Harvard scientists get permission to do human cloning-for-research; a right to do such research is constitutionalized in California and endorsed in several other states. We did not get the preferred convention passed at the United Nations. We have lost much ground."

So there you have it - groups still soldiering on in their attempts to ban promising medical research that will lead to longer, healthier lives. These efforts have greatly damaged progress by scaring away vast pools of potential private funding for new medical technologies based on therapeutic cloning and embryonic stem cell research, as well as encouraging the sort of legislative interference and nonsense that has dominated the field over the past few years. I strongly encourage you to contact your elected representatives to make your opinions known on this matter.

Slate writes about the work of biogerontologist Aubrey de Grey and his efforts to invigorate the field of longevity research through the M Prize. Like many recent articles on de Grey it is an odd mix of insulting, respectful, pessimistic and enthusiastic: "OK, so de Grey isn't doing hard science himself. His theories may all prove wrong when tested. And in any case, I'm sure I'll be long gone before anyone cures old age. But who says an enthusiast can't contribute? If someone, someday, gets to live a lot longer than we will because Aubrey de Grey brought more buzz to [aging research], it doesn't matter if he grows his beard to his knees." If fully funded, serious anti-aging research offers the possibility that those of us reading this now will benefit from a "cure for old age."

Link: http://slate.msn.com/id/2115015/

The latest Longevity Meme article is excerpted from Ramez Naam's More Than Human; a compact examination of the likely future of population in the light of advancing healthy life extension technologies. "How will longer lives affect world population? Certainly anything that keeps people alive longer will increase the number alive at any given point. However, the details of population growth can be rather counterintuitive. Consider that today the countries with the longest life expectancies at birth have populations that are remaining steady or even shrinking. ... If the developing world can attain the present level of affluence of the developed world by 2050, we'll see overall world population level out and begin to drop."

Link: https://www.fightaging.org/archives/2005/03/from-more-than-human.php&page=1

SFGate reports that obesity is bad for you: as bad as the average risk of cancer, as studies of life expectancy show. It is important to note that life expectancy is a statistical measure; it is not a prediction of future longevity, and is only useful for these sorts of comparisons of the relative risks of lifestyle and disease. Here, for example, the life expectancy calculations assume increasing rates of obesity but no advances in medical technology - obviously not the case in the real world, but very helpful when trying to tease out the effect of obesity on healthy life span from the data. The weight of scientific evidence strongly suggests that excess fat greatly increases the risk of age-related disease and reduces life span - so take action accordingly.

Link: http://www.sfgate.com/cgi-bin/article.cgi?f=/c/a/2005/03/17/OBESITY.TMP&type=health

Ramez Naam examines the future of population in the light of advancing healthy life extension technologies, a discussion reprinted with permission from his book More Than Human.

Copyright © Ramez Naam.

How will longer lives affect world population? Certainly anything that keeps people alive longer will increase the number alive at any given point. However, the details of population growth can be rather counterintuitive. Consider that today the countries with the longest life expectancies at birth have populations that are remaining steady or even shrinking. For example, the UN Population Division expects the populations of Japan, Italy, Germany, and Spain to all decrease over the next 50 years, despite the fact that Japan has the highest life expectancy of any large country, and the Western European nations are not far behind. At the other extreme, the countries with the fastest growing populations are those with relatively low life expectancies - countries like India, China, Pakistan, and Nigeria.

Throughout most of human history, birth rates and death rates were both extremely high. In the year 1000 AD, birth rates were around 70 births per 1000 people per year, and death rates were about 69.5 deaths per 1000 people per year. So each year a town of 1000 people would on average increase its population by half a person. That's a 0.05 percent rate of growth.

As societies advance, nutrition, sanitation, and medicine all serve to lower the death rate. When births outstrip deaths, population soars, as happened through the twentieth century. But in the last few decades the birth rate has also dropped sharply, particularly in the rich developed nations of the world. As countries gain in wealth and education, and especially as women in those countries gain greater rights, resources are increasingly devoted to education and career, rather than raising a family. This demographic trend is spreading from Europe, Japan, and North America to the rest of the world. Worldwide the birth rate is now 21 births per year per 1,000 people. The death rate is around 10 deaths per year per 1,000 people. So overall the world population is growing at roughly 1 percent, slower than at any time in the last few centuries.

Because the birth rate is double the death rate, phenomena that affect fertility can have a far larger impact than similar size effects on the death rate. For example, between 2000 and 2050, the UN expects around 3.7 billion people on earth to die, while another 6.6 billion are born. Cutting the death rate in half would increase population by around 1.9 billion people. Doubling the birth rate would increase population by a further 6.6 billion. Thus the birth rate is a more significant lever on the size of the population.

Projecting population growth into the future is a tricky thing. It depends on just how quickly economic growth improves healthcare, sanitation, and nutrition. It also depends on how quickly those important birth rates come down. The United Nations Population Division produces high, medium, and low estimates for future population. Birth rates and death rates differ by just a few percent between the scenarios, but over decades it adds up. In 2000, world population stood at 6 billion people. Looking forward, the UN predicts that in 2050, world population will be somewhere between 8 billion and 11 billion, with a "medium" prediction of 8.9 billion.

8.9 billion people is half again as many as are alive today. Yet in real terms it represents a growth rate about half as fast as the last 25 years. World population grew by 50 percent between 1975 and 2000. The next 50 percent increase is predicted to take until sometime after 2050, around twice as long. Ultimately the UN's "medium" model projects world population hitting a plateau of 10 billion people in 2100. Of course, projections 100 years in the future are perilous. They rely on a generally smooth progression of current trends. They don't take into account the possibility of global plagues, world wars, or technologies that radically alter mankind.

Life extension is just one of those technologies, yet its impact on population is surprisingly small. Demographer Jay Olshansky, despite being a pessimist about the prospects for slowing human aging, has shown that extending human life would have an incremental, rather than exponential, effect on population. "The bottom line is that if we achieved immortality today, the growth rate of the population would be less than what we observed during the post World War II baby boom", he says. If everyone were made completely immortal today, he calculates, and taking into account declining birth rates, global population would hit about 13 billion in 2100, rather than the 10 billion currently projected.

The immortality Olshansky is talking about isn't achievable. If we halted all aging, accidents, homicide, suicide, and infectious diseases would still kill people. Nor is complete halting of the aging process in our sights today. More likely, we'll achieve the technology to slow but not halt the rate of aging in the next 10 to 20 years. Then it will take additional years for people around the world to gain access to the technology. Even then, the impact on population won't be instant. Those who are already old won't benefit much from techniques that slow their aging rate. Instead, it will be the middle aged and young who reap most of the benefits. The combination of those factors suggests a gradual impact on worldwide population.

Here's a simple mathematical way to look at this. We can't predict exactly when life extension techniques will first be available or how quickly they'll spread, so we'll need to make some guesses. Imagine that life extension techniques first appear on the market in 2015. In the year after that (2016), let's say the overall death rate around the world drops by 1 percent as a result. And let's say that it decreases by another 1 percent each year thereafter, so that in 2017 age-slowing techniques have reduced the global death rate by 3 percent, and that by 2050 they've reduced it by 35 percent. That's quite an optimistic scenario. It implies that by 2050 we've managed to increase life expectancy in the developed world to around 120, and in the developing world to around 113 - an unprecedented rise in life expectancy, even compared to what's happened in the last two centuries.

If this extremely optimistic rise in life expectancy occurred, how large would the impact on global population be? If we simply reduce the number of deaths the UN forecasts each year by the percentages above (1 percent in 2016 climbing up to 35 percent in 2050), we get a total population in 2050 of 9.4 billion people, instead of the 8.9 billion the UN projects.

Five hundred million additional people are nothing to sneeze at, but as a proportion of the projected world population for 2050, it's less than 6 percent. To put this in context, that's less than the percentage change in world population between 1970 and 1973 - a noticeable change, to be sure, but not a catastrophic one.

It's also worth noting that some demographers believe that birth rates in the developing world will drop faster than the UN's middle scenario. Just a 5 percent lower birth rate yields a scenario where global population tops out at around 8 billion in 2050, and may come back down to below the year 2000 level of 6 billion in 2100. Achieving this is entirely plausible if the right resources are applied. A plateau and eventual reduction in global population depends on the spread of wealth, education, and freedom in the developing world. For example, the UN expects the population of Europe (not counting immigration) to shrink by about 0.4 percent per year between now and 2050. The overall population of the developed world (again not counting immigration) is expected to remain fairly constant. If the developing world can attain the present level of affluence of the developed world by 2050, we'll see overall world population level out and begin to drop.

When debating the views and opinions of Leon Kass, chair of the President's Council of Bioethics, it's rather hard to get past the point at which he says he wants to use government power to ensure medical technology for healthy life extension is never developed or used. While there may or may not be wonderous subtleties and interesting points being made, they're being made in the service of arguing for legislated murder. We can debate differences all we like, but using state power to enforce bans on the use of healthy life extension technologies is a form of murder, condemning millions to slow, painful death by age-related degeneration that they could otherwise have avoided. So you can see that after a man says "I would like to ensure that you die" it is somewhat hard to continue to treat anything he says with dignity and gravitas.

This and other points are made well by Justin at Classical Values in response to a post by Daniel Moore (and another here):

You say he's on the side of life? I say he's on the side of life as he knows it, as he has chosen to define it. And he doesn't think anyone should try to change that definition. Bad Things might happen. I don't believe that. Doubling the human lifespan would not be a Bad Thing. Do you believe that, Daniel? You know that he believes that. What's worse, he wants to Do Something about it. Am I making a bad call here? Honestly? If you think I'm misreading him, it's hard for me to see how. Shorn from context, words can be twisted, but that technique only takes you so far. I think that I am reading him loud and clear.

...

Now tell the truth. If there were a pill that could add ten healthy years to your life, wouldn't you take it? No icky pieces of embryos, no religious proscriptions or anguished moral dilemmas, just a simple magical pill, guaranteed to work. So would you? Would you want your girlfriend to take it too? How about your Dad, or your Mom, or Best Friend or Dog?

Would you ever tell those people that they shouldn't take it? Just how well would that go over, anyway?

And let's say the ten years go by, and it's time to take the pill again. Do you have qualms? He does.

And again, ten years after that, can you picture yourself as saying "Dad, wait! Don't do it! Doctor Kass says you have to wither for us to flourish fully! Mom, please stop and think! I'm worried about the whole human race here!"

Put that way, how ridiculous do these Kassian musings begin to sound? Think concretely. Think simply. We are talking about real people's real lives. Some of them may be people you know. If you are out on your own now, getting an education, making a living, wooing and winning, do your parents really have to wither and die to validate your life?

I am genuinely curious.

My point here is that the personal will trump the theoretical almost every time. Barring the odd fanatic, of course. Got a sick wife? You'll want that pill. Got a failing favorite aunt? You'll want that pill.

Even if you think it's "bad for society", you'll want that pill. Forego the pill and you will still be far, far outnumbered by the shallow, thoughtless people like me who don't care for philosophy. We'll want that pill.

(Though replace "pill" with "medical intervention" for a better reflection of the likely near future reality of working anti-aging medicine). This particular exchange surfaced as a result of Kass' latest initiative - noted in a piece at Tech Central Station - aimed at banning biotechnologies he finds offensive. Most of these relate in some way to medical research that will extend the healthy human life span, at least incidentally, which goes a long way towards explaining Kass' opposition - as Virginia Postrel noted recently:

I've long argued that there are two completely distinct worldviews here: one (the traditional zygotes-are-persons view) that supports the end (longer, healthier lives) but not the means (embryo research) and another (the Kass view) that opposes the end and, only incidentally, the means (embryo research). If there's one thing Leon Kass isn't, it's pro-life.

Jay Fox has put a fair amount of time into thinking about the Methuselah Mouse Prize and whether or not other animals - such as flies, for example - would be a better choice for present day healthy life extension research. In a recent post at Longevity First, he makes the case for mice:

Shrews have perhaps the perfect lifespan for studies, but are not well understood. Mice, on the other hand, live about three years, and the oldest mouse ever recorded lived a week shy of five years. Also, next to humans, they are one of the most thoroughly studied species in the animal kingdom.

Performing an anti-aging treatment that doubles lifespan in mice would only take a decade at most to test, compared to a century in chimps. In middle-aged mice, a treatment could be tested in less than five years, compared to decades in chimps. A study in shrews would be even faster, but the studies would take longer to design and longer to validate, given the poor knowledge base the science community has to work with in shrews.

Thus, when all is said and done, mice really are the best choice for studying aging.

The choice of mice for the Methuselah Mouse Prize was made in full knowledge of the various trade-offs between different species. How well we understand their biochemistry; how long they live; how costly experiments will be; how many laboratories and scientists are equipped to participate; what duration do we expect for the Prize initiative. Note that there is no one correct answer here - even after walking through these points, a case could still be made for good science to be done with flies or zebrafish.

It is hard to argue with success, however. The Methuselah Mouse Prize is doing well at its first intended goal - to attract attention to longevity research and educate the public. The next step, as the prize fund grows, is to get the science done. As we advance down that path, I see a role for smaller, faster prizes focusing on species with shorter life spans that require less costly laboratories.

Unromantic improvements in infrastructural technologies drive the pace of medical research. Medical News Today reports on a very promising step forward for embryonic stem cell research - a way to greatly cut the costs of production. "Researchers at Ohio State University have developed a method for mass-producing embryonic stem cells. That's important because traditional laboratory methods used to grow these cells are costly and don't produce cells fast enough to respond to increasing demands for human embryonic stem cells." More to the point, less money spent on raw materials means more money to work on cures for age-related conditions. "Mass-producing cells like this could reduce stem cell production costs by at least 80 percent."

Link: http://www.medicalnewstoday.com/medicalnews.php?newsid=21315

While debates continue in a number of US states over public initiatives similar to the California Institute for Regenerative Medicine, polling suggests that state funding in New Jersey would pass at at the ballot. "By a wide margin of 61-31 percent, New Jersey registered voters back a statewide bond initiative to raise $250 million for stem cell research ... Overall support for embryonic stem cell research on an unaided basis stood at a strong 68-24 percent. ... Most voters want to see stem cell research get a full opportunity to explore possible cures to such diseases as Parkinson's, Alzheimer's and others." As always, take polls for what they are worth. I have reservations about public funding and legislation, but the level of public support for medical research to cure age-related conditions is encouraging.

Link: http://biz.yahoo.com/prnews/050316/dcw029_2.html

I'm pleased to note that Kevin Perrott - another of the very active Methuselah Foundation volunteers - has expanded his activities to include a healthy life extension focused blog. A recent post on the high cost of aging is worth reading for a set of eye-opening figures - unless we do something about age-related degeneration, you and I will be footing a sizeable part of this bill in the years ahead.

The Alliance for Aging Research has summarized the current costs of looking after the dependent elderly. Note that these costs are for institutionalized adults, not those who are being cared for by their family members and other care-givers. The figures should actually be much higher. ... For a total of 218 Billion Dollars... PER YEAR! and this amount is set to increase by 600% over the next couple of decades. The cost is mind boggling.

You should all head on over to Health Extension and welcome Kevin to the blogosphere.

(From SAGE Crossroads). The idea that there is - somehow - a maximum limit to human life span past which we cannot go, no matter how good our technology, is strangely pervasive given the evidence against it. "'This whole idea that there's a wall came from people spouting stuff off the top of their head,' says evolutionary zoologist Steven Austad ... Biodemographer James Vaupel [argues] that life expectancy has increased linearly - about 3 years per decade - for the past 160 years, and he sees no reason it should stop. ... This argument that we've maxed out - the data don't bear it out ... What's more, none of these estimates takes into account the possibility that researchers will develop treatments that will keep us living longer."

Link: http://www.sagecrossroads.net/Default.aspx?TabID=28&newsType=ArticleView&articleId=106

Medical News Today reports on continuing progress in understanding telomerase: "UCLA biochemists have determined the three-dimensional structure of a major domain of telomerase, the enzyme that helps maintain telomeres - small pieces of DNA on the ends of chromosomes that act as protective caps - allowing DNA ends to be copied completely when cells are replicated. This is the first major piece of telomerase for which the structure is known. Telomerase plays a key role in most cancers, and this work ultimately may lead to targets for drug intervention. ... In the natural aging process, the telomeres eventually get so short that cells can no longer divide, and they die. While telomerase is turned off in most types of healthy cells in our bodies, it is active in the vast majority of cancer cells."

Link: http://www.medicalnewstoday.com/medicalnews.php?newsid=21017

Forbes reports on scientific investigations into adult stem cells in the brain. "The activation of dormant stem cells in the patient's own brain could someday allow doctors to re-grow lost cells without resorting to surgery, and in ways that target exactly those areas of the brain -- and specific types of cells -- damaged by disease. ... While stem cells sourced from embryos or bone marrow have received the most media attention, residual amounts of these regenerative cells exist throughout the body. According to Mehler, about 0.3 percent of brain cells may be dormant stem cells. Just why they so often remain dormant -- even when the brain experiences injury -- remains a mystery."

Link: http://www.forbes.com/lifestyle/health/feeds/hscout/2005/03/14/hscout524474.html

A fascinating article from the New York Times looks back at the past few years of research and progress into repairing heart damage with adult stem cells. "[In April 2001] stem cells from bone marrow, injected into the damaged hearts of mice, had morphed into the special cardiac muscle cells that the body cannot replace after a heart attack. ... But four years later, the treatment has yet to demonstrate whether it will fulfill its promise. ... Ten human trials of the marrow-to-heart approach have been completed in clinics around the world, all but one with positive results. But the overall degree of improvement in the patients' heart function has been modest. At the same time, the original research that provided the rationale for many of the trials has come under severe criticism from scientists."

Link: http://www.nytimes.com/2005/03/14/health/14heart.html?pagewanted=print

I've mentioned the use of stem cells in Russia before; it's an environment that captures the worst aspects of both regulated and unregulated medicine. Matters continue:

While scientists worldwide are only studying stem cells, dozens of Russian clinics and beauty salons claim they are already using both adult and embryonic stem cells to treat everything from wrinkles to Parkinson's disease to impotence.

Scientists warn that while stem cells are still being researched in laboratories, treatment by clinics claiming to use stem cells may cost patients their health and fortunes. Moreover, they say, even though it's illegal, enforcement is lax and no one knows if the injections patients are getting contain stem cells.

More to the point, no-one really knows what potential consequences this sort of "treatment" may cause even if they are using stem cells - increased risk of cancer would be a good guess, however.

As I'm sure you're all aware, I consider cryonics - placing humans and animals into a low-temperature, biologically unchanging state immediately after clinical death, with the expectation that advances in medical technology may eventually enable full restoration to life and health - to be an important insurance policy and ethical necessity for those of us interested in healthy life extension. In an ideal world, advances in biotechnology and nanomedicine would defeat aging and allow rejuvenation in time to save all of us ... but in the real world, there are decades yet to go. Even those of us who are young enough to almost assuredly benefit from the future of real anti-aging medicine might still fall victim to fatal accidents.

The Cryonics Society is an advocacy group that "aims to foster support for the emerging science of cryonics by educating the public, advocating for more research, and by providing objective and unbiased information about cryonics and its benefits to everyone." I'm pleased to see this sort of work taking place, alongside the efforts of Alcor to expand and improve the cryonics industry. The Cryonics Society recently send out this e-mail:

Throughout its history, cryonics has faced a problem that has crippled its hopes and aspirations and that could still put an end to the cryonics movement and the lives of everyone who supports it.

A new organization has been formed that hopes to solve that problem - and your help is needed to make it succeed.

The new organization is the Cryonics Society. Its goal is to end the distorted negative presentation of cryonics that the media sends to the public and to replace it with positive information and positive support.

We don't have to tell you why such an effort is needed. People in cryonics have been saying for years that we need to put a better and more positive message about cryonics before the public. They're right. Cryonics is consistently misrepresented and sensationalized by the media. Government agencies and legislators have treated it with harshness and interference and regulation.

Perhaps even worse is what cryonics has suffered because of the lack of popular support. If cryonics organizations had received a tiny fraction of the donations and grants many charities receive, millions in funds might be available right now for research and development and patient care. Cryonics as we envision it might be a reality today, instead of a dream.

The general public has not rejected cryonics because they're foolish. They've rejected cryonics because they're constantly being given a biased and inaccurate picture of cryonics that invites rejection. Give them a true and accurate and inspiring picture and they'll react as cryonics members have - with acceptance and support.

If cryonics is going to fulfill its promise, if cryonics is going to survive at all, it needs acceptance and support from the general public and the scientific community. To get it, a systematic professionally-run campaign to change public opinion has to be undertaken by an organization whose main focus is to turn this situation around.

The Cryonics Society is that organization.

The Cryonics Society does not perform suspensions or maintain patients. It's here to be a credible voice bringing an optimistic message about the compassionate humane possibilities of cryonics to people that so far may only have been exposed to alienating distortions.

The Cryonics Society was founded and is led by communications professionals who have over fifty years experience between them in the fields of marketing, advertising, direct mail, and public communications. It's a team that has a long successful track record of getting results - and everyone on the leadership team is a cryonics member. Not outsiders, but people who belong to Alcor, the Cryonics Institute, and to other cryonics organizations.

We all know that professionally promoted products and services sell. Professional promotional techniques have even gotten people to buy things that are harmful and destructive, from cigarettes and alcohol to worse.

If the public can be sold on death, it can be sold on life.

But only people with seasoned skills and experience can be expected to promote cryonics effectively. We all have the deepest respect for existing cryonics organizations and the way they've kept cryonics alive since its beginnings. But existing cryonics service providers have to focus their time, staff, and funds on member and patient care. The Cryonics Society could significantly help them in the area of public perceptions.

Should a member of an existing cryonics organization join the Cryonics Society? Yes. Of course. The Cryonics Society's goals are to get every legitimate cryonics organization more members, more research funding, more public support. We're here to help, and helping us will help them.

And such help is needed. Existing organizations have done the best they could, and perhaps the best anyone could do under the circumstances. But the facts are plain. The way cryonics has been presented to the public to date simply has not worked. Forty years of business as usual has not gotten us the results we want. Some of us can't wait another forty years. If we want things to be different, we have to do something new.

The Cryonics Society thinks it's time to take action.

It's already done so. Already the Cryonics Society has sent an outreach letter to over ten thousand individuals. You can read it yourself at http://www.CryonicsSociety.org/outreachletter.html. The letter generated members, requests for information and updates, and donations. But what most encouraged and surprised us was that the Society received not one hostile or critical remark from the public.

We've gotten into the habit of thinking that the public is anti-cryonics. But what we've found out so far is that the public responds positively - to a positive approach. And isn't that great news for us all?

The Cryonics Society plans to send many such future mailings, and hopes to do so on a regular basis.

But mailings and similar outreach efforts have to be paid for. To do that, we need continuing support. We need continuing help in the form of memberships and volunteer support and donations. The Cryonics Society mailing was made possible only because of a generous donation. We need more such contributions if our efforts are to continue. We need the kind of help that only you can give. Because if the people already committed to cryonics won't help, who will?

Is getting an optimistic and supportive message out to the public the only benefit the Cryonics Society has to offer? The Society offers more than that.

In a field that is sometimes marked by divisive arguments and factionalism, the Cryonics Society can offer a haven where all supporters of cryonics can come together in friendship and unity and work toward our common goals.

In a field where there are many legitimate disagreements, the Cryonics Society can provide a neutral and objective voice.

To a world that normally sees cryonics organizations presented as being in conflict with regulators or performing controversial surgical procedures, the Cryonics Society offers a picture of a fresh new organization working purely in support of scientific research and public education and life.

To members, the Cryonics Society already offers a number of special benefits as well, including a free subscription to the Society newsletter, FutureNews. Membership also includes member assistance in obtaining a treatment provider, an emergency hot-line, and more.

And to people interested in cryonics or in becoming Cryonics Society members, we provide news and information and updates at no charge. Would you like to get mailings from CS, or let a friend interested in cryonics know about us? Then go to http://www.CryonicsSociety.org/addressform.html and type in a mailing or email address and stay informed.

How much is Basic membership in the Cryonics Society? Only $20. Yes, you can join online using Visa or other major credit cards. Yes, the Society can take donations online too -- and every dollar you contribute now towards the CS outreach program will send a positive message about cryonics to at least three people who may never have heard a single good or true thing about it.

Help them find out. Help your own chances for survival, and all our chances. Learn more about what we're trying to accomplish, and why it could have a direct impact on your own hopes and chances for survival. Visit our web site. Subscribe to FutureNews at http://www.CryonicsSociety.org/futurenews/index.php, and hear about what we're doing. Join us.

We believe that getting wider public support is the most important issue facing cryonics today. Until we present a better picture to the public, cryonics will remain under-funded, under-staffed, and facing the threat of being shut down. We can turn this around. But we can't do it without you.

So become a member. Contribute. Tell your friends. Help us make a
difference.

The future of cryonics depends on you.

David Pascal
Public Relations Director
The Cryonics Society
http://www.CryonicsSociety.org

P.S. Next month the Cryonics Society will be putting a fresh new series of public outreach letters in the mail. How many people will be reading those letters? It depends on you. Your membership and your contribution will directly enable us to send out a greater number of positive messages about cryonics to more and more people. So if you want to see cryonics get the respect and support it deserves, contribute now, as generously as you can.

You can contribute online at http://www.CryonicsSociety.org/helping.html.

You can join online at http://www.CryonicsSociety.org/joining.html.

What you do now can make a difference. Start by joining the Cryonics Society today.

A great article from the Times examines the concept of escape velocity in healthy life extension and aging research: "Sally's life prospects are optimum for a human child in 2005. According to current projections, she can expect to live well into her eighties. But it's not going to be like that, because Sally is not going to die until 3194." As the author - and Aubrey de Grey - point out, plausible, working anti-aging medicine will bring great changes. "Almost any of the traditional answers would be dismissed as deluded mythologies - attempts 'to rationalise this tragedy as a good thing' - constructed in the face of what we took to be the inevitability of death. If death is not inevitable, all such mythologies becomes meaningless."

Link: http://www.timesonline.co.uk/printFriendly/0,,1-525-1522606-525,00.html

(From Betterhumans). A number of publications note recent work from Advanced Cell Technology - a company that deserves another round of venture funding if ever there was one - that removes a major obstacle for the use of embryonic stem cell based therapies in humans. "The researchers report deriving a new embryonic stem cell line from human embryos under conditions free of animal cells and serum. They say that even after six months of unspecialized growth the cells retained their potential to become a range of tissues. The technique is considered important for the therapeutic use of stem cells because it's thought that most available stem cell lines are contaminated with animal material."

Link: http://www.betterhumans.com/News/news.aspx?articleID=2005-03-09-5

From Newsday.com, an update on research into genes associated with longevity: "Having any one of these genes can confer a longer and healthier life. ... He studied 300 Ashkenazi Jews between 95 and 108 years old and their children, many of whom themselves have lived beyond the average life span - 77.6 years. Thirty percent of these families had any one of these three genes, compared with 5 percent of people without a history of longevity." You may recall that two of these genes relate to cholesterol and lipoprotein regulation; the last is involved in inflammation and insulin regulation. These mechanisms appear to be important determinants for the rate at which cellular damage accumulates in the body or the risk of suffering common age-related degenerative conditions.

Link: http://www.newsday.com/news/health/ny-hsold124173451mar12,0,1226662.story

Tech Central Station profiles Michael Milken's FasterCures initiative: "Going forward, it's worth keeping an eye on FasterCures to see whether researchers are using these findings to spur a wave of innovation in industries currently hampered by a lack of funding, gaps in public awareness or government over-regulation. The pace of innovation does not have to be dependent on federal government dollars flowing to centralized research institutions. As the example of FasterCures shows, thinking about problems in new ways and then tapping into resources at the 'edge' of an industry can often lead to innovation that is faster, cheaper and more relevant." Socialization, centralization and over-regulation of medicine is a very serious problem with very serious consequences for those affected by it - it must be fought.

Link: http://www.techcentralstation.com/031105E.html

You can find this comment beneath the recent Slashdot post on the M Prize $1,000,000 goal:

...You need an analogy to make it all clear.

I will play for you the most wondrous song that you have ever heard. It will be a song to stir the soul, and make the angels weep in joy for the beauty of it all.

But, here's the catch. I will now renege on my promise and play you only a small part. A fraction of a part. A fraction of that fraction.

This fraction has been rendered so short, that all beauty has been stolen. There is no context, there is no continuance. You will never be able to appreciate the song at all from this snippet, but only get a sense of what majesty you had the possibility to experience.

Tell me: out of the million million fractional slices of this wondrous song of the Ages - which should I play you?

Oh, wait. You don't know; you can't know. And there is almost no point in experiencing it, if that is all you will get.

Life's something like that :)

Alternatively, people may just be happy to spend a rainy Sunday afternoon doing nothing, and would appreciate the opportunity to have a million more of those rainy Sundays to spend in exactly the same way :)

I've spoken about boredom and healthy life extension before, but I think the above comment hits all the right notes. Life is a wonderful thing when you have your health - more of it can only be good.

Philanthropist Paul F. Glenn - a donor to the M Prize for anti-aging research - has launched a new institute at Harvard to "accelerate the pace of research into the molecular mechanisms that govern aging." The lab will be directed by David Sinclair, the Sirtris cofounder known for work on calorie restriction mimetics. "A significant portion of the resources will be used to recruit two additional faculty members focused on aging research and to build out the labs with advanced research technology and animal models. Additionally, research pilot grants will be awarded by a steering committee to investigators wanting to investigate novel areas of molecular research addressing critical questions in the normal aging process. These pilot grants will produce data that can be used to attract larger government grants." Good news indeed!

Link: http://www.hms.harvard.edu/news/releases/3_11glenn.html

A number of different research groups have been making inroads into fixing age-related degenerative blindness in recent years. Betterhumans reports on the latest: "A variation in a single gene may cause half of all cases of age-related macular degeneration (AMD), the leading cause of blindness in the elderly. ... Once we determine which genes are responsible for macular degeneration, we can screen the population and manipulate biological pathways to develop treatments." Moving from identification of a gene to understanding how that gene causes a degenerative condition can now be accomplished very rapidly - expect to hear more from this research group before the end of the year.

Link: http://www.betterhumans.com/News/news.aspx?articleID=2005-03-10-4

A little science from PubMed for your entertainment today; signs that the investigation of calorie restriction mimetics and metabolism is proceeding apace.

[Sir2 or sirtuins are] important for many cellular processes including gene silencing, regulation of p53, fatty acid metabolism, cell cycle regulation, and lifespan extension. Resveratrol, a polyphenol found in wines and thought to harbor major health benefits, was reported to be an activator of Sir2 enzymes in vivo and in vitro. In addition, resveratrol was shown to increase lifespan in three model organisms through a Sir2-dependent pathway. Here, we investigated the molecular basis for Sir2 activation by resveratrol.

At this rate - coupled with venture investment in this field of research - we should expect to see interesting results in few years. A treatment to replicate the beneficial effects of calorie restriction on health and life span does not seem far fetched at the moment.

RedNova is running a column by Janet Street-Porter on Aubrey de Grey and the M Prize for anti-aging research - it's a good demonstration that most folks do actually want to live longer, healthier lives. "De Grey studied computer science, and works as a researcher in the Department of Genetics at Cambridge University. As an engineer, he believes that eventually technology will be created which will be able to repair cell damage and so, not only will we halt ageing, we will be able to revert to youth. Hoorah! ... In the interests of democracy and a longer life for all, I'm pledging my [10 pounds sterling] to the Methuselah Mouse prize now - it's a lot more fun than the Lottery, and if I can make it to 82 reasonably intact, I'll be only too happy to learn new skills, be a thoroughly adaptable member of the workforce and pay tax till I'm 149!"

Link: http://www.rednova.com/news/display/?id=131454

ABC News reports on projected timelines for regenerative dental therapies: "Presentations at a dental meeting demonstrate that techniques using stem cells and gene therapy to regenerate teeth are producing promising results, suggesting this technique may not be far off. ... Clearly, techniques that involve adding new tissue to already-existing teeth are 'probably a bit closer on the horizon,' perhaps within a 'handful of years,' Smith predicted. Techniques that grow teeth from scratch will likely take at least another 10 years to perfect." Similar promising beginnings and projected timelines for regenerative medicine can be seen for many other organs and body parts, from hair to heart. Let the research roll on!

Link: http://abcnews.go.com/Health/wireStory?id=565671

Virginia Postrel hits the nail on the head with her assessment of Leon Kass, an unfortunately influential fellow who is strongly opposed to healthy life extension in any form.

I've long argued that there are two completely distinct worldviews here: one (the traditional zygotes-are-persons view) that supports the end (longer, healthier lives) but not the means (embryo research) and another (the Kass view) that opposes the end and, only incidentally, the means (embryo research). If there's one thing Leon Kass isn't, it's pro-life.

Kass has declared himself willing to use government power to limit life spans - a fairly threatening stance for the head of the President's Council on Bioethics whatever one may think about the likelihood of such a state of affairs coming to pass. From where I stand, based on even a cursory examination of 20th century history, it's never too early to take a stand against the terrible excesses of government.

A useful analogy appears in the SF Examiner: "Opposition to stem cell research is reminiscent of another wrongly waged battle against gene splicing almost 30 years ago ... 'They were wrong,' said Robert N. Klein, chairman of the Independent Citizens Oversight Committee of the California Institute of Regenerative Medicine. ... In the mid-1970s, critics fought the development of recombinant DNA - gene splicing, where segments of genetic material from one organism are transferred to another. Critics said gene splicing was wild, uncontrolled science that would take decades to return benefits, Klein said. But by 1978, the first artificial human insulin was developed at UCSF. Now there are heart and cancer treatments. 'It was a great lesson to all of us. We have a legacy, a duty to move the frontier forward.'"

Link: http://www.sfexaminer.com/articles/2005/03/08/news/20050308_ne05_debate.txt

Good news for research into biochemical mechanisms at the junction of calorie restriction, metabolism and aging: Sirtris Pharmaceuticals has closed its series B funding round at a healthy $27M. Venture capitalists are a conservative breed, so this indicates that at least one field of healthy life extension research is hot right now; for every million dollars that we hear about, there is much more that we don't. Sirtris is named for sirtuins, enzymes currently considered to be "universal regulators of aging in virtually all living organisms [that] represent a prime target for new anti-aging drugs. ... Now the race is on, Sinclair said, to find the most potent sirtuin stimulators -- or create synthetic ones -- and test their ability to extend the lives not only of cells, flies and worms but also of mice, monkeys and humans."

Link: http://www.sirtrispharma.com/press/press.3.7.05.html

You might recall the recent work by Thomas Rando on selective rejuvenation of mouse tissue: old cells exposed to a younger environment (blood from a genetically identical younger mouse in this case) regain some of their youthful characteristics, such as response to injury. Lou Pagnucco pointed me to an article I'd missed from last month that goes into more detail:

Old cells may regain a youthful phenotype when exposed to a young cell environment ... The results, say the authors, indicate that aged satellite cells have an intrinsic ability to regenerate.

...

What Rando and colleagues found "argues against the idea that diminishing regenerative potency with age is a reflection of exhaustion of the stem cell population, and this gives great hope for restoring regenerative efficiency in aging individuals, since it is in principle easier to manipulate a systemic signaling system than to restore stem cells to diffuse tissues"

This is very good news when looked at in this light, and certainly merits much more investigation.

As you may have noticed, Aubrey de Grey and Dave Gobel's M Prize for anti-aging research has topped $1,000,000 in pledges. The first of many more millions, we all hope! Jay Fox has a write-up and comments over at Longevity First:

The Million Dollar barrier has an almost magical quality. Half a million, two million, five million, these are all just allusions to the Million Dollar mark, the barrier that really matters in people's minds.

Breaking that barrier was once again done in an exciting fashion. Many of the donors who have pledged $25,000 to the M Prize, present author included, are just ordinary people with ordinary incomes. Some are students, still in college, with all sorts of bills to pay, but they still see this cause as worth the sacrifice of $85 a month.

But the Million Dollar barrier wasn't broken by one of us, it was broken by the "Father of Regenerative Medicine", "Dr. William Haseltine, biotech pioneer of Human Genome Sciences fame".

...

So what's all the excitement about, anyway? Okay, so it's fascinating how the prize is growing, and the big names that it has attracted. The M Prize is an effort to raise awareness about anti-aging research. Research prizes have a long and successful history of inspiring breakthroughs in science and engineering. The M Prize seeks to build on that history, by offering a financial and fame incentive to scientists to try to engineer extremely long-lived mice.

Mice are mammals, and genetically speaking, there are much more similar to humans than you might suspect by looking at them. Mice have been used as models for studying almost every major disease, from diabetes to heart disease to stroke to Alzheimer's to cancer. They age much like humans, and thus they offer a nearly ideal model for studying aging. They only live about three years, so it shouldn't take longer than five years to know if a therapy is highly successful. In humans, true trials of anti-aging therapies would take several decades at the least.

The million dollar mark coupled with William Haseltine coming aboard as a member of The Three Hundred is definitely a high note - but we must not forget those everyday folk like you and I who joined forces to make this ongoing success possible. The M Prize has already done a great deal to raise awareness of the near future possibilities of healthy life extension, as well as the need for more research dollars for directed, serious anti-aging research. I hope to see much more of that in the future as the prize fund continues to grow.

Have your say! Put in a few dollars to tell scientists and funding organizations that you want to see radical human life extension in your life time.

The M Prize for anti-aging research has reached the $1,000,000 mark in pledges, with William Haseltine, founder of Human Genome Sciences, taking it over the line. "I am delighted that my decision to join the Three Hundred has pushed the prize fund over its first one million dollars, which I trust is only the first of many millions. There's nothing to compare with this effort, and it has already contributed significantly to the awareness that regenerative medicine is a near term reality, not an IF. ... Encouraging researchers to compete for the most dramatic advances in the science of slowing, even reversing aging, is a revolutionary new model that is making its mark." Congratulations to all involved, and many thanks to the numerous other donors and sponsors!

Link: http://www.marketwire.com/mw/release_html_b1?release_id=82349

Chronic inflammation of tissue is linked to many age-related conditions; Reliability Theory suggests that the cellular damage caused by inflammation plays a large role in decreasing healthy life span. This Nature article discusses the first steps taken to uncover the biochemistry of fish oil (or rather the omega-3 fatty acids it contains) and how it suppresses inflammation. "[Charles Serhan's] group is also looking at the other lipids that derive from fish oil. He suspects that each one has a part to play in orchestrating the inflammatory response. Understanding how they work could lead to the development of a range of new drugs to counteract inflammation, he predicts."

Link: http://www.nature.com/news/2005/050307/full/050307-8.html

The NIH reports that "Using specially modified segments of DNA, NCI researchers Paola Scaffidi, PhD, and Tom Misteli, PhD, reversed the abnormalities seen in [Hutchinson-Gilford Progeria Syndrome] HGPS cells by correcting defects associated with the key protein, lamin A. By demonstrating that HGPS cellular characteristics are reversible, this [study] brings scientists one step closer to understanding this devastating childhood disease and might provide insights into the normal aging process." Research into Progeria and other accelerated aging syndromes is shedding light on the processes of normal aging, but this latest work - while certainly good news for Progeria sufferers - does not have any direct impact on healthy life extension research. Yet.

Link: http://www.nih.gov/news/pr/mar2005/nci-06.htm

Two articles of interest showed up today, both relating to the use of stem cells (embryonic and adult) in the repair of damage caused by heart disease.

Stem Cells Regenerate Damaged Heart

Researcher and graduate student Atta Behfar from the Mayo Clinic in Rochester, Minn., explained embryonic stem cells are an emerging source for treatment of diseased hearts. However, implanting stem cells into the heart has been thought to carry risks for uncontrolled growth of the stem cells on host tissue in the heart muscle.

...

Integration of stem cells into the middle muscle of the heart was associated with normalized structure, replenished interior wall, little scarring, and fewer signs of the death of heart tissue. In contrast, placebo-treated infarcted hearts did not show these benefits and showed a decline in the function and health of the heart.

Behfar concludes that embryonic stem cells can contribute to a stable beneficial outcome on the function and remodeling of the heart after a heart attack. To avoid production of tumors from over-proliferation of the stem cells, he says the number of stem cells delivered needs to be limited.

Is the UK losing its way with stem cells?

Various small studies have suggested stem cells taken from a patient's bone marrow and injected into the heart can repair the damage from heart disease.

...

Doctors at Barts and The London NHS Trust are setting up a four-year research programme involving 600 patients but, like many experts involved in stem cell research in the UK, they are struggling to raise the money.

Dr Anthony Mathur, a consultant cardiologist at the trust, said: "This is a potentially revolutionary treatment for heart disease. It could transform the lives of people living with this debilitating condition. ... But the problem we face is raising the money. Charities find it quite hard to commit large sums of money to one project."

And he added industry was not that interested in funding research such as his as using the body's own cells in the way the trust is doing makes it hard to get a patent.

Medical News Today discusses new findings in the relationship between insulin mechanisms, diabetes and Alzheimer's disease: "What we found is that insulin is not just produced in the pancreas, but also in the brain. And we discovered that insulin and its growth factors, which are necessary for the survival of brain cells, contribute to the progression of Alzheimer's. This raises the possibility of a Type 3 diabetes. ... It has previously been known that insulin resistance, a characteristic of diabetes, is tied to neurodegeneration. While scientists have suspected a link between diabetes and Alzheimer's disease, this is the first study to provide evidence of that connection."

Link: http://www.medicalnewstoday.com/medicalnews.php?newsid=20838

It occurred to me - as I was putting up the latest run of ads - that I had not mentioned the new site design over at SAGE Crossroads. Unfortunately, old links to content won't pass through to the same content in the new site, but other than that it's a good upgrade. The SAGE expert trading cards are a cute touch; they're taking suggestions for more names and faces, so feel free to suggest your favorite scientists.

The new SAGE Crossroads banner ads here and at the Longevity Meme are, as always, bringing in more funding for the M Prize for anti-aging research. Have you donated?

The Boston Herald looks at the work of the new Harvard Stem Cell Institute - including therapeutic cloning: "At Daley's lab, a satellite in Harvard's 'virtual institute,' researchers have been able to take skin cells from mice afflicted with a genetic disease, transplant the nucleus from the cell into a mouse egg that has had it's chromosomes removed, grow an embryo and derive stem cells. Researcher have then performed repairs on the stem cells to fix the genetic malfunction and injected the repaired cells back in the mouse. The result: a much healthier mouse. 'We're not only interested in curing mice, we're interested in curing people with diseases. We want to use the same procedure we're using in mice on people, but we need approval to do that.'"

Link: http://business.bostonherald.com/businessNews/view.bg?articleid=71762

(From the Seattle Times). The development of sophisticated protheses and artifical replacements for failing organs continues to be overshadowed by advances in regenerative medicine and tissue engineering, but the science is moving forward. "The properties of artificial muscle are getting much closer to that of biological muscle ... At the University of California, Irvine, biomedical engineer William Tang and one of his students have launched a project to develop a prosthetic hand with artificial muscles. ... Implants also are in the works. Mohsen Shahinpoor, director of the Artificial Muscle Research Institute at the University of New Mexico, has designed an eye implant to correct bad vision."

Link: http://seattletimes.nwsource.com/html/nationworld/2002198502_muscles06.html

Lifeline Neutraceuticals will be launching their Protandim brand pills fairly soon. This seems to be an appropriate time to remind those interested in supplements that these pills are not the same as the protandim (or CMX-1152) compound tested by Ceremedix and widely discussed in the healthy life extension community.

CereMedix's peptide technology for decreasing age-related deterioration, resulting from accelerating and cumulative oxidative damage has the potential to be of major benefit in this regard. One potential candidate for the healthy life expectancy has already been identified, CMX-1152. This is an orally available, naturally occurring peptide, which has demonstrated improved longevity in mice.

As I noted previously, the Lifeline product doesn't appear to be at all related to CMX-1152.

UPDATE (June 03 2005): In light of all the recent interest, visitors might find it helpful to read my latest post on the topic of Lifeline and Protandim.

An article in SFGate provides a good sense of the cut and thrust behind the scenes of biotechnology commerce; how regional government, development organizations and corporations interact. "A second biotechnology firm is moving to San Francisco's Mission Bay area ... The Sirna move was lauded by city business leaders who want San Francisco -- with Mission Bay as the centerpiece -- to become a major player in the growing biotech industry ... San Francisco is also hoping to capitalize on the requirement that all $3 billion in grants from [CIRM's] 10-year stem cell research funding program must go to companies or institutions located in California." Even limited competition is good - it's the alchemy by which greed and self-interest are transformed into technological progress.

Link: http://www.sfgate.com/cgi-bin/article.cgi?f=/c/a/2005/03/05/BUGMTBKQNM1.DTL

Ascribe has a more science-focused article on recent work that examines the biochemistry of fasting. "Critical organs rely on sugar -- specifically glucose -- for the energy to function. In people with diabetes, however, the liver doesn't sense the incoming calories, and it keeps making glucose when it shouldn't ... in fasting mice, the liver's production of sugar kicked into high gear because amounts and activities of the two proteins, called sirtuin1 and PGC1-alpha, increased when dietary calories weren't available. Once mice were fed, levels of the two proteins went down and sugar production ceased." This relates to work on the mechanisms of calorie restriction (CR), although the jury is still out on whether alternate methodologies of CR - such as intermittent fasting - are as effective in extending healthy life span.

Link: http://newswire.ascribe.org/cgi-bin/behold.pl?ascribeid=20050225.063123

(From the Boston Globe). As noted at Fight Aging!, the battle over embryonic stem cell research legislation in Massachusetts is accumulating a fair amount of spilled ink. "[A bill] will pass both houses of the Legislature by the end of March, Democratic leaders predicted yesterday, but they remained unsure whether they can override an anticipated veto by Governor Mitt Romney, a Republican. ... The bill the House and Senate are expected to pass does not include state money for stem cell research. Though stem cell research is taking place in Massachusetts, Travaglini and business leaders want to pass a law expressly permitting such work ... The lawmakers and business leaders say they want to encourage the growth of the industry here and continue to compete with California."

Link: http://www.masslive.com/metrowest/republican/index.ssf?/base/news-8/110983989621790.xml

While reading articles about Maria Olivia da Silva in Brazil, a lady who has allegedly hit the grand old age of 125, it is worth recalling remarks from a recent profile of the Gerontology Research Group:

GRG's 40 volunteers - a loose, international network of demographers, gerontologists, epidemiologists and self-styled "hobbyists" - are dedicated to verifying the ages of the world's oldest people, and to learning the secrets of their longevity. But to do so, they must contend with dishonest schemers, governments that gleefully support false claims and what researchers call "the invisible barrier of 115."

Because almost no one who reaches age 114 ever sees 115, the group is skeptical of any claims to ages higher than that. GRG investigators dismiss a man now being celebrated in Cuba who says he is 124 but who has no documents. A woman in the Caribbean island nation of Dominica supposedly was 128 when she died in 2003. Her ripe old age was "a falsehood perpetrated by the tourism industry there," says GRG co-founder L. Stephen Coles, a physician and stem-cell researcher at UCLA's David Geffen School of Medicine, where GRG is based. GRG counts just 12 undisputed cases of people ever reaching 115.

...

The oldest human ever certified was a French woman who died at age 122 in 1997.

The Kansas City Star reports on the legalization of embryonic stem cell research in Brazil: "As Brazilians in wheelchairs cheered, legislators voted to legalize stem cell research using human embryos - offering hope of one day finding treatments for ailments such as diabetes, Parkinson's disease and spinal cord injuries. ... The bill now goes to President Luiz Inacio Lula da Silva, who is expected to sign it into law." You may recall that adult stem cell therapies for heart disease were trialed in Brazil while the FDA blocked any such work in the US. The Brazilian research community is hard at work on other stem cell projects, so I expect to see more from them in the years ahead.

Link: http://www.kansascity.com/mld/kansascity/news/local/11043385.htm

April Smith, fundraiser for the Methuselah Foundation, recently posted an analysis of the attitudes and backgrounds of early donors to the M Prize for anti-aging research.

When I first began the process of surveying our donors, one of my blog readers asked, "Are they mostly wealthy people who want to live forever?" I said I'd get back to you after doing more survey calls, but that so far, it seemed that M Prize donors were on average middle class people who are unusually engaged with the world around them and want to enjoy living in good health for as long as possible.

...

Several are somewhere in the software industry. I solicited guesses as to why that is. Some absolutely brilliant responses came back. For instance: "One thing which may attract computer geeks is the similarity of the genetic code to program code. Hacking the human genome seems to be attractive to many of these individuals."

...

Another large group of donors is entrepreneurs. The M Prize seems to attract successful business people. Their fields are very diverse, but several of them have taken tremendous risks, both personally and financially, to try something that had not been done before. Donors like this tend to answer, "Why did you decided to support the M Prize?" with phrases like, "most cost effective way to motivate research" or "successful business model."

...

Overall, my calls were extremely positive. I've done a lot of "cold calling" in my life time, and I was amazed at how friendly, positive, and willing to help M Prize donors were. Even donors with no connection whatsoever to any kind of community around extending healthy lifespans were willing to talk with me at length about their perspectives on the prize, life, health, and how supporting the M Prize fits into their life philosophy.

Mary, another calorie restriction blogger, posted some related thoughts on the desire to live a longer life:

I think of a new project I would like to work on every week. I have lists and lists. I could keep an army of graduate students busy working on all my ideas. I could live a 1000 years and still entertain myself easily. Today, my son and I discussed one of these many ideas. I would like to take some classes in science education and then work with my husband in putting together a curriculum in science and engineering related critical thinking skills. Teach kids how to analyze and make decisions. I use all these techniques all the time in my job - there are lots of methods that are basic enough that even 8th graders could learn them. It would improve the world. But then, this is just idea number 1,231 (I am joking - I do not actually keep a list or number them). This is why I never managed to get a PhD. It takes too much energy concentrated on a single thing. I couldn't do it.

So, I would like to live longer so I can do at least some of these projects. And I would like time to learn all the many things I don't know that interest me. I just don't understand why anyone wouldn't want to live longer. But then, few people are as curious as I am, or as obsessively analytical, or as restless mentally.

I can identify with this attitude - I can't see myself running out of major projects I would like to accomplish any time soon. There's a few lifetimes of work sitting on the backburner, and I think most motivated folk are just the same. Ben Best captures this well in his article "Why Life Extension?", or as he asks next, "why live at all?" All the good reasons for living at all are reasons to live a longer, healthier life.

What would I do with a thousand-year lifespan? I'd probably spend some of it trying to find a way to live longer. But I would not otherwise lack for things to do. It would take me at least 200 years to read my way through my book collection. I would like to gain mastery of mathematics, physics and chemistry. I would like to learn and practice medicine. I want to understand jurisprudence and practice law. I would like to master carpentry, plumbing and electrical skills -- and build houses. I would like to master industrial design & fabrication, computers and biotechnology so as to start & operate productive businesses. I want to build financial empires. I want to learn to play musical instruments and explore the many worlds of music. I want to join and organize communities for social experimentation. I want to write great books. I want to do experimental scientific research. I want to explore the planet Earth with a deep enough knowledge of flora & fauna & geology that I can appreciate what I am seeing, hearing, smelling and touching. I want to learn foreign languages, live & work in many different countries and gain a direct sense of the lives, histories & cultures of others. And I want to explore to the fullest my own loves, hates, fears and joys. I want to fathom love, my capacities for love and the limitless mystery of love & sexuality.

But telling people what I would do with my extended life will not satisfy those who don't know what to do with themselves. Enthusiasm for living is the driving force behind the desire to live. To someone who equates extended life with extended boredom, a list of possible activities will only seem like a list of chores.

I don't expect the world to stand still. Many exciting changes are possible in a world of accelerating technological development. Benjamin Franklin wrote that he dearly wished he could be chemically preserved so that he could see the future. But I am not a person enduring a "veil of tears" in my present life only on the basis of hope for some future technological paradise. I am enthusiastic about life right now. The present world is such a rich treasure-store of marvelous opportunities that my most abiding interest in the possibilities of the future is the possibility of extending life.

Forbes is carrying the best of recent articles on advances in the understanding of the biochemistry of metabolism, aging and calorie restriction. "If caloric restriction has such a huge benefit, couldn't we get it in an easier-to-swallow package? Such as, say, a pill? New research appearing in the journal Nature could be a big step in that direction. It shows how starvation triggers a particular gene that has already been linked by years of research to the processes of aging." There are uncertainties and much more research to go: "The genetic domino effect that his team uncovered may have less to do with extending life, he says, then with making it possible to survive caloric restriction at all. The life-extending results of caloric restriction could still be caused by something else."

Link: http://www.forbes.com/sciencesandmedicine/2005/03/03/cx_mh_0303aging.html

Forbes reports that researchers have identified a second gene associated with age-related Alzheimer's disease - this is good news. "Even though truly effective treatments for Alzheimer's remain elusive, identifying genetic factors in the disease should prove crucially important in the not-so-distant future, in both the diagnosis and treatment of the illness. ... It's really a two-pronged attack: First, we find all the genes involved to help identify those at risk, and then, from the other side, we learn from the genes what's going wrong." Modern medical research moves very fast once genes are identified; it usually takes less than a year to understand the biochemistry behind the association.

Link: http://www.forbes.com/lifestyle/health/feeds/hscout/2005/03/02/hscout524291.html

The Life Extension Foundation News notes that "The Hong Kong University of Science and Technology received 175 million HK dollars [about US$22.5 million] donation Wednesday from the Hong Kong Jockey to develop drugs against age- related diseases. The university will apply part of a major donation and partner with the San Francisco-based Geron Corporation to establish a biotechnology company, TA Therapeutics Limited, in Hong Kong. The new company will conduct researches, predominantly in Hong Kong, and develop telomerase activator drugs that restore the regenerative and functional capacity of cells to help fight against age-related and neurodegenerative diseases." More research into understanding and manipulating telomeres is a good thing.

Link: http://www.lef.org/news/LefDailyNews.htm?NewsID=1903&Section=AGING

The Poughkeepsie Journal reports on an initiative in New York state to fund a research institute after the California model. "A Republican senator announced Tuesday he'd introduce a bill to invest $1 billion worth of state dollars in stem cell research as a way to help New York compete with other states for biotech research. ... 'We can't afford to fall behind other states,' he said, rattling off California, New Jersey and Connecticut as states that have committed public money to lure research companies and scientists." It's hard to say at this stage whether all this public funding and legislation will end up producing a net gain in the rate of healthy life extension research, or whether state interest will simply speed the ongoing socialization of medicine and research in the US.

Link: http://www.poughkeepsiejournal.com/today/localnews/stories/lo030205s9.shtml

This will chiefly be of interest to those of you with a subscription to the journal of the European Molecular Biology Organization or $20 to spend on per-article access; Aubrey de Grey has a sharp, to the point article in the latest issue entitled "Curing Aging and the Consequences." (That's doi:10.1038/sj.embor.7400354 for those who use that methodology). Some teasers:

There is a consensus within society that ageing is not a disease and therefore not an appropriate target for the biomedical approach. That's the problem.

...

The idea that one engenders unwarranted optimism by talking about serious life extension is disgraceful. We now have comprehensive and reasonable ideas for how to cure ageing. That turns the irresponsibility the other way around. It means one is irresponsible to remain silent, because that simply perpetuates the pessimism in the public. That in turn means that research doesn't get funded and lives are lost. I'm very strongly of the view that it's irresponsible to remain silent now.

...

I think it's important to be realistic about it. For each problem one has to think about the options. For example, pensions. The fact that we've got laws at the moment that say everyone gets a pension over 65 doesn't mean we can't change the law. Pensions exist for frail people, and there won't be any frail people. Retirement will still exist but it will be a periodic voluntary thing.

(From ScienceDaily). By applying new techniques to control embryonic stem (ES) cell differentiation, researchers have succeeded in reversing hemophilia - a genetic defect of the liver - in mice. "In the study, ES cells were treated with fibroblast growth factor for seven days prior to injection. As expected, this resulted in ES cells differentiating into early endoderm like precursors, which the researchers named 'putative endoderm precursors,' or PEPs. Endoderm refers to the inner layer of early embryonic cells that develops into the digestive and respiratory systems. Not only do ES cells differentiate into PEPs, they also engraft, persist, differentiate further and then function following injection ... the PEP cells robustly engraft within the liver and were not recognized by the immune system as foreign."

Link: http://www.sciencedaily.com/releases/2005/02/050222194021.htm

You can listen and participate in a discussion about anti-aging research at PBS; the focus is on calorie restriction and the groups seeking to develop healthy life extension medicine based on the underlying genetics and biochemistry that cause calorie restriction to provide health benefits and extend life span. This field of dedicated longevity medicine is currently the most well known and well funded - but it may not be the best path forward towards radically extended healthy life spans. Regardless, there is no such thing as useless knowledge in biology, and researchers are uncovering important information about the way in which metabolism and aging interact at the most fundamental level.

Link: http://www.pbs.org/newshour/science/aging/index.html

Here are some life expectancy and mortality statistics; a comparison between figures for 2002 and 2003 show the rate of increase is continuing much as expected.

Life expectancy for Americans reached an all-time high of 77.6 years in 2003, and the gap between men and women narrowed, according to preliminary results from state death certificates released Monday. According to the report from the National Center for Health Statistics, life expectancy was up from 77.3 years in 2002.

...

With aging taken into account, death rates declined for eight of the 15 leading causes of death, including the two leading causes -- heart disease (down 3.6 percent) and cancer (down 2.2 percent). Declines were also noted for stroke deaths (4.6 percent), suicide (3.7 percent), flu-pneumonia (3.1 percent), chronic liver disease and cirrhosis (2.1 percent), and accidents/unintentional injuries (2.2 percent). Mortality increased by 5.9 percent for Alzheimer's disease, and by 5.7 percent due to hypertension, 3.4 percent for Parkinson's disease and by 2.1 percent for kidney disease.

I should note, for those of us who aren't statisticians, that life expectancy in this sense doesn't necessarily have much to do with longevity or longevity projections:

Life expectancy [at birth] is a measure of current conditions. It is not a prediction about how long somebody will live. But it's a measure of how long a person, a baby would live if that baby was confined to this year, could not get out of this year, was stuck with the conditions of this year.

In other words, it's a useful measure of how (and how well) medical science is progressing over the years, but it isn't a prediction of life span in the actual, ever-changing real world. From the very high level perspective, decreasing mortality rates for various diseases are a sign of progress across the board in medical technology. Increasing mortality rates - especially in neurodegenerative diseases - are a sign of longer life spans running into progressive degenerative conditions we still know little about ... along with increasing obesity and all that comes with it.

If you accept the premises of the Reliability Theory of Aging, it is clear that most improvements in medicine will lead to some degree of incidental healthy life extension. Your body is a complex machine; on average, and absent bad luck, better preventative maintenance and repair will lead to a longer, healthier life span. The trouble - from my point of view - is that incidental healthy life extension isn't providing anywhere near large enough gains. We need to invest much more time, effort and money into medical research if we want to reach "acturial escape velocity", the point at which medical science allows remaining life span to increase more than a year each year. This will likely require directed research into the root causes of aging, rather than the continual accumulation of specific cures and generally better preventative medicine.

A final thought on this topic from Ian Clements:

But [life spans] have STEADILY increased - and THAT is the point. There is a linear increased lifespan for all adult ages, including the very old, over the recorded couple of centuries we've had figures. This is the basis for maintaining that there is no 'natural' upper limit; if there was, then the increase in lifespans would be levelling off.

So don't let's worry that the increases are small, but note that they are continuously linear (or even increasing). This gives hope that we can uncover the mechanisms which cause steady degeneration, and slow or reverse them.