When you're young, you expect to have a great deal of time ahead of you. You haven't spent much time yet, and so what remains seems like a fortune in comparison - enough to squander. Think of the way that wealthy children so often turn out despite the best efforts of their parents, their view of the value of money and economic common sense poisoned by having grown up with access to a great deal of money. But before you look down on them or pity them, think of your own situation with respect to the expected time remaining in your life. Your viewpoint on time, life, and the future was poisoned by having what appeared to be a great deal of remaining time, far more than it was easy to compare against what little you had lived to date ... so you valued time poorly.

We are evolved to squander the resources that shower upon us and gather in their piles, while spending a great deal of care, thought, and worry on resources that are scarce. So we care little about air, not so very much more about water, and not at all about time when we are young. But that stock of time diminishes as you grow old, and because there is less of it, it becomes more valuable. This is one reason why people are willing to spend greatly on medical technologies at the end of their lives - and here I am talking only of willingness, not any need to spend more. Aging brings with it degeneration and disease, and the cost of remaining alive and able to enjoy life accelerates with the passing years: the old spend increasingly more than the young because they have to in order to stay in the game. Note that "have to in order to stay in the game" is not the same thing at all as "willing to."

To be old is to live in in the mirror image of youth: time and no money has turned into money and no time. The value of money to an old person is typically less than it is to a young person, and that is nothing more than a measure of how much of the stuff you have: old people are typically much wealthier. The converse is true of remaining time, of which the young have a great deal, whilst the old are time-poor; thus the exchange rate between the time and money is radically different at the opposite ends of life. A young person will give away an hour to gain a small number of dollars, while an old person will spend ten times that sum to gain another hour. A cynic might suggest there is some form of arbitrage to found in this truth of human nature. If you like thinking along these lines, you might look back at past ruminations on the nature of wealth in a past post.

Time is everything. How much have time you spent reading this far? Could you have been doing something more useful, more optimal from your perspective? We make these small evaluations constantly, because time is the most valuable thing we have.

There are always people in the academic world who'd rather spend time looking at factors other than the obvious ones when it comes to aging and economic activity, of course:

Low opportunity cost, weak influence of quality of life in the face of death, the social value of life extension to others, shifting psychological reference points, and hope have been proposed as factors to explain why people apparently perceive marginal life extension at the end of life to have disproportionately greater value than its length. Such value may help to explain why medical spending to extend life at the end of life is as high as it is, and the various factors behind this value might provide normative rationale for that spending.

Upon critical analysis, however, most of these factors turn out to be questionable or incompletely conceived; this includes hope, which is examined here in special detail. These factors help to explain complexity and nuance in the normative issues, but they do not provide adequate justification for spending as high as it often is. In any case, two additional factors must be added to the descriptive explanation of high spending, and they throw its normative justification into further doubt: the "insurance effect" and provider-created demand. Overall, the perception of especially high value of life at the end of life provides some normative justification for high spending, but seldom strong justification, and not for spending as high as it often is.

The trouble begins with a person deciding that an entire clade of people are making systematically incorrect assessments of value despite having access to complete and correct data. Value is subjective, not objective, and it shouldn't be at all surprising that at the end of life there are radical shifts in the value placed by a dying person upon money and time. Note that I don't say "perceived value" - that phrase is just a subtle way of suggesting that the author is correct and the members of the clade are systematically wrong, which is in turn a subtle way of suggesting that value can be objective.

If you have bad or incomplete data, the value you ascribe will probably prove to be unhelpful if you act upon it, but it is still your subjective value: there is no "wrong" or "right" here, just a record of the outcome of a series of actions. People have a way of saying that you valued something wrongly if, by your actions based on that value, you manage to do yourself harm, economic or otherwise. But that really isn't a helpful way to look at subjective value: it is what it is, at any given moment. Either way, I'd argue that when it comes to life, longevity, and medical technology, there's a lot of reliance on bad and incomplete data taking place these days, given the possibilities presented by longevity science and the level of public ignorance of those possibilities. A fraction of people alive today will have the opportunity to live for centuries or longer, but consideration of that possibility is almost entirely absent from their economic calculations.

I suppose I should also mention that this short discussion has nothing much to say in connection with the horrible state of medical economics in the US. Participation in the heavily regulated marketplace for medical technology and services is a pit of horrors for both old and young: everyone suffers from the effects of regulation, lack of accountability for costs incurred, and the general miasma of government-induced systems failure. So arguments based on differential willingness to spend on medicine by age stand apart from that mess.

The neat endpoint to this post, if you want one, is that it can't hurt to think on the value you place on the time remaining in your life expectancy, and to look at whether you are basing both expectation and value on factual data.

Here is another piece in the exceedingly complicated puzzle of metabolism and longevity, touching on some other pieces that have shown up here before, such as adenylate cyclase: "Despite the various roles of regulator of G protein signaling (RGS) protein in the G protein signaling pathway that have been defined, the function of RGS has not been characterized in longevity signaling pathways. We found that reduced expression of Loco, a Drosophila RGS protein, resulted in a longer lifespan of flies with stronger resistance to stress, higher MnSOD activity and increased fat content. In contrast, overexpression of the loco gene shortened the fly lifespan significantly, lowered stress resistance and reduced fat content, also indicating that the RGS domain containing GTPase-activating protein (GAP) activity is related to the regulation of longevity. Interestingly, expressional changes of yeast RGS2 and rat RGS14, homologs to the fly Loco, also affected oxidative stress resistance and longevity in the respective species. It is known that Loco [reduces] activity of adenylate cyclase (AC) and RGS14 interacts with activated H-Ras and Raf-1 kinases, which subsequently inhibits ERK phosphorylation. We propose that Loco/RGS14 protein may regulate stress resistance and longevity as an activator in AC-cAMP-PKA pathway and/or as a molecular scaffold that sequesters active Ras and Raf from Ras*GTP-Raf-MEK-ERK signaling pathway. Consistently, our data showed that downregulation of Loco [leads to] higher resistance to the oxidative stress."

Link: http://www.ncbi.nlm.nih.gov/pubmed/21776417

DNA methylation is proposed to be a good biomarker of aging, and here researchers show that calorie restriction slows the progression of DNA methylation in the hippocampus - continuing the expected trend of calorie restriction slowing near every identified biological change that occurs with aging: "Aberrant DNA methylation patterns have been linked to molecular and cellular alterations in the aging brain. Caloric restriction (CR) and upregulation of antioxidants have been proposed as interventions to prevent or delay age-related brain pathology. Previously, we have shown in large cohorts of aging mice, that age-related increases in DNA methyltransferase 3a (Dnmt3a) immunoreactivity in the mouse hippocampus were attenuated by CR, but not by overexpression of superoxide dismutase 1 (SOD1). Here, we investigated age-related alterations of 5-methylcytidine (5-mC), a marker of DNA methylation levels, in a hippocampal subregion-specific manner. Examination of 5-mC immunoreactivity in 12- and 24-month-old wild type (WT) mice on control diet, mice overexpressing SOD1 on control diet, wild type mice on CR, and SOD1 mice on CR, indicated an age-related increase in 5-mC immunoreactivity in the hippocampal dentate gyrus, CA3, and CA1-2 regions, which was prevented by CR but not by SOD1 overexpression. ... These findings suggest a crucial role for DNA methylation in hippocampal aging and in the mediation of the beneficial effects of CR on aging."

Link: http://www.ncbi.nlm.nih.gov/pubmed/21764481

To my eyes, Chronosphere is chiefly important as an insider's personal view of the 40-year history of modern cryonics movements. For decades, people have been working on the indefinite low temperature storage of the deceased, aiming to preserve the fine structure of the brain that encodes the mind's data. There is, to my eyes, still far from enough of a recounting of that history, the lessons learned, and efforts made - the more memoirs and personal accounts presented online the better. So here are pointers to a couple of recent Chronosphere posts on what went on, back in the day, when cryonics was a younger initiative, both of which are liberally scattered with photographs:

In Camera Historia: Cryonics Institute Facility, 1978

On 21 March, 1978 the Cryonics Institute (CI) acquired their first facility, a storefront building in the Detroit Metro area. The CI building was the first wholly owned (cash purchase) patient storage facility in the history of cryonics, and remains one of only two in the world today. ... As was the case with all cryonics organizations' initial facilities, the CI facility was small and cramped. It also lacked the ceiling height necessary for upright (open at the top) cryostats and this limitation was an additional impetus for CI to develop the fiberglass-epoxy resin type of cryostat (using perlite and low vacuum insulation) that they currently use to store their patients.

The Armories of the Latter Day Laputas, Part 7

The Alcor Life Extension Foundation, Inc. (Alcor) and its brother for-profit organization, Manrise Corporation (Manrise), were founded in 1972 by Fred and Linda Chamberlain ... The Chamberlains had previously been members of the Cryonics Society of California (CSC) and both had served as officers of CSC. When they became suspicious about the integrity of CSC's financial and cryogenic patient care operations and were unable to obtain answers to their questions, they left CSC and founded Alcor/Manrise. As was the model at the time, Alcor was the 501c3 non-profit organization tasked with accepting cryonics patients under the Uniform Anatomical Gift Act (UAGA) and acting as their custodian and advocate until such time as reanimation might become possible.

If this were a better world then cryonics or a similar industry based on plastination would be large and well known, and a majority of people would be spared the oblivion of the grave. We don't live in that world, evidently, and is a sad statement on vision, priorities, and human nature that cryonics remains a small industry.

Hormesis is the name given to the processes by which a little damage at the cellular level can actually be beneficial, as it spurs repair and maintenance systems to greater efforts - the result is a net gain. Here researchers demonstrate one method of inducing hormesis in nematode worms: "As organisms age, cellular proteins, lipids and nucleic acids sustain damage that can lead to functional deficits in tissues and, ultimately, death. The free radical theory of aging proposes that aging results, at least in part, from damage to cellular components by reactive oxygen species (ROS) ... Indeed, oxidative modification is a major form of damage detected in aging tissues ... Here, we report that hormetic chemicals can be modified to optimize beneficial effects and minimize toxicity in C. elegans, a model for studying aging in whole organisms. C. elegans is well-suited to this problem due to the short lifespan, ease of genetic manipulation and transparent anatomy. First, we examined whether lifespan extension is common among biological toxins with various chemical structures and mechanisms of action. In a small screen of natural phytochemicals, we identified two ROS generating compounds, plumbagin and juglone, which extended lifespan at subtoxic doses. Mean lifespan extension by plumbagin was dependent on SKN-1, a cap'n'collar transcription factor that promotes antioxidant gene expression in response to oxidative stress. We further screened a collection of six plumbagin analogs, identifying three additional naphthoquinones that activated expression of a skn-1 target. One of these could extend lifespan over a larger range of doses than plumbagin, demonstrating the utility of stress hormesis mechanisms as promising prolongevity intervention."

Link: http://dx.doi.org/10.1371/journal.pone.0021922

From TechNewsWorld: "In America, a large part of funding for regenerative medicine comes from the Department of Defense, whose goal is to repair soldiers who come home wounded. That is an effort everyone recognizes as important. Yet, when it comes to repairing older people whose hearts and lungs are failing, society seems at peace accepting their demise because that is all humanity has ever known - a state of mind that some call the 'pro-death trance.' ... A Swedish hospital recently announced that a cancer patient was saved after doctors grew him a new windpipe in the lab using a synthetic structure and the man's own stem cells. That might have sounded like science fiction just a few years ago, but today it is landmark news. Regenerative medicine has the ability to usher in radically longer and healthier lives, yet few are considering the implications. The ability to grow new replacement parts for humans when original organs break down is a game-changer when it comes to extending human 'health spans' - the amount of time one is alive and healthy. A handful of human subjects have already benefited from innovations in this area and dozens of organs have been successfully grown in the lab, including a rat heart. ... The coming changes will be enormous - but on the whole, positive. Why then, is there no sustained dialog about how to get to that point sooner? ... Humans now have the opportunity to live much longer and healthier lives - for the greater benefit of all. It is time to break free from the pro-death trance and work toward speeding the revolution."

Link: http://www.technewsworld.com/story/America-Its-Time-to-Snap-Out-of-the-Pro-Death-Trance-72907.html

Over at h+ Magazine you'll find a question and answer session with Aubrey de Grey that covers some old ground and some new ground. The SENS Foundation, which de Grey cofounded, is presently deploying a modest million-dollar yearly budget to work on the biotechnologies needed to repair the cellular and molecular damage that causes aging. A great deal of that budget presently goes towards the first of the Foundation's programs, an effort focused on using bacterial enzymes to break down harmful waste chemicals that build up in our cells and contribute to a range of age-related diseases and degenerations.

I should mention that SENS Foundation funding is due entirely to philanthropic donations - including those of a few high net worth individuals - and I know that many of the readers here are long-standing supporters dating back to the years when the SENS Foundation's work was a program of the Methuselah Foundation. I find it very gratifying to see that so much has been made of the early efforts, when it was a matter of a few dollars given at time. I would hope that the rest of you feel the same way.

The SENS Foundation will also be hosting the forthcoming SENS5 conference in Cambridge at the end of August - there's a lot going on at the moment. But back to the h+ Magazine piece:

H+: SENS describes a whole battery of medical treatments that could theoretically defeat the aging process. These treatments range from relatively simple ones like injecting people with enzymes that can break down tough wastes inside of cells, to highly advanced ones like genetically altering trillions of somatic cells in full grown adults. Considering the differential technical challenges, what SENS therapies will most likely become available first, and which will be developed last?

AdG: Some of them are already pretty close: probably the closest is in fact not the enzyme therapy you mention, but the use of vaccines to eliminate extracellular aggregates (especially amyloid). But when we consider the others, actually I wouldn't like to make the call, because the hardest ones are the ones that the SENS Foundation and I are prioritizing in terms of the early research. In other words, we're hoping that they will start to catch up with the easier ones. I suspect that the challenge of genetically modifying a high proportion of cells by somatic gene therapy will have been largely solved before we complete the development of all the genes that we want to introduce.

...

H+: Are you worried that a single company or government might obtain the secrets to longevity first and then use its monopoly on the science to hold the human race hostage forever (or even for just a long period of time)?

AdG: There's no chance whatever of this scenario, because the defeat of aging will depend on the simultaneous application of a lot of different interventions, all of which will first have been developed in the laboratory rather than in humans.

There's a lot more in that vein, so read the whole thing. The point on gene therapy in the quote above is an interesting and important one. A great many very promising demonstrations in the laboratory depend upon gene therapy in one form or another - take the method of largely preventing atherosclerosis I pointed out earlier today for example. If we want to see these lines of research become more than simply interesting technology demonstrations then selective, tissue-specific gene therapy for humans must become routine and safe.

Does blood type in any way affect longevity? A resounding "maybe" from what little work exists on the topic, which suggests that if there is any effect then it is small in comparison to other factors. But we'll never know unless the research community looks into the matter, and so here is another batch of evidence to add to the pile: "Centenarians are the best example of extreme human longevity, and they represent a selected population in which the appearance of major age-related diseases, such as cancer, and cardiovascular diseases among others, has been consistently delayed or escaped. The study of the long-lived individual genetic profile has the purpose to possibly identify the genes and the allelic variations influencing extended life expectancy, hence considering them as biomarkers of age-related diseases onset and development. The present study shows no significant differences between allelic variations of ABO blood groups among a group of centenarians from Western Sicily."

Link: http://www.ncbi.nlm.nih.gov/pubmed/21766224

Via EurekAlert!, news of a promising study in rabbits: "A one-dose method for delivering gene therapy into an arterial wall effectively protects the artery from developing atherosclerosis despite ongoing high blood cholesterol. ... As applied in our study, the introduced genes can produce proteins that counteract the fundamental processes that drive atherosclerosis, including preventing lipid accumulation inside the artery wall and decreasing recruitment of inflammatory cells. We found both of these effects. ... Gene transfer would move the production of the therapeutic 'drug' (in this case a therapeutic gene) directly to the site of atherosclerosis development: the blood vessel wall. The approach maximizes delivery of the drug to the artery wall and minimizes side effects in the rest of the body. ... The deployed gene produces a protein that is likely responsible for the beneficial effects of high-density lipoprotein, or HDL, commonly known as good cholesterol. This substance is apolipoprotein A-1, or apoA-1. It pumps out harmful cholesterol from the scavenger-type cells that ingest fats and congregate in early atherosclerotic lesions. ApoA-1 appears to remove cholesterol from the lesions and is capable of transporting it to the liver, where it can be excreted from the body. Lack of a suitable vector to transfer apoA-1-manufacturing genes into the cells lining the arterial wall has hampered the progress of this approach. Normally apoA-1 is produced by cells in the liver, stomach and intestine and enters the artery wall only after circulating through the blood. [The] researchers successfully used a helper-dependent adenovirus (HDAd) as the vehicle to transfer a genomic clone of rabbit apo-A1 into the carotid artery. This large blood vessel sends oxygenated blood to the brain. After the vector was infused into the artery, the gene was taken up almost exclusively by the cells in the thin layer that lines the carotid's inner surface and is in contact with circulating blood."

Link: http://www.eurekalert.org/pub_releases/2011-07/uow-gtd071911.php

Cryonics, as I'm sure you're all aware, has for decades been the best and only shot at a long life in the future for people who die before the advent of rejuvenation biotechnologies capable of reversing the damage of aging. That is a massive number of people, possibly including you and I unless we get our act together - and sadly, all too few will choose to be cryopreserved, even though they have the opportunity and the means. Cryonics is, in essence, a form of indefinite low temperature storage of the body and brain immediately following death. It is carried out with the reasonable expectation, based on present scientific knowledge, that it preserves the fine structure of the brain that stores the information of the mind - you might not be running, but all your data is backed up.

We can envisage the technologies needed to restore a preserved person to active life once again, and none of it is prohibited by the laws of physics. It most likely require a far greater understanding of the structure human brain, the ability to build a new body from scratch, the use of a molecular manufacturing technology base and swarms of nanoscale medical robots, capable of manipulating and repairing cellular machinery - and the computational power to support sophisticated use of these medical technologies. But all of these are foreseeable, and presently being worked on by a range of research groups. It isn't pie in the sky to expect there to be a chance of resuscitation for cryopreserved individuals. Their lives are on hold, but not gone - you are only irrevocably gone if you choose the grave.

But how does a cryopreservation work in practice? How does one go from the last weeks of life to being safely stored in liquid nitrogen, awaiting the future? As I've noted in the past, it takes a fair amount of organization to do well, and the regulatory environment surround end of life choices doesn't make a good cryopreservation any easier - you are not allowed to choose when to do it, and in most jurisdictions no-one is allowed to help you plan your death to be at the time of your choosing either. If you want to learn more about how a cryopreservation tends to unfold, then you should note that cryonics provider Alcor publishes case summaries on a regular basis, as patients are preserved. You'll find some referenced back in the Fight Aging! archives, and here are a couple of recent case summaries:

Case Summaries: A-1408 and A-2357:

This past quarter, Alcor cryopreserved two of its members. The first member, A-1408, lived just north of the Tampa, FL area. Alcor team members initiated a standby at the hospital for three days during the time the individual was listed as critical and medical providers anticipated that he might stop breathing. The member stabilized and Alcor ended the standby while continuing to monitor the patient's condition remotely. When his medical condition deteriorated again, Alcor was on the verge of initiating a standby for another member and therefore decided to request Suspended Animation to provide the standby this time.

On the afternoon of the fourth day of the standby (May 26, 2011), the member was pronounced, stabilized and cooled on-site, followed by a field washout. The transport commenced the next morning by commercial airlines and the patient was brought to Alcor with the surgical team at the ready. After the neuro cryopreservation ensued, member A-1408 became Alcor's 105th patient.

Case Report for A-1614 (PDF)

Wesley Du Charme authored a book: Becoming Immortal: Nanotechnology, You and the Demise of Death in 1995, which discussed the opportunity for virtual immortality through combining nanotechnology and cryonics. He lived life fully while always looking to the future; he joined Alcor in hopes of living in the far future.

....

The tests showed that Wesley now had pancreatic cancer with metastases to the liver and duodenum. At this point, the oncologist said that his condition was terminal and nonoperable, and Wesley would not respond to chemo or radiation treatments. When asked how long Wesley had to live, he responded with "...longer than three days, but less than six months."

Given Wesley's greatly weakened condition, the family desired to have him admitted to hospice care in Scottsdale, Arizona, close to Alcor. As Wesley was currently hospitalized, his physician who was supportive of the cryopreservation directives, prescribed TPN (Total Parenteral Nutrition) as a way to increase Wesley's strength and stamina to endure the trip to Arizona. Alcor personnel helped facilitate communication between the hospice facility and the family to finalize the admittance process.

You should read the whole PDF document, and be appreciative of the folk who were thoughtful enough to allow a detailed account of the arrangement of Du Charme's cryopreservation to be published. The end of a life and the terminal breakdown of a body's necessary systems are never pretty, and most people prefer to sweep all of that behind the curtain - and the same goes for the hundred small organizational details that go into managing death and cryopreservation. But if they aren't published, we don't learn.