As noted back in the Fight Aging! archives, scientists have been picking away at the knot that is p66(Shc) for a while now, tying the activity of this protein to many of the other mechanisms of metabolism considered important to longevity and resistance to common age-related damage and disease. Here's more on the topic: "The notion that mice carrying a targeted mutation of the p66(Shc) gene display prolonged lifespan, reduced production of intracellular oxidants, and increased resistance to oxidative stress-induced apoptosis prompted a series of studies aimed at defining the biochemical function of p66(Shc) and its possible implication in cardiovascular diseases. Indeed, p66(Shc-/-) mice are protected against vascular, cardiac, and renal impairment attributable to hypercholesterolemia, aging, diabetes, and ischemia/reperfusion. ... On the whole, the evidence so far reported and here discussed supports the concept that pharmacological modulation of p66(Shc) expression and activity may be a novel and effective target for the treatment of atherosclerotic vascular disease as well as myocardial adaptation to hypertrophic, inflammatory and neuro-hormonal stimuli in the overloaded heart."
ScienCentral on trials of one particular gene therapy aimed at ameliorating the symptoms of Parkinson's disease: "The gene therapy study was to look at an area of the brain called the subthalamic nucleus. The area is overactive when you have Parkinson's disease. ... treatment relaxed brain activity in the motor network, making a patient with severe over-activity look like a person with moderate or mild Parkinson's disease. And because patients only received the therapy on one side of their brains, the researchers used the untreated side as a control. ... The network activity in the treated side went down while the other network in fact got worse over the period of time. It was as if the disease had progressed on one side of the brain, but not the other. But just as important was to determine whether the gene therapy affected the thinking network - and results show it did not. ... [researchers] plan to start their next [phase II] clinical trial in early 2008." While this is more patch than regeneration of causative damage in Parkinson's, we should welcome advances in safely manipulating the brain. However the future of healthy life extension progresses, we are going to have to become very proficient at repairing brain biochemistry in situ.
Aging researchers Leonid Gavrilov and Natalia S. Gavrilova have posted a draft on genetics and aging to Longevity Science. Recall that these two are behind the reliability theory of aging; I find their perspectives are usually quite different to those at the biogerontological end of the research community. If I had to sum it up in a few words, these researchers work somewhere toward the more analytical end of the triangle formed by systems theory, biogerontology and actuarial studies. Differing perspectives are hard to create and their collision is often the source of new insight - therefore they are valuable.
In molecular genetic studies of human aging traits, the gene association studies remain the most common research approach. In these studies the effect of candidate genes on longevity is analyzed by comparing gene frequencies between affected individuals (cases) and unaffected control individuals. Comparison of candidate gene frequencies among centenarians and younger controls is a typical example of such studies. Another molecular genetics approach - the genome-wide linkage scan of genes, is a relatively new direction of research. Linkage analysis is a mapping of genetic loci using observations of related individuals (pairs of affected and nonaffected siblings, for example). This direction of research has a potential for obtaining interesting results, although the success of genome-wide scans of complex human diseases requires large sample sizes, considerable effort and expense.
A review of gene-longevity association studies revealed that different studies often produced inconsistent and even contradictory results.
Most chronic diseases in later life are complex multifactorial disorders. Multifactorial disorders are influenced by multiple genes, often coupled with the effects of environmental factors. Many diseases common to old age, such as late-onset Alzheimer's disease, heart disease, diabetes are now considered to be multifactorial disorders. Most genes associated with multifactorial disorders have low penetrance, which means that the likelihood of developing disease among genotype carriers is low. Thus, the individuals with disease-related genes do not necessarily succumb to disease. With favorable lifestyle and environment there is an opportunity for individual with genetic risk factor to delay and even to avoid the disease.
All of which suggests we should be realistic when it comes to the likelihood of finding any simple correlations within the fantastically complex system formed by a lifetime of interaction between genes, the machinery that carries out their programming, and the world within which the resulting humans operate.
Not to harp on the same point over and over, but this helps to demonstrate why it is imperative we do all we can to intelligently reduce the complexity of our attempts to extend the healthy human life span. Categorizing changes in our biochemistry with age and developing the means to revert or repair those changes is a good deal less complex than either (a) gaining a complete understanding of human biochemistry or (b) attempting to change that biochemistry to produce the damage of age more slowly.
To put it more clearly, why does it matter exactly how it is our metabolism develops broken mitochondrial DNA with age if we have identified that change as pivotal and important, and know how to develop the means to repair it? Let's repair it first, then worry about the rest of the picture. It's important to get the priorities straight.
People built good, workable bridges long before the development of mathematical and engineering tools required to formally determine the best bridge-building strategy in any given case. Engineering our way to a cure for aging is no different in essence: good results are possible in the absence of complete understanding of the system, and by constraining the complexity of the work, it becomes much more plausible to see significant progress in our lifetimes.
Some punchy thoughts on the AGEMAP project by the Grailsearcher: "Databases are usually quite dull. They are filled with tedious gobs of data like shoe size, date of birth and other boring tidbits that are meaningless on their own. Having to work with them on a day to day basis can sometimes makes you want to bore a hole in your head with a spoon. The AGEMAP database kicks ass though and I'll tell you why. ... 906 gene expressions were shown to change with age across the various mouse tissues. Who cares? You do. It sets the stage for similar human studies and understanding why gene expressions change will lead to therapies that will very likely extend your healthy lifespan in the coming decades. Significantly. ... This is the century where the human race will see significant and perhaps even radical extensions in lifespan due to research taking place now. Decoding the human genome was a big step in that direction and the subsequent leaps such as the AGEMAP database which details specific gene expressions are already taking place." Unvarnished enthusiasm is a good thing, for it it is inenvitably the enthusiasts who help to make progress happen.
Robin Hanson at Overcoming Bias notes that the prospects for healthy life extension have "sparked many debates, conferences etc. over the last few years. The invited participants have naturally been intellectuals who have published on the topic recently, mainly activists and bioethicists. We economists have not published on this topic, and so have not been included. But this is not because we have nothing to say. Instead, no economist has anything special to say. We can all easily see that standard economic theory seems to say longer healthy lives are a good thing. So none of us thinks any of us should get precious academic publication credit for saying such an obvious thing. As a result, life extension debates ignore economic theory. ... it still seems to me a shame that observers of this debate can remain unaware of what standard economic theory seems to say on this subject."
You might recall that different fatty acid or lipid composition in cell membranes was floated as a reason for the ninefold longevity of naked mole-rats over related rodent species. Plenty of oxidative stress in the older mole-rats, but little sign of biochemical damage resulting from it - in comparison to those other rodents long since aged to death, that is. Better, more damage-resistant building blocks down at the molecular level might be the cause:
Underlying causes of species differences in maximum life span (MLS) are unknown, although differential vulnerability of membrane phospholipids to peroxidation is implicated. ... membranes of longer-living, larger mammals have less polyunsaturated fatty acid (PUFA). ... Both species had similar amounts of membrane total unsaturated fatty acids; however, mice had 9 times more docosahexaenoic acid (DHA). Because this n-3PUFA is most susceptible to lipid peroxidation, mole-rat membranes are substantially more resistant to oxidative stress than are mice membranes ... suggesting that membrane phospholipid composition is an important determinant of longevity.
Offspring of long-lived individuals are a useful model to discover biomarkers of longevity. The lipid composition of erythrocyte membranes from 41 nonagenarian offspring was compared with 30 matched controls. Genetic loci were also tested in 280 centenarians and 280 controls to verify a potential genetic predisposition in determining unique lipid profile.
Erythrocyte membranes from nonagenarian offspring had significantly higher content of C16:1 n-7, trans C18:1 n-9, and total trans-fatty acids, and reduced content of C18:2 n-6 and C20:4 n-6.
We concluded that erythrocyte membranes derived from nonagenarian offspring have a different lipid composition (reduced lipid peroxidation and increased membrane integrity) to that of the general population.
Note there again - reduced lipid peroxidation, as for the naked mole-rats, and therefore more resistant to oxidative stress. This is quite an interesting line of research, demonstrating some plausible indications of a structural contribution to longevity at the cellular level. I'm sure we'll be seeing more of this in the future, as research and debate continues.
As reported in the Orlando Sentinal, immunotherapies aimed at Alzheimer's disease are reaching late stage clinical trials: "The immunization -- gradually injected into a patient's bloodstream with a needle -- is one of several experimental treatments that use antibodies to attack what are called beta-amyloid protein plaques that form in the brains of Alzheimer's patients. Many scientists think such plaques can cause the disease or its symptoms. ... It is a phase-three trial, which means it could be the final step before the drug gets federal approval for more widespread use. Eventually, the trial will involve 1,600 patients in about 200 centers worldwide. ... The immunotherapy approach now being tested uses antibodies, either made by scientists or by the patient's own immune system, to attack and dissolve the plaques. The drug is administered through the veins in the arm and repeated every three months to replenish the antibodies. Patients' progress is charted through tests and brain scans." These first attempts are not expected to do more than slow progression of the condition. The next generation of therapies will be much more impressive, judging by progress in the labs today - but of course the inane and expensive regulatory hurdles mean it will be a decade before any of it is available, if at all.
Metabolism, the workings of our cells in concert, is a process of tremendous complexity. This is why many seemingly important correlations remain to be explored and understood: "Protein synthesis is a tightly regulated cellular process that affects growth, reproduction, and survival in response to both intrinsic and extrinsic cues, such as nutrient availability and energy levels. A pronounced, age-related decline of the total protein synthesis rate has been observed in many organisms, including humans. The molecular mechanisms underlying this decline and their role in the aging process remain unclear. A series of recent studies in the nematode, Caenorhabditis elegans, have revealed a novel link between protein synthesis and aging. Remarkably, these research findings, in their totality, converge to indicate that reduction of mRNA translation prolongs life in worms. Signal transduction cascades implicated in aging, such as the insulin/insulin growth factor-1 pathway, interface with mechanisms regulating protein synthesis via a battery of key mRNA translation factors. Are the effects of these pathways on aging mediated, in part, by alterations in protein synthesis? This is an intriguing possibility in light of the latest discoveries."
Oxidative stress is believed to play a role in neurodegenerative diseases such as Alzheimer's and Parkinson's. Some of the symptoms of aging such as arteriosclerosis are also attributed to free-radical induced oxidation of many of the chemicals making up the body. Despite the broad role that oxidative stress plays in human disease, medicine has been limited in its development of treatments that counteract free radical damage and the ensuing burden of oxidative stress. In contrast, in the field of engineering, considerable effort has been developed to counter the effects of oxidative stress at the materials science level. ... Our initial results suggest that cerium oxide nanoparticles extend cell and organism longevity through their actions as regenerative free radical scavengers. Additional studies suggest that these nanoparticles are also potent anti-inflammatory agents. Although much work remains to be done in this realm, ceria nanoparticles hold high promise for future development of nanopharmacological agents to treat age related neurodegenerative disorders and inflammatory disorders.
This sort of initiative is but a tiny step on a very long path that leads to nanomedical robotics, artificial blood cells a thousand times better than the real thing, and even more impressive feats of engineering. But you have to start with what is presently possible. Some more on cerium oxide in this paper:
Here, we summarize the work on the biological antioxidant actions of cerium oxide nanoparticles in extension of cell and organism longevity, protection against free radical insult, and protection against trauma-induced neuronal damage. We discuss establishment of effective dosing parameters, along with the physicochemical properties that regulate the pharmacological action of these new nanomaterials. Taken together, these studies suggest that nanotechnology can take pharmacological treatment to a new level, with a novel generation of nanopharmaceuticals.
"Radical nanomedicine" means different things to different folk of course - anything from the mass-produced artificial blood cell nanomachines of the 2030s to next year's application of somewhat better and more useful nanoparticles. But the trend towards engineering your way out of unwanted biological conditions at the scale of molecules and cells is very welcome and to be encouraged. Engineers put the pieces together and get the job done - don't underestimate the power of that approach to problems.
One caveat on any work involving antioxidants is the evidence produced to date indicating that it matters greatly where your antioxidants do their work. Are they meandering around uselessly, far from the points at which oxidative stress is generated or causing damage? Are they interfering in the signaling mechanisms that actually use oxidizing molecules?
Rabinovitch's group genetically engineered mice to produce a natural antioxidant enzyme called catalase. The mice lived 20 percent longer than normal mice - on average they lived five and a half months longer than the control animals, whose average life span was about two years ...
We had differing hypotheses about where putting catalase might do the best in terms of the advantage to life and health of the mice," Rabinovitch explains. So they targeted the gene in three different places in the mouse cells - the cytoplasm, the nucleus - where they thought it might protect the all-important DNA of the cell - and the powerhouses of the cells, the mitochondria - where cells "burn" glucose for energy and churn out high levels of these oxidizing free-radicals. The mice that lived longest had the gene in their mitochondria.
Here's another approach indicating that it matters where you put your antioxidants:
Instead of gene therapy, Skulachev's group has found a viable biochemical strategy for effectively localizing ingested antioxidants in the mitochondria; clever.
But if you're a clever engineer, this is all just another challenge to build around.
Telomeres shorten over time in mammals, are lengthened by telomerase, and this all seems to be important for aging, cancer and age-related disease. But many of the important details are still up for debate, even as companies are working on telomere-based therapies. This paper caught my eye as illustrative of the complexities that bedevil any sort of biological research. Given a brace of storm-petrels, what can you determine about telomeres and longevity? As it turns out, even the fundamental points are a challenge: "Given that telomeres generally shorten with age, it was surprising to find that in a population of a long-lived seabird, Leach's storm-petrel, telomeres appear to lengthen with age. This unique finding suggested that the longest-lived individuals are able to elongate telomeres, an interpretation we call the Elongation Hypothesis. Alternatively, the Selection Hypothesis states that the longest-lived individuals start with the longest telomeres and variation in telomere length decreases with age due to the selective disappearance of individuals with short telomeres." The Selection Hypothesis wins, but "the oldest adults also show little or no accumulation of short telomeres over time, a pattern unknown in other species. Long telomeres are thought to provide a buffer against cellular senescence, and be generally indicative of genome stability and overall cell health." Biology is always more complex than you'd like it to be.
I was just talking about the "inequality for any is worse than death for all" meme over at Fight Aging!, though the definitive examination is back somewhat further in the archives. Here is another example, via Studies in Ethics, Law, and Technology, demonstrating that the "death for all" school of thought is sadly thriving: "longevity and immortality research exhibits the same discourse problems as the other new and emerging technology discourses, namely that [it] makes light of potential and real social risks that it tailors to a minority of the world and ignores the marginalized majority of the world." I see this sort of viewpoint - that we should block progress at the speartip while the hindmost are brought up to par - as a fundamental misconception of economics and human nature. Equality is the mirage that leads to death in the desert. The world works this way in reality: we can labor and trade to move everyone ahead, benefits for all and inequalities for all, or we can redistribute what presently exists - which at best leads to stagnation and no progress, and at worst becomes a repetition of Soviet era Russia and Eastern Europe. In both cases, inequality will exist - you can't kill it. The choice is between open inequality in comparative and advancing wealth or painful inequality in stagnant, deteriorating poverty, disease and rubble.
Videoblogging, much like those newfangled social networks, is passing me by - but online video has proven to be a tremendously effective tool for reaching people, and more power to those who are making it work:
My End Aging Challenge is simple: Create and post a reply to this video on YouTube explaining why you support Dr. Aubrey de Grey's and the Methuselah Foundation's mission to end aging. I will donate $10 to the Methuselah Foundation for every video response. If you have the means, I also suggest that you offer in your video response to match me with a donation of your own for every video. After you shoot your video, follow this link to post your video reply.
Good show. If you want something done, no matter how daunting or large the task, the best way to go about it is to get out there and help make it happen. Put your shoulder to the wheel and lead by example. It matters not the size and weight of that wheel, as many hands make light work. It matters greatly that you show that the job exists, and that someone is willing to work at getting it done. Where is one willing worker exists, there will soon be more.
And so there are: see the responses to date over at YouTube. I encourage all of you with the inclination to create your own video messages to get out there and show your support. More from Kevin Dewalt here:
For those of you thinking about replying with a video I encourage you to have some fun and get creative with it. Why do you want to cure aging and live a few hundred more years? Do you want to visit the moon? Bring about world peace? Start a new career? Or perhaps you don’t care at all about yourself and just want to help relieve the suffering of others.
It is of a sea of many modest efforts that great storms arise. Want to change the world? Want a better, longer, healthier future? Then do something to help make it happen.
By way of a little reminder to folk such as I just how far behind the curve we are, I recently discovered the existence of a fair-sized and well maintained Facebook group for the book Ending Aging, the Methuselah Foundation and Strategies for Engineered Negligible Senescence (SENS) research. 900 members isn't to be sniffed at; you'll need a Facebook account to see it, however. As I understand the way Facebook-like social networks operate, a group is a way to show your affiliation to a cause or ideal, a repository for links, files and other resources of interest, and a place for discussion. A web site in miniature, contained with the social network, in other words, and which can be used in much the same way in support of advocacy and activist goals. Social networks like Facebook are one part of the ongoing process of lowering the cost of advocacy, making it possible for more people to meaningfully support a cause with small investments of time. When the cost of making a modest difference is close to zero, everyone who so desires can be a part-time patient advocate for longevity research. This can only be a good thing.
From the Transhumanist Declaration: "Humanity will be radically changed by technology in the future. We foresee the feasibility of redesigning the human condition, including such parameters as the inevitability of aging, limitations on human and artificial intellects, unchosen psychology, suffering, and our confinement to the planet earth." The World Transhumanist Association (WTA), an organization supportive of healthy life extension science and advocacy, is presently holding a pledge drive to match $25,000 before the end of January: "Bill Faloon of Life Extension Foundation and Brian Cartmell of Cartmell Holdings, LLC, have generously offered to help us kick off our first fundraising event by matching your donations up to $25,000 until January 31, 2008. We need 250 members to give $100 each, so your donations can be doubled. This is a unique opportunity we cannot afford to miss!" The pledge drive website explains how the funds will be used to expand the reach of transhumanist ideas.
The latest Rejuvenation Research is available online. I've pointed out a couple of the more interesting papers already in the past weeks, as they appeared on PubMed:
- Cell Fusion and Regenerative Therapies
- Xenotransplanting New Mitochondria
- Can We Build a Longevity Therapy Atop Mitoptosis?
The theme for today is the way in which reality eventually starts to impinge upon unrealistic viewpoints. That is a point for hope, as there are a great many unrealistic viewpoints in the world that would hinder or halt longevity research, either directly or indirectly. Viewpoints like "the more regulation the better", "prove that you will do no harm at all before we'll let you move forward," or "let us redistribute all property and remove incentives for success and progress, for inequality for any is worse than death for all" spring to mind. In this latter context, "social justice" is a particularly pernicious phrase, being a shorthand for forceful redistribution of wealth by government fiat - institutionalized theft, aimed exactly at the point at which it will do the greatest damage to progress by removing incentives for success.
The world works this way: we can labor and trade to move everyone ahead, benefits for all and inequalities for all, or we can redistribute what presently exists - which at best leads to stagnation and no progress, and at worst becomes a repetition of Soviet era Russia and Eastern Europe. In both cases, inequality will be there - you can't kill it. The choice is whether it's inequality in comparative wealth or inequality in poverty, disease and rubble. Progress is absolutely dependent on freedom and the incentives of wealth earned through hard work and invention.
Fortunately, some folk are starting to realize that the stakes are much higher now than in the past. At one time you could be a parasite upon the body politic, propagating theories of no worth or that would cause great harm if enacted, without damaging your own prospects significantly. Now, however, we're talking about the difference between living to see the technologies of radical life extension - and thus living for a long, long time in good health - or dying because the development of those technologies is delayed. So we start to see papers like this:
According to one account of distributive justice, called the Sufficiency View, justice only requires that we bring everyone above some critical threshold of well-being and nothing more. This account of justice no doubt explains why some people believe it is unfair to invest scarce public funds into combating aging. In this paper I show why the sufficiency view is wrong. Furthermore, I argue that the real injustice occurs when we disparage or ignore all potential avenues of extending healthy living. We must be both ambitious and imaginative in our attitudes towards health extension.
You'll find analogous issues - and unhelpful, unrealistic viewpoints - within the scientific community. The most important of those have been set out at length in the past, such as in the essay "The Curious Case of the Catatonic Biogerontologists", or some of my past comments here at Fight Aging!:
The road to a cure for aging, like the road to a cure for cancer, has many waystations - each representating some level of treatment, some level of extended healthy life spans. Conservative gerontology ignores the existence of those waystations. Can you imagine a world in which cancer research proceeded that way, pure research with no funding invested in application and the development of therapies?
Fortunately, that state of affairs is somewhat on the way out - and not before time too. There's only so many years it could continue whilst watching vastly extended healthy life spans engineered in animals and work on calorie restriction science in humans. Sooner or later the same calculus applies: the personal risk of slowing down progress in healthy life extension is too great to hold onto unrealistic or unhelpful viewpoints.
A string of recent and forthcoming conferences, organized not only by those at the forefront of life-extension research but also by highly influential mainstream groups, have publicly endorsed the Methuselah Foundation's goal of defeating aging. The field of biomedical gerontology - the interface between biogerontology and geriatrics, where biological knowledge is focused on developing the geriatrics of tomorrow - is not a traditional component of gerontology, having been poorly appreciated by biogerontologists and geriatricians alike, but these developments show that it is rapidly taking its place at that table.
Some of the core strands of the modern day discussion of greatly increasing healthy human longevity through the advancement of medical science can be found in the first issue of Studies in Ethics, Law, and Technology:
As advances in medicine and the life-sciences continue offer the opportunity to “enhance” humans and other species, it becomes clear that the discussion of human enhancement raises questions in philosophy, religion, science, medicine, sociology, history, law, and many other disciplines.
There is something to be said for pushing aside the normal self-serving blather that populates this sort of region of ethical debate, colonizing the space with determined intent and hard science to support it. Chase out the bad with the good, and spread the meaningful debates that have taken place within the healthy life extension community: how, how long, what must be done to reach the goals of radical life extension.
The pace of a given strand of scientific research, whether purely curiosity-driven or motivated by a particular technological goal, is strongly influenced by public attitudes towards its value. In the case of research directed to the radical postponement of aging and the consequent extension of healthy and total lifespans, public opinion is entrenched in a "pro-aging trance" - a state of resolute irrationality. This arises from the entirely rational attitude to a grisly, inevitable and relatively far-off fate: putting it out of one's mind allows one to make the most of what time one has, free of preoccupation with one's demise, and it is immaterial how irrational the arguments that one uses to achieve this are, e.g. by persuading oneself that aging is not such a bad thing after all.
As biotechnology increasingly nears the point where aging will no longer be inevitable, however, this studied fatalism has become a core part of the problem, making people reluctant to join the crusade to hasten that technology's arrival. An effective way to address this hesitation is to promote debate about the reasons people give for fearing the defeat of aging, most of which are sociological. Such debate exposes people to the glaring flaws in their own logic. Thus, the more the debate is sustained and promoted, the harder it is for those flaws to be ignored.
Biogerontologist Aubrey de Grey has suggested that one of the reasons we as a society invest so little in research on combating aging is because we are in an intellectual trance. We think the effort will be futile: aging is immutable, so why try? A healthy skepticism can be a good thing but it is a major mistake to bet against the irresistible force of inexorable technological progress. Over the next few decades, nanotechnology will come to play a pivotal role in the solution to the problem of human aging. Medical nanorobotics, if it can be made to work, can unquestionably offer convenient solutions to all known causes of age-related damage and most likely can also successfully address any new causes of senescence that remain undiscovered today.
These two papers illustrate one of the core debates within the healthy life extension community - but it is a subtle debate, not addressed openly to the extent it deserves. Many people see activism in support of longevity science to be of limited necessity because they believe, I think, that general advances in technological capabilities drive entrepreneurial development cycles that drive public support for new uses. In effect, this is a belief in the robustness of a free market to explore every possible economically viable avenue for human betterment, and to leap upon newly viable avenues as soon as they arise.
My position is that this is probably the case in the long term. However, as always, it is easy to point out many economically viable and technologically possible projects that have not been started, in medicine or other fields, in the decades since they became viable. In addition to the economy of the free market, there exist economies of regulation, attention, understanding and philantrophic support - just because something is viable does not mean it will happen within your lifetime.
There of course is the crux of the matter. If we are to benefit from healthy life extension therapies, from medical technologies capable of repairing the damage of aging, progress must be rapid. Healthy life extension through scientific advancement is inevitable - but not for us, unless we get our act together.
Theorizing on evolutionary effects and diversity in human life span via PhysOrg.com: "researchers point out that one characteristic unique to but common among many pygmy populations is their short lifespan compared to other humans. With this in mind, the researchers suggest that pygmies represent the 'fast' extreme of life history strategies, with short stature being a side effect. ... when I went to the field, and started to interview them, I noticed the very high mortality rates – really high compared to any other population. So when we checked that different pygmy groups followed the same pattern, we thought that these facts should be linked. Also, life history theory has been used for a long time to understand body size diversity among mammals, and we thought it should also apply to the understanding of human diversity ... Because of their short life expectancies, the researchers speculate that pygmies have had to shift their reproductive years forward. The average life expectancy at birth for different pygmy populations ranges from just 16 years to 24 years." We humans are not immune from the historical environments that have shaped animal species - and we will extend our own healthy life spans, just as we are extending the healthy life spans of laboratory animals today.
In this video presentation in the Google Techtalk series, biomedical gerontologist Aubrey de Grey discusses the role of mitochondrial DNA (mtDNA) in aging: "Among other things, mitochondria perform the chemistry of breathing - they extract energy from nutrients by exquisitely regulated chemical reactions that consume oxygen and create [carbon dioxide]. This vital function depends on the 13 proteins encoded by the mitochondrial DNA (mtDNA), as well as on hundreds of proteins that are encoded in our more famous genome and imported across the mitochondrial surface after construction in the body of the cell. The mtDNA accumulates mutant, non-functional variants far faster than our main genome, so 20 years ago scientists began looking at the idea of putting copies of the 13 genes of interest into the nucleus after making modifications that would cause them to be processed by the same 'protein import' machinery that processes the mitochondrion's many other proteins, thus making the mtDNA itself superfluous and mutations in it harmless. ... Progress has been very erratic in the meantime but is now very rapid, partly because of Methuselah Foundation-funded research. However, this approach may still prove impossible, so many other, ostensibly simpler ideas - some more promising than others - have been proposed, and I will describe some of these too."
Here is an interesting view of the mechanics of aging and regeneration in stem cells: "Harnessing cellular fusion as a potential tool for regenerative therapy has been under tentative investigation for decades. A look back the history of fusion experiments in gerontology reveals that [some] have demonstrated that fusion can be used as a tool to revoke cellular senescence and induce tissue regeneration. Recent findings about the role of fusion processes in tissue homeostasis, replenishment, and repair link insights from fusion studies of previous decades with modern developments in stem cell biology and regenerative medicine. We suggest that age-associated loss of regenerative capacity is associated with a decline of effectiveness in stem cell fusion. We project how studies into the fusion of stem cells with tissue cells, or the fusion between activator stem cells and patient cells might help in the development of applications that 'rejuvenate' certain target cells, thereby strategically reinstating a regeneration cascade."
A good last word from Ronald Bailey in the Cato Unbound discussion:
My vision of a future in which effective longevity treatments are available is one in which individuals get to choose to use them or not - no government gets to decide how long its citizens will be allowed to live. That would truly be tyranny. In the meantime, if Callahan chooses to go "gentle into that good night" I wish him well of it, but his job is to warn us the dangers he sees arising from radically extended lives and that’s all very well. He should allow the rest of us to ignore his advice and find out for ourselves whether he is right or wrong. Let us learn freely from trial and error as people always have done.
Freedom and choice are two vital portions of the fundament of a society worth living in. The freedom to be alive, and work on remaining that way, is the greatest of all freedoms - for without life, there is nothing: no possibilities, no human action, no building of a better world. We forget, in our comparative comfort, that to be able to choose to live another day in good health and do your part to move humanity into a better era is a luxury, considered in the grand scheme of human history.
We should value the freedom to remain alive and healthy far more so that we presently do, and thus rationally choose to work hard to extend that freedom for as many and as long as possible - in other words to work to defeat aging in addition to all other threats to life and health. This should go without saying, as an axiom of the human condition, and it is a great pity that that is not the case.
From the Methuselah Foundation: "A veritable stampede of generous donations flattened our first $25,000 matching challenge from Michael Cooper in something under a week. Well done! Strategies for Engineered Negligible Senescence (SENS) research will move that much further and faster for your efforts. Now Doug Arends has picked up the torch with another $25,000 matching challenge for SENS research. As before, when combined with Peter Thiel's $3 million matching fund, donations are tripled. Donate $100 and $300 will go to SENS research - so don't hold back!" If you haven't yet made a year-end charitable donation, here is a good place for it. The SENS research program, aimed at developing a foundation of biotechnology for rejuvenation through the repair of aging, is a bright spot of invention and determination in the biomedical research community. It deserves your support.
This paper illustrates one the reasons why exercise is good for healthy longevity, diving into the mechanics of damage to mitochondria and its role in aging: "Mitochondrial dysfunction is commonly thought to result from oxidative damage that leads to defects in the electron transport chain (ETC). ... we highlight new research indicating that there are early changes in mitochondrial function that precede ETC defects and are reversible thereby providing the possibility of slowing the tempo of mitochondrial aging and cell death. ... Increased mitochondrial uncoupling - reduced adenosine triphosphate (ATP) produced per [oxygen molecule] uptake - and cell ATP depletion are evident in human muscle nearly a decade before accumulation of irreversible DNA damage that causes ETC defects. New evidence points to reduction in activators of [mitochondrial] biogenesis [and] to degradation of mitochondria allowing accumulation of molecular and membrane damage in aged mitochondria. The early dysfunction appears to be reversible based on improved mitochondrial function in vivo and elevated gene expression levels after exercise training." The more time you have before needing to benefit from the mitochondrial repair therapies of the future, the greater the chance those therapies will exist when you need them.
The Scientist looks at present initiatives in mass production of engineering autologous organs for transplant. Note the elephant in the room when people wonder why medical development is so challenging: if phase II trials go well, "the company will schedule a larger, Phase III trial. What happens then is still somewhat unclear. The FDA has never been asked to approve an autologous human organ. What safety criteria will it consider? What kind of quality control procedures and infrastructure will the company need to employ? 'It's not like we're stamping out a million pills a day. We have to custom-grow a new organ for every patient.' ... 'I think the task of trying to commercialize this type of custom-made organ for patients is pretty daunting.' From the beginning, the company interacted with the agency to educate it about how the technology works, scheduling 'at least five' pre-IND meetings. 'The FDA had to create new sets of standards for us,' Sender says. A handful of bladders is one thing; mass producing them is quite another. ... You can probably understand maybe doing one at a time, two at a time, three at a time.Now imagine having to grow thousands of organs a year. Or maybe thousands at one time." In a sane world, those laboring to bring benefits to humanity would just get on and do the job, absent the ball and chain of regulation for the sake of regulation.
As you might have noticed, PubMed entries for papers in the next issue of Rejuvenation Research have been showing up of late. One of those papers looks at the prospects for harnessing mitoptosis as a longevity intervention, a topic guaranteed to catch my attention. What is mitoptosis? You can find a discussion thread on the topic with references over at the Immortality Institute. In essence, keeping it short, mitoptosis is the programmed destruction of mitochondria in your cells, a process analogous to apoptosis, or programmed cell death.
Mitoptosis was described as a sort of mitochondrial death program. It could be associated with both necrosis and apoptosis, although degenerating mitochondria are also found in autophagic vacuoles. It was demonstrated that several molecules might contribute to the remodeling and rearrangement of mitochondrial membranes, leading to mitochondria rupture and disruption. Here, we hypothesize that, at least in T cells, two main pathways of mitoptosis can occur: an inner membrane mitoptosis (IMM), in which only the internal matrix and cristae are lost while the external mitochondrial envelope remains unaltered, and an outer membrane mitoptosis (OMM) where only swollen internal cristae are detected as remnants.
But back to the Rejuvenation Research paper:
There is an imperative need for exploring and implementing mitochondria-rejuvenative interventions that can bridge the current gap toward the step-by step realization of strategies for engineered negligible senescence (SENS) agenda. Recently discovered in mammals, natural mechanism mitoptosis - a selective "suicide" of mutated mitochondria - can facilitate continuous purification of mitochondrial pool in an organism from the most reactive oxygen species (ROS)-producing mitochondria.
Mitoptosis, which is considered to be the first stage of ROS-induced apoptosis, underlies follicular atresia (a "quality control" mechanism in female germline cells that eliminates most germinal follicles in female embryos). Mitoptosis can be also activated in adult postmitotic somatic cells by evolutionary conserved phenotypic adaptations to intermittent oxygen restriction (IOR) and synergistically acting intermittent caloric restriction (ICR).
IOR and ICR are common in mammals and seem to underlie extraordinary longevity and augmented cancer resistance in bowhead whales (Balena mysticetus) and naked mole rats (Heterocephalus glaber). Furthermore, in mammals IOR can facilitate continuous stromal stem cells-dependent tissue repair. A comparative analysis of IOR and ICR mechanisms in both mammals, in conjunction with the experience of decades of biomedical and clinical research on emerging preventative, therapeutic, and rehabilitative modality - the intermittent hypoxic training/therapy (IHT) - indicates that the notable clinical efficiency of IHT is based on the universal adaptational mechanisms that are common in mammals. Further exploration of natural mitochondria-preserving and -rejuvenating strategies can help refinement of IOR- and ICR-based synergistic protocols, having value in clinical human rejuvenation.
To understand why this is interesting, you'll want to wander back in the Fight Aging! archives and read up on the mitochondrial free radical theory of aging. To cut a long story short, damaged mitochondria in a cell will breed more damaged mitochondria in that cell. Repeated over and over, this eventually causes a small but significant number of cells to export damaging free radicals throughout your body, causing great harm to health and life span over time. One focus of SENS and SENS-like research is to cut this process short at the "damaged mitochondria" phase. Eliminate the damaged mitochondria aggressively and often, and that portion of the aging process is gone.
Mitoptosis may be an existing mechanism that can be adapted to this end - though whether this is the case, and whether it is at the root of some exception longevity in the animal kingdom, remains to accumulate greater weight of evidence. For example, much of the recent published work on naked mole-rat biochemistry has suggested that crucial cellular components are more resistant to oxidative damage than those in other rodents, being built of a different mix of biochemicals, rather than being more aggressively recycled and repaired.
The greater the number of potential avenues of approach to each aspect of SENS, each facet of a true therapeutic approach to rejuvenation and the repair of aging, the better off we are. Competition drives the wheel of progress, and choice of approach is a sign of real progress in science. So I am always pleased to see new additions to the stable of potential future medical technologies.
We've seen a lot of ingenuity in bioengineering attacks on cancer with viruses or the immune system. Here's an example of a mixed method - a little of both: "Researchers zeroed in on immature T-cells from bone marrow, programming them to respond to specific threats to the immune system while delivering a cancer-destroying virus to the tumor cells. To deliver the virus, researchers removed T-cells from a healthy mouse, loaded them with the virus and injected the T-cells back into the mouse. Researchers found that once the T-cells returned to the lymph nodes and spleen, the virus detached itself from the T-cells, found the tumor cells, selectively replicated within them and extracted tumor cells from those areas. ... In mice with lung cancer metastasis, cancer cells were significantly reduced in one-third of mice and completely eradicated in two-thirds of mice. Efforts to clear metastases from colorectal tumors were similarly effective. Lung and colorectal tumor cells were purged from lymph nodes. Also, the spleens of mice that had lung cancer developed immunity to the cancer after the treatment."
From Kevin Dewalt: "Person #1: 'Every day 100,000 people die a horrible death after a period of prolonged suffering. I want to stop this from happening.' Person#2: 'That may not be a good idea. It might lead to some unintended consequences.' ... I don't know about you, but the glaring next step in the debate between Persons #1 and #2 is as follows: Person#2 is on the hook to provide a very, very compelling reason to say why saving 100,000 lives a day is a bad idea. This brings me to the point of this post: Don't want to cure aging? The onus is on you - not us - to explain why. ... We may have an opportunity in the next several decades to develop treatments to end the suffering and death for 100,000 people EVERY DAY on this planet. If you think solving this problem is a bad idea, you had better come up with both some very compelling arguments and some facts to support your position. The onus is on you. And that, my friends, should end most of these discussions. So when you find yourself engaged into (yet another) one of these absurd discussions with someone who may be more eloquent, more educated, or better read than yourself, fear not because you have a safety net: The onus is on them to explain why we shouldn't reverse aging. It really is that simple."
A few unrelated papers caught my eye whilst winding my way through PubMed today. This first is an animal study building directly on the very rapid progress in understanding Hutchinson-Gilford progeria syndrome (HGPS), an accelerated aging syndrome.
We recently reported that a protein farnesyltransferase inhibitor (FTI) improved several disease phenotypes in mice with a HGPS mutation (Lmna(HG/+)). Here, we investigated the impact of an FTI on the survival of Lmna(HG/+) mice. The FTI significantly improved the survival of both male and female Lmna(HG/+) mice. Treatment with the FTI also improved body weight curves and reduced the number of spontaneous rib fractures. This study provides further evidence for a beneficial effect of an FTI in HGPS.
This is intervening directly in the mechanisms left broken and malfunctioning by Lamin A (Lmna) mutations. You'll find a more clear explanation of the involvement of farnsylation in an earlier, similar mouse study:
Several progeroid disorders are caused by mutations that lead to the accumulation of a lipid-modified (farnesylated) form of prelamin A, a protein that contributes to the structural scaffolding for the cell nucleus. In progeria, the accumulation of farnesyl-prelamin A disrupts this scaffolding, leading to misshapen nuclei.
The point of interest to all of the rest of us in this research is that cells in the normal elderly appear to be suffering from the same issues. A working therapy for progeria is likely also a therapy of benefit to those suffering from ordinary aging processes.
Switching topics: it's often the case that studies in laboratory animals are criticized for using breeds that are far from wild-type animals, having been bred for generations in the absence of selective pression, wild-type conditions, and so forth. That is a valid criticism when dealing with complex biological systems of many variables, so it is good to see someone filling in the gaps, as in this paper:
Dietary restriction is known to promote longevity in a variety of eukaryotic organisms. Most studies of dietary restriction have been performed on animals bred for many generations under conditions that differ substantially from their natural environment, raising the possibility that some apparent beneficial effects of dietary restriction are due to adaptation to laboratory conditions. To address this question in an invertebrate model, we determined the effect of dietary restriction by bacterial deprivation on life span in five different wild-derived Caenorhabditis elegans strains and two strains of the related species Caenorhabditis remanei. Longevity was enhanced in each of the wild-derived C. elegans strains, in most cases to a degree similar to that observed in N2, the standard laboratory strain. Both strains of C. remanei were substantially longer lived any of the C. elegans isolates, produced larger brood sizes, and retained the ability to produce offspring for a longer period of time. Dietary restriction failed to increase mean life span in one C. remanei isolate, but significantly increased the maximum life span of both C. remanei strains. Thus, we find no evidence that adaptation to laboratory conditions has significantly altered the aging process in C. elegans under either standard or food-restricted conditions.
There you have it.
Switching topics once more, this last paper on the origins of osteoporosis caught my eye more for the sentiments of the researchers than for the contents:
We suggest that future osteoporosis therapy will likely focus on prevention of aging in general as a means to prevent the development of osteoporosis.
I can't overemphasis how much of a sea change it is to see more of this kind of talk in the scientific community. This first decade of the 21st century is a real turning point for aging research, wherein the mainstream slowly realigns itself to to goal of healthy life extension, while the cutting edge is running ahead with the defeat of aging in mind. We live in interesting times.
As I might have remarked once or twice, the efficient construction of blood vessels is a crucial infrastructural goal for the field of tissue engineering. Further progress absolutely depends upon it: "The work focuses on vascular tissue, which includes capillaries, the tiniest blood vessels, and is an important part of the circulatory system. The team has created a surface that can serve as a template to grow capillary tubes aligned in a specific direction. ... The surface is patterned with ridges and grooves that guide the cells' growth. ... The cells, known as endothelial progenitor cells (EPCs), not only elongate in the direction of the grooves, but also align themselves along the grooves. That results in a multicellular structure with defined edges, also called a band structure. Once the band structures form, the researchers apply a commonly used gel that induces cells to form three-dimensional tubes. Unlike cells grown on a flat surface, which form a network of capillary tubes extending in random directions, cells grown on the nano-patterned surface form capillaries aligned in the direction chosen by the researchers."
As Wired notes, the old school drug development community is making some inroads into altering the level of age-related damage suffered by mitochondria, and thereby improving health. This is small potatoes compared to what will soon be possible, but inroads are inroads: "The drugs target mitochondria, the cellular power generators that provide our bodies with chemical energy. Over time, mitochondria accumulate damage, causing cells and eventually tissues to malfunction and break down. Some scientists believe that such seemingly disparate diseases as cancer, Parkinson's, Alzheimer's, diabetes and heart disease - all of which become more common with age - share a mitochondrial root. Fix the mitochondria, and you might fix aging itself. Preliminary research suggests that mitochondria-rejuvenating drugs are capable, at least in lab animals, of halting these diseases and extending longevity." Unfortunately, more than just repairing mitochondria is required to sort out aging - a number of other classes of age-related biochemical damage are also important and must be addressed.
The Longevity Meme Folding@Home team has been steadily rising through the ranks since its inception, thanks to the volunteer efforts of the many team members. The team is closing in on rank 200, a point that has been marked as a milestone for while. The lower ranks are a tough slog, but the team has been doing well - growing and producing results.
I have decided that the best thing to do to mark the passage of rank 200, rather than send out another round of Longevity Meme tchotchkes, is to donate a chunk of change to the Methuselah Foundation, where it can be put to good use in advancing longevity science. Here is my incentive for the team: pass rank 200, and stay beneath that level for a week, and I'll donate $1000 in support of Strategies for Engineered Negligible Senescence (SENS) research carried out by the Foundation.
You might look at the recent progress report from the Methuselah Foundation for a detailed look at how research funding is spent, and what progress has been made to date.
Comments are welcome.
One of the reasons the aging immune system fails in its job is the reduction of naive T cells, ready to tackle new threats. One approach to tackling this problem is to eliminate the cause - that too great a fraction of the immune system's limited resources is uselessly devoted to CMV-targeted memory cells. Another approach is outlined here: make more naive T cells available. "Throughout our lives, naive T-cells divide very slowly in our bodies. This helps maintain sufficient numbers of naive T-cells while we are young. As we age, naive T-cells are lost and the remaining ones speed up their division to make up for the losses in their numbers. Interestingly, after a certain point, this actually causes the numbers of naive T-cells to dwindle over time. Our data shows that once the number of naïve T-cells drops below a critical point, the rapidly dividing naive cells are very short lived. Based on this finding and other information, research suggests that some of the aging Americans may be better protected against disease by finding a way to jumpstart production of new naive T-cells instead of through revaccination. ... Even a slight boost in the number of these important T-cells could protect an aging person against disease for several years."
It's always interesting to see community institutions from a fresh perspective. Here, Anne C. discovers the Buck Institute for Age Research: "I'm tremendously pleased to see that the Institute exists, and I really like their up-front focus on improving the health of the elderly. ... The notion of 'strategic aging' as described here is actually quite similar to the SENS paradigm on which the Methuselah Foundation is basing its research objectives. Of course everyone is going to get old someday (it's one of those inevitable consequences of being born), but there's no fundamental reason why getting old should have to lead to painful, fatal illness. The notion of 'strategic aging' recognizes that people's health needs change as they age, and that it makes much more sense to address these changing needs proactively than wait until a person sits at death's door. This proactive approach is becoming more and more of a realistic one, and if all goes well, it will hopefully become the default paradigm within a few decades or so." I'd have placed the Institute in that part of the research community that has yet to come around to the importance of repair over metabolic tinkering in addressing aging - which I consider far more important a division than intent.
If there is even a single simplicity lurking within cancer, a single commonality of biochemistry, a single dominant class of mechanism that passes through a bottleneck of complexity, then cancer will soon be a thing of the past. The technologies and research communities of this present biotechnology revolution will run it over and squash it flat. The common thread will be found, and therapies cranked out in short order to disrupt or suppress its operation.
So we can hope that varieties of the "cancer's evolutionary tendencies guarantee its unlimited variance and unremitting complexity" argument turn out to be false in the end. It's a reasonable thing to hope for, given the way in which evolved systems tend to be constructed. Take this research reported in EurekAlert!, for example:
researchers have devised a way to generate large numbers of human breast cancer stem cells in mice and have discovered a genetic switch that regulates critical properties of the cells. The regulator, which belongs to a class of molecules called microRNAs, pushes the stem cells to become more differentiated and less tumorigenic through its ability to switch off particular genes.
With a ready supply of cancer stem cells, the researchers were able to measure levels of microRNAs, small gene regulators that are known to influence a gene’s ability to create proteins important for cell growth and differentiation. They found that cancer stem cells contained low amounts of several microRNAs compared to more mature tumor cells or stem cells that had differentiated in culture.
They zeroed in on a tumor-supressing microRNA called let-7. When the team activated let-7 in the stem cells, they lost their ability to self-renew and began to differentiate. The cells also became less able to form tumors in mice or to metastasize. Further studies showed that let-7 did this by switching off two cancer-related genes: the oncogene Ras, and HMG2A, which when switched off caused the cells to differentiate.
If this finding applies to other tumor types, let-7 may offer a unique opportunity to attack tumor stem cells using therapeutic RNA. Delivery of the let-7 RNA to tumors could potentially deplete stem cells by pushing them down the path of differentiation.
This is one of a hundred different investigations into the biomechanisms of cancer that might - maybe - expand out to something that could be called a cure for cancer. If there is key, or class of keys to the creation of cancer - a point at which a spanner can be thrown into the works with the biotechnologies of the 2000s and 2010s - I'll wager it will be found and exploited sometime within the next decade.
The Methuselah Foundation fills us in on progress to date: "We are currently sponsoring research in two of the seven strands of the SENS program; the preventing the harm caused by mitochondrial mutations (MitoSENS) and degrading damaging long-lived cellular debris (LysoSENS) ... our teams have already seen interesting results and are moving forward rapidly. ... When these projects began in the summer of 2005, there was no strong evidence to suggest that any enzymes or organisms degrading intracellular junk existed in nature [but] reseach volunteers had successfully cultured [7-ketocholesterol (7KC)] degraders before the end of 2005. ... 2006 saw further characterization of the 7KC degraders and corroboration of the results. In summer 2007, six undergraduate research assistants and one additional PhD candidate [helped] with synthesizing additional target compounds, such as A2E and CML (a major [advanced glycation end-product]). ... [today, researchers] are preparing to move them into a cell model of age-related macular degeneration for initial safety and efficacy testing. Various other projects [are] at earlier stages. Novel targets include artificial lipofuscin and the infamous glucosepane AGE-crosslink."
More evidence for autophagy as a good thing - above and beyond its apparently pivotal role in calorie restriction benefits - from ScienceDaily: "Suppressing a cellular cleanup mechanism known as autophagy can accelerate the accumulation of protein aggregates that leads to neural degeneration. [Scientists] report for the first time that the opposite is true as well: Boosting autophagy in the nervous system of fruit flies prevented the age-dependent accumulation of cellular damage in neurons and promoted longevity. ... We discovered that levels of several key pathway members are reduced in Drosophila neural tissue as a normal part of aging. Which suggests there is an age-dependent suppression of autophagy that may be a contributing factor for human neurodegenerative disorders like Alzheimer's disease. ... Keeping cells free of damaged molecules is critical for neurons because unlike many cells, they do not divide or replace themselves once created at birth. ... They rely on autophagy together with other clearance and detoxification pathways to keep themselves healthy and functioning for decades."
I am always pleased to see the continued spread of serious, intelligent discussion of healthy life extension and longevity science. Public dialog is a tide, buoying awareness and education, raising the boats of research funding. The more the better.
If a technology existed to eliminate the physical effects of aging, it would be a boon to mankind, and it would be atrocious to forbid it. People should be allowed to experience aging if they wish, of course, but if science could make it optional, then the option should be available.
And yes, I would take it. I would definitely want to live a thousand years or more. I would want all of my loved ones with me, and my only regret would be that some of them are already gone and cannot be. You and I are among the first of our species for whom physical immortality is even an outside possibility, but if the choice ever came up, I assure you that I would go for it.
Anti-aging drugs would not confer invulnerability. We could still kill tyrants, and it would still be morally legitimate to do so. The prospect of living in Stalin’s dictatorship forever makes the duty of doing away with tyrants all the clearer. It wouldn’t just be a matter surviving for a few more years until the old guy croaks. It would be an eternity, and the obligation would be obvious. This is probably a good thing as far as I’m concerned.
I may be against the death penalty, but I’m all in favor of term limits, with outright tyrannicide as their most extreme manifestation. A big part of what makes Stalin “Stalin” was simply that he controlled a vast army and secret police apparatus. That’s the real enemy here, not life extension. Arguing for life extension does not mean that I’m arguing for an extension of the personal rule of anyone.
That's a well-formed response to the "eternal tyrant" version of the stagnation objection to radical life extension. Tyrants, or indeed any bad social order, is only as eternal as people allow it to be. Revolution against limits, against oppression, against evil - that's a personal, individual choice and obligation.
The story of any life is change, not stasis. People grow, change and engineer their lives, and through their individual choices, trades and collaborations produce a living, breathing, dynamic society. That won't stop when people live an extra 10 years, 100 years or 1000 years - but the range of individual freedom to experience change, growth and choice increases with each extra year.
That is a very good thing, and how could it be otherwise? People who would sacrifice billions in a futile attempt to hang onto the cultural norms they are used to are people who, in my view, suffer from some fundamental flaw in their moral compass. It's a pity there are so many of them - but all the more reason for those of us who support health, longevity and life to work harder at our goals.
Gene Engineering News is broadening its scope with podcasts on late, such as this interview with researcher Michael Rose: "science is now gaining a better understanding of the human aging process, with the ultimate goal of exerting some control over it. During this week's podcast, Dr. Michael Rose, developer of the long-lived Methuselah fruit fly line and one of the pioneers in aging research, offers his insights on the science of aging. He addresses such questions as 'why we age' and 'are aging and age-related disease synonymous?' Does the concept of humans one day living to be 150-years-old or more lie in the realm of science or science fiction? A specialist in evolutionary biology, Dr. Rose talks about how can advances in evolutionary biology can help us postpone aging. He discusses why severe caloric restriction will not substantially increase the lifespans of humans although it often does so in animal models. Dr. Rose also presents his case that there is a serious, hardcore, mathematical, scientific theory that underlies aging, but that a paucity of mathematically-inclined biologists is inhibiting discussion and further advances in the scientific study of aging based [on] this theory."
From Chris Patil Ouroboros: "If p53 were to somehow go AWOL in a cell, it would bode poorly for cancer prevention. Lacking this critical checkpoint control, genetically damaged cells could go on cycling, perhaps developing additional genomic changes that further encourage unrestricted growth, and eventually becoming frankly neoplastic. A recent study from Arnie Levine's lab shows that the p53 response to one form of genotoxic stress (ionizing radiation) becomes less efficient [in] old mice. If this finding is general to other humans, it could partially explain why the risk of tumors increases exponentially with age. ... I wonder whether a contributing factor might be adaptation of the signaling pathways involved. Signaling pathways almost always involve some negative feedback; among other things, this serves to prevent inappropriate activation of a pathway in response to a low baseline level of stimulus, to preserve the dynamic range of the system and reset the threshold so that it can be triggered only by really noteworthy events." Patil goes on to suggest an off the cuff theory as to how declines in p53 - and increased propensity to cancer - might operate, some tests of the hypothesis, and how the system might be reset if true.
As I'm sure you know, Cato Unbound has been hosting an exchange of essays and opinions on death and radical life extension over the past ten days. On the pro-being-alive-and-healthy side are Aubrey de Grey and Ronald Bailey, while Diana Schaub and Daniel Callahan preach the wonders of deathism. I was following along up to the Callahan essay over at the Longevity Meme:
We lock people up for the same amount of time if they kill people with a gun or with a booby-trap bomb, even though the interval between the murderer's action and the victim’s death differs by several orders of magnitude in the two cases. The same irrelevance of that interval applies to the saving of lives, since action and inaction are morally indistinguishable. We are close enough today to defeating aging that serendipity does not define the timeframe: the sooner and harder we try to do it, the sooner we'll succeed. Thus, our inaction today costs lives - lots of lives.
It is sad that so many people would choose the stasis of the now - and death and suffering without end, over and over - rather than immensely positive change and opportunity through longevity science. Talking nonsense about petrified, unchanging ageless societies is projection, methinks.
the highest expression of human nature and dignity is to strive to overcome the limitations imposed on us by our genes, our evolution and our environment. Future generations will look back at the beginning of the 21st century with astonishment that some well-meaning and intelligent people actually wanted to stop biomedical research just to protect their cramped and limited vision of human nature. Our descendants will look back, I predict, and thank us for making their world of longer, healthier lives possible.
The first four essays - the three above, and my stopping point of Daniel Callahan - form a basis for further responses. Both Ronald Bailey and Aubrey de Grey have posted more as of today.
Obviously then Callahan must regard the hundreds of millions of his fellow human beings who would take advantage of cheap effective age-retardation treatments as being somehow delusional - they don’t know their own best interests. I suppose that’s possible, but it is far more likely that Callahan is especially deep in thrall to what de Grey calls the “pro-aging trance.”
Callahan then tries to suggest that we have no evidence that radical life extension would be “good for us as human beings” - and this is where he embarks on the main thrust of his argument, the primacy of society over the individual. First of all, he seems to have a very curious idea of what does and does not constitute evidence for or against a proposition. If the only admissible evidence that something will happen is that it has already happened, I challenge Callahan to tell me why he believes that the sun will rise tomorrow. The true nature of evidence, of course, is that things have happened which have various features in common, and which thereby lend support to a general hypothesis that all things of a particular sort that happen in the future will have a particular property. In this case, the body of evidence is rather formidable: it is hard to find people in good health, of any age, who will volunteer to die tomorrow (and, again, if we do find such people we call the Samaritans).
Accepting any form of primacy of "society" (whatever that might be) over the individual is where everything starts to go wrong. It is the top of of a very long and jagged slope down to the worst excesses of facism and communism. Place nebulous concepts above the well-being and self-determination of individuals, and the institutions of theft, redistribution, force and violence will spread - for any individual right is up for sacrifice to the icons.
Here we have one small part of that struggle in the present day: the incredible fact that we even feel it necessary to debate those who would use the power of the state to limit our lives and access to medical technology even more drastically than is presently the case. When the resources of government are so great and stifling that it affects every part of our lives, we are right to be wary of those who might turn those resouces to our detriment.
I think you'll agree this is an intriguing addition to the stable of potential methods to replace damaged mitochondria, and thus remove their contribution to aging and age-related disease: "Mitochondrial DNA [or mtDNA] mutations are the direct cause of several physiological disorders and are also associated with the aging process. The modest progress made over the past two decades towards manipulating the mitochondrial genome and understanding its function within living mammalian cells means that cures for mitochondrial DNA mutations are still elusive. Here, we report that transformed mammalian cells internalize exogenous isolated mitochondria upon simple co-incubation. We first demonstrate the physical presence of internalized mitochondria within recipient cells using fluorescence microscopy. Second, we show that xenogenic transfer of murine mitochondria into human cells lacking functional mitochondria can functionally restore respiration in cells lacking mtDNA." I'm sure you can speculate on how one would build therapies upon this basis, should it be made safe and reliable.
From Kevin Dewalt: "My End Aging Challenge is simple: Create and post a reply to this video on YouTube explaining why you support Dr. Aubrey de Grey's and the Methuselah Foundation's mission to end aging. I will donate $10 to the Methuselah Foundation for every video response. If you have the means, I also suggest that you offer in your video response to match me with a donation of your own for every video. After you shoot your video, follow this link to post your video reply." Good show. If you want something done, no matter how daunting or large the task, the best way to go about it is to get out there and help make it happen. Put your shoulder to the wheel and lead by example. It matters not the size and weight of that wheel, as many hands make light work. It matters greatly that you show that the job exists, and that someone is willing to work at getting it done. Where is one willing worker exists, there will soon be more.
Kevin Dewalt continues his series of posts looking at the common knee-jerk, poorly throught through reasons people give in support of aging to death, and not seeking to develop working rejuvenation medicine.
Let's now dispense with the misconception so common that it has a name: the infamous Tithonus Error, the assumption that radically extending human lifespan equates to a state of prolonged misery of decades in nursing homes. (Tithonus is a figure from Greek mythology).
Aging IS ghastly. After only 15-20 years of optimal [adult] health, human beings begin a slow, steady decline that eventually leads to years or decades of suffering for them, their loved ones, and society. It is only natural that all of us would fear extending this period of misery and frailty.
Fortunately, this is not the future we are pursuing. By reversing aging we hope to keep all of us in a state of optimal health for eternity. Moreover, the possibility of extending the period of infirmity seems very, very unlikely because aging kills us as a result of accumulated damage. Unless we figure out a way to undo this damage, we probably won't survive much longer than we already do. Chris Lawson has dealt with this subject at length
Personally, I love life. I love being young (enough) and living each day to its fullest. I can’t recall a single instance of a person in good mental and physical health telling me that he or she is ready to die.
So, no, I don’t see the potential issue of boredom being a reason to not cure aging.
There's more on the issue of boredom back in the Fight Aging! archives:
How could anyone feel that they would be bored? In part, this might stem from the Tithonus Error itself. A person may assume they would be old and incapacitated in their extended life span, thus unable to do interesting things. But if you have the body and physical capabilities of a 30 year old, why not go clubbing in a new city to new music at 90. Or 190?
Even active, inventive, happy people often assume that longer healthy lives will bring boredom through repetition, however. Ask someone you know how long it would take them to run out of new things to do and become bored if they could live in good health forever. Your friend will give you an outrageously low number of years, I'll bet. If you stop to think about it - rather than just going on instinct - you'll soon realize that you are never going to be any more likely to become bored of life than you are right now. There is simply too much to do, too many different things to think, feel, do and accomplish. In fact, the advance of technology means there is always more to do with each new passing year. New possibilities, activities and enhancements to the quality and variety of life are constantly opening up.
Your life is what you make of it, and the defeat of aging would keep that statement true for as long as you cared for it to be true. As I've often said, the real goal of a cure for aging is to enable a choice we do not presently have: the choice to see what tomorrow will bring, for so long as it interests us to do so. Therein is freedom.
This PDF analysis looks at challenges and advances for the next 15 years of tissue engineering, as seen by scientists in the field: "highly strategic issues often may not lie at the forefront of our day-to-day conception of the most important foci in the field, making such analyses more important to undertake. For example, the strategically most important category, angiogenic control [or engineering blood vessels], was supported by only four contributed ideas. However, its dominance over nine other concepts and its low level of present progress propelled it to the top of the list of strategic concepts. Clearly, mastering the control of angiogenesis will be at the heart of any attempts to grow larger tissue engineered constructs than have thus far been achievable. This will apply whether such growth occurs in vitro or within the body as a response to cell and/or scaffold implantation. Stem cell science is the second most strategic concept. [It] may well be that the understanding and control of stem cell development will enable us to short circuit some of the tissue engineering methods used heretofore - perhaps allowing the concurrent growth of vascular systems with parenchymal tissues."
From the Methuselah Foundation: "With the flood of generous year-end donations during this time of triple matching challenges, we're pleased to announce that the grand total of pledges and donations to the Methuselah Foundation has passed $10 million! This counts the Mprize for longevity science, SENS research - which itself recently passed the $5 million mark - and expense donations. This wonderful goal has been accomplished in just four years due to the hard work and generosity of many hundreds of people, volunteers, donors and supporters. We thank you all, and look forward to keeping up the accelerating pace over the next four years." The Methuselah Foundation is one of the great success stories of the transhumanist community. People moved beyond just talking about the future and stepped up to help shape that future. The $10 million dollar mark is a great milestone, and an impossibly distant milestone when we were looking at Dave Gobel's idea for the Three Hundred back in 2004 - but here we are, and onward we go. Thank you all.
I seem to recall salmon held up as an argument for programmed aging in general - as opposed to aging as wear and tear - due to their very fast decline into senescence following spawning. This circumstance is very specific to salmon, however, having much more to do with evolutionary adaptation and the appetites of bears than any broader form of programmed aging:
Pacific salmon are noted for not feeding during their breeding period, relying instead on stored energy reserves and for their rapid senescence - the physiological deterioration associated with aging - once breeding is over. It is, thus, more beneficial for bears to consume fish with fewer signs of senescence because these fish have more energy reserves. However, these “fresh” fish are also more vigorous and harder to catch and so are more effectively caught in smaller, shallower streams.
Carlson and colleagues studied populations of salmon and brown bears in six creeks in southwest Alaska to determine whether the rate of senescence in salmon was driven primarily by the rate of predation by bears or by the tendency of the bears to prey on salmon with less evidence of senescence. They measured the reproductive lifespan of each fish as the number of days between stream entry and death and recorded the mode of death for each fish. They found that the selectivity of the bears for salmon of various senescent conditions was the prime factor determining the rate of senescence in the salmon.
In populations where bears killed old, decrepit salmon, the salmon senesced more slowly relative to populations where bears killed young, “fresh” salmon. This result contrasts with the established expectation that senescence evolves because of the number of individuals killed by predators, rather than their physical characteristics.
Here's the original paper via PLoS One:
We found that the degree of condition dependence in extrinsic mortality was very important in driving senescence: populations where bears selectively killed fish showing advanced senescence were those that senesced least rapidly.
Lazy bears mean longer lived salmon - an extreme example of the way in which evolution favors successful mechanisms for early reproductive success over the longevity of those mechanisms. Evolutionary circumstances are wildly difference for different species, however, and we should expect to see wildly different mechanisms, rates and circumstances of aging - and so we do. Few variations out there in the animal kingdom will be directly relevant to the quest to intervene successfully in human aging, but until you dig in you won't know for sure.
The People Database blog continues a sterling job of recording the dialogue of the healthy life extension community: "There are many ways we can define cryonics. Sometimes it is presented as a scientific experiment done on humans. The direction that we are headed in now is to present it as a long-term form of critical care medicine. ... The point is, doctors tend to be a rather stilted lot. They don't necessarily embrace things that work just because they work. They have to go through a kind of culturalization. As far as cryonics goes, leaving the realm of science fiction and entering the realm of critical care medicine, the entry point will be fairly rigorous and will involve randomized double-blind studies to show potential. Of course, you have to remember that the whole point of science is imagination. This is imaginative. Anything that is imaginative is welcome. If it can be shown to have some scientific rationality, if it can be shown to make sense, eventually it will slowly blend into a very stilted bunch of people who don't accept things readily."
Good news from the Methuselah Foundation: "You might recall in 2006 that Peter Thiel made a $3 million Matching Challenge to SENS Research, where he matches 50% of donations to research until the end of 2009. Well, our performance and Thiel's example have prompted a supporter and Three Hundred Member, Michael Cooper, to join in. He is offering a $25,000 Matching Challenge of his own until the end of this month. ... Your donations to speed research into repairing the damage of aging and extending the healthy human lifespan will be matched 2-to-1 until the end of 2007, expanding your donation threefold. ... The two presently open Donation Challenges match donations to SENS Research cumulatively. That is, newer matching pledges are evaluated first and the amount matched is added to the incoming donation before the amount for the next matching pledge is calculated, magnifying the value of the donation substantially. At present, a $100 donation (enough for a free autographed copy of 'Ending Aging') is leveraged to $300!" If you've been thinking about stepping up to help make a real difference to the field of aging research, now is the time. If not now, when?
I would go so far as to say that there are only three things that you can do today to be as sure as present science allows that you have increased your remaining healthy life expectancy. The gold standard for weight of scientific evidence is a narrow platform at present:
- responsibly practice calorie restriction
- exercise regularly
- support the most proactive, plausible longevity research
None of this should really be a surprise. I'd add a fourth item for modest supplementation, but any discussion of the scientific support there gets bogged down very quickly - it's an enormously broad and complex topic, beset by a noisy band of marketeers ready to tell you anything that will make you shell out for whatever it is they're selling today.
If the future of longevity research goes the way we'd all like it to go, calorie restriction and exercise will increase - for most people - the chances of living in good health to benefit from the first real, working rejuvenation therapies. It's smart to do those easy, low cost things that raise the odds, just as it's smart to recognize that these are odds. The future is never certain, even when we're setting out to craft it in the manner we would like.
On the subject of exercise, aging and longevity, you'll find a raft of papers on PubMed from the Applied Physiology, Nutrition, and Metabolism journal. The few excepts below look at some of the ways in which regular exercise beneficially changes the operation of metabolic processes.
Although not completely understood, the mechanisms underlying the aging process may partly involve inflammatory processes, oxidative damage, mitochondrial dysfunction, and apoptotic tissue degeneration. These hypotheses are based on epidemiological evidence and data from animal models of aging, as well as interventional studies. Findings from these studies have identified possible strategies to decrease the incidence of age-related diseases and delay the aging process. For example, lifelong exercise is known to extend mean life-span, whereas calorie restriction (CR) increases both mean and maximum life-span in a variety of species. Optimal application of these intervention strategies in the elderly may positively affect health-related outcomes and possibly longevity.
moderate regular exercise attenuates oxidative stress. The mild oxidative stress possibly elicited by regular exercise appears to manifest a hormesis-like effect in nonmuscular tissues, constituting beneficial mechanisms of exercise by adaptively upregulating various antioxidant mechanisms, including antioxidative and repair-degradation enzymes for damaged molecules. Importantly, the adaptation induced by regular exercise was effective even if initiated late in life.
Reactive oxygen species (ROS) are continuously generated during aerobic metabolism. Certain levels of ROS, which could be dependent on the type of cell, cell age, history of ROS exposure, etc., could facilitate specific cell functions. Indeed, ROS stimulate a number of stress responses and activate gene expression for a wide range of proteins. It is well known that increased levels of ROS are involved in the aging process and the pathogenesis of a number of neurodegenerative diseases. Because of the enhanced sensitivity of the central nervous system to ROS, it is especially important to maintain the normal redox state in different types of neuro cells.
It appears that exercise-induced modulation of the redox state is an important means by which exercise benefits brain function, increases the resistance against oxidative stress, and facilitates recovery from oxidative stress.
The bottom line: over the long term, these sorts of changes add up to additional years of health. Exercise reduce the rate at which some of the cellular and biomolecular damage of aging accumulates, either by slowing the ongoing addition of new damage, or by modifying the processes of repair. In a future of rapidly advancing biotechnology, even a single additional year of time to wait for new therapies is a big deal. So swing the odds in your favor.
The mitochondria are to the eukaryotic cell what the heart is to the body. Responsible for maintaining cellular energy balance, mitochondria also lie at the nexus of the signaling pathways controlling apoptosis, or programmed cell death. As a result, mitochondrial trouble - especially oxidative stress produced by metabolic defects - can wreak havoc with multiple organ systems simultaneously, blurring medical science's conventional boundaries.
"All the people under the age of 35 have nice full-length mitochondrial DNAs; all us old duffers over the age of 50 all had a different array of mitochondrial mutations," he says. In chimpanzees, which live about half as long as humans, the researchers found that the same number of mitochondrial DNA mutations accumulate in about half the time. Mitochondria in mice mutate even faster, in direct proportion to the much shorter lifespans of these animals. "So in fact there seems to be a nice correlation between accumulation of somatic mutations and aging," says Wallace.
To test this correlation, the team created transgenic mice that express the catalase enzyme in their mitochondria. Catalase breaks down the reactive species hydrogen peroxide, and the reduction in oxidative stress allows these mice to live about 20% longer than their wild-type brethren.
Besides helping to drive generalized aging, reactive oxygen species may also mediate the progression of specific diseases.
Developing the means to repair our mitochondrial DNA - or cleverly make damage to that DNA irrelevant - is clearly important. It's one of many lines of research in the fight to defeat degenerative aging, but like the others, we can clearly see the finish line from where we are now. A number of different approaches presently exist, and some, like protofection, have been demonstrated in the laboratory.
This achievement has important implications for medicine: protofection technology works in vivo, and should be capable of replacing damaged mitochondrial genomes.
What is needed, and what is lacking, is funding, support, and widespread understanding of just how close we are to real progress in the development of the first generation of working rejuvenation medicine.
Back to Cato Unbound we go, for Ronald Bailey's contribution to the present debate. "Schaub offers no data nor even a plausible line of reasoning that longer healthy lives will result in 'social sclerosis.' In fact, the available evidence cuts the other way. Social and technological innovation has been most rapid in those societies with the highest average life expectancies. Yale University economist William Nordhaus estimates that the huge increase in average life expectancy in the United States, from forty-seven years in 1900 to seventy-seven years today, has been responsible for about 40 percent of the increase in our standard of living. ... the highest expression of human nature and dignity is to strive to overcome the limitations imposed on us by our genes, our evolution and our environment. Future generations will look back at the beginning of the 21st century with astonishment that some well-meaning and intelligent people actually wanted to stop biomedical research just to protect their cramped and limited vision of human nature. Our descendants will look back, I predict, and thank us for making their world of longer, healthier lives possible." Just so. Do we need death? "No. Next question."
More on the nuts and bolts of lamin A, the root of accelerated aging in progeria (HGPS), from PLoS One: "90% of HGPS cases carry the [lamin A mutation], activating a splice donor site that results in production of a dominant negative form of lamin A protein, denoted progerin. Screening 150 skin biopsies from unaffected individuals (newborn to 97 years) showed that a similar splicing event occurs in vivo at a low level in the skin at all ages. While progerin mRNA remains low, the protein accumulates in the skin with age in a subset of dermal fibroblasts and in a few terminally differentiated keratinocytes. Progerin-positive fibroblasts localize near the basement membrane and in the papillary dermis of young adult skin; however, their numbers increase and their distribution reaches the deep reticular dermis in elderly skin. Our findings demonstrate that progerin expression is a biomarker of normal cellular aging and may potentially be linked to terminal differentiation and senescence in elderly individuals." This enlarges upon earlier work demonstrating the presence of lamin A defects in normal individuals.
The first of the response essays to Aubrey de Grey's piece at Cato Unbound epitomizes mild-mannered deathism; the instinct that any radical change to the human condition brought on by healthy life extension must be bad. If I had to pick out the one thing the archetypical human hates and fears above all else, it'd be the prospect of change - and that always shows through in discussions of radically increasing the healthy human life span. "Even without the threat of vastly extended tyranny, a nation of ageless individuals could well produce a sclerotic society, petrified in its ways and views. Senescence escorts us, more or less gracefully, off the stage, making room for fresh generations. The aging of individuals may be one condition for societal renascence. Fascinatingly, longevity research in animals suggests that one cost of age-retardation is sterility or decreased fertility. If there are trade-offs between long life and new life, then the quest for individual immortality may pose dangers for the well-being of the human collective, whether at the level of the family, the nation, or the species. While frailty and finitude don't seem such good things, they may be inextricably entwined with other very good things that we would not want to sacrifice." It is sad that so many people would choose the stasis of the now - and death and suffering without end, over and over - rather than immensely positive change and opportunity through longevity science. Talking nonsense about petrified, unchanging ageless societies is projection, methinks.
If we knew exactly how stem cells, progenitor cells and other developing cells can produce regeneration without generating new tissue themselves, then we wouldn't need the cells. An example of that truism in action is provided by ScienceDaily: "a protein called connexin43, expressed by the transplanted embryonic heart cells, improved electrical connections to other heart cells. The researchers showed that the improved connections helped activate the transplanted cells deep within the damaged section of the heart tissue. The technique reversed the risk of developing ventricular arrhythmias after a heart attack ... In the past, scientists have transplanted a variety of cell types into failing hearts with modest improvement of function, although transplanting skeletal muscle cells made things worse and led to more arrhythmias. Surprisingly, when [researchers] transplanted embryonic cardiac cells, the hearts' electrical stability and function returned to normal. ... we were able to see how cells used in therapy are working with other cells in a complex organ within a living animal, establishing the mechanism of the therapeutic effect ... [researchers] engineered skeletal muscle to express connexin43 and achieved the same restorative results as they did with the embryonic heart cells."
Researcher Attila Chordash has some comments to make on a rather dismissive review of Ending Aging in Nature by a "neuroethics expert."
Unfortunately Illes completely mixes transhumanism with the belief that robust life extension is possible and desirable due to handling the 2 books together and I think this is not a fair angle on life extension. Consequently she can say on the whole that those beliefs are "going well beyond what might be imaginable, or ethical today."
While reading Chordash's comments, and some of the excerpts, it struck me that a scientist-turned-ethicist is a scientist who doesn't like change. This is to say a scientist who has cast aside the core, essential function of the practice of the scientific method, which is to bring positive change to the state of human knowledge, and thus positive change to the world through the application of that knowledge. The ethicist gives up that noble first cause in favor of dropping caltrops onto the path to tomorrow, and structuring a life in which success is measured by how greatly progress is impeded.
The ethics movement in science is fear of change writ large, so large that those scientists who follow that path forget the roots of their calling.
The Scientist looks at the future of tissue engineered, perfect eyes: "Picture-perfect vision, with lovely dark pupils and irises of any color you want. Who wouldn't want that? Every person who wears glasses or contact lenses, or who just has that classic wish of the pilot or bird watcher - to see just a little bit better, farther, or more clearly at night - or who, vanity of vanities, wants slightly brighter green eyes, would be delighted to hear that stem cell research is moving us closer to the day when eyes might be created in the lab and implantable. Looming is the prospect of creating human eyes (or at the very least, central components of the eye) for the purposes of replacing, repairing, or regenerating unhealthy or damaged tissue. Scientists are finding pieces of the puzzle, those factors that control the generation of eyes ... If you knew all the genes, and how to turn them on, that you needed to make an eye, you could start with very early embryonic cells and turn on all the right genes and grow an eye in a dish."
If you head over to the Methuselah Foundation, you'll see that the total pledged for Strategies for Engineered Negligible Senescence (SENS) research has topped $5 million dollars - all raised in the past couple of years. That's a hefty chunk of change, considering one can set up a noteworthy, focused research institute at a major university with just twice that amount these days. Much of the $5 million has been donated by people just like you or I, who know the sort of world they'd like to live in, and who stepped up to the plate to make a difference. This is the sort of thing we all like to see, as supporters of meaningful longevity research and a wide-open future of longer, healthier lives. Widespread support and significant funding for direct, vocal scientific attempts to defeat aging are the best foot forward on the road to that future. Aging will come for us all until we band together and do something about it. When taking advantage of the medical technology of the 2030s, don't you want to be one of the people who can say "we made this technology happen, we saved billions of lives?"
Bay Area public radio station KQED yesterday looked at aging and longevity research - as Chris Patil was pleased to note a few days ago:
The Buck Institute for Age Research will be featured [on] KQED’s morning talk show, Forum. The program starts at 9 AM PST; I’ve just learned that the show will be broadcasting live from the Buck itself. ... Note that Forum is a call-in show, and it might be nice to have some actual biogerontologists phone in a few good questions. I’m just sayin’.
On a personal note, my baymates and I are tickled pink because our beloved postdoctoral advisor, Judy Campisi., will be among the interviewees.
Those of you arriving late can find the program in two parts in the Forum audio archive:
Forum discusses the history of research on aging, the process of aging and the latest studies in a live remote broadcast from the Buck Institute for Age Research.
In the second hour of a live remote broadcast from the Buck Institute for Age Research, the show looks at social and policy implications of aging populations.
Regular readers will probably find the first half of the show more interesting. "Social and policy implications" is usually a keyword for "unimaginatively telling other people how to live their lives."
From EurekAlert!, more experimental metabolic engineering: "the research team bred large numbers of mice, fed them a normal chow diet and followed each mouse until its natural death. Half were genetically engineered to make more of a protein in their muscle tissue called uncoupling protein-1. Their littermates did not make excess uncoupling protein. In muscle tissue, uncoupling protein-1 converts the energy from food into heat and mimics the effects of exercise. ... Uncoupling basically means generating inefficient metabolism ... We were a little bit disappointed because we had hoped uncoupling in muscle would slow aging, but maximum lifespan didn't increase. However, the odds of reaching that maximum lifespan did improve in the uncoupled mice. ... mice with the genetic alteration were more likely to live longer, presumably because they were able to avoid age-related diseases. One result appeared in all of the experiments: Decreasing body fat and inflammation in the animals by accelerating muscle metabolism with uncoupling protein delayed death and diseases, including atherosclerosis, diabetes, hypertension and even cancer."
The inflammaging model is starting to percolate into the popular science press, such as Discover: "In recent years, gerontologists have overturned much of the conventional wisdom about getting old. Aging is not the simple result of the passage of time. According to a provocative new view, it is actually something our own bodies create, a side effect of the essential inflammatory system that protects us against infectious disease. As we fight off invaders, we inflict massive collateral damage on ourselves, poisoning our own organs and breaking down our own tissues. We are our own worst enemy. This paradox is transforming the way we understand aging. It is also changing our understanding of what diseases are and where they come from. Inflammation seems to underlie not just senescence but all the chronic illnesses that often come along with it: diabetes, atherosclerosis, Alzheimer's, heart attack. ... Inflammatory factors predict virtually all bad outcomes in humans. It predicts having heart attacks, having heart failure, becoming diabetic; predicts becoming fragile in old age; predicts cognitive function decline, even cancer to a certain extent." Strangely, the article fails to talk about the pivotal role of excess body fat in chronic inflammation.
The Immortality Institute volunteers have pulled together a great lineup from the aging and longevity research community for the regular Sunday chat events over the past few weeks, including Aubrey de Grey and S. Jay Olshansky.
This coming weekend, December 9th, the chat guest is researcher Michael Rose:
Another in the recent line-up of great guests, Dr. Michael Rose will be joining Imminst for the Sunday Night Chat this Sunday December 9th at 6:30pm CST U.S. (0030 GMT). Dr. Rose is famous for his work discovering biological immortality in fruit flies. For a primer check here for his 2005 Imminst conference presentation or look here for a discussion of SENS-E.
Chat Room: http://www.imminst.org/chat
Sun December 9th
Note that here, "biological immortality" doesn't mean what you might think it means. It's more of a statistical term for change in mortality rates. A good explanation can be found in Rose's essay in The Scientific Conquest of Death (PDF), a book released by the Immortality Institute back in 2004 and now freely available for download.
If there is such a thing as biological immortality, it cannot mean survival under all conceivable conditions.
Instead, we can describe immortality more sensibly as a feature of rates of survival or reproduction. An important side issue is whether or not fertility should be included with survival in definitions of aging. For some medical professionals, the loss of fertility with age in both men and women is a clear manifestation of aging. For other professionals, it is merely incidental.
If we use a definition of aging based on declining survival and fertility, we can define immortality intelligibly. If aging can be defined as the persistent decline of these biological variables, then it makes sense to define immortality as a property of organisms that do not exhibit such declines. They may have never exhibited declining survival and reproduction, or they may have reached a point of equilibration at which further sustained declines have ceased.
Rose is a fan of rapid progress in healthy life extension science, something we'd like to see much more of in the broader scientific community. Take a look at his SENS3 conference presentation for a sampling of his viewpoint.
As noted at EureAlert!, scientists are making progress in the quality of their technology demonstrations: "Although [domamine or DA] cell-replacement therapy by transplantation of human fetal mesencephalic tissue has shown promise in clinical trials, limited tissue availability means that other sources of these cells are needed. ... [researchers] have identified a new source for DA cells that provided marked benefit when transplanted into mice with a [Parkinson's or PD]-like disease. ... DA cells were derived from ventral midbrain (VM) neural stem cells/progenitors by culturing them in the presence of a number of factors - FGF2, sonic hedgehog, and FGF8 - and engineering them to express Wnt5a. This protocol generated 10-fold more DA cells than did conventional FGF2 treatment. Further analysis revealed that these cells initiated substantial cellular and functional recovery when transplanted into mice with PD-like disease. Importantly, the mice did not develop tumors, a potential risk that has precluded the clinical development of embryonic stem cells as a source of DA cells." Tissue engineering is a fearsomely complex business, but great improvement in quality and cost is inevitable.
As mentioned over at the Methuselah Foundation blog, the foundation volunteers are back on the cutting floor to produce a series of short videos to explain some of the basics of modern longevity science:
Aubrey de Grey and I will be recording several short videos explaining the science of SENS, the Strategies for Engineered Negligible Senescence, for the benefit of the general public. These videos are intended to serve as an intermediate step between the brief text overviews at the SENS website and the scientific literature. This is a similar niche to that successfully occupied by Ending Aging, but intended to address a slightly different target demographic.
The resulting videos will be hosted at the Foundation website, as well as being uploaded to YouTube and Google Video. We hope they do as wonderful a job of raising awareness that 'SENS makes sense' as the many existing presentations and interviews with Aubrey have done in past years.
You'll be pleased to see a first set of short videos are available for viewing at the Foundation website as a Video FAQ on Life Extension Therapies. Here's the list:
- What are 'life extension therapies'?
- When did life extension studies first begin?
- What is 'rejuvenation therapy'?
- What is your master plan for extending the human lifespan?
- Is SENS endorsed by mainstream gerontologists?
- What is 'tissue rejuvenation'?
- What are 'stem cells'?
- How might stem cells increase my life span?
- How might organ transplants extend my life?
- What is 'gene therapy'?
- What is 'calorie restriction' CR?
- How safe and effective is calorie restriction?
- What is 'cryonics'?
- What is a 'growth hormone'?
- How safe and effective are growth hormones?
- How much will life extension therapies cost?
- What types of experiments are necessary to test life extension therapies?
An article by Aubrey de Grey appears at Cato Unbound, hammering on the basics: "When thoroughly cornered on the question of whether the defeat of aging would be a good thing, [apologists for aging] generally turn as a last resort to the cry 'Okay, but first things first!' The fact that efforts to postpone human aging will definitely not bear much fruit for at least a few decades is held as a reason to deprioritize such efforts in favor of combating already preventable problems. It is trivial to expose the ethical bankruptcy of this position. We lock people up for the same amount of time if they kill people with a gun or with a booby-trap bomb, even though the interval between the murderer's action and the victim’s death differs by several orders of magnitude in the two cases. The same irrelevance of that interval applies to the saving of lives, since action and inaction are morally indistinguishable. We are close enough today to defeating aging that serendipity does not define the timeframe: the sooner and harder we try to do it, the sooner we'll succeed. Thus, our inaction today costs lives - lots of lives."